Identification of an APOE ε4–specific blood-based molecular pathway for Alzheimer's disease risk

TY - JOUR

T1 - Identification of an APOE ε4–specific blood-based molecular pathway for Alzheimer's disease risk

AU - Tao, Qiushan

AU - Zhang, Chao

AU - Mercier, Gustavo

AU - Lunetta, Kathryn

AU - Ang, Ting Fang Alvin

AU - Akhter-Khan, Samia

AU - Zhang, Zhengrong

AU - Taylor, Andrew

AU - Killiany, Ronald J.

AU - Alosco, Michael

AU - Mez, Jesse

AU - Au, Rhoda

AU - Zhang, Xiaoling

AU - Farrer, Lindsay A.

AU - Qiu, Wendy Wei Qiao

N1 - Funding Information: The authors are saddened that Dr. Ronald J. Killiany passed away during the submission of this manuscript. The authors dedicate this manuscript to memorialize Dr. Killiany's long‐term contribution to the ADNI study. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The data used in this study was obtained from the ADNI data. ADNI data collection and sharing for the project was funded by the Alzheimer's Disease Metabolomics Consortium (National Institutes on Aging RO1AG046171, RF1AG051550 and 3U01AG024904‐09S4). This study was supported by National Institute on Aging grants U19‐AG068753 (LAF, RA), AG‐09899 (WQ), and K24AG050842 (WQ). The sponsor institutes did not play any role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: The authors are saddened that Dr. Ronald J. Killiany passed away during the submission of this manuscript. The authors dedicate this manuscript to memorialize Dr. Killiany's long-term contribution to the ADNI study. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The data used in this study was obtained from the ADNI data. ADNI data collection and sharing for the project was funded by the Alzheimer's Disease Metabolomics Consortium (National Institutes on Aging RO1AG046171, RF1AG051550 and 3U01AG024904-09S4). This study was supported by National Institute on Aging grants U19-AG068753 (LAF, RA), AG-09899 (WQ), and K24AG050842 (WQ). The sponsor institutes did not play any role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: © 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

PY - 2023/10/1

Y1 - 2023/10/1

N2 - INTRODUCTION: The precise apolipoprotein E (APOE) ε4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. METHODS: Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by APOE genotype. RESULTS: The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C-reactive protein (CRP), complement C3, and complement factor H (CFH), had dose-dependent associations with CSF p-tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. DISCUSSION: The study identifies the APOE ε4–specific CRP–C3–CFH inflammation pathway for AD, suggesting potential drug targets for the disease. Highlights Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD. CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes. Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.

AB - INTRODUCTION: The precise apolipoprotein E (APOE) ε4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. METHODS: Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by APOE genotype. RESULTS: The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C-reactive protein (CRP), complement C3, and complement factor H (CFH), had dose-dependent associations with CSF p-tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. DISCUSSION: The study identifies the APOE ε4–specific CRP–C3–CFH inflammation pathway for AD, suggesting potential drug targets for the disease. Highlights Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD. CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes. Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.

KW - age-related macular degeneration

KW - Alzheimer's disease

KW - amyloid beta peptide

KW - apolipoprotein E

KW - C-reactive protein

KW - cerebrospinal fluid phosphorylated tau

KW - cognitive impairment

KW - complement C3

KW - complement factor H

KW - hypometabolic convergence index

KW - positron emission tomography

UR - http://www.scopus.com/inward/record.url?scp=85174615367&partnerID=8YFLogxK

U2 - 10.1002/dad2.12490

DO - 10.1002/dad2.12490

M3 - Article

AN - SCOPUS:85174615367

SN - 2352-8729

VL - 15

JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring

JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring

IS - 4

M1 - e12490

ER -