DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA

Abstract

BackgroundThe apolipoprotein E ɛ4 (APOE4) allele is the strongest genetic risk factor identified for developing Alzheimer’s disease (AD). Among brain lipids, alteration in the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) homeostasis is implicated in AD pathogenesis. APOE4 may influence both brain DHA metabolism and cognitive outcomes.MethodsUsing positron emission tomography, regional incorporation coefficients (k*), rates of DHA incorporation from plasma into the brain using [1-11C]-DHA (J in), and regional cerebral blood flow using [15O]-water were measured in 22 middle-aged healthy adults (mean age 35 years, range 19–65 years). Data were partially volume error-corrected for brain atrophy. APOE4 phenotype was determined by protein expression, and unesterified DHA concentrations were quantified in plasma. An exploratory post hoc analysis of the effect of APOE4 on DHA brain kinetics was performed.ResultsThe mean global gray matter DHA incorporation coefficient, k*, was significantly higher (16%) among APOE4 carriers (n = 9) than among noncarriers (n = 13, p = 0.046). Higher DHA incorporation coefficients were observed in several brain regions, particularly in the entorhinal subregion, an area affected early in AD pathogenesis. Cerebral blood flow, unesterified plasma DHA, and whole brain DHA incorporation rate (J in) did not differ significantly between the APOE groups.ConclusionsOur findings suggest an increase in the DHA incorporation coefficient in several brain regions in APOE4 carriers. These findings may contribute to understanding how APOE4 genotypes affect AD risk.

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

“…Also in 2017, the same group [13] reviewed original articles, systematic reviews, and meta-analyses of omega-3 studies in AD that were published before August 20, 2016 and concluded that while randomized clinical trials of omega-3 in symptomatic AD reported negative findings, several observational and clinical trials of omega-3 in the pre-dementia stage of AD suggest that omega-3 supplementation might slow early memory decline in 4 carriers. Tambini et al [97] conducted an in vitro experiment whose results are consistent with the increased lipid metabolism observed by Yassine et al [96]. Using an astrocyte-conditioned media model, this group measured the synthesis of phospholipids and cholesteryl esters and reported a significant increase in cells treated with APOE 4containing astrocyte-conditioned media as compared to those treated with APOE 3-containing-astrocyteconditioned media.…”

“…Young subjects having at least one copy of the 4 allele reportedly possess a number of advantages that might facilitate survival in harsh environments including the following among others: more rapid improvement in VO 2max following exercise [51]; increased fertility at high pathogen burdens [52,53]; more rapid infant development [105]; prophylaxis against cognitive deficits associated with severe diarrhea [122][123][124]; resistance to certain infections, e.g., hepatitis [76] and malaria [83]; faster reaction times [121]; better spatial memory [111,102,119,120]; and slight superiority in direct or indirect measures of IQ [135,134,126,141]. Some of these advantages appear to come at the expense of differences in neural processing that might place higher metabolic demands per unit time on the brains of young 4 carriers [143,111,96].…”

“…The strongest direct evidence that some of the macromolecular components comprising the synapses of 4 carriers might be turned over at a higher rate than comparable macromolecular synaptic components in non-4 carriers has been provided by Yassine et al [96]. This group studied 22 middleaged healthy adults (mean age 35 years, range 19-65 years) and found that k*, the mean global gray matter DHA incorporation coefficient, was significantly higher (16%) among 4 carriers (n = 9) than among non-carriers (n = 13, p = 0.046).…”

APOE ε4 Allele-associated Alzheimer's disease risk is consistent with increased lifetime exposure to a neurotoxic process

“…The increased rate of DHA incorporation into neuronal membranes reported by Yassine et al [39], and higher brain activity seen in young, healthy APOE ε4-positive individuals both support a higher rate of turnover in synaptic macromolecules associated with the APOE ε4 allele, regardless of explanation. Although neurogenesis can occur in the adult hippocampus [52], and increased neurogenesis increases the rate of synapse formation, synaptogenesis and synaptic pruning occur in the absence of neurogenesis.…”

“…Recently, Yassine, et al [39] used positron emission tomography to demonstrate increased docosahexaenoic acid (DHA) uptake in several brain regions in APOE ε4 carriers. In the AD-susceptible entorhinal sub-region, the mean global gray matter DHA incorporation coefficient was 16% higher among APOE ε4 carriers (n = 9) than among APOE ε3 and APOE ε2 carriers (n = 13, p = 0.046).…”