# Nicotinamide riboside (NR; NIAGEN capsules, exact salt and batch unverified) × Improvement in 10-week change in MoCA total score in older adults with clinical MCI Verdict 3094 · Evidence Check Stored-material review date: 2026-10-05 Original evidence date: 2026-09-15 Review-criteria version: NGM-v3094-ORAL-NIAGEN-MCI-MOCA-REPORTED10W-1.1 Public page/material preparation date: 2026-11-01 Clinical papers were not read directly; existing review summaries were checked. No new clinical-literature search was performed. Unverified does not mean that research is absent or that there is no effect. ## Assessment scope - Population: Clinical MCI in adults aged 65 years or older; diagnosed through TARCC or by the investigator; newly evaluated candidates: MoCA below 26 and preserved ADL/IADL; subtype unverified - Ingredient, formulation and route: Capsules with NR as the single active ingredient; exact salt, crystal form, purity, batch and release profile unverified · oral - Dose: 250→500→750→1000 mg/day escalation; target 500 mg 2 times daily - Comparator: Placebo supplied by ChromaDex; composition and complete common-care inventory unverified; not an add-on to cognition drugs - Measured outcome: NR−placebo between-group comparison of change in MoCA total score from screening/baseline to the final visit; Figure 1 study weeks 1 and 13, reported treatment of 10 weeks; primary (1st) outcome in the article - Duration: Reported 10-week course; exact number of days at the target dose unverified - Questions outside this scope: nicotinamide/niacinamide; nicotinic acid/niacin; NMN; NAD/NADH; tryptophan; NR combination product; normal-aging population; dementia population; frailty-walking outcome; MMSE; RBANS; memory subtest; NAD biomarker; brain perfusion ## Checklist items ### N01 · Which single MoCA comparison is being tabulated? Verification status: Met Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The original /ko/effect concerns improvement in 10-week change in MoCA total score in older adults with clinical mild cognitive impairment. The assessment-question identity specifies NIAGEN dose escalation versus placebo in MCI at age 65 years or older. subclaims is an empty array, and this table covers the original single main question. - Why unverified: The question has been linked to the preserved claim under assessment and its actual structure. This does not mean that the evidence is sufficient for MoCA efficacy. - Reason for missing information: The exact number of exposure days, analysis denominator and formulation details remain for subsequent conditions. - Required materials and conditions: The current claim under assessment, the identity of the assessment question, facets, subclaims and canonical URL. - Materials to obtain first: The current claim under assessment, the identity of the assessment question, facets, subclaims and canonical URL. - Further research: Compare included materials against an eligibility table for population, intervention, comparator, scale and timing, then examine each to determine whether it addresses the same question. - Conditions for verification: Fix the direction of change in MoCA total score for clinical MCI, age 65 years or older, oral NIAGEN with NR as the single active ingredient, dose escalation, a reported 10-week course and placebo. - Why this condition is needed: Needed to avoid combining general cognitive function or multiple endpoints into a single effect for this question. - Application exceptions: subclaims is an empty array. Do not automatically create questions about RBANS, dementia events, gait speed or other B3 forms. - Remaining uncertainty: The original boundary is a development question narrowed after identifying the direct trial; it is not a preregistered review. - Referenced methods: Question-clarification principles in M03 §3.1 and §3.2.1–3.2.4; detailed separation rules are designed specifically for this review — a specific adaptation for the independent question. Not official methodological certification. - Related sources: S01, S05 ### N02 · Have Orr’s five reports been linked as one direct trial family? Verification status: Met Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: In the original evidence, Orr’s NCT02942888 has S01–S05 grouped as the F01 direct family. Wu’s NCT04078178 is F02 and Martens’s NCT03482167 is F03, with direct-replication flags set to false. S10–S12 are indexed leads to separate registrations, not obtained MoCA results. - Why unverified: Preserves the same/different family relationships and directness boundaries confirmed in the current records. The number of reports does not represent the number of independent replications. - Reason for missing information: Results, completion status and overlap across all candidate registrations have not been separately verified in this review. - Required materials and conditions: DOI, PMID and NCT for each report, and the original evidence field’s family_id and direct-eligibility/replication flags. - Materials to obtain first: DOI, PMID and NCT for each report, and the original evidence field’s family_id and direct-eligibility/replication flags. - Further research: Cross-check duplicate reports using a linkage table for identifiers, populations, durations and scales, and leave any new family identities unresolved. - Conditions for verification: Group S01–S05 with the same DOI/PMID/NCT as F01, and separate the adjacent F02/F03 studies and candidate registrations from direct replications. - Why this condition is needed: Needed to avoid counting the article, publisher page, index, PMC and registry as five independent trials. - Application exceptions: Preserve the original direct_trial_family_count=1, without newly summing unique trials or total participants across all registrations. - Remaining uncertainty: Do not count the first block and crossover results, or repeated citations of an article/registration, as new replications. - Referenced methods: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an application developed for this review; M04 §4.6.1–4.6.2, M15 §15.3.1; application developed for this review — a specific adaptation for trial families. Not official methodological certification. - Related sources: S01, S02, S03, S04, S05, S06, S07, S10, S11, S12 ### N03 · Has reading the summaries in this review been distinguished from external access at the time? Verification status: Met Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The current KO/EN text, structure, evidence and bibliography were read in full. The original S01 records a visual PDF table comparison, and S06–S09 record HTML full-text access, among other access methods, with a recorded accessed date of 2026-09-15. S02 ESM 1 DOCX was not obtained at the time; S03 reused earlier abstract/metadata, and S04 consists of indexed text with direct access failure at the time. For all external materials in this review, access was not attempted, and the materials were not obtained or read. - Why unverified: Current actions and the original material-specific access records are recorded separately. Material-reading conditions and completion of the table-preparation review are separate matters. - Reason for missing information: No external document bytes were obtained in this review, and no actual full-text, registry or appendix re-verification was performed. - Required materials and conditions: Original URLs, material types, access_level, locator and accessed, and records of copies actually obtained and reading events. - Materials to obtain first: Original URLs, material types, access_level, locator and accessed, and records of copies actually obtained and reading events. - Further research: When materials are actually obtained later, separately record their bytes, format, native location, access dates and reading dates, and cross-check them against the summary links. - Conditions for verification: Distinguish reading the currently archived summary in its original bytes, the per-citation 2026-09-15 access records, and external access not attempted/materials not obtained/not read in this review. - Why this condition is needed: Needed to avoid treating a historical full_text record or the existence of a link as full-text reading in this review. - Application exceptions: S03’s prior reuse/lack of an obtained body and S04’s access failure at the time are not current failures. The accessed entries for 12 citations do exist and are preserved. - Remaining uncertainty: Historical full_text records and access dates do not prove successful reading in this review. - Referenced methods: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are designed specifically for this review; M04 §4.5, §4.6.3; limits on the current conversion of materials derive from the user’s scope and this review’s design — a specific adaptation for reading history. Not official methodological certification. - Related sources: S01, S02, S03, S04, S05, S06, S07, S08, S09, S10, S11, S12 ### N04 · What are the clinically defined MCI population and eligibility boundaries of the direct trial? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The original population consists of adults aged 65 years or older with clinical MCI, diagnosed through TARCC or by the investigator. Newly evaluated candidates were required to have MoCA below 26, preserved ADL/IADL and exclusion of relevant confounding factors. Inclusion of normal cognition and dementia is recorded as false. - Why unverified: The main eligibility criteria have been linked, but the details of TARCC diagnosis and all baseline distributions have not been confirmed. - Reason for missing information: Detailed TARCC diagnosis, representativeness and the distribution of concurrent conditions remain unresolved. - Required materials and conditions: Recruitment pathways, MCI diagnostic procedures, baseline function, inclusion/exclusion criteria and the actual population distribution. - Materials to obtain first: Recruitment pathways, MCI diagnostic procedures, baseline function, inclusion/exclusion criteria and the actual population distribution. - Further research: Cross-check eligibility tables by diagnostic pathway and examine the scope of application of baseline function, age and exclusion criteria. - Conditions for verification: Link age 65 years or older, TARCC or PI diagnosis, MoCA<26 with preserved ADL/IADL for newly evaluated candidates, and exclusion of confounding factors. - Why this condition is needed: Needed to avoid substituting results from healthy aging, dementia or frailty populations for the MCI MoCA comparison. - Application exceptions: Do not infer that the MoCA criterion for newly evaluated candidates was the same diagnostic procedure for every TARCC participant. - Remaining uncertainty: MoCA screening scores alone cannot establish that all MCI subtypes and biological diagnoses are the same. - Referenced methods: M03 §3.2.1; detailed population conditions are designed specifically for this review — a specific adaptation for MCI selection. Not official methodological certification. - Related sources: S01 ### N05 · Are MCI subtype and baseline nutritional status known? Verification status: Unverified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: MCI subtype, actual baseline nutritional status and sex restrictions in the direct trial are unverified. The AD-biomarker requirement and selection for baseline deficiency were recorded as false. Do not copy the diagnosis of amnestic MCI in Martens’s study to all of Orr’s population. - Why unverified: The question’s population has been defined, but there are no data to verify applicability by subtype or nutritional status. - Reason for missing information: Identification of baseline deficiency, MCI subtype and estimates by sex stratum remain unresolved. - Required materials and conditions: Definitions of MCI subtypes, baseline nutritional testing, sex/status distributions and prespecified subgroup plans. - Materials to obtain first: Definitions of MCI subtypes, baseline nutritional testing, sex/status distributions and prespecified subgroup plans. - Further research: Classify only studies with obtained status data into diagnostic/nutritional strata, and cross-check whether interaction analyses were prespecified. - Conditions for verification: Record the actual extent of verification for amnestic subtype, AD biomarkers, nutritional status, selection based on deficiency, and sex strata. - Why this condition is needed: Needed to avoid automatically transferring effects of deficiency correction or amnestic-MCI trials to the direct population. - Application exceptions: Do not fill unverified nutritional status with either normal status or deficiency. AD biomarkers not being required does not mean biomarker negativity. - Remaining uncertainty: A record of no selection based on deficiency does not prove absence of deficiency or equal effects in particular strata. - Referenced methods: M03 §3.2.1; detailed population conditions are designed specifically for this review; M03 §3.2.1–3.2.4; details of dose, duration and