Sex differences in plasma p-tau181 associations with Alzheimer’s disease biomarkers, cognitive decline, and clinical progression

Abstract

Studies have shown that women on the Alzheimer’s disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-β (Aβ) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aβ and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aβ positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

Plasma biomarkers identify older adults at risk of Alzheimer's disease and related dementias in a real‐world population‐based cohort

“…Notably, females showed higher GFAP and NfL levels, also corroborating recent findings 40 . Lower plasma p‐tau181 in females has also been reported 41 . While Aβ42/40 ratio was not affected by education, NfL, GFAP, and p‐tau181 were lower in the more‐educated groups.…”

Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force

“…A secondary analysis from the ADNI study shown that sex may impact the clinical interpretation of plasma p-tau181 concentrations ( 25 ). In women, high plasma p-tau levels were associated with worse phenotypic markers (i.e., greater cortical Aβ deposition, higher CSF p-tau181 levels, lower brain glucose metabolism) compared with men.…”

Sex differences in blood biomarkers and cognitive performance in individuals with autosomal dominant Alzheimer's disease

“…Findings from community and population-based AD studies found that levels of plasma P-tau217 did not differ between males and females, 2,5 while a recent study showed that higher plasma P-tau181 was associated with greater amyloid and entorhinal cortex tau accumulation, lower brain glucose metabolism, and faster cognitive decline in females, relative to males. 30 Research examining the effect of sex/gender on plasma biomarkers of neurodegeneration in AD cohort studies have also yielded mixed findings. Several studies have not found sex/gender differences in plasma NfL 5,12,31 or total tau.…”