Identifying Individuals with Non-Alzheimer's Disease Co-pathologies: A Precision Medicine Approach to Clinical Trials in Sporadic Alzheimer's Disease

Overview

Journal Alzheimers Dement

Specialties Neurology
Psychiatry

Date 2023 Sep 4

PMID 37667412

Authors

Duygu Tosun

Ozlem Yardibi

Tammie L S Benzinger

Walter A Kukull

Colin L Masters

Richard J Perrin

Michael W Weiner

Arthur Simen

Adam J Schwarz

Affiliations

Soon will be listed here.

Abstract

Introduction: Biomarkers remain mostly unavailable for non-Alzheimer's disease neuropathological changes (non-ADNC) such as transactive response DNA-binding protein 43 (TDP-43) proteinopathy, Lewy body disease (LBD), and cerebral amyloid angiopathy (CAA).

Methods: A multilabel non-ADNC classifier using magnetic resonance imaging (MRI) signatures was developed for TDP-43, LBD, and CAA in an autopsy-confirmed cohort (N = 214).

Results: A model using demographic, genetic, clinical, MRI, and ADNC variables (amyloid positive [Aβ+] and tau+) in autopsy-confirmed participants showed accuracies of 84% for TDP-43, 81% for LBD, and 81% to 93% for CAA, outperforming reference models without MRI and ADNC biomarkers. In an ADNI cohort (296 cognitively unimpaired, 401 mild cognitive impairment, 188 dementia), Aβ and tau explained 33% to 43% of variance in cognitive decline; imputed non-ADNC explained an additional 16% to 26%. Accounting for non-ADNC decreased the required sample size to detect a 30% effect on cognitive decline by up to 28%.

Discussion: Our results lead to a better understanding of the factors that influence cognitive decline and may lead to improvements in AD clinical trial design.

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