effect modification are designed specifically for this review — a specific adaptation for subtype and nutritional status. Not official methodological certification. - Related sources: S01, S07 ### N06 · Have the actual NR salt, batch and basis for the active amount been verified? Verification status: Unverified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The original intervention is NR as the single active ingredient in ChromaDex NIAGEN. The exact salt, crystal form, manufacturing source, purity, batch, release profile and salt mass versus NR moiety basis are null or unverified. Retain the mg amounts shown in the original article. - Why unverified: The brand and molecule have been linked, but the detailed identity of the actual trial batch has not been verified. - Reason for missing information: Salt, crystal form, manufacturing/purity, batch, release profile and the basis for the labeled amount remain unresolved. - Required materials and conditions: Evidence of trial-batch composition, the exact salt/active-amount basis, manufacturing source, and quality/release-profile data. - Materials to obtain first: Evidence of trial-batch composition, the exact salt/active-amount basis, manufacturing source, and quality/release-profile data. - Further research: Individually compare the salt, active amount, excipients and purity in trial product/batch materials against the label; do not perform unsupported conversions. - Conditions for verification: Link NIAGEN with NR as its single active ingredient, and the exact salt, crystal form, source, purity, batch and basis for the labeled amount, separately. - Why this condition is needed: Needed to avoid using the brand or NR name to copy the chemical form, mass or effects of other formulations. - Application exceptions: Do not use EFSA’s NR chloride as the trial’s verified salt, and distinguish it from nicotinamide, niacin, NMN and NAD/NADH. - Remaining uncertainty: The same brand or an official assessment of another formulation does not prove equivalence of the trial product. - Referenced methods: M03 §3.2.2–3.2.3; reverse labeling and adaptations of checks are designed specifically for this review — a specific adaptation for NR identity. Not official methodological certification. - Related sources: S01, S02, S08, S09 ### N07 · Have the oral capsules and supplied products been linked to the actual trial? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The original formulation is an oral capsule with NR as the single active ingredient, and both NR and placebo were supplied by ChromaDex. The reported capsule strength is 250 mg. The exact placebo composition, excipients and release profile are unverified. - Why unverified: The route, capsules and supplier have been verified, but a detailed comparison of the actual composition remains. - Reason for missing information: There are no data on placebo excipients or the active product’s detailed label/release profile. - Required materials and conditions: Trial product labels, capsule strength, administration route and evidence of placebo composition/excipients. - Materials to obtain first: Trial product labels, capsule strength, administration route and evidence of placebo composition/excipients. - Further research: Code each product’s active ingredient, excipients and route separately, and cross-check the actual trial batch and administration records. - Conditions for verification: Distinguish capsules with NR as the single active ingredient, the oral route, ChromaDex-supplied NR/placebo and unverified excipients. - Why this condition is needed: Needed to avoid combining intravenous preparations, NR combination products or unverified placebo composition with a trial of oral NR as the single active ingredient. - Application exceptions: A single active ingredient does not mean that all excipients have been verified. Do not import formulations of other B3 forms. - Remaining uncertainty: A shared supplier alone does not confirm matching composition or sensory characteristics for blinding. - Referenced methods: M03 §3.2.2–3.2.3; reverse labeling and adaptations of checks are designed specifically for this review — a specific adaptation for route and capsules. Not official methodological certification. - Related sources: S01, S02 ### N08 · Has the target dose been distinguished from weekly escalation and individual modifications? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The reported weekly steps are 250, 500, 750 and 1000 mg/day, with the target dose at week 4 as tolerated. The target is 500 mg per dose 2 times daily, reportedly 250 mg capsules with 2 per dose. uniform_1000mg_all_10weeks=false, and the possibility of individual modifications is recorded. - Why unverified: The planned steps and target dose have been linked, but actual individual doses and adherence over the entire period have not been verified. - Reason for missing information: Individual daily dosing, attainment of the target dose and dose-reduction/discontinuation histories remain unresolved. - Required materials and conditions: Weekly dosing schedules, medication-taking records, adherence/discontinuation/dose reductions by arm, and records of exposure to the target dose. - Materials to obtain first: Weekly dosing schedules, medication-taking records, adherence/discontinuation/dose reductions by arm, and records of exposure to the target dose. - Further research: Compare planned dosing schedules against individual adherence and dose-reduction records to examine the difference between the effect of assignment and actual exposure. - Conditions for verification: Link the 250→500→750→1000 mg/day escalation, the target of 500 mg 2 times daily and actual modifications for tolerability. - Why this condition is needed: Needed to avoid turning the 1000 mg target into every participant’s actual dose throughout the entire period. - Application exceptions: A specified target capsule count does not prove that capsules were taken on every actual date. Do not recalculate or convert to equivalent doses. - Remaining uncertainty: Do not present the target dose as an optimal dose, uniform exposure or a safe personal dosing regimen. - Referenced methods: M03 §3.2.2–3.2.3; reverse labeling and adaptations of checks are designed specifically for this review; M03 §3.2.3, M08 §8.2.2–8.2.3; application developed for this review — a specific adaptation for escalation and actual dose. Not official methodological certification. - Related sources: S01 ### N09 · Do the reported 10 weeks and the durations stated for each stage agree? Verification status: Conflicting records Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The original duration states a reported overall course of 10 weeks. The text describes 250/500/750 mg/day in the first three treatment weeks and, at week 4, 1000 mg/day; the Figure description gives each preceding stage as 1 week, followed by 1 g until the end for 6 weeks. The original schedule_status is conflicting_or_ambiguous_exact_days, and exact_target_dose_days=null. - Why unverified: The original material leaves the exact number of days in the same dosing schedule ambiguous/inconsistent, so this was not arbitrarily resolved. - Reason for missing information: The actual start/end of each stage and the total number of days at the target dose remain unresolved. - Required materials and conditions: The original dosing schedule, explanations/corrections for the text and figure, and individual dates and target-dose exposure data. - Materials to obtain first: The original dosing schedule, explanations/corrections for the text and figure, and individual dates and target-dose exposure data. - Further research: Cross-check the reference visits and the start/end of each stage in the original schedule, and link author explanations/corrections with actual dosing dates. - Conditions for verification: Preserve separately the overall 10 weeks, the stages in the text, and Figure 1’s final 1 g for 6 weeks, leaving the exact number of days unverified. - Why this condition is needed: Needed to avoid arbitrarily adding different schedule descriptions to create a new total duration. - Application exceptions: Do not resolve ambiguities in the text/figure by substituting a new 9-week duration or a confirmed 10-week target-dose period. - Remaining uncertainty: Do not fill in the total dosing duration or participant-specific dates through new summation. - Referenced methods: M03 §3.2.2–3.2.3; reverse labeling and adaptations of checks are designed specifically for this review; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is designed specifically for this review — a specific adaptation for the dosing-duration conflict. Not official methodological certification. - Related sources: S01 ### N10 · Have the MoCA visit labels, actual individual assessments and intervals from the last dose been verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: Figure 1 places MoCA at study weeks 1 and 13. The manuscript distinguishes these from the reported 10-week dosing period and leaves the exact assessment interval and interval after the last dose for each individual unverified. - Why unverified: Visit labels are available in the figure, but actual individual measurement intervals have not been verified. - Reason for missing information: Individual assessment dates, allowable visit windows and intervals from the final dose are unavailable. - Required materials and conditions: Actual dates of each assessment, intervals between the last dose and assessment, and visit schedules/allowable windows. - Materials to obtain first: Actual dates of each assessment, intervals between the last dose and assessment, and visit schedules/allowable windows. - Further research: Cross-check visit, dosing and assessment timelines separately to verify the actual measurement window for the selected change score. - Conditions for verification: Distinguish Figure 1’s visits at study weeks 1 and 13 from the reported 10-week dosing period, and record the extent of verification of actual assessment dates, visit windows and intervals after the last dose. - Why this condition is needed: Needed to avoid using the treatment duration as the exact interval between the two score measurements. - Application exceptions: Study week numbers are not individual elapsed days or intervals after the last dose. - Remaining uncertainty: Do not convert study week 1/week 13 into a newly calculated exact elapsed duration. - Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are designed specifically for this review; M08 Table 8.2.a, M03 §3.2.4; application developed for this review — a specific adaptation for the assessment interval. Not official methodological certification. - Related sources: S01 ### N11 · Have the comparator arm, common care and changes been verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The placebo was supplied by ChromaDex, and its composition is unverified. The original retained record explains that prescribed exercise/cognitive training cointerventions were not described in the reviewed main text, and records the exclusion of AD drugs and several centrally acting medications. A complete inventory of usual medications and diet is unverified, and the intervention is not an add-on to a fixed regimen of cognition drugs/statins. - Why unverified: The comparator type and some exclusions are known, but concurrent exposures in each arm have not been comprehensively verified. - Reason for missing information: Placebo composition and complete records of medications, diet, changes, adherence/rescue interventions remain to be verified. - Required materials and conditions: Detailed inventories of placebo/usual medications, diet, treatments, changes and adherence in both arms, and their handling in the analysis. - Materials to obtain first: Detailed inventories of placebo/usual medications, diet, treatments, changes and adherence in both arms, and their handling in the analysis. - Further research: Compare records of concomitant interventions, medication changes and adherence in both arms to review the actual comparison of interest and their effects on the analysis. - Conditions for verification: Distinguish ChromaDex placebo and actual concomitant interventions/exclusions, adherence and rescue interventions/changes from the contrast based on assignment to NR. - Why this condition is needed: This is needed to avoid attributing the effects of add-on therapy to cognition drugs or other concurrent interventions to NR. - Application exceptions: The absence of a description of prescribed exercise/cognitive training in the reviewed main text does not mean that all concomitant interventions were absent. - Remaining uncertainty: Do not equate nonreporting with the actual absence of concomitant interventions or require all changes in both arms to be identical. - Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are custom-designed; M03 §3.2.3, M08 §8.2.2–8.2.3; custom application — item-specific adaptation for placebo and concomitant interventions. No official