16 January 2017 - High-Dose Omega-3 May Lower AD Risk in APOE4 Carriers

Giving long-term high doses of docosahexaenoic acid to carriers of the apolipoprotein E ε4 (APOE4) allele before the onset of Alzheimer's disease (AD) dementia may reduce the risk for AD, or delay the onset of symptoms, and should be studied, according to an expert review.

While the review of landmark observational and clinical trials that assessed supplementation with ω-3 fatty acids such as docosahexaenoic acid (DHA),revealed it was not beneficial in symptomatic AD, several observational and clinical trials of ω-3 supplementation in the pre-dementia stage of AD suggested it may slow early memory decline in APOE4 carriers, reported Hussein Yassine, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles, and colleagues.

Results were mixed in patients with mild or no cognitive impairment, they wrote in JAMA Neurology.

DHA is critical to the formation of neuronal synapses and membrane fluidity, the authors explained.

"We hypothesize that DHA supplementation in APOE4 carriers can result in beneficial outcomes if the timing of the intervention precedes the onset of dementia. Given the safety profile, availability, and affordability of DHA, refining an interventional prevention study in APOE4 carriers is warranted," they noted, adding that advanced brain imaging techniques could be used to identify optimal timing of DHA supplementation and treatment efficacy could be evaluated using specific biomarkers.

Their review of original articles, systematic reviews, and meta-analyses of ω-3 studies in AD showed that most associated higher levels of seafood, ω-3 consumption, or ω-3 blood levels with decreased incidence of AD, better cognitive measures, or preserved brain volume in AD-vulnerable regions.

One summary of 21 studies in a meta-analysis of of 181,580 participants, with 4,438 dementia cases identified over follow-up of 2 to 21 years, concluded that a single weekly serving of fish was associated with significantly lower risk for AD dementia.

A 2015 meta-analysis concluded that ω-3 supplementation significantly improved episodic memory in cognitively healthy older individuals.

"These studies indicate that APOE4 is a modifiable AD risk factor, and that the effect of APOE4 on AD pathologic changes can be attenuated with DHA supplementation," Yassine's group said.

Individuals with a single ε4 allele are three to four times more likely to develop AD as those without an ε4 allele, and people with two ε4 alleles have a 12-fold higher risk of developing AD, the researchers pointed out.

In an email to MedPage Today, Yassine stressed that the review was not intended to act as a recommendation for DHA supplementation. It was done "to stimulate interest in refining the role of high-dose DHA supplementation in a population at increased risk of AD using appropriately designed interventions. We think that long-term high-dose DHA supplementation in APOE4 carriers who are not avid seafood consumers may result in reducing AD incidence. This is evident from some of the epidemiology studies, but was difficult to demonstrate in randomized clinical trials given the limitations of trial designs."

His group proposed that APOE4 carriers be classified into three stages based on disease severity.

In the earliest pre-dementia phase of the disease (stage I), participants would have evidence of brain imaging changes in areas vulnerable to AD. However, no cognitive changes, or only subtle ones, would be detectable.

"In this stage, brain DHA metabolism is altered by APOE4, and brain imaging or CSF biomarkers can be used to select at-risk individuals and monitor the efficacy of supplementation," they explained.

It is for patients in an early prodromal stage of disease (stage II) that long-term high dose DHA supplementation could slow cognitive decline, the researchers stated. Patients in this group would have evidence of memory and/or executive decline but no significant impairment in activities of daily living.

Stage III would represent clinical AD with impairments in multiple cognitive domains. DHA supplementation would probably not be beneficial in this group.

Steven DeKosky, MD, of the McKnight Brain Institute in Gainesville, Fla., agreed that "it is almost surely correct that DHA won't help much if at all in people with full-blown disease."

But he cautioned that "the jury is still out on pre-AD. There isn't much to say to clinicians about how they should act on this information other than to know that we somehow have to get a trial going to prove if it does help or not," he told MedPage Today.

"This frequently gets translated into 'My doctor said I should take DHA supplements,'" noted DeKosky, who was not involved in the review.

Calling the hypothesis "thoughtful," DeKosky predicted that getting "evidence [of DHA supplementation's value] for the jury" would not be easy. Such a study would have to run long enough to demonstrate the DHA supplementation is effective in delaying onset or emergence of signs or symptoms of AD, he stated.

"Given that DHA is not patented, no pharma will fund a study that long since many companies could sell it," DeKosky said. "But that would be the evidence we would need."

Yassine's group plan to identify whether APOE4 carriers in the pre-dementia stage have measurable changes in brain DHA homeostasis, using novel imaging methods or cerebrospinal fluid DHA levels as an index of brain DHA. Then they will test to see whether high-dose DHA supplementation can offset these changes before the onset of AD dementia, Yassine explained.