Proteomic Subtyping of Alzheimer’s Disease CSF links Blood-Brain Barrier Dysfunction to Reduced levels of Tau and Synaptic Biomarkers

Alzheimer’s disease (AD) is characterized by significant clinical and molecular heterogeneity, influenced by genetic and demographic factors. Using an unbiased, network-driven approach, we analyzed the cerebrospinal fluid (CSF) proteome from 431 individuals (483 samples), including 111 African American participants, to identify core protein modules associated with AD, race, sex, and age. Our analysis revealed ten co-expression modules linked to distinct biological pathways and cell types, many of which correlated with established AD biomarkers such as β-amyloid, tau, and phosphorylated tau. To further resolve disease heterogeneity, we applied a proteomic subtyping approach, identifying six distinct CSF subtypes spanning the clinical and pathological spectrum. These subtypes were validated across independent cohorts, with many aligning with previously defined AD subtypes, including those linked to neuronal hyperplasticity, immune activation, and blood-brain barrier (BBB) integrity. Notably, the BBB subtype, enriched with African Americans and men, was characterized by low CSF tau, high CSF/serum albumin ratios, and reduced synaptic protein levels. This subtype also exhibited increased levels of proteolytic enzymes, including thrombin and matrix metalloproteases, that cleave tau. Plasma dilution into the neuronal hyperplastic AD subtype CSF led to reduced tau and synaptic protein module levels, indicating that plasma protease activity contributes to tau and synaptic protein depletion independent of underlying brain pathology. These findings highlight the impact of BBB integrity on CSF tau levels, particularly in men and African Americans, and underscore the need for diversity-informed AD biomarker strategies to improve diagnostics and therapeutic targeting across populations.