methodological certification. - Related sources: S01, S02 ### N12 · Have allocation and concealment in the actual parallel RCT been verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The original direct trial was recorded as a randomized double-blind placebo-controlled safety pilot. Details of the random sequence and allocation concealment remain in critical_unknowns, and the post-allocation MRI-related exclusions in Figure 2 are retained separately. - Why unverified: The actual design type has been linked, but materials for a detailed review of allocation/concealment remain unverified. - Reason for missing information: Comparison of the procedures for sequence generation, concealment and post-allocation exclusions, and of their effects, remains outstanding. - Required materials and conditions: Random sequence generation/concealment procedures, allocation lists, baseline tables, the protocol and explanations of subsequent exclusions. - Materials to obtain first: Random sequence generation/concealment procedures, allocation lists, baseline tables, the protocol and explanations of subsequent exclusions. - Further research: Compare procedures before allocation and exclusions after allocation in chronological order, and review the limitations they impose on the effect of interest. - Conditions for verification: Compare sequence generation, concealment, baseline balance and subsequent exclusions in the randomized double-blind placebo-controlled pilot. - Why this condition is needed: This is because the RCT label alone cannot establish that all problems in the allocation process have been resolved. - Application exceptions: Do not describe unverified allocation concealment as not performed. Requirements for handling crossover/cluster designs do not apply to the direct parallel trial. - Remaining uncertainty: Do not turn unverified information into nonperformance, confirmed bias or a new risk grade. - Referenced methods: M08 §8.1–8.2.3; custom application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed — item-specific adaptation for allocation and concealment. No official methodological certification. - Related sources: S01, S05 ### N13 · Have the scale version, assessment blinding and repeated measurements been verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The endpoint is change in MoCA total score, with a higher change favoring NR. The original trial was described as double-blind, but the MoCA version, language, education adjustment and detailed testing procedures are unverified. - Why unverified: The scale and direction have been verified, but detailed comparison of procedural consistency and measurement limitations remains outstanding. - Reason for missing information: Records of the test version, education/language adjustment and assessor-specific procedures/blinding are unavailable. - Required materials and conditions: Records of the MoCA version, language, education adjustment, alternate forms/assessment procedures and assessor blinding. - Materials to obtain first: Records of the MoCA version, language, education adjustment, alternate forms/assessment procedures and assessor blinding. - Further research: Compare the version, assessors, education adjustment and repeat-testing conditions across arms, and review the actual measurement limitations. - Conditions for verification: Compare the MoCA total score, score direction, version/language/education adjustment, assessor blinding and measurement conditions in each arm. - Why this condition is needed: This is needed to avoid treating the scale name and the trial's double-blind description as proof that the actual testing procedures were fully identical. - Application exceptions: Unverified test details do not establish that MoCA was not used or that measurement bias is confirmed. - Remaining uncertainty: Do not conclude from unverified blinding alone that the score difference is entirely measurement error. - Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M08 Table 8.2.a, M03 §3.2.4; custom application — item-specific adaptation for MoCA measurement. No official methodological certification. - Related sources: S01 ### N14 · Has alignment of the article's outcome hierarchy and statistical objectives with the prospective registration/SAP been verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: Orr primarily investigated safety/tolerability and described MoCA as the article's primary (1st) outcome. The primary statistical objective was estimation of within-NR change, and the between-group test was described as a Welch t test. prospective_registered_hierarchy_verified=false, and prospective alignment with the full registry history/SAP is unverified. - Why unverified: The reported objectives/hierarchy have been linked, but no comprehensive comparison of alignment between the prospective plan and actual reporting is available. - Reason for missing information: The initial registration, reasons for amendments and full protocol/SAP remain to be verified. - Required materials and conditions: The article's outcome hierarchy and statistical section, initial registration/amendment history, protocol and SAP. - Materials to obtain first: The article's outcome hierarchy and statistical section, initial registration/amendment history, protocol and SAP. - Further research: Compare the endpoints, time points and effects of interest in the initial/amended registration and SAP with the article's hierarchy/analyses, and record differences and their reasons. - Conditions for verification: Link the safety/tolerability purpose, the article's MoCA primary (1st) outcome and the primary statistical objective of within-NR estimation, and separately verify whether the initial/amended registration and SAP align with the actual reporting. - Why this condition is needed: This is needed to avoid automatically equating the article's primary designation with a prospective plan for confirmatory between-group efficacy testing. - Application exceptions: Do not turn failure to obtain the original registry record into a conclusion of nonregistration or confirmed selective reporting. - Remaining uncertainty: Do not elevate the article's primary (1st) designation to sufficient evidence of effect or prospective confirmation. - Referenced methods: M08 Table 8.2.a, M04 §4.6.3; custom application; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed — item-specific adaptation for endpoint hierarchy. No official methodological certification. - Related sources: S01, S05 ### N15 · Have the NR within-arm change/CI and the corresponding analysis denominator, variance and model been verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The reported mean MoCA change in the NR arm is −0.30 points, and its within-arm 95% CI is −2.21~1.61. Preserve the public_core_values_ko fields nr_change and nr_within_ci95 exactly. This CI is not a between-group NR−placebo CI. - Why unverified: The within-arm values have been linked, but endpoint n and variance/model details remain to be verified. - Reason for missing information: The observed change-score variance, endpoint analysis n and details of the within-arm estimation model are unverified. - Required materials and conditions: Within-arm change, CI definition, model, endpoint-specific n and variance from the original results tables/statistical section. - Materials to obtain first: Within-arm change, CI definition, model, endpoint-specific n and variance from the original results tables/statistical section. - Further research: Code each value in the results tables by arm, time point and statistical measure, and compare within-arm/between-group model outputs. - Conditions for verification: Link the NR mean change of −0.30 points and within-arm 95% CI [−2.21,1.61] to a before–after estimate in the same arm, and record the extent to which endpoint n, observed change-score variance and model details have been verified. - Why this condition is needed: This is needed to avoid relabeling the NR arm's own CI as the CI for the difference in change versus placebo. - Application exceptions: A within-arm before–after CI is not an interval estimating the randomized between-group effect. - Remaining uncertainty: Do not establish causal cognitive worsening from NR or a difference versus placebo on the basis of a negative within-arm change alone. - Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M08 §8.2.2, M15 §15.3.1; custom application; M15 §15.3.1–15.3.3; custom application — item-specific adaptation for NR within-arm values. No official methodological certification. - Related sources: S01 ### N16 · Have the placebo within-arm change/CI and the corresponding analysis denominator, variance and model been verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The reported mean MoCA change in the placebo arm is −0.89 points, and its within-arm 95% CI is −2.19~0.41. This is also an interval for the placebo arm's own before–after change and is not used as a between-group effect CI. - Why unverified: The placebo within-arm values and interval have been preserved, but direct between-group precision data remain separately unverified. - Reason for missing information: The placebo arm's endpoint n, observed change-score variance and model details remain to be verified. - Required materials and conditions: Placebo results tables, within-arm CI/model definitions, endpoint-specific n and change-score variance. - Materials to obtain first: Placebo results tables, within-arm CI/model definitions, endpoint-specific n and change-score variance. - Further research: Compare whether the arms use the same scale, time points and model, and link between-group results as a separate item. - Conditions for verification: Link the placebo mean change of −0.89 points and within-arm 95% CI [−2.19,0.41] to the placebo arm's own before–after estimate, and record the extent to which endpoint n, observed change-score variance and model details have been verified. - Why this condition is needed: This is needed to avoid constructing a comparative effect by selecting the results of only one arm. - Application exceptions: Do not substitute overlap of the arms' within-arm CIs or a difference in their separate significance findings for a between-group test. - Remaining uncertainty: Do not draw a new conclusion that the effects in the arms are the same or different from within-arm CIs alone. - Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M08 §8.2.2, M15 §15.3.1; custom application; M15 §15.3.1–15.3.3; custom application — item-specific adaptation for placebo within-arm values. No official methodological certification. - Related sources: S01 ### N17 · Have the reported between-group test, existing arithmetic and formal between-group effect/CI been verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The between-group comparison is P=0.57. +0.59 points is the simple difference between the NR change of −0.30 and the placebo change of −0.89, as rounded at the time; the original calculation C01 is recorded as calculated_not_reported_official_effect. No new calculation is performed here, and this arithmetic is not used as an official adjusted between-group effect or a between-group CI. - Why unverified: The reported test and historical arithmetic have been distinguished, but the official between-group effect/CI and an applicable important difference remain to be verified. - Reason for missing information: The adjusted between-group difference in change, CI and variance/denominator are unverified. - Required materials and conditions: The reported between-group test, official effect/CI, and records of the inputs, status and direction of existing calculations. - Materials to obtain first: The reported between-group test, official effect/CI, and records of the inputs, status and direction of existing calculations. - Further research: Compare the sources and directions of the reported test and existing arithmetic, and link official model effects/CIs separately if available. - Conditions for verification: Distinguish the meaning of between-group P=0.57 from the historical +0.59-point arithmetic, and separately record the actual extent of verification of the formal adjusted between-group effect, CI and denominator/variance. - Why this condition is needed: This is needed to avoid elevating a positive arithmetic direction to significant improvement or an official between-group estimate. - Application exceptions: Do not recalculate the existing arithmetic based on rounded changes. Do not turn a nonsignificant P into a 0 effect or equivalence. - Remaining uncertainty: Failure to demonstrate improvement in this comparison does not mean an exactly 0 effect, equivalence or exclusion of important benefit. - Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is custom-designed; M08 §8.2.2, M15 §15.3.1; custom application — item-specific adaptation for between-group P and historical arithmetic. No official methodological certification. - Related sources: S01 ### N18 · Have the effect of assignment and the actual analysis population been