PROJECT SUMMARY Alzheimer’s disease (AD) and other tau-mediated neurodegenerative diseases are characterized by aggregation and spread of pathological tau protein in the brain. Despite decades of research, effective interventions to these diseases are still lacking. It is well-evidenced that women typically show greater tau pathology than men on the AD trajectory; yet the reason for such sex differences is poorly understood. A better understanding of the mechanisms underlying the greater tau deposition in women can benefit all by informing causal pathways of disease and therapeutic targets and strategies that are optimal for each sex. Clinical evidence suggests that low testosterone levels correlate with poorer cognitive function and greater risk for AD. In particular, a recent study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) revealed that women with lower testosterone tend to have higher levels of phosphorylated tau (p-tau) in cerebrospinal fluid (CSF), particularly among ApoE4 carriers. This suggest that lower testosterone levels that typically characterize women may predispose them to pathological tau, and contribute to sex differences observed in AD. To take these correlative findings to the necessary next step, our overall objectives are to establish the causal relationship between testosterone and tau in females, to explore the clinical applicability of testosterone therapy, and to elucidate the underlying molecular mechanisms. Given testosterone’s anti-inflammatory actions and neuroprotective effects on AD-related outcomes, we hypothesize that pharmacological induction of high testosterone protects against pathological tau accumulation and spread, diminishes neuroinflammation and ameliorates cognitive deficits associated with tau pathogenesis, particularly in ApoE4 females. Based on published preclinical studies on testosterone, we further hypothesize that the protective effects of testosterone are linked to androgen receptor signaling in astrocytes and neurons, leading to enhanced neuronal survival, synaptic integrity and reduces neuroinflammation. This project is a new direction in our research program: In collaboration with experts on reproductive biology and gene expression, we will combine our expertise in tau biology, sex hormones and transcriptomics to determine how testosterone modulates tau pathogenesis in a sex-specific manner. We will: 1) Determine how increase of testosterone levels affects tau pathogenesis in female tau transgenic mouse models with human ApoE4/E3 knock-in; 2) Elucidate the molecular mechanism underlying the protective effects of testosterone in ApoE4 females by single nucleus RNA sequencing, and determining the involvement of neuronal and astrocytic androgen receptor signaling. This project aims to close critical gaps in our understanding of mechanisms underlying sex differences in tau pathophysiology, and provide novel insights into the influence of androgen on molecular mechanisms central to A...