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.

Fig. 1. Sex modulates plasma p-tau181 associations with brain amyloid-β deposition.

Scatter plots demonstrating sex differences in the cross-sectional association between plasma p-tau181 levels and brain amyloid-β deposition (measured by amyloid-β PET in cortical summary region) in each diagnostic group. SUVR standardized uptake value ratio.

Fig. 2. Sex modulates plasma p-tau181 associations with cerebral glucose metabolism.

Scatter plots depicting sex differences in the cross-sectional association between plasma p-tau181 levels and brain glucose metabolism (measured by FDG-PET) in each diagnostic group. SUVR standardized uptake value ratio.

Fig. 3. Sex modulates the association between plasma p-tau181 and entorhinal cortex tau deposition.

Scatter plot depicting sex differences in the cross sectional association between plasma p-tau181 levels and entorhinal cortex tau deposition (measured using tau PET). SUVR standardized uptake value ratio.

Fig. 4. Sex modulates plasma p-tau181 associations with CSF p-tau181.

Scatter plots depicting sex differences in the cross-sectional association between plasma p-tau181 and CSF p-tau181 in each diagnostic group.

Fig. 5. Sex modulates the association between baseline plasma p-tau181 levels and cognitive decline.

Scatter plots demonstrating sex differences in the association between baseline plasma p-tau181 levels and decline in A MMSE and B MoCA performance over time in participants diagnosed with mild cognitive impairment. MMSE Mini Mental Status Examination, MoCA Montreal Cognitive Assessment.