verified? Verification status: Unverified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The direction of interest is NR total-score change−placebo total-score change. The article's primary statistical objective is within-NR change, and its between-group test is recorded as Welch t. MoCA analysis n, ITT/PP, the adjusted between-group effect and handling of post-allocation exclusions have not currently been directly verified. - Why unverified: The test name and direction of interest are known, but the actual analysis population and handling for estimating a causal effect remain to be compared. - Reason for missing information: The MoCA analysis population, ITT/PP status, handling of exclusions/missing data/adherence and adjusted model are unavailable. - Required materials and conditions: The SAP, analysis-population definition, handling of post-allocation exclusions/missing data, between-group model and adjustment variables. - Materials to obtain first: The SAP, analysis-population definition, handling of post-allocation exclusions/missing data, between-group model and adjustment variables. - Further research: Check the effect of interest, target population, handling of exclusions/adherence and model against the analysis plan and results tables. - Conditions for verification: Compare the effect of interest for NR−placebo change with within-arm estimation, the Welch between-group test, the actual analysis population/adjustment and ITT/PP. - Why this condition is needed: This is needed to avoid automatically treating the number of completers and the primary within-arm objective as an ITT effect in all assigned participants. - Application exceptions: If the original source does not specify the analysis population, do not fill it in as ITT. Do not impose crossover carryover considerations on the direct parallel trial. - Remaining uncertainty: Do not carry the recorded 20 completers over as the ITT analysis denominator. - Referenced methods: M08 §8.2.2, M15 §15.3.1; custom application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed — item-specific adaptation for the effect of interest and analysis. No official methodological certification. - Related sources: S01, S05 ### N19 · Have conflicting baseline values across tables and the type of ± been distinguished? Verification status: Conflicting records Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The original historical calculations preserve Table 3 NR 23.1→22.8 and placebo 24.0→23.11 as inputs. It is explicitly stated that the Table 1 placebo baseline of 24.20 conflicts with the Table 3 value of 24.0, and C03 used Table 3. The type of ± in Table 3 is unverified. - Why unverified: The retained record leaves the difference between tables for the same baseline as a conflict, and has not resolved the type of dispersion either. - Reason for missing information: Exact analysis denominators for each table, the definition of ± and an explanation of the baseline discrepancy are needed. - Required materials and conditions: Original Table 1/3, each table's denominator/scale, the definition of ±, and original corrections/author explanations. - Materials to obtain first: Original Table 1/3, each table's denominator/scale, the definition of ±, and original corrections/author explanations. - Further research: Compare arms, time points, denominators and definitions of means/variance by table, and review discrepancies for the same item when an original correction is available. - Conditions for verification: Preserve both arms' baseline/final values in Table 3, the placebo-baseline discrepancy involving Table 1's 24.20, and the unverified meaning of ± separately. - Why this condition is needed: This is needed to avoid combining baselines from different tables or assuming that ± is SD/SE to create a new effect/CI. - Application exceptions: The original historical arithmetic C02/C03 is only a record of cross-checks at that time, not a new calculation or resolution of the conflict. - Remaining uncertainty: Do not arbitrarily average/correct differences between tables or use ± to create a new SD/SE or between-group CI. - Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is custom-designed — item-specific adaptation for baseline tables and ±. No official methodological certification. - Related sources: S01 ### N20 · Have the 22 assigned participants been distinguished from the 20 in the main text and the 20 completers? Verification status: Conflicting records Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: Figure 2 shows 22 randomized participants, 2 MRI-related exclusions and 20 completers (10 in each arm). The abstract/main text states that 20 were randomized. At the time, C04 checked only the internal flow arithmetic and did not resolve this conflict or establish MoCA analysis n. - Why unverified: The allocation and completion stages have been linked, but the discrepancy in the wording of the randomized count remains. - Reason for missing information: The timing of exclusions immediately after allocation, allocation counts by arm and explanations of corrections to the abstract/main text are unavailable. - Required materials and conditions: The original CONSORT diagram, timing of allocation/exclusions, participant counts by arm and explanations of corrections to the abstract/main text. - Materials to obtain first: The original CONSORT diagram, timing of allocation/exclusions, participant counts by arm and explanations of corrections to the abstract/main text. - Further research: Compare allocation, subsequent exclusions and completion in a chronological stage table, and update the conflict only on the basis of author explanations/corrections. - Conditions for verification: Keep the Figure 2 counts of 22 randomized, 2 MRI-related exclusions and 20 completers separate from the abstract/main-text count of 20 randomized. - Why this condition is needed: This is needed to avoid relabeling completers as assigned participants without resolving the conflict between participant-flow stages. - Application exceptions: The original C04 calculation 22−2=20 is a historical check within the participant flow; it neither resolves the textual conflict nor determines endpoint n. - Remaining uncertainty: Do not use 20 completers or 10 in each arm as confirmed allocation counts or endpoint analysis counts. - Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is custom-designed; M08 §8.1–8.2.3; custom application — item-specific adaptation for the allocation/completion conflict. No official methodological certification. - Related sources: S01 ### N21 · Have the MoCA endpoint analysis denominator and handling of missing data been verified? Verification status: Unverified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: evidence_core.analysis_n and public_core_values_ko.MoCA_analysis_n are null. The 20 completers/10 in each arm and 2 MRI-related exclusions are participant-flow records; do not substitute them for MoCA endpoint-specific analysis counts or missing-data handling. - Why unverified: Direct information on the required endpoint analysis denominator and handling of attrition is unverified. - Reason for missing information: Measurement/analysis counts by arm, reasons for missing data/exclusions, their handling and sensitivity results are unavailable. - Required materials and conditions: Endpoint-specific measurement/analysis tables, missing data/exclusions by arm, their handling/SAP and sensitivity analyses. - Materials to obtain first: Endpoint-specific measurement/analysis tables, missing data/exclusions by arm, their handling/SAP and sensitivity analyses. - Further research: Check endpoint-specific participant flow, the actual population included in the model and missing-data handling/sensitivity analyses against the source data. - Conditions for verification: Link MoCA measurement/analysis n, missing data by arm and reasons for/handling of exclusions separately from allocation and completion counts. - Why this condition is needed: This is needed to avoid substituting the number of completers for the denominator of the score analysis. - Application exceptions: Do not assume that MRI exclusions equal the number with missing MoCA data or fill in an unavailable analysis n. - Remaining uncertainty: The fact that the original participant count is small is separate from a confirmed magnitude of the effect of missing data. - Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed; M08 §8.2.2, M15 §15.3.1; custom application — item-specific adaptation for the MoCA denominator and missing data. No official methodological certification. - Related sources: S01, S05 ### N22 · Can the between-group CI and an applicable important difference be interpreted? Verification status: Unverified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The between-group CI, MoCA analysis n and MCID are null. The original not_calculated record explains that observed change-score variance/between-group CI are unavailable and planning SD/correlation are assumptions. A standardized effect, NNT or MCID classification was not calculated then and is not calculated here either. - Why unverified: No direct interval/criterion is available for judging what magnitudes of between-group effect remain compatible with the evidence. - Reason for missing information: The official between-group CI, observed change-score SD/SE/covariance, endpoint n and an appropriate MCID remain to be verified. - Required materials and conditions: The official between-group estimate/CI, observed change-score variance/denominator and evidence on importance appropriate to this population and measure. - Materials to obtain first: The official between-group estimate/CI, observed change-score variance/denominator and evidence on importance appropriate to this population and measure. - Further research: Compare the reported interval with a justified between-group importance criterion; if none is available, leave an interpretive gap. If needed, design a follow-up trial on that basis. - Conditions for verification: Link the between-group CI, observed change-score variance/covariance, denominator and applicable between-group MCID, and preserve their unverified status. - Why this condition is needed: This is needed to avoid declaring adequate precision or the exclusion of important benefit from sample size, within-arm CIs or nonsignificance alone. - Application exceptions: Planning SD/correlation are not observed variance, and an individual-level MCID is not substituted for a between-group criterion. - Remaining uncertainty: Do not present a single direct trial family, a small study size, or P=0.57 as meeting the precision requirement or establishing an effect of 0. - Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed; M15 §15.3.1–15.3.3; custom application — item-specific adaptation for between-group precision. No official methodological certification. - Related sources: S01 ### N23 · Have the ESM DOCX and registry history/SAP actually been compared? Verification status: Unverified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The S02 locator records ESM 1 DOCX, not retrieved. S05 records indexed MoCA outcome and full registry history/SAP/results not obtained. The full supplement and registry text have still not been compared with the actual plan. - Why unverified: The original lack of acquisition has been preserved, and the required prospective/supplementary material has not actually been compared. - Reason for missing information: The ESM DOCX text, initial/amended registrations, SAP, and complete official results are needed. - Required materials and conditions: ESM 1 DOCX; complete initial/amended registrations; protocol/SAP; official results tables. - Materials to obtain first: ESM 1 DOCX; complete initial/amended registrations; protocol/SAP; official results tables. - Further research: Compare actually obtained supplement/registry versions with the article by document identity, date, endpoint, analysis, and time point, and record the reasons for changes. - Conditions for verification: Retain the limits: ESM 1 DOCX was not obtained from the publisher preview, and the prospective plan was not compared using the registry shell/index. - Why this condition is needed: Needed to prevent the existence of a link from being recast as a completed comparison of the full supplement and prospective plan. - Application exceptions: The direct DOCX URL is absent from the original source, so do not invent it; distinguish the publisher entry link from the unobtained file. - Remaining uncertainty: The existence of a registration number and filename does not prove consistency with the plan or completeness of results reporting. - Referenced methods: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application — item-specific adaptation for the supplement and prospective plan. Not official methodological certification. - Related sources: S02, S05 ### N24 · Have NAD, cerebral blood flow, and pTau217 been kept from being recast as MoCA results? Verification status: Met Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: