Proteomic subtyping of Alzheimer's disease CSF links blood–brain barrier dysfunction to reduced levels of tau and synaptic biomarkers

INTRODUCTION: Alzheimer's disease (AD) shows clinical and molecular heterogeneity shaped by demographic and genetic factors. METHODS: To resolve this heterogeneity, we performed a network-based proteomic analysis of cerebrospinal fluid (CSF) from 431 individuals, including 111 African Americans, to identify protein co-expression modules and define AD subtypes. RESULTS: Ten co-expression modules reflecting diverse pathways and cell types were identified, many linked to demographics and AD biomarkers. One subtype, enriched in African Americans and males, showed low CSF tau, elevated plasma proteins, and reduced synaptic proteins, features consistent with blood-brain barrier (BBB) dysfunction. This subtype also showed the highest levels of thrombin activity, capable of cleaving tau. Introducing plasma into CSF ex vivo recapitulated the BBB subtype signature, supporting a causal role for plasma proteases in tau and synaptic protein depletion. CONCLUSION: These findings link BBB dysfunction and plasma proteases to CSF tau loss and highlight the need for diversity in AD-biomarker research. HIGHLIGHTS: Race and sex correlate with key AD proteomic network modules. We identify six proteomic subtypes with distinct demographic and AD biomarker profiles. Subtype 3 demonstrates an A+/T- phenotype and a profile suggestive of BBB dysfunction. Low CSF tau and neuronal proteins may stem from infiltrating plasma protease cleavage. Plasma spike-in experiments show decreased endogenous CSF tau and neuronal proteins.