Abstract / Summary
The contribution of sex differences in lipid metabolism to the pathophysiology of Alzheimer’s disease (AD) remains under Investigation. This study aimed to investigate sex-stratified associations of fatty acid (FA) profiles in cerebrospinal fluid (CSF) and plasma across the AD continuum, and their associations with AD pathology and progression. FA profiles were analyzed in 198 CSF and 286 plasma samples from AD, mild cognitive impairment (MCI), and control subjects using GC-FID. The MCI subjects were followed up for 58 (± 12.5) months. Analysis of FA profiles of control subjects revealed minor sex differences in both CSF and plasma biofluids. In men, a higher CSF anti-inflammatory index was associated with lower odds of AD than MCI (OR = 0.025), whereas higher CSF α-linolenic acid (C18:3n-3) levels were associated with higher odds of AD (OR = 2.826). In women, higher CSF levels of palmitoleic acid (C16:1n-7) were associated with lower odds of amyloid-β (Aβ) positivity (OR = 0.500). Higher plasma oleic acid (C18:1n-9) levels were associated with lower odds of MCI-to-AD progression in men (OR = 0.666) and a longer time to progression in women (HR = 0.404). Our results suggest that higher plasma oleic acid levels were associated with slower disease progression in both men and women, whereas higher CSF anti-inflammatory index and α-linolenic acid were associated with AD diagnosis in men. These findings may reflect differences in lipid metabolism associated with AD across men and women, although reverse causation and residual confounding cannot be excluded.