Orr’s changes in NAD and some cerebral blood flow measures and Wu’s pTau217 signal have been preserved in their original positive context. These measures are not direct results for MoCA total-score improvement or dementia prevention. Do not import brain NAD values absent from the current input. - Why unverified: The attribution boundary between positive measures and the fixed clinical functional endpoint has been preserved. - Reason for missing information: A verified link/mediation analysis between changes in these measures and the fixed MoCA endpoint is currently unavailable. - Required materials and conditions: Actual measurements, time points, denominators, and analyses for each measure, and material directly comparing them with MoCA total score. - Materials to obtain first: Actual measurements, time points, denominators, and analyses for each measure, and material directly comparing them with MoCA total score. - Further research: List each measure separately in the endpoint dictionary, and check whether relationships between changes in a measure and MoCA were prospectively analyzed/directly verified. - Conditions for verification: Separate mechanisms/biomarkers from clinical functional scales, and preserve positive results under the endpoints actually measured. - Why this condition is needed: Needed to prevent a biological response from being automatically transferred into evidence of improved cognitive scores. - Application exceptions: Retain the current manuscript’s NAD/some cerebral blood flow and pTau217 signals, while adding no brain NAD values that are absent. - Remaining uncertainty: Neither a mechanistic response nor benefit automatically proves a between-group cognitive effect for the fixed question. - Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M03 §3.2.4; internally defined extension boundary — item-specific adaptation for mechanisms and other measures. Not official methodological certification. - Related sources: S01, S06 ### N25 · Are Wu’s population-specific and scale-specific results, and MoCA data matching the fixed question, verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: Wu NCT04078178 F02 is a placebo lead-in crossover trial in a mixed SCD/MCI population. In the first 8 weeks, the RBANS total scaled-score between-group result was P=0.55, and the nominal attention difference was not significant after adjustment. The pTau217 signal is also a separate measure. Keep the first-block and crossover results in the same family, and do not add them to direct MoCA replications. - Why unverified: The original indirect results and differences in conditions are known, but no separate result directly matching the fixed MoCA comparison is available. - Reason for missing information: The between-group MoCA result for an MCI-only population over the reported 10 weeks in the fixed question is unverified. - Required materials and conditions: Wu population composition; crossover/first-block analyses; results by scale; adjustments; duration; trial-family material. - Materials to obtain first: Wu population composition; crossover/first-block analyses; results by scale; adjustments; duration; trial-family material. - Further research: Compare populations, scales, durations, analyses, and results before/after adjustment by trial family to distinguish direct eligibility from indirect relevance. - Conditions for verification: Preserve the mixed SCD/MCI population, first 8-week/crossover RBANS P=0.55, and adjusted results as recorded, while separately retaining whether they are directly eligible and verified for the fixed clinical-MCI, reported 10-week MoCA result. - Why this condition is needed: Needed to prevent no-difference results or positive signals in other populations/scales from being combined as confirmation/refutation of the same MoCA result. - Application exceptions: The first block and crossover belong to the same F02; they are neither independent replications nor denominators for a direct MoCA analysis. - Remaining uncertainty: Non-significance on another scale or a positive biomarker result is not an exact replication that refutes/confirms Orr’s MoCA result. - Referenced methods: M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — item-specific adaptation for Wu indirect results. Not official methodological certification. - Related sources: S06 ### N26 · Are Martens’s cognitive results and replication data matching the fixed MoCA endpoint and duration verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: Martens NCT03482167 F03 is a 12-week randomized controlled phase 2 pilot trial in amnestic MCI. It reported no significant cognitive improvement on CVLT-III, WMS-IV, NIH Toolbox, and other tests. The original evidence records indirect context with mismatches in scale, MCI definition, and schedule, and records direct replication as false. - Why unverified: The original results from the other trial have been preserved, but they are not a direct replication of the fixed MoCA endpoint/duration. - Reason for missing information: No separate direct estimate of MoCA total-score change in clinical MCI over the reported 10 weeks is available. - Required materials and conditions: Diagnosis; formulation/exposure; duration; results for each cognitive test and their analysis denominators; trial-family identity. - Materials to obtain first: Diagnosis; formulation/exposure; duration; results for each cognitive test and their analysis denominators; trial-family identity. - Further research: Compare diagnoses, exposures, scales, time points, and result distributions by study family, and record reasons for inclusion/exclusion for the direct question. - Conditions for verification: Preserve NCT03482167’s 12-week amnestic-MCI results on other cognitive scales, and separately retain whether direct replication results matching the fixed MoCA endpoint/duration have been verified. - Why this condition is needed: Needed to prevent trials with different subtypes, durations, and scales from being numerically pooled as direct MoCA replications. - Application exceptions: Do not use another trial’s denominator as the direct MoCA n. Do not generalize to a lack of effect under all NR conditions. - Remaining uncertainty: No difference in another population does not mean equivalence for this question or ineffectiveness of all NR use. - Referenced methods: M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — item-specific adaptation for Martens indirect results. Not official methodological certification. - Related sources: S07 ### N27 · Are the identities and actual results of other registrations, and their direct relevance to the fixed MoCA comparison, verified? Verification status: Unverified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: S10 has a registration title about bioenergetics/oxidative stress in MCI/AD, S11 about passive sensing/digital biomarkers in MCI/mild AD, and S12 about cognition/sleep in older veterans. The original access level for all is indexed_registry_excerpt, with verified efficacy result not extracted recorded. - Why unverified: There are leads indicating bibliographic/registration existence, but material for comparing actual results and direct relevance to the fixed question is unverified. - Reason for missing information: The full registrations, histories, results, linked articles, and direct-eligibility comparisons are unavailable. - Required materials and conditions: Actual registration text/history, completion/publication, results, and linked reports for NCT04430517, NCT05245903, and NCT05500170. - Materials to obtain first: Actual registration text/history, completion/publication, results, and linked reports for NCT04430517, NCT05245903, and NCT05500170. - Further research: Link registration/publication identities, and compare populations, formulations, scales, time points, and whether results are public using each actual document. - Conditions for verification: Preserve the registration/index identities of S10–S12, and distinguish the verified scope of the actual registration histories, results, linked reports, and direct eligibility for the fixed question. - Why this condition is needed: Needed to prevent registration titles or the existence of studies from being elevated to acquired MoCA results or independent replications. - Application exceptions: Not querying them this time does not establish the absence of results, noncompletion, or nonpublication; retain only the scope of the existing indexed leads. - Remaining uncertainty: Do not count 3 registrations as 3 direct results or 3 independent replications. - Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/result linkage is an internal application; M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the current material conversion follow the user’s scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application — item-specific adaptation for registry candidates. Not official methodological certification. - Related sources: S10, S11, S12 ### N28 · Are funding, product provision, author roles, and the scope of independence verification all verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The manuscript records both NIH/VA public support and ChromaDex provision of NR/placebo. Brenner is an inventor of NR intellectual property, a ChromaDex scientific adviser, and an equity holder; his role was described as NAD-metabolite interpretation/manuscript editing, without participation in design/conduct. Orr’s separate neuronal-senescence patent was also disclosed. Retain the original I1 and the explanation that the same facts were not counted twice. - Why unverified: Verified disclosures have been linked, but this does not prove an actual absence of bias or independent clinical review. - Reason for missing information: Undisclosed interests and funding/roles across all indirect trial families have not been exhaustively verified. - Required materials and conditions: Reports’ funding, product provision, patents/employment/disclosures and roles, and material linking institutions/trial families. - Materials to obtain first: Reports’ funding, product provision, patents/employment/disclosures and roles, and material linking institutions/trial families. - Further research: Compare disclosures, provision, and roles by trial family, and attach claims of independent funding/replication only within the verified scope. - Conditions for verification: Link NIH/VA, ChromaDex, and the known disclosures/roles of Brenner/Orr, while separately retaining the unverified scope of supply/role chains and institutional/trial-family relationships. Do not recast the existence of disclosures as an actual absence of bias. - Why this condition is needed: Needed to prevent public support alone from being taken to mean no commercial interests, or the same fact from being counted again on a new axis. - Application exceptions: Do not automatically exclude results because interests exist, and do not recalculate the original I1. - Remaining uncertainty: Do not make a new judgment that results are invalid or quantify bias based solely on mixed funding. - Referenced methods: Chamgap’s own independence/attribution conditions. The official-method sections used in this pilot do not vouch for all these detailed items — item-specific adaptation for funding and interests. Not official methodological certification. - Related sources: S01 ### N29 · Are the numbers of people with AEs and event counts, event definitions/collection, safety denominators, and exposure time verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The direct trial reported adverse events in NR 7/10 people, with 18 events, and placebo 7/10 people, with 21 events. Distinguish person denominators from event counts, and do not count multiple events in the same person as separate people. Do not import this denominator of 10 people as the MoCA analysis n. - Why unverified: The reported aggregates for both arms have been linked, but details of event collection, exposure time/event overlap, and safety analyses remain unresolved. - Reason for missing information: Systematic collection/severity definitions, arm-specific safety-analysis populations, individual exposure times, and the scope of event disclosure are needed. - Required materials and conditions: Safety tables; exposure/safety-analysis denominators; event definitions/collection; overlapping events; follow-up/exposure time. - Materials to obtain first: Safety tables; exposure/safety-analysis denominators; event definitions/collection; overlapping events; follow-up/exposure time. - Further research: Compare people/event counts, event overlap, duration, and collection by arm in an event table without personal identifiers to review the scope of reported aggregates. - Conditions for verification: Distinguish NR 7/10 people and 18 events from placebo 7/10 people and 21 events, and retain the actual scope of verification of safety-analysis populations, event overlap, event definitions/collection, and observation/exposure time. - Why this condition is