Apolipoprotein E and sex modulate fatty acid metabolism in a prospective observational study of cognitive decline

Abstract

Background Fatty 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. Methods In 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. Results When 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. Conclusions Altogether, 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.

Association between plasma Vitamin B5 levels and all‐cause mortality: A nested case‐control study

“…Many common disorders, such as CVD, cancer, obesity, and Alzheimer's disease (AD), are now understood to be influenced by chronic inflammation. In addition, several prospective studies have shown that participants with higher circulating vitamin B5 have greater odds of cognitive decline 7 and, similarly, that dietary intake of vitamin B5 is linearly associated with Aβ load in several regions of the brain 13 . In addition, some studies have shown that hypertension increases the risk of AD 19 .…”

“…A case‐control study also noted that serum vitamin B5 levels were significantly higher in type 2 diabetes mellitus (T2DM) patients with higher body mass index (BMI), which may be associated with IR 11,12 . In addition, in neurodegenerative disease, studies have indicated that circulating levels of vitamin B5 were higher among those participants who had greater odds of cognitive decline over a 12‐year follow‐up 7 . Vitamin B5 intake may be associated with increased cerebral amyloid‐b peptide (Aβ) burden in patients with cognitive impairment 13 .…”

“…11,12 In addition, in neurodegenerative disease, studies have indicated that circulating levels of vitamin B5 were higher among those participants who had greater odds of cognitive decline over a 12-year follow-up. 7 Vitamin B5 intake may be associated with increased cerebral amyloid-b peptide (Aβ) burden in patients with cognitive impairment. 13 Additionally, a 12-month prospective study found a significant association between increased levels of vitamin B5 intake and increased rates of genome damage, 14 a biomarker for higher cancer risk.…”

“…3 However, epidemiological research on vitamin B5, specifically on the connection between vitamin B5 and death, is scant. Vitamin B5 has been associated with lipid metabolism, 4 inflammation, 5 insulin resistance (IR), 6 cognitive dysfunction, 7 and cancer, 8 although the mechanisms behind these associations remain unknown. According to the available research, vitamin B5 may be a double-edged sword.…”

Complex association of apolipoprotein E–containing HDL with coronary artery disease burden in cardiovascular disease

“…Moreover, ApoE-containing HDL particles promote cholesterol efflux from extrahepatic cells (10) by ABCA1-and ABCG1-dependent processes, and this process is antagonized by the presence of ApoC-III (9). Finally, it has been shown that cognitive decline might be dependent on the ApoE-ε4 genotype and sex through FA metabolism and related metabolic pathways (27).…”