Omega-3 fatty acids as an intervention for Alzheimer’s disease may not be dead in the water just yet. A new study may reinvigorate interest in the fish oils. Researchers led by Helena Chui at the University of Southern California have used PET and MRI scans to correlate markers of Alzheimer’s disease with blood levels of the essential fatty acid docosahexaenoic acid (DHA). They report that people with the least amount of DHA have the most amyloid and atrophy in brain regions associated with AD. The findings, published August 8 in JAMA Neurology, do not prove that DHA blocks AD pathology, however they do mesh well with animal studies suggesting the fatty acid thwarts Aβ accumulation. “The … study has the potential to rekindle interest in the therapeutic potential of DHA,” wrote Joseph Quinn of Oregon Health & Sciences University in Portland in an editorial that accompanied the paper. Quinn headed a previous DHA clinical trial, but was not involved in the current study.
“The unique value of this study stems in great part from the scarcity of published evaluations of the effect of omega-3 fatty acids on brain pathology,” commented Frédéric Calon of the University of Laval in Quebec (see full comment below).
DHA is the most abundant fatty acid in the brain, and must be obtained in the diet. Nuts, leafy greens, and meats contain some DHA or its precursor, alpha-linolenic acid, but seafood—especially fatty fish such as salmon—comes loaded with it. According to epidemiological studies, fish consumption and/or elevated levels of DHA in the blood correlate with a lower incidence of AD (see Tully et al., 2003; Cunnane et al., 2012). Preclinical work using animal models indicates that DHA treatment reduces amyloid burden, tau tangles, and damage to synapses (see Lim et al., 2005; Green et al., 2007; and Sep 2004 news). However, clinical trials of DHA supplementation in people with mild to moderate AD fell flat, despite some indication that DHA bestows cognitive benefits to healthy elders (see Oct 2006 news; Nov 2010 news; Yurko-Mauro et al., 2010; and Nov 2015 conference news). If DHA works as an anti-amyloid agent in people as it does in animals, then perhaps trials failed because they started too late, reasoned first author Hussein Yassine.
Against this backdrop, Yassine and colleagues wanted to home in on the potential link between DHA, amyloid, and neurodegeneration. They assessed amyloid deposition via PiB-PET imaging, brain volume via MRI, and DHA levels in serum of 61 participants in the Aging Brain Study in California, which measures vascular contributions to cognitive impairment. Many of the participants, ranging in age from 67 to 88, had risk factors for vascular disease including diabetes or obesity. Nearly half (30) of the participants were cognitively healthy, 29 had a Clinical Dementia Rating (CDR) score of 0.5, on par with mild cognitive impairment, and two had higher CDR scores. Based on a PiB standard uptake value ratio cut-off of 1.08, 23 people in the study tested positive for cerebral amyloid.
The researchers found that brain amyloid inversely correlated with serum DHA. Compared with people who tested negative for cerebral amyloidosis, people in the PiB-positive group had 23 percent lower serum DHA. This was measured as a proportion of their total serum fatty acids. Of all of the risk factors considered in the study, only two—serum DHA and ApoE4 genotype—independently predicted whether a person would have cerebral amyloid. The correlation between DHA and amyloid deposition was strongest in people lacking the ApoE4 allele.
On closer analysis, the amyloid-DHA correlation only held in people whose serum DHA fell into the bottom quartile. This extrapolates to a very low DHA intake—corresponding to less than one serving of fish per month, Yassine told Alzforum.
What about brain volume? The researchers found that serum DHA across all quartiles correlated with a larger hippocampus, especially in the left subiculum, right and left CA4, and presubicular areas. The association extended to the cortex as well, because higher DHA correlated with greater total cortical gray matter, and with larger left entorhinal, left inferior temporal, and precuneus regions. No association emerged with white-matter volume or lesions, or the size of the primary motor cortex, suggesting that DHA levels correlated with the volume of regions most affected by AD.
Finally, the researchers compared DHA levels to performance on cognitive tests. They found that higher DHA associated with better nonverbal memory scores, but this association disappeared after accounting for ApoE4 status.
Yassine and other researchers stressed the correlative nature of the findings. Yassine said the field needs to further test the effects of DHA on readily measurable biomarkers, such as brain glucose metabolism and neuronal activity. “These are the kinds of studies that will be most useful at figuring out whether intervention could be useful at the preclinical stage,” he said.
Hilkka Soininen of the University of Eastern Finland in Kuopio found Yassine’s results encouraging, despite the obvious caveats of the study, such as its small size and the substantial burden of vascular disease among its participants. Yvonne Freund-Levi of the Karolinska Institute in Sweden wrote that any conclusions about the effects of limited seafood intake on amyloid deposition would be premature, especially given the lack of healthy aged people unburdened by vascular risk factors in the study, and the absence of controls for body mass index, weight, and gender in some of the statistical analyses. “The recommendation for the future is to design randomized controlled trials with inquiries about diet and omega 3 supplementation, where healthy elderly and prodromal AD patients will be followed longitudinally every six months for as long as possible using amyloid-PET and structural MRI,” she wrote to Alzforum.
Calon pointed out that measuring DHA as a proportion of the total serum fatty acids may produce different results than measuring the absolute concentration of DHA, or DHA in erythrocyte membranes, which is a more accurate predictor of dietary DHA intake. Researchers conducting the Multidomain Alzheimer Preventive Trial (MAPT), in which erythrocyte DHA is measured, will soon report results that jibe with Yassine’s, according to MAPT investigator Bruno Vellas of University of Toulouse in France (see Carrié et al., 2012). In the placebo arm of the three-year DHA intervention trial, cognition deteriorated in normal older people in the lowest quartile of erythrocyte DHA, but not in those in the other three quartiles, Vellas wrote to Alzforum. Vellas presented some of the MAPT’s data at the CTAD meeting last November (Nov 2015 conference news), but many researchers have refrained from commenting until the full data has been published.
Yassine and colleagues are currently recruiting cognitively normal ApoE4 carriers to measure potential benefits of DHA on neuronal connectivity via functional MRI. Although DHA more strongly associated with amyloid in ApoE4 non-carriers in the Aging Brain Study, Yassine said ApoE4 carriers make a better test group, since they are most likely to develop AD. One caveat is that Yassine and colleagues recently reported that ApoE4 and amyloid accumulation prevent uptake of DHA into the brain (see Yassine et al., 2016). While this could potentially diminish the effectiveness of DHA treatment in ApoE4 carriers, Yassine hopes that high enough doses will compensate. The researchers will measure the amount of DHA that makes it into the brain via CSF sampling.—Jessica Shugart
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