needed: Needed to prevent repeated-event counts from being converted into incidence among people or carried over as efficacy denominators. - Application exceptions: 18/21 are event counts, and 7/10 are records of people. Do not create new risk ratios/differences, pooled denominators, or annual incidence rates. - Remaining uncertainty: Do not establish long-term safety, changes in risk, or NR causation from aggregates alone. - Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptation is internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application — item-specific adaptation for people and events. Not official methodological certification. - Related sources: S01 ### N30 · Are the timeline, alternative causes, and assessment material for nausea/heartburn and dose changes verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: 1 NR participant reduced the dose from 1000→750 mg/day for 1 week because of severe nausea/heartburn, then returned to the target dose. The original record does not provide a permanent-discontinuation count or confirmed NR causation, so do not recast it in those terms. - Why unverified: The reported event and dose change have been verified, but material for reviewing exact timing, alternative causes, and causality remains outstanding. - Reason for missing information: Details of event dates, recovery, concurrent exposures, causality/seriousness assessments, and whether discontinuation occurred are unavailable. - Required materials and conditions: Event onset/recovery; dates of dose reduction/return; concomitant medicines/conditions; assessments; discontinuation records. - Materials to obtain first: Event onset/recovery; dates of dose reduction/return; concomitant medicines/conditions; assessments; discontinuation records. - Further research: Compare exposure/event/dose-reduction/return timelines and alternative causes, and separate severity, seriousness, and causality assessments. - Conditions for verification: Preserve the reduction for 1 NR participant from 1000→750 mg/day for 1 week and return to the target dose, and distinguish the verified scope of event dates, recovery, concomitant medicines/conditions, causality/seriousness, and whether discontinuation was permanent. - Why this condition is needed: Needed to prevent severe symptoms or temporal relationships from being automatically translated into SAE/confirmed causation or permanent discontinuation. - Application exceptions: The severity described by severe nausea differs from a seriousness classification; do not invent improvement after dose reduction without support in the manuscript. - Remaining uncertainty: Do not newly count 1 person with a temporary dose reduction as 1 person who discontinued treatment or 1 person with a serious event. - Referenced methods: M03 §3.2.2–3.2.3; reverse-direction indicators and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2 design-specific harm questions; temporal-relationship details are internally designed; M19 §19.2.2–19.2.4 design considerations; detailed recording of confounders is internally designed — item-specific adaptation for dose reduction and nausea. Not official methodological certification. - Related sources: S01 ### N31 · Has the conflict between the statement of no serious adverse events and the report of a placebo stroke been preserved? Verification status: Conflicting records Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: Record that the original “no serious adverse events” sentence and the report of stroke in 1 placebo participant conflict in seriousness classification. Retain both descriptions and the attribution to placebo, and do not resolve the event classification in this work. - Why unverified: The manuscript explicitly notes inconsistency within the same safety report, so material resolving it is needed. - Reason for missing information: The original SAE assessment/definition for the stroke and the reason for the difference between the table and sentence are unverified. - Required materials and conditions: Original event tables; SAE definitions/assessments; course of the placebo stroke; explanations in the text/corrections. - Materials to obtain first: Original event tables; SAE definitions/assessments; course of the placebo stroke; explanations in the text/corrections. - Further research: Compare event definitions, arms, and classifications against the text/tables/protocol, and update the conflicting status only through official corrections/explanations. - Conditions for verification: Leave unresolved the seriousness-classification conflict between the original no serious AE sentence and the report of stroke in 1 placebo participant. - Why this condition is needed: Needed to prevent inconsistency in harm records from being recast as an absence of events or a conclusion that NR is safe. - Application exceptions: Do not attribute the placebo stroke to NR causation or newly apply severity/seriousness criteria. - Remaining uncertainty: Do not arbitrarily conclude that there were no SAEs, that overall safety was established, or that the stroke was caused by NR. - Referenced methods: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; Chamgap’s own interpretive boundary. M19 principles are referenced, without execution of a formal causality tool — item-specific adaptation for conflicting seriousness classification. Not official methodological certification. - Related sources: S01 ### N32 · Within what scope is worsening of a pre-existing gait disorder in another trial interpreted? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: In the separate Wu F02 trial, 1 event of worsening of a pre-existing gait disorder during NR was classified as a possibly related serious adverse event. The manuscript explains that causation is not confirmed. Do not count it as a repeat of the same event as Orr’s nausea/placebo stroke. - Why unverified: The original signal level has been preserved, but detailed timelines and material on alternative causes to verify causality/risk magnitude are unavailable. - Reason for missing information: Details of exact exposure/course, concomitant medicines, baseline conditions, and assessment remain outstanding. - Required materials and conditions: Wu event tables; baseline gait disorder; exposure/onset/recovery; causality assessments; concomitant-treatment material. - Materials to obtain first: Wu event tables; baseline gait disorder; exposure/onset/recovery; causality assessments; concomitant-treatment material. - Further research: Link unique trial-family/event identities, and compare baseline status, exposure, course, alternatives, and the level of the original assessment. - Conditions for verification: For F02, separate the 1 event of worsening of a pre-existing gait disorder during NR, an SAE recorded as possible related, from the direct MoCA family. - Why this condition is needed: Needed to prevent signals from different events/trial families from being combined as repeated events in the same direct trial or as confirmed causation. - Application exceptions: Distinguish worsening of a pre-existing condition from new onset of a gait disorder, and do not translate “possible related” as confirmed causation (“caused”). - Remaining uncertainty: The existence of different events in different families does not prove independent replication of the same harm. - Referenced methods: M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2 design-specific harm questions; temporal-relationship details are internally designed; M19 §19.2.2–19.2.4 design considerations; detailed recording of confounders is internally designed; M04 §4.6.1–4.6.2; adaptation of harm material is internally designed; Chamgap’s own interpretive boundary. M19 principles are referenced, without execution of a formal causality tool — item-specific adaptation for the Wu harm signal. Not official methodological certification. - Related sources: S06 ### N33 · Are the low-eGFR discontinuation signal and material for reviewing laboratory tests, baseline status, course, and causality verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: In Martens’s different 12-week trial, 1 NR participant discontinued because of a low eGFR laboratory value. The manuscript explicitly states that this does not establish that NR caused kidney injury. Do not add this participant/event to the fixed Orr MoCA denominator/events. - Why unverified: The signal of laboratory-based discontinuation has been linked, but material establishing a kidney-injury diagnosis/NR causation is unavailable. - Reason for missing information: Details of values, baseline eGFR, repeat testing/recovery, concurrent exposures, and assessment remain outstanding. - Required materials and conditions: Laboratory values/units; baseline renal status; repeat testing; exposure/discontinuation/recovery; concurrent causes; assessments. - Materials to obtain first: Laboratory values/units; baseline renal status; repeat testing; exposure/discontinuation/recovery; concurrent causes; assessments. - Further research: Compare laboratory testing, discontinuation, repeat testing/course, and baseline/concurrent causes, and separate the discontinuation decision from clinical diagnosis/causality. - Conditions for verification: For F03, preserve the discontinuation of 1 NR participant following a low-eGFR test result, and separately retain the verified scope of the original laboratory value, baseline/repeat testing, course, concurrent causes, and diagnostic/causality material. - Why this condition is needed: Needed to prevent discontinuation based on a laboratory value from being elevated to diagnosed NR-induced kidney injury. - Application exceptions: Do not invent low-eGFR values, risk ratios, or event denominators absent from the input. - Remaining uncertainty: Laboratory-based discontinuation and confirmed clinical renal harm are not the same outcome. - Referenced methods: M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2 design-specific harm questions; temporal-relationship details are internally designed; M19 §19.2.2–19.2.4 design considerations; detailed recording of confounders is internally designed; M04 §4.6.1–4.6.2; adaptation of harm material is internally designed; Chamgap’s own interpretive boundary. M19 principles are referenced, without execution of a formal causality tool — item-specific adaptation for eGFR discontinuation. Not official methodological certification. - Related sources: S07 ### N34 · Are the nominal GDS P value and data on direction, effect/interval, hierarchy, adjustment, and importance verified? Verification status: Partly verified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The original safety description includes a nominal between-group P=0.035 for the GDS depression scale. Retain the limitation that this was not interpreted as clinical mood harm supported by verified multiplicity adjustment, or as MoCA improvement. - Why unverified: The separate nominal result is retained, but detailed interpretation of adjustment, clinical importance, and direction remains unverified. - Reason for missing information: The GDS effect direction/magnitude, interval/denominator, prespecified hierarchy, and multiplicity adjustment remain to be verified. - Required materials and conditions: GDS results, denominator/direction, prespecified hierarchy, adjustment, clinical importance, and related plans. - Materials to obtain first: GDS results, denominator/direction, prespecified hierarchy, adjustment, clinical importance, and related plans. - Further research: Compare the endpoint hierarchy and analyses before and after adjustment, and record scale changes and clinical events at separate levels. - Conditions for verification: Retain the separate nominal between-group GDS P=0.035 and state the extent to which direction, effect magnitude/interval, denominator, prespecified hierarchy, multiplicity adjustment, and clinical importance have been verified. - Why this condition is needed: This is needed to avoid selecting a significant result on another scale as a positive result for the MoCA question in which improvement was not demonstrated, or treating it as confirmed harm. - Application exceptions: If the original direction, variance, and clinical diagnosis are unavailable in the current input, do not derive an effect magnitude or causality from P alone. - Remaining uncertainty: Do not transfer statistical significance of a P value on another scale to success on the fixed question or to confirmed harm. - Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application; M19 §19.1.2–19.2.4; internal application — individual adaptation for the nominal GDS result. Not certification of an official method. - Related sources: S01 ### N35 · Are long-term safety and laboratory values verified for the same MCI population, trial formulation, and exposure? Verification status: Unverified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The manuscript leaves long-term MCI safety and complete verification of liver and kidney laboratory values unverified. S08/S09 are