In
Alzheimer's disease (AD), the most common cause of
dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited. Here, we comprehensively examined and validated 7,006 aptamers targeting 6,162
proteins in cerebral spinal fluid (CSF) from 2,077
amyloid/tau positive cases and controls to identify sex-specific proteomic signatures of AD. In discovery (N=1,766), we identified 330 male-specific and 121 female-specific proteomic alternations in CSF (FDR <0.05). These sex-specific
proteins strongly predicted
amyloid/tau positivity (AUC=0.98 in males; 0.99 in females), significantly higher than those with age, sex, and APOE-ε4 (AUC=0.85). The identified sex-specific
proteins were well validated (r≥0.5) in the Stanford study (N=108) and Emory study (N=148). Biological follow-up of these
proteins led to sex differences in cell-type specificity, pathways, interaction networks, and drug targets. Male-specific
proteins, enriched in astrocytes and oligodendrocytes, were involved in postsynaptic and axon-genesis. The male network exhibited direct connections among 152
proteins and highlighted PTEN, NOTCH1, FYN, and MAPK8 as hubs. Drug target suggested
melatonin (used for sleep-wake cycle regulation),
nabumetone (used for
pain),
daunorubicin, and
verteporfin for treating AD males. In contrast, female-specific
proteins, enriched in neurons, were involved in
phosphoserine residue binding including
cytokine activities. The female network exhibits strong connections among 51
proteins and highlighted JUN and
14-3-3 proteins (YWHAG and YWHAZ) as hubs. Drug target suggested
biperiden (for muscle control of
Parkinson's disease),
nimodipine (for
cerebral vasospasm),
quinostatin and
ethaverine for treating AD females. Together, our findings provide mechanistic understanding of sex differences for AD risk and insights into clinically translatable interventions.