Abstract
BackgroundFatty acids play prominent roles in brain function as they participate in structural, metabolic and signaling processes. The homeostasis of fatty acids and related pathways is known to be impaired in cognitive decline and dementia, but the relationship between these metabolic disturbances and common risk factors, namely the ɛ4 allele of the apolipoprotein E (ApoE-ɛ4) gene and sex, remains elusive.MethodsIn order to investigate early alterations associated with cognitive decline in the fatty acid-related serum metabolome, we here applied targeted metabolomics analysis on a nested case-control study (N=368), part of a prospective population cohort on dementia.ResultsWhen considering the entire study population, circulating levels of free fatty acids, acyl-carnitines and pantothenic acid were found to be increased among those participants who had greater odds of cognitive decline over a 12-year follow-up. Interestingly, stratified analyses indicated that these metabolomic alterations were specific for ApoE-ɛ4 non-carriers and women.ConclusionsAltogether, our results highlight that the regulation of fatty acids and related metabolic pathways during ageing and cognitive decline depends on complex inter-relationships between the ApoE-ε4 genotype and sex. A better understanding of the ApoE-ɛ4 and sex dependent modulation of metabolism is essential to elucidate the individual variability in the onset of cognitive decline, which would help develop personalized therapeutic approaches.
Highlights
Fatty acids play prominent roles in brain function as they participate in structural, metabolic and sign‐ aling processes
Medication intake was significantly higher within cases, whereas lower scores for the five neuropsychological tests employed here (i.e., Mini-Mental State Examination test (MMSE), Benton Visual Retention Test (BVRT), Isaac’s Set Test (IST), Trail-Making Test part A (TMTA) and Trail-Making Test part B (TMTB)) were observed among Cognitive decline (CD) participants
It is worth noting that notorious inconsistencies have been reported in previous metabolomics-based studies aimed at investigating the dysregulation of fatty acids in CD and Alzheimer’s disease (AD) [9], which could be attributed to discrepancies in the lipid fraction under study (i.e., Free fatty acid (FFA), total fatty acids, fatty acids contained within specific lipid classes)
Summary
Fatty acids play prominent roles in brain function as they participate in structural, metabolic and sign‐ aling processes. The homeostasis of fatty acids and related pathways is known to be impaired in cognitive decline and dementia, but the relationship between these metabolic disturbances and common risk factors, namely the ɛ4 allele of the apolipoprotein E (ApoE-ɛ4) gene and sex, remains elusive. Neu et al reported that, among ApoE-ɛ4 carriers, the risk for developing AD or mild cognitive impairment (MCI) is not significantly different between men and women when considering a broad age window (55-85 y), but women are at increased risk compared to men at younger ages (65-75 y for AD, 55-70 y for MCI) [7] In this context, metabolomics has demonstrated great potential to investigate the profound impact of CD and dementia on metabolism and the final phenotype [8, 9]. Stratified analyses are mandatory for elucidating the mechanisms underlying the intertwined modulation of CD by ApoE-ɛ4 and sex, as recently proposed by others as well [10,11,12]
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