EFSA use/safety documents on NR chloride; the exact salt in the fixed trial is unverified. Harms from other B3 forms are not copied to NR, and research doses are not used as personal dosing instructions. - Why unverified: Direct evidence for long-term safety in this MCI population and exposure is insufficient, and the formulation/use scope of the official documents cannot be considered identical. - Reason for missing information: Direct long-term laboratory values, rare events, vulnerable groups/interactions, and an exact formulation comparison remain to be verified. - Required materials and conditions: Direct MCI data on long-term safety, original liver/kidney laboratory values, exposure, and vulnerable groups, together with the formulation/population/use conditions in official documents. - Materials to obtain first: Direct MCI data on long-term safety, original liver/kidney laboratory values, exposure, and vulnerable groups, together with the formulation/population/use conditions in official documents. - Further research: Compare the molecule, dose, population, and exposure duration in regulatory documents and the trial, and separately review any required long-term or vulnerable-group harm evidence using an appropriate follow-up design. - Conditions for verification: Distinguish the short-term MCI record from EFSA's different conditions for NR chloride use, and state the extent to which long-term harms, original liver/kidney laboratory values, and vulnerable-group data for the same trial formulation, population, and exposure have been verified. - Why this condition is needed: This is needed to avoid extrapolating a short study or an official use assessment for a different formulation to long-term safety at high doses in MCI. - Application exceptions: Do not use NR chloride from the EFSA documents to fill in the unverified trial salt, or turn an approval/recommendation into personal dosing instructions. - Remaining uncertainty: Short-term tolerability and official assessments of other formulations do not establish overall safety or absence of risk. - Referenced methods: M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptation are internally designed; M19 §19.1.2–19.2.4; internal application — individual adaptation for long-term and official safety assessments. Not certification of an official method. - Related sources: S01, S06, S07, S08, S09 ### N36 · Are complete event collection, exposure/observation denominators, alternative causes, and the scope of causal statements verified? Verification status: Unverified Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The direct trial's person/event counts, dose reduction, and conflicting SAE wording, together with the separate Wu/Martens events, are retained. However, collection/classification, timing, concomitant treatments/baseline status, and follow-up losses for all events were not exhaustively verified within the current summary scope. Do not create new incidence rates, causality rates, or safety grades. - Why unverified: Detailed source data needed to assess complete harm collection and causality/frequency remain to be reviewed. - Reason for missing information: Prespecified collection definitions, all events/discontinuations, exposure time, follow-up losses, and alternative causes/judgments are unverified. - Required materials and conditions: Prespecified safety collection/diagnostic criteria, tables of all events/discontinuations, exposure by group, concomitant treatments/baseline status, follow-up losses, and causality judgments. - Materials to obtain first: Prespecified safety collection/diagnostic criteria, tables of all events/discontinuations, exposure by group, concomitant treatments/baseline status, follow-up losses, and causality judgments. - Further research: Compare prespecified event definitions, collection methods, observation/exposure by group, alternative causes, and omissions, and review the boundaries between statements about signals, comparative risks, and causality. - Conditions for verification: Compare all event definitions, collection, exposure/observation denominators, timing, concomitant treatments, and discontinuations/losses in direct and adjacent families, and record whether the current materials verify a signal, a comparison, or causality. - Why this condition is needed: This is needed to avoid elevating the existence of harm records to complete collection, incidence rates, or safety certification. - Application exceptions: Do not use unverified details of collection to mean 0 events or no other causes. Do not combine families reporting different events as repeated confirmation of the same harm. - Remaining uncertainty: Do not turn limited reporting into absence of events or a verified magnitude of increased risk. - Referenced methods: M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application; M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application; M04 §4.6.1–4.6.2; adaptation of harm data is internally designed; Chamgap's own interpretive boundary. References M19 principles; not implementation of an official causality tool — individual adaptation for collection and interpretation of harms. Not certification of an official method. - Related sources: S01, S06, S07 ### N37 · Are optimal dose, subgroups, and persistence after discontinuation imposed as mandatory for this question? Verification status: Not applicable Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: This table concerns the MoCA comparison of NIAGEN under the fixed escalation and reported 10-week course versus placebo. It does not claim an optimal dose, persistence after discontinuation, or efficacy across all MCI subtypes, so separate extension-study requirements do not apply. Gaps in exact dosing days and subtype data remain under N09/N05 and other relevant conditions. - Why unverified: The extension requirement does not apply because it lies outside the narrow assessment target. Not applicable was not substituted for insufficient direct evidence. - Reason for missing information: Direct comparisons, follow-up, and prespecified interactions for the extension question are currently unverified. - Required materials and conditions: Randomized dose comparisons, long-term/post-discontinuation follow-up, and prespecified interaction plans needed when such extensions are actually claimed. - Materials to obtain first: Randomized dose comparisons, long-term/post-discontinuation follow-up, and prespecified interaction plans needed when such extensions are actually claimed. - Further research: If an extension question is newly proposed, separate it from the original result, prespecify the effects of interest for dose/follow-up/subgroups, and review the corresponding comparative design. - Conditions for verification: Distinguish the MoCA comparison under the fixed escalation/reported course from questions about direct dose comparisons, long-term persistence, and prespecified subgroups. - Why this condition is needed: This is needed to avoid requiring every extension study for the narrow assessment target or concluding that a dose is optimal from the main effect. - Application exceptions: The current assessment target does not extend to optimal-dose, persistent, or stratum-specific efficacy, so those extension requirements do not apply. Actual exposure and timing for this question remain unverified. - Remaining uncertainty: Do not interpret the study's target amount as an optimal dose or as having the same effect in all populations. - Referenced methods: M03 §3.2.1–3.2.4; details on dose, persistence, and effect modification are internally designed; M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed — individual adaptation for non-applicability of extended comparisons. Not certification of an official method. - Related sources: S01 ### N38 · Is an event trial of dementia prevention imposed as mandatory for MoCA change? Verification status: Not applicable Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: The manuscript classifies MoCA as a clinical cognitive-function scale and explains that it is neither an NAD surrogate nor a hard event of dementia prevention. This table does not also adjudicate prevention of dementia onset or improvement in daily functioning, so an event-trial requirement does not apply. - Why unverified: The assessment target does not extend to event prevention, so that requirement is not applied. - Reason for missing information: Direct event-comparison data for dementia prevention/daily functioning were not verified in this table. - Required materials and conditions: The relevant event definitions, direct comparisons, and incidence/follow-up data needed when event prevention is actually claimed. - Materials to obtain first: The relevant event definitions, direct comparisons, and incidence/follow-up data needed when event prevention is actually claimed. - Further research: When defining a separate event question, specify the event, follow-up, denominator, and effect of interest, and compare only its direct evidence. - Conditions for verification: Distinguish change in the clinical functional scale MoCA from separate clinical questions about dementia onset, daily functioning, and death. - Why this condition is needed: This is needed to avoid extending cognitive-score changes or NAD measures to prevention of clinical events. - Application exceptions: Do not impose a dementia event trial as a prerequisite for a question about a MoCA value. The conditions for a direct MoCA comparison remain mandatory. - Remaining uncertainty: A change on a scale or the existence of a direct family does not demonstrate sufficient evidence for prevention of events. - Referenced methods: M03 §3.2.4; internally designed extension boundary; M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is internally designed — individual adaptation for non-applicability of event prevention. Not certification of an official method. - Related sources: S01, S06, S07 ### N39 · Were the preservation scope, original judgment, and boundaries for subsequent updates maintained? Verification status: Met Reading scope: Summary read: the current archived summaries were actually read; external original texts, registries and old separate files were not read. - Current findings: Record from the time the preservation table was prepared: The original grade D, score 28, B/P/R1/I1/E0/B2/CX, no_human_study=false, and other native values, together with 4 historical calculations, are preserved. The evidence reference date is 2026-09-15, and the review at that time was limited to the preserved archived summaries. The original document quality A reflects self-review by a single assistant, and the server record had deployed_at=null. No external search, calculation, reassessment, or deployment was performed during that preparation. - Why unverified: The original values, dates, and scope of the preservation review were linked to update triggers. This does not mean that clinical gaps were resolved. - Reason for missing information: The latest complete literature, registry results, corrections/retractions, original ZIP, and separate calculation/search ledgers are unverified this time. - Required materials and conditions: Original evidence/identity, revision policy, grade/score/axes, calculations, document/publication metadata, and actual subsequent evidence/correction records. - Materials to obtain first: Original evidence/identity, revision policy, grade/score/axes, calculations, document/publication metadata, and actual subsequent evidence/correction records. - Further research: For subsequent evidence/corrections, compare the complete pre-change record while distinguishing the event, condition version, observation, and display, and reconsider the question/family boundaries. - Conditions for verification: Separate the original evidence reference date of 2026-09-15, the current summary review date, D28/axes/native values, historical calculations, and unverified matters from new update events. - Why this condition is needed: This is needed to prevent table preparation/technical review from being mistaken for a current exhaustive search, a new efficacy/safety grade, or completed public publication. - Application exceptions: The original document quality A and self-review by the same ChatGPT are not independent clinical certification. The source first_published_at is not a date of completed server deployment. - Remaining uncertainty: The original D28 is not a 0 effect, a personal probability of success, a safety score, or a document-quality score; no new score is created. - Referenced methods: M04 §4.5, §4.6.3; limits on the current data transformation follow the user's scope and internal design; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed — individual adaptation for reference dates and original values. Not certification of an official method. - Related sources: S01, S02, S03, S04, S05, S06, S07, S08, S09, S10, S11, S12 ## Evidence and sources ### S01 Orr et al. A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment [Source](https://www.brennerlab.net/wp-content/uploads/2023/12/Orr23.pdf) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: The within-group NR change is −0.30 points/95% CI −2.21~1.61, the placebo change is −0.89 points/−2.19~0.41, and the between-group P=0.57. The +0.59 points is historical arithmetic, not an official adjusted between-group effect/CI. Retain the conflict between 22 allocated and 20 in the body text, the 20 completers and unverified MoCA analysis n, the dosing/assessment periods, and the conflicting table baselines. Keep NR 7/10 people and 18 events, placebo 7/10 people and 21 events, NR dose reduction, the SAE statement/placebo stroke conflict, and nominal GDS P as separate boundaries. