HAI Book 2025 - Flipbook - Page 394
Li, Annie
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Sex moderates the association between regional tau and longitudinal
cognitive decline in A4 and LEARN studies
Annie Li1, Hannah M. Klinger1, Mabel Seto3, Colin J. Birkenbihl1, Michelle Farrell1, Emma
Thibault1, Robert A. Rissman2, Michael Properzi1, Aaron P. Schultz1, Diana L. Townsend1, HyunSik Yang1,3, Keith A. Johnson1,3, Rema Reman2, Oliver Langford2, Michael Donohue2, Reisa A.
Sperling1,3, Rachel F. Buckley1,3,4, Gillian T. Coughlan1
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
Neurology Department, Brigham and Women’s Hospital, Boston, MA, US
4
Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, AU
2
Background: Existing literature suggests that women exhibit higher tauopathy relative to men, but evidence for
sex moderating the association between tauopathy and cognitive decline is sparse. To address this gap, we
investigated sex differences on cognitive trajectories as a function of tau burden.
Methods: The study included 436 clinically normal adults from the Anti-Amyloid Treatment in Asymptomatic
Alzheimer9s Disease trial (A4) and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration
(LEARN) study (Table 1), with at least one baseline tau-positron emission tomography (PET) scan and cognitive
follow-ups (mean(SD)=3.34(2.19)years, range=0.03-9.04 years). Four Alzheimer9s disease-related tau regions were
selected: parahippocampus, amygdala, entorhinal, and inferior temporal gyri. Cognitive outcomes were measured
using Preclinical Alzheimer Cognitive Composite (PACC) scores. Random-effects regression models estimated
the interaction between sex (men/women) and regional tau (continuous) on longitudinal PACC, adjusting for age
and education over time, including participant-specific intercepts and slopes. PACC slopes were extracted, and a
linear model was used in the floodlight analysis to identify baseline tau thresholds required to detect sexdivergent cognitive trajectories.
Results: Among those with elevated parahippocampal tau (´=0.08, 95%CI:0.00-0.16, P=0.038), amygdala tau
(´=0.11, 95%CI:0.03-0.19, P=0.009), inferior temporal tau (´=0.10, 95%CI:0.02-0.18, P=0.014), and entorhinal tau
(´=0.08, 95%CI:0.00-0.16, P=0.043), women exhibited significantly faster rates of cognitive decline relative to
men. At low levels of tau, women maintained superior PACC performance. Floodlight analysis identified tau
thresholds for a significant association between sex and cognitive change (1.25-1.32 tau-SUVR), except for
entorhinal tau. These thresholds were used to categorize participants for visualizing trajectories by sex (Figure).
Adjusting for substudy, treatment, and baseline amyloid level did not alter findings (Table 2).
Conclusion: Higher regional tau levels in women may contribute to a greater risk of cognitive decline relative to
men. These findings emphasize the importance of considering sex-specific tau levels at the baseline of clinical
trials.
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