Biological drivers of sex differences in frontotemporal dementia

ABSTRACT Dementia prevalence and disease course differs by sex. Yet, despite being the leading cause of young onset dementia, very little is known about sex differences in frontotemporal dementia (FTD). Our accumulating data suggest females with FTD show patterns of “cognitive resilience” consistent with delayed symptom manifestation, despite higher neurodegenerative burden. We hypothesize that female-specific biology drives the unique clinical course of women suffering from FTD. Our overarching goal is to deeply characterize understudied female biology to unlock new insights into FTD pathophysiology, precision treatments, and novel dementia risk and resilience targets for all brains. To do so, our proposal will leverage two deeply phenotyped, longitudinally-followed local and international cohorts of genetic and sporadic forms of FTD and healthy controls (n=1095). We will be the first comprehensive evaluation of biological sex differences in FTD. Our Aims will: 1) Prospectively assay longitudinal sex hormone levels in plasma (e.g.,17𝛽-estradiol, testosterone, progesterone), 2) Identify sex-specific proteomic signatures of FTD from cerebrospinal fluid and plasma, 3) Collect a new female reproductive health history measure (e.g., age of menopause, pregnancies), and 4) Develop disease progression models that incorporate sex-specific factors to precisely prognosticate FTD trajectories in males and females. This proposal contributes to a high priority, underserved scientific area. For instance, among neuroimaging papers published since the 1990s, <0.5% consider factors specific to the female body. This knowledge gap creates treatment inequities as evidenced by the currently available therapy for Alzheimer’s disease (Lecanemab), which shows less than half the efficacy in females compared to males. Our proposal will therefore address a major health disparity, advance precision approaches to FTD before treatment inequities arise, and leverage overlooked female biology to discover new insights into dementia prevention targets relevant for all brains.