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full article PDF | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: full_text_pdf_with_visual_table_check. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S02 Orr article landing page and supplementary-information link [Source](https://link.springer.com/article/10.1007/s11357-023-00999-9) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: This is the publisher_preview for the same DOI; retain the original locator stating Abstract/Declarations and ESM 1 DOCX, not retrieved. Do not count it as completed comparison of the full supplement or composition/SAP, or as a separate independent result. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Publisher article preview HTML | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: publisher_preview. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | | Article supplementary DOCX (direct URL unverified) | Direct file URL not acquired; publisher-link lead available | Not attempted this time | Not read | The supplementary DOCX's direct URL and historical file-access date are unverified. Only the publisher entry point and filename are retained; access to the external file was not attempted this time, and the file was neither acquired nor read. | ### S03 PubMed record for Orr et al. [Source](https://pubmed.ncbi.nlm.nih.gov/37994989/) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: This is the record for PMID37994989 and the same DOI. The original access_level is reused_abstract_and_metadata; the locator refers to S05 in the earlier package and failure to obtain usable body text in the fetch at that time. Do not recast this as a current lookup failure, or count it as newly acquired full text or an independent trial. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | PubMed bibliographic and abstract HTML | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: reused_abstract_and_metadata. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S04 PMC record for Orr et al. [Source](https://pmc.ncbi.nlm.nih.gov/articles/PMC10828186/) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: PMC10828186 has the same DOI. The original record states indexed_text_with_direct_access_failure and a direct page challenge. Access was not attempted this time, and the historical record of indexed text is not elevated to reading the PMC full text this time. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | PMC article-link HTML (direct access failed at that time) | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: indexed_text_with_direct_access_failure. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S05 ClinicalTrials.gov NCT02942888 [Source](https://clinicaltrials.gov/study/NCT02942888) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: This is the indexed MoCA outcome for NCT02942888, but full registry history/SAP/results not obtained. Prospective alignment of the article's MoCA hierarchy and the primary statistical objective of within-NR estimation with the registry history/SAP is unverified, and the registry results are not described as actually acquired. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | ClinicalTrials.gov registry web page | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: registry_shell_and_indexed_excerpt. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S06 Wu et al. Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside supplementation in older adults with subjective cognitive decline and mild cognitive impairment [Source](https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70023) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: In the first 8 weeks, the reported between-group RBANS total-score comparison had P=0.55; the nominal attention difference was not significant after adjustment. The pTau217 signal concerns another measure. The 1 case of worsening pre-existing gait impairment during NR was an SAE with possible relatedness, not confirmed causation. The first block/crossover belongs to the same F02 family and is not combined as a direct replication of 10-week MoCA. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full publisher article HTML | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: full article HTML. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S07 Martens et al. A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment [Source](https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71605) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: In the 12-week amnestic-MCI trial, no significant cognitive improvement was reported on CVLT-III, WMS-IV, or NIH Toolbox. Although 1 NR participant discontinued because of a low eGFR laboratory value, NR-induced kidney injury was not established. This is not added to the denominator or direct replications for the fixed MoCA question. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full publisher article HTML | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: full article HTML. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S08 EFSA 2021 Extension of use of nicotinamide riboside chloride as a novel food [Source](https://www.efsa.europa.eu/en/efsajournal/pub/6843) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: The record states that conditions, human safety studies, and conclusions in the document on extended NR chloride uses were reviewed at that earlier time. The actual trial salt is unverified, and this document does not substitute for long-term safety at high doses in MCI or MoCA efficacy of the single-active NIAGEN intervention. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full EFSA official assessment HTML | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: full article HTML. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S09 EFSA 2019 Safety of nicotinamide riboside chloride as a novel food [Source](https://www.efsa.europa.eu/en/efsajournal/pub/5775) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: This is the historical access record for the identity, conditions of use, and conclusions in the novel-food safety document on NR chloride. NR is distinguished from other B3 forms, but this document is not used to fill in the unverified trial salt, batch, or basis of the labeled amount, or to make a new judgment of no risk. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full EFSA official assessment HTML | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: full article HTML. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S10 Effects of Nicotinamide Riboside on Bioenergetics and Oxidative Stress in Mild Cognitive Impairment/Alzheimer’s Dementia [Source](https://clinicaltrials.gov/study/NCT04430517) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: This is only a search-index record: verified efficacy result not extracted. Direct MoCA results, completion/unpublished status, and unique independent replication were not verified this time. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | ClinicalTrials.gov registry-link HTML | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: indexed_registry_excerpt. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S11 Passive sensing/digital biomarker study with NR in MCI or mild Alzheimer disease [Source](https://clinicaltrials.gov/study/NCT05245903) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: This is only a search-index record: verified efficacy result not extracted. Do not turn the registry title into a MoCA effect or into current reading of actual registry results. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | ClinicalTrials.gov registry-link HTML | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: indexed_registry_excerpt. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ### S12 Benefits of Nicotinamide Riboside Upon Cognition and Sleep in Older Veterans [Source](https://clinicaltrials.gov/study/NCT05500170) Materials actually read: The corresponding Korean and English summaries and bibliographic records in the archived manuscript were read. The linked external source materials have not been read this time. Findings recorded in the summary: This is only a search-index record: verified efficacy result not extracted. Do not use registrations for other populations/outcomes as the analysis n for the fixed MoCA question, as independent replications, or as proof that results are absent. Record level: This is content recorded in the archived manuscript. It is not the result of a new comparison against external source materials this time. Independent replication: S01–S05 form a single direct F01 family, while F02/F03 are adjacent; the existence of candidate or official documents is not newly added up as direct replications. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | ClinicalTrials.gov registry-link HTML | Currently unverified | Not attempted this time | Not read | Historical access date for this material: 2026-09-15; recorded level: indexed_registry_excerpt. This time, only the archived summaries were read; access to external materials was not attempted, and those materials were neither acquired nor read. | ## Review criteria and methods These are Chamgap's own application conditions, informed by the relevant sections of official methodological guidance. They do not constitute official assessment-tool certification or a new efficacy score. - M03 [Cochrane Handbook 6.5 (2024), chapter updated 2023-08](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03) · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13 · Clearly record the question, eligibility conditions, and reasons for changes, and distinguish variations in interventions. · Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool. - M04 [Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04) · §4.5, §4.6.1–4.6.3, MECIR C42 · Distinguish studies from reports and link them; do not exclude a study solely because its results are unreported. · Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool. - M08 [Cochrane Handbook 6.5 (2024), chapter updated 2019-10](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08) · §8.1–8.2.3, Table 8.2.a · Fix the outcome and effect of interest when reviewing randomization, deviations, missingness, measurement, and selective reporting. · Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool. - M15 [Cochrane Handbook 6.5 (2024), chapter updated 2023-08](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15) · §15.2.4, §15.3.1–15.3.3 · Distinguish effect estimates, intervals, importance, and applicability. Precision is not determined by sample size alone. · Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool. - M19 [Cochrane Handbook 6.5 (2024), chapter updated 2019-10](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19) · §19.1.2, §19.2.1–19.2.4 · Questions about harms may require designs, populations, and follow-up different from those for efficacy. Case reports do not establish incidence rates. · Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool. ## What the statuses mean - Met: The identity, values, and attribution/interpretation boundaries for this condition were verified in the archived materials. This is separate from clinical sufficiency or certification. - Partly verified: Some materials have been linked, but details, directness, and comparison remain to be resolved. - Unverified: The necessary materials/values are unverified within the preserved scope that was read. This does not mean no effect, 0 events, or an incomplete production review. - Conflicting records: The original discrepancy/ambiguity within the same item is retained without arbitrary correction. - Not applicable: An extension requirement outside the narrow assessment target does not apply. This differs from insufficient materials or materials not read. - Not applicable (alias): Alias for the gray display of Not applicable. - Not read: External materials have not been directly read this time. This is separate from reading the currently archived summaries. - Review incomplete: The individual review for preparation of the table remains unfinished. This is separate from unverified materials. ## Change history 2026-11-01 · Public page/materials 1.0. Public-facing display and data were created from the existing 39 items. No new clinical searches, changes in verification status, or scoring were performed.