Higher plasma oleic acid is associated with slower progression from mild cognitive impairment to Alzheimer’s disease in men and women

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. Elongation of Very Long-Chain Fatty Acids Gas chromatography with flame ionization detection National Institute on Aging–Alzheimer’s Association Phosphorylated tau protein at position 181 Polyunsaturated fatty acids from the n-3 series Polyunsaturated fatty acids from the n-6 series We would like to express our sincere gratitude to all of the patients and members of the dementia unit at the Hospital Universitari Santa Maria. M.J. is a “Serra Húnter” Fellow.

We thank David Argiles for technical support. FD and GPR received a grant from the Instituto de Salud Carlos III (ISCIII), co-funded by the European Union (ERDF/ESF+) (PI25/01702). GPR received funds from the Government of Catalonia, Department of Health (PERIS 2019 SLT008/18/00050), the Agency for Management of University and Research Grants (2021SGR 00761), Instituto de Salud Carlos III and was co-funded by the European Union (ERDF/ESF, “Investing in your future” and “A way to build Europe”) (PI22/01687), and Diputació de Lleida-IRBLleida (PP10950-PIRS2024).

RP received grants from the Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades), co-financed by FEDER funds from the European Union ‘A way to build Europe’ (grants RTI2018-099200-B-I00 and PID2023-152233OB-I00); a grant from the Diputació de Lleida (PP10605-PIRS2021); and a grant from the Agency for Management of University and Research Grants, operated by the Government of Catalonia (2021SGR00990). JLC received grants from the Spanish Ministry of Economy and Competitiveness (PID2020-119978RB-I00), CIBERNED, Alzheimer’s Association (AARG-NTF-22-924702), the Junta de Andalucía (PY20_00858), and the Andalucía-FEDER Program (UPO-1380913). IRBLleida is a CERCA Program of the Government of Catalonia.