Omega-3 fatty acid supplements are commonly used by older adults for presumed cognitive protection, yet clinical evidence for this practice remains mixed. Although observational and preclinical studies have suggested potential neuroprotective effects, randomized trials have generally failed to show consistent cognitive benefit. This study examined whether omega-3 supplementation was associated with cognitive decline in older adults and whether any association was mediated by Alzheimer’s disease (AD)-related brain pathology.

Using longitudinal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), investigators compared 273 omega-3 supplement users with 546 propensity score–matched non-users. Matching was based on age, sex, APOE ε4 status, and diagnosis. Participants included cognitively normal older adults, individuals with memory concerns or mild cognitive impairment, and patients with AD dementia. Median follow-up was 5 years. Cognitive outcomes included the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale–Cognitive Subscale 13 (ADAS-Cog13), and (Clinical Dementia Rating–Sum of Boxes) CDR-SB scores. Neuroimaging outcomes included amyloid-β PET, tau PET, structural MRI gray matter volume, and FDG-PET as a marker of cerebral glucose metabolism and synaptic function.

Omega-3 supplementation was associated with faster cognitive decline across all three measures. Compared with non-users, omega-3 users had a more rapid decline in MMSE scores (β = -0.266; p < .001), greater worsening on ADAS-Cog13 (β = 0.823; p < .001), and greater worsening on CDR-SB (β = 0.205; p < .001).

This association was not mediated by amyloid-β deposition, tau pathology, or gray matter atrophy. Instead, omega-3 users showed greater longitudinal decline in FDG-PET cerebral glucose metabolism in AD-vulnerable regions. FDG hypometabolism significantly mediated the association between omega-3 supplementation and cognitive decline, accounting for 30.8% of the effect on MMSE, 40.8% on ADAS-Cog13, and 19.0% on CDR-SB.

The investigators also examined cognitive and FDG-PET trajectories before supplement initiation and found no significant pre-existing differences between future omega-3 users and matched non-users, reducing—but not eliminating—the possibility of reverse causality.

These findings challenge the assumption that omega-3 supplementation is uniformly protective for cognition in older adults. However, because this was an observational study, residual confounding remains possible. Supplement dose, adherence, formulation, and oxidation status were not available, and most reported use involved fish oil. Clinicians should be cautious about recommending omega-3 supplements specifically for cognitive protection in older adults without a clear indication. Further randomized studies are needed to clarify whether effects vary by dose, formulation, baseline omega-3 status, diagnosis, and APOE ε4 status.

Reference:
ZB Liao et al. J Prev Alzheimers Dis . 2026 Jun;13(6):100569. Abstract