Stage-Dependent Cognitive Effects of a Multinutrient Intervention in Alzheimer's Disease: A Stage-Stratified Meta-Analysis.

A specific multinutrient intervention provides precursors and cofactors for synaptic membrane synthesis. Randomized trials across the Alzheimer's disease (AD) continuum have reported mixed findings. We conducted a systematic review and stage-stratified meta-analysis of randomized, placebo-controlled trials. MEDLINE, Embase, CENTRAL, Web of Science, Scopus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform were searched through February 28, 2026. Disease stage was prespecified as an effect modifier. Standardized mean differences (SMDs; Hedges' g) were synthesized using restricted maximum likelihood random-effects models. Four trials met the inclusion criteria; three contributed to the quantitative synthesis (analyzed n = 906). Souvenir I was retained for qualitative synthesis because its distinct co-primary outcomes and reporting did not permit a compatible SMD for the prespecified pooled analysis. The exploratory pooled cognitive effect was small and not significant (SMD = 0.08; 95% CI, -0.09 to 0.26; p = 0.35; I2 = 41.8%). For biomarker-confirmed prodromal AD, the 24-month primary neuropsychological test battery (NTB) 5-item composite endpoint showed a small, nonsignificant effect (SMD = 0.16; 95% CI, -0.08 to 0.41; original trial p = 0.166). The primary NTB memory endpoint in mild, drug-naive AD showed a small effect (SMD = 0.21; 95% CI, -0.06 to 0.49; original longitudinal-model p = 0.023), whereas the primary Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) endpoint in treated mild-to-moderate AD showed no benefit (SMD = -0.06; 95% CI, -0.25 to 0.13; p = 0.513). At 36 months, the LipiDiDiet extension reported significant differences in the NTB 5-item composite, clinical dementia rating - sum of boxes (CDR-SB), memory, and brain-volume outcomes. The intervention was well tolerated. The evidence is compatible with a potential early-stage signal, but the small evidence base, lack of replication across stages, and manufacturer sponsorship warrant cautious interpretation.