Aβ-related Cerebrospinal Fluid Proteins in Alzheimer’s Disease Reflect Gene Expression Levels Found in The Healthy Cortex

Topic/Product:
CNS Disease Panel 120
Disease Area:
Alzheimer's Disease
Sample Type:
CSF

Abstract

A growing body of evidence indicates that CSF proteomic signatures shift with increasing brain amyloidosis in Alzheimer’s disease (AD). However, it remains unknown whether protein profiles within cortical regions that are vulnerable to early amyloid-beta (Aβ) deposition contribute to, or predict, CSF Aβ-related protein measures. To address this question, we examined 220 cognitively unimpaired (CU) and cognitively impaired (CI) older participants from the TRIAD cohort who had Aβ- and tau-PET scans, MRI, and CSF NULISA™seq CNS panel data. Aβ-related hierarchical clustering identified 12 clusters corresponding to biologically interpretable gene ontology processes, supported by bootstrap resampling, silhouette analysis, and dynamic tree cutting. Clusters’ composite scores for tau-markers, neuronal-injury, and APOE4 correlated strongly with global neocortical Aβ-PET SUVR (p < 0.001) and showed elevated odds ratios (OR) of Aβ positivity (ORs: 10.4, 2.4, and 4.0, respectively). The Aβ42 cluster, as expected, was inversely associated with brain Aβ burden and predicted reduced Aβ positivity (OR = 0.13). Voxel-wise analyses revealed distinct spatial signatures for each cluster, such as associations in cortical regions (tau-markers, neuronal-injury, and APOE4 clusters), white matter (axonal metabolic injury cluster), and periventricular areas (synaptic signaling and cellular response clusters). The magnitude of Aβ-related cortical associations and CSF protein clusters correlated with the magnitude of regional mRNA expression derived from the Allen Brain Atlas. Our findings support the notion that CSF protein expression reflects underlying regional mRNA expression in cortical regions vulnerable to AD pathophysiology.

Authors & Affiliations

Pedro Rosa-Neto¹, Seyyed Ali Hosseini², Yi-Ting Wang², Nesrine Rahmouni², Etienne Aumont², Arthur Macedo², Ilaria Pola³, Tevy Chan², Gleb Bezgin², Brandon Hall², Aurélie Lebrun², Jaime Fernandez-Arias², Kely Quispialaya-Socualaya², Yansheng Zheng², Marina Goncalves², Juliana Godoy², Stuart Mitchell², Delphine Oliva-Lopez², Rodrigo Paes², Gabriela Baldasso², Firoza Lussier⁴, Robert Hopewell², Sanjeev Chawla⁵, Vladimir Fonov², Gassan Massarweh², Jean-Paul Soucy², Thomas Karikari⁴, Andréa Benedet³, Nicholas Ashton⁶, Henrik Zetterberg³, Jesse Klostranec⁷, Maxime Montembeault², Paolo Vitali², Kaj Blennow³, Tharick Pascoal⁴, D. Louis Collins², and Marcel Woo⁸

¹ McGill University
² McGill University
³ University of Gothenburg
⁴ University of Pittsburgh
⁵ University of Pennsylvania
⁶ Banner Sun Health Research Institute
⁷ McGill University
⁸ University Medical Center Hamburg-Eppendorf

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.