Maria Carrigan, Colin Birkenbihl, Hannah M Klinger, Oliver Langford, Gillian T Coughlan, Mabel Seto, Jane A Brown, Annie Li, Madison Cuppels, Michael Properzi, Jasmeer Chhatwal, Julie Price, Aaron Schultz, Dorene Rentz, Rebecca Amariglio, Harm J Krugers, Rik Ossenkoppele, Keith Johnson, Reisa Sperling, Timothy J Hohman, Michael Donohue, Rachel F Buckley
Relative feature importance in sex-specific expectation models differed in 97.7% of variables (false discovery rate-adjusted p value < 0.001). Age and Aβ burden associated with male resistance, while Clinical Dementia Rating, latent Preclinical Alzheimer's Cognitive Composite, and adjusted hippocampal volume were associates in both sexes.
INTRODUCTION: As amyloid beta (Aβ) accumulates, tau pathology spreads beyond medial temporal lobe (MTL) into neocortical (NEO) regions, though some older adults resist this progression, or what we call here "caTAUstrophe." Given previous evidence of higher tau levels in women, we tested how tau resistance presented in men and women separately.
METHODS: Employing data from 872 Aβ+ older adults across three cohorts, we trained sex-specific penalized linear regression models in individuals experiencing caTAUstrophe (females: NTrain = 172; males: NTrain = 121) to predict the expected NEO tau levels. We estimate resistance as lower-than-expected NEO tau levels in training-independent individuals (NTest = 579) to assess sex-specific resistance associates.
RESULTS: Relative feature importance in sex-specific expectation models differed in 97.7% of variables (false discovery rate-adjusted p value < 0.001). Age and Aβ burden associated with male resistance, while Clinical Dementia Rating, latent Preclinical Alzheimer's Cognitive Composite, and adjusted hippocampal volume were associates in both sexes.
DISCUSSION: Our study highlights sex-specific biological and clinical factors in the prediction of NEO tau and associates of resistance. Understanding sex-specific resistance pathways informs targeted Alzheimer's interventions.