Blood-Based Biomarkers Predict Differential Longitudinal Decline in Alzheimer’s Disease Psychosis: Evidence from Two Cohorts

Product:

CNS Disease Panel 120

Topic:

CNS

Disease Area:

Alzheimer's Disease

Sample Type:

Plasma

Topic/Product:

CNS Disease Panel 120

Disease Area:

Alzheimer's Disease

Sample Type:

Plasma

Abstract

INTRODUCTION Psychosis affects 40% of individuals with Alzheimer’s disease (AD) and is associated with accelerated cognitive decline. Blood-based biomarkers, particularly plasma phosphorylated tau (ptau), have demonstrated utility in predicting cognitive decline in AD, with ptau217 showing superior performance in many studies. However, whether these biomarkers predict differential cognitive trajectories in AD with psychosis (ADP) remains unknown.

METHODS Two independent cohorts were analyzed: Alzheimer’s Disease Neuroimaging Initiative (ADNI; n=659: 172 cognitively unimpaired [CU], 406 AD, 81 ADP) and Litwin-Zucker Research Center (LZ; n=142: 68 CU, 57 AD, 17 ADP) with 6-year follow-up. Psychosis was defined by non-zero Neuropsychiatric Inventory delusions or hallucinations scores. In ADNI, plasma ptau181, ptau217, ptau231, amyloid-β42/40, GFAP, and NfL were quantified using NULISA. In LZ, ptau181, ptau205, ptau212, ptau217, amyloid-β42/40, GFAP, and NfL were quantified using Simoa. Linear mixed-effects models assessed prediction of cognitive decline across memory, language, visuospatial, and executive function domains.

RESULTS In ADNI, baseline ptau181 predicted differential ADP decline in language (p<0.05), visuospatial (p<0.05), and executive function (p<0.05); ptau217 predicted language (p<0.05) and visuospatial (p<0.05) decline; GFAP predicted language (p<0.05) and visuospatial (p<0.05) decline; and NfL visuospatial decline (p=0.01). In LZ, ptau181 predicted decline in memory (p<0.05), language (p<0.0001), visuospatial (p<0.05), and executive function (p<0.05); ptau217 predicted memory (p<0.05) and visuospatial (p<0.05) decline; and GFAP predicted language decline (p<0.05). Johnson-Neyman analyses revealed ADP-AD divergence at low ptau181 thresholds in ADNI, while LZ showed crossover patterns with steeper ADP decline at low biomarker levels that attenuated at high levels where AD decline was steeper.

DISCUSSION ADP exhibited accelerated cognitive decline across domains driven by a distinct biomarker landscape compared to non-psychotic AD. Plasma ptau181 demonstrated broader domain-specific associations with decline in ADP than other blood-based biomarkers and associated exclusively with executive function impairment, indicating its unique utility for predicting cognitive trajectories in this pathophysiological subtype.

Authors & Affiliations

Jesus J. Gomar, PhD¹; Marc L. Gordon, MD¹,³; Erica Christen¹; Luca Giliberto, MD, PhD¹; Linda Keehlisen¹; Michelle Gong¹; Nichole Hoehn¹; Emma Morley¹; Allyson O’Neil²; Danica Wuelfing²; Kishore Malyavantham, PhD²; Blaine Greenwald, MD³; Philippe Marambaud, PhD¹; Leslie Adrien¹; Heidy Jimenez¹; Peter Davies, PhD¹†; Jeremy Koppel, MD¹,³*

¹ Litwin-Zucker Research Center for the Study of Alzheimer’s Disease and Memory Disorders, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York

² Quanterix Corporation, Billerica, Massachusetts

³ Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York †Deceased *Corresponding author

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.