Sex specificity of resistance to caTAUstrophe

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: N Train = 172; males: N Train = 121) to predict the expected NEO tau levels. We estimate resistance as lower‐than‐expected NEO tau levels in training‐independent individuals (N Test = 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.