HAI Book 2025 - Flipbook - Page 512
Coughlan, Gillian
Sex moderates relationships between P-Tau217 and longitudinal tau-PET: A
multi-cohort study
Gillian Coughlan1, Hannah Klinger1, Tobey Betthauser6, Rebecca Langhough6, Karly Cody6,
Mabel Seto3, Colin Birkenbihl1, Annie Li1, Michelle Farrell1, Emma Thibault1, Robert Rissman2,
Michael Properzi1, Aaron Schultz1, Diana Townsend1, Hyun-Sik Yang3, Keith Johnson1,4, Rema
Raman2, Oliver Langford2, Michael C. Donohue2, Sterling Johnson6, Reisa Sperling1,3, Rachel
Buckley1,3,5
1
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US
Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, US
3
Brigham and Women’s Hospital, Boston, MA, US
4
Gordon Center for Medical Imaging, Department of Radiology, Boston, MA, US
5
Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, AU
6
Department of Medicine, University of Wisconsin-Madison, USA, Madison, WI, US
2
Background: Women exhibit elevated insoluble tau aggregates and greater tau proliferation relative to agematched men. Whether this is due to sex differences in upstream soluble phosphorylated tau(p-tau) is unclear.
We examined whether sex and amyloid-´(A´) predict baseline soluble p-tau217 and whether baseline p-tau217
predicts tau positron emission tomography(PET) trajectories in a sex-specific manner.
Methods: 796 clinically normal individuals (mean-age:70; 311 APOEε4 carriers; 450 A´-positive; Table) from the
Anti-Amyloid Treatment in Asymptomatic Alzheimer9s Disease trial, the companion Longitudinal Evaluation of
Amyloid Risk and Neurodegeneration study(A4/LEARN), the Wisconsin Registry for Alzheimer9s Prevention(WRAP)
and Harvard Aging Brain Study(HABS) had multiple tau-PET scans and at least one measurement of ptau217 and
A´-PET. Average tau-PET follow-up time was 3.3 years (range=1.3-8.9years). Cross-sectional sex differences in A´
dependent soluble pTau217 were characterized using regression models. Longitudinally, random-effects models
estimated the sex×baseline-p-tau217×time interaction on each of nine tau-PET regions previously showing crosssectional sex differences including participant-specific intercepts and slopes. The tau-PET regions included
rostral middle frontal gyri, fusiform gyrus, inferior temporal and parietal gyri, the superior parietal lobule,
precuneus, lateral occipital cortex, parahippocampal and amygdala. All models adjusted age and education.
Women were the reference.
Results: In A4/LEARN, women exhibited elevated p-tau217 concentrations at baseline relative to men, particularly
at higher neocortical-A´ (´=-0.16, P=0.008). Longitudinal sex×baseline-p-tau217×time interactions were
significant in five, seven and four tau-PET regions in A4/LEARN, WRAP and HABS cohorts, respectively. Across all
significant interactions, women showed worse tau trajectories than men, particularly at higher p-tau217
concentrations (see Figure 1 for A4/LEARN and Figure 2 for WRAP and HABS). Additionally, covarying for APOEε4status and baseline neocortical-A´ did not alter the longitudinal sex effects (Table 2).
Conclusions: These findings suggest that sex differences in tau proliferation are exacerbated by upstream
soluble p-tau levels. Earlier therapeutic approaches reducing soluble p-tau levels might be particularly important
in women.
HAI2025 - 512
