Shared and disease-specific pathways in frontotemporal dementia and Alzheimer’s and Parkinson’s diseases

Product:

CNS Disease Panel 120

Topic:

Neurology

Disease Area:

Alzheimer's Disease, Frontal Temporal Dementia (FTD)

Sample Type:

Plasma

Topic/Product:

CNS Disease Panel 120

Disease Area:

Alzheimer's Disease, Frontal Temporal Dementia (FTD)

Sample Type:

Plasma

Abstract

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and frontotemporal dementia (FTD), exhibit distinct yet overlapping pathological mechanisms. Leveraging large-scale plasma proteomics data from the Global Neurodegeneration Proteomics Consortium, we analyzed 10,527 plasma samples (1,936 AD, 525 PD, 163 FTD, 1,638 dementia and 6,265 controls) to identify disease-specific and shared proteins across NDs. We identified 5,187 proteins significantly associated with AD, 3,748 with PD and 2,380 with FTD that revealed both common and divergent proteomic signatures, which were confirmed by multiple analytical approaches and orthogonal validation. PD and FTD showed the highest overlap (r² = 0.44) and AD and PD the least (r² = 0.04). Immune system, glycolysis, and matrisome-related pathways were enriched across all NDs, while disease-specific pathways included apoptotic processes in AD, endoplasmic reticulum–phagosome impairment in PD and platelet dysregulation in FTD. Network analysis identified key upstream regulators (RPS27A in AD, IRAK4 in PD and MAPK1 in FTD) potentially driving these proteomic changes. These findings reveal distinct and shared mechanisms across NDs, highlighting potential regulatory proteins and pathways for diagnostic and therapeutic strategies in neurodegeneration.

Authors & Affiliations

Muhammad Ali¹²¹³, Buddhiprabha Erabadda³¹³, Yike Chen¹², Ying Xu¹², Katherine Gong¹², Menghan Liu¹², Alexa Pichet Binette⁴, Jigyasha Timsina¹², Daniel Western¹², Chengran Yang¹², Gyujin Heo¹², Jacob W. Vogel⁵, Betty M. Tijms⁶⁷, Varsha Krish⁸, Farhad Imam⁸, The Global Neurodegeneration Proteomics Consortium (GNPC)*, Oskar Hansson⁴⁹, Laura Winchester³¹³, and Carlos Cruchaga¹²¹⁰¹¹¹²¹³

¹ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
² NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA
³ Department of Psychiatry, University of Oxford, Oxford, UK
⁴ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
⁵ Department of Clinical Sciences Malmö, SciLifeLab, Lund University, Lund, Sweden
⁶ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
⁷ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands
⁸ Gates Ventures, Seattle, WA, USA
⁹ Eli Lilly, Stockholm, Sweden
¹⁰ Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
¹¹ Hope Center for Neurological Disorders, Washington University, St. Louis, MO, USA
¹² Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
¹³ Consortia: The Global Neurodegeneration Proteomics Consortium (GNPC)

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.