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

Product:

CNS Disease Panel 120

Topic:

Neurology

Disease Area:

Alzheimer's Disease

Sample Type:

CSF

Topic/Product:

CNS Disease Panel 120

Disease Area:

Alzheimer's Disease

Sample Type:

CSF

Abstract

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.

Authors & Affiliations

Madison C. Bangs 1,2 , Joshna Gadhavi 1,2 , E. Kathleen Carter1,2, Lingyan Ping1,2, Duc M. Duong1,2, Eric B. Dammer2 , Fang Wu1,2, Anantharaman Shantaraman1,2, Edward J. Fox1,2, Erik C.B. Johnson2,3,4, James J. Lah2,3,4, Allan I. Levey2,3,4* , and Nicholas T. Seyfried1,2,3,4*

Affiliations:

Department of Biochemistry, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Center for Neurodegenerative Disease Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Goizueta Alzheimer’s Disease Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Neurology, Emory University School of Medicine, Atlanta, GA 303

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.