1. Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression.
- Author
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Duggan MR, Gomez GT, Joynes CM, Bilgel M, Chen J, Fattorelli N, Hohman TJ, Mancuso R, Cordon J, Castellano T, Koran MEI, Candia J, Lewis A, Moghekar A, Ashton NJ, Kac PR, Karikari TK, Blennow K, Zetterberg H, Martinez-Muriana A, De Strooper B, Thambisetty M, Ferrucci L, Gottesman RF, Coresh J, Resnick SM, and Walker KA
- Subjects
- Humans, Male, Female, Aged, Longitudinal Studies, Proteome metabolism, Middle Aged, Brain metabolism, Aging metabolism, Aging immunology, Aged, 80 and over, Amyloid beta-Peptides metabolism, Alzheimer Disease metabolism, Alzheimer Disease blood, Alzheimer Disease immunology, Alzheimer Disease genetics, Disease Progression, Positron-Emission Tomography methods, Biomarkers blood, Biomarkers metabolism
- 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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers, has served at data monitoring committees for Julius Clinical and Novartis, has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. R.M. has scientific collaborations with Alector, Nodthera and Alchemab, and has been consultant for Sanofi. B.D.S. is or has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies. B.D.S is also a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics., (Published by Elsevier Inc.)
- Published
- 2024
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