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High-dose supplements of docosahexaenoic acid (DHA), an omega-3 fatty acid, penetrated the brain in both APOE4 carriers and non-carriers before dementia onset, the placebo-controlled PreventE4 trial showed.

The treatment did not influence hippocampal volume, said Hussein Yassine, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles. However, increases in brain DHA in both the treatment and placebo arms were associated with better cognitive measures in APOE4 carriers, Yassine reported at the Clinical Trials on Alzheimer's Disease annual meeting in Madrid.

"Omega-3s are good for the APOE4 brain when started before dementia symptoms," Yassine told MedPage Today. "This is different in dementia, when APOE4 carriers have a lower increase in brain DHA after supplementation than non-carriers," he pointed out.

"What's novel about these findings is that the benefit was greater for those with Alzheimer's genetic risk," he added.

Lower blood omega-3 levels have been correlated with worse cognitive function in several observational cohorts, particularly among APOE4 carriers, but the effect of omega-3 supplementation on cognitive outcomes in clinical trials has been inconsistent, he noted.

"In general, very few studies have examined brain DHA delivery as a metric for treatment efficacy," Yassine said.

DHA is mostly obtained from fatty fish consumption. It's the predominant omega-3 in the brain by weight and comprises up to 40% of fatty acids in gray matter.

Earlier studies showed that the brains of young (age 35) cognitively normal APOE4 carriers were than non-APOE4 brains.

"This means that the APOE4 brain is taking more DHA from plasma into the brain for its normal biological processes," Yassine said. "It consumes more DHA, like a specific engine that requires a specific oil to function."

Since plasma DHA levels are largely determined by dietary intake, this finding implies vulnerability of APOE4 carriers to a low DHA diet, he noted.

was a double-blind, single-center trial of cognitively unimpaired individuals with at least one vascular dementia risk factor and limited seafood consumption (DHA intake less than 200 mg/day). People who used omega-3 supplements in the last 3 months were excluded. By design, half the study population had at least one APOE4 allele.

Mean age in the study was 66 years, and 59% were women. Roughly 40% of participants were Hispanic. About 13% had less than 12 years of education, 39% had a body mass index over 30, 51% had hypertension, and 69% had hyperlipidemia.

Participants were randomized to DHA supplements 2 g/day or placebo for 2 years. All participants received a vitamin B complex supplement.

The primary outcome was the ratio of DHA to arachidonic acid (AA), an omega-6 fatty acid, in cerebrospinal fluid (CSF) at 6 months. Secondary outcomes included MRI data. An exploratory analysis looked at effects on cognition at 24 months using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Though 365 people enrolled in the study, only 225 completed it -- 127 in the DHA group, and 98 in the placebo group. "A large dropout rate coincided with the COVID pandemic," Yassine said.

The intervention increased CSF DHA/AA ratios in cognitively unimpaired people, independent of APOE genotype. Exploratory analyses showed that changes in CSF DHA/AA ratios correlated with changes in RBANS scores at 24 months in APOE4 carriers. "This was not seen in APOE4 non-carriers," Yassine observed.

The study was not powered to assess cognition, he acknowledged. The trial ended recently, and analyses of structural and functional connectivity data are ongoing.

It's not clear how APOE4 might affect the DHA/AA balance or what role the gut microbiome might play, Yassine noted. More research is also needed to understand whether there's a personalized approach to DHA supplementation in APOE4 carriers that might be beneficial, he said.

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