Plasma neurofilament light reflects more severe manifestation of Alzheimer’s disease in men

Plasma neurofilament light (NfL) protein is a promising non-invasive biomarker for detecting neuronal damage in Alzheimer’sdisease (AD). However, its clinical utility is limited by the lack of standardized threshold values. Sex is an important factor thatshould be considered when setting these thresholds, but only a few studies have examined sex differences in plasma NfL levels inAD, with inconsistent findings. Even fewer have explored whether sex influences the relationship between plasma NfL levels anddisease severity. To investigate this, we first analyzed data from 860 participants in the Alzheimer’s Disease Neuroimaging Initiative(ADNI) database. Linear regression models were used to assess sex differences in the correlation between plasma NfL levels,cognitive deficits, and neuroimaging metrics. A Cox model with bootstrap resampling was used to evaluate sex differences indementia risk, calculating the hazard ratio for men versus women for a given increase in plasma NfL. Our results showed that,compared to women, men with higher plasma NfL levels exhibited more severe cognitive defects and brain hypometabolism, alongwith smaller hippocampal volume. These findings were validated using data from 619 participants in the Chinese PreclinicalAlzheimer’s Disease Study (C-PAS) cohort and 86 participants from a publicly available dataset. In addition, we found that increasein plasma NfL levels were predictive of faster cognitive decline and a higher likelihood of AD progression in men compared towomen. In conclusion, sex differences influence the relationship between plasma NfL levels and AD symptoms. Men exhibit greatercognitive and neuropathological defects with rising plasma NfL levels, underscoring the need for considering sex when using NfL asa biomarker for neuronal damage in AD.

原文链接: 10.1038/s41380-025-03149-z