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Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression

Duggan, Michael R; Gomez, Gabriela T; Joynes, Cassandra M; Bilgel, Murat; Chen, Jingsha; Fattorelli, Nicola; Hohman, Timothy J; ... Walker, Keenan A; + view all (2024) Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression. Brain, Behavior, and Immunity , 120 pp. 604-619. 10.1016/j.bbi.2024.07.002. Green open access

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Abstract

While immune function is known to play a mechanistic role in Alzheimer's disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aβ accumulation, including causal relationships with Aβ PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.

Type: Article
Title: Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bbi.2024.07.002
Publisher version: https://doi.org/10.1016/j.bbi.2024.07.002
Language: English
Additional information: This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Alzheimer’s disease, Amyloid-beta, Positron emission tomography, Proteomics
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10194799
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