Sex-Specific lipid peroxidation profile and clinical features in a cognitive impairment cohort

Alzheimer's disease (AD) displays a sex imbalance; women represent two-thirds of cases and often progress faster. Lipid peroxidation contributes to AD neurotoxicity from the oxidation of fatty acids can. However, how sex modulates plasma lipid peroxidation across clinical stages remains poorly characterized. This study examines sex- and AD clinical stage-related patterns in these plasma compounds.

Plasma lipid peroxidation compounds were quantified by liquid chromatography/mass spectrometry in a clinical cohort stratified into 6 groups (cognitively unimpaired (without AD (n = 93), with AD (n = 27)), mild cognitive impairment (due to AD (n = 105), not due to AD (n = 45)), mild dementia (due to AD (n = 84), not due to AD (n = 34))).

Across clinical groups, women showed a more severe clinical profile, while men showed higher neurofilament light chain (NfL) levels in several groups. Specifically, 10 lipid peroxidation compounds showed impaired levels in women with AD, while only 2 compounds in men. Notably, significant positive correlations were observed between certain lipid peroxidation compounds and cerebrospinal fluid (CSF) biomarkers exclusively in women. Positive correlations were observed between isoprostanes/neuroprostanes and some neuropyschological tests (CDR, MMSE, ADCS-ADL-MCI) in women, as well as mixed correlations between lipid peroxidation compounds and two tests (RBANS, FAQ) in men. Furthermore, multivariate analysis confirmed that clinical diagnosis was the main determining factor rather than biological sex, with 4 lipid peroxidation compounds (10-epi-10-F_4t-NeuroP, 17-epi-17-F_2t-dihomo-IsoP, total IsoP and total NeuroP) showing differences among clinical groups with distinct patterns of progression, specifically men showing higher levels in preclinical stages, while women showed more complex fluctuations throughout AD progression.

Plasma lipid peroxidation follows sex-dependent biological patterns across clinical stages of AD, highlighting a wider variety of altered biomarkers in women, which underscores the need to evaluate sex-stratified approaches for the diagnosis and AD staging.