Sex-Specific Associations of α-Synuclein Pathology With Tau Accumulation

TL;DR

Women with α-synuclein pathology show faster tau accumulation than men, suggesting sex-specific differences in Alzheimer's disease progression.

Contribution

Identifies sex-specific associations between α-synuclein pathology and tau accumulation in Alzheimer's disease.

Findings

Women with α-synuclein positivity had significantly faster tau accumulation than other groups.

Men with α-synuclein positivity did not show significant differences in tau accumulation.

Clinical trials may need larger sample sizes for SAA-negative women to detect treatment effects.

Abstract

Is α-synuclein pathology differentially associated with tau accumulation in women and men across the Alzheimer disease continuum?

In this cohort study of 415 participants from the Alzheimer’s Disease Neuroimaging Initiative who underwent longitudinal tau positron emission tomography, women with positive α-synuclein seed amplification assay results had significantly faster tau accumulation than all other groups, whereas men with positive results did not differ significantly from men with negative results.

These findings suggest that α-synuclein copathology in women is associated with faster tau accumulation, supporting sex-specific biomarker interpretation and trial stratification in Alzheimer disease.

This cohort study examines whether α-synuclein positivity is associated with tau accumulation in women vs men across the Alzheimer disease continuum.

Sex differences are increasingly recognized as modifiers of Alzheimer disease and related dementias, with women exhibiting greater tau burden and faster cognitive decline than men. Even though α-synuclein copathology frequently occurs in Alzheimer disease, its contribution to sex differences in disease progression is unclear.

To test whether α-synuclein positivity, measured using cerebrospinal fluid seed amplification assay (SAA), is differentially associated with tau accumulation in women vs men across the Alzheimer disease continuum.

This cohort study used longitudinal tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative collected between 2015 and 2023, with a median (IQR) follow-up of 1.23 (0.00-3.84) years. Participants were stratified by cerebrospinal fluid α-synuclein seed amplification assay status and sex. Participants were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline.

Cerebrospinal fluid α-synuclein status determined by SAA and dichotomized as SAA negative or SAA positive.

Tau burden was quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest. Linear mixed-effects models tested SAA by sex by time interactions on longitudinal tau accumulation, adjusting for baseline age, baseline cognitive status, apolipoprotein E ε4 carrier status, and site. Sample size estimates were calculated to detect 25% and 50% treatment effects with 80% power in those with cognitive impairment.

Among 415 participants (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), there was a significant interaction between SAA status, sex, and time on tau accumulation (β, 0.061; 95% CI, 0.030-0.093; P < .001). Women with positive SAA results exhibited the fastest tau accumulation compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year; P < .001). Clinical trials targeting tau pathology in cognitively impaired individuals with 18-month follow-up would require 129 SAA-positive women to detect a 25% treatment effect with 80% power, compared with 518 SAA-negative women.

In this cohort study of participants across the Alzheimer disease continuum, α-synuclein copathology was associated with faster tau accumulation in women than men. These findings may inform sex-specific interpretation of α-synuclein biomarkers and trial design.

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