Cited by 25Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification

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Zhong, Huan, Zhou, Xiaopu, Uhm, Hyebin, Jiang, Yuanbing, Cao, Han, Chen, Yu, Mak, Tiffany T. W., Lo, Ronnie Ming Nok +10 more·2024·Alzheimer's & Dementia

Abstract

INTRODUCTION: Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS: Bulk RNA‐sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co‐expression network analysis (WGCNA) and deconvolution analysis identified AD‐associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD‐associated genes, gene modules, cell types, and established AD classification models. RESULTS: WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell‐type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION: This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. Highlights: We comprehensively analyze the blood transcriptomes of a well‐characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune‐associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease.

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  • Peripheral blood transcriptome analyses can classify patients into immune and metabolic subgroups with diagnostic performance comparable to established biomarker frameworks like Amyloid, Tau, and Neurodegeneration (ATN).

    “Complementary analyses of peripheral blood transcriptomes have enabled patient classification into immune and metabolic subgroups, achieving diagnostic performance comparable to established biomarker frameworks like Amyloid, Tau, and Neurodegeneration (ATN)71,349,351,398.”

    From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [349]

    The Discussion reports that blood-transcriptome gene modules classified patients with Alzheimer’s disease with accuracy comparable to plasma ATN biomarkers. The Results section on stratification reports five subgroups (C1–C5) associated with different disease stages or states, and describes an immune-related module, but does not identify the subgroups as immune and metabolic. The comparison is specifically with plasma ATN biomarkers, not ATN frameworks generally; no page numbers are available in our copy. (LLM, conf=0.88)

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Authors
Zhong, H., Zhou, X., Uhm, H., Jiang, Y., Cao, H., Chen, Y., Mak, T. T. W., Lo, R. M. N., Wong, B. W. Y., Cheng, E. Y. L., Mok, K. Y., Chan, A. L. T., Kwok, T. C. Y., Mok, V. C. T., Ip, F. C. F., Hardy, J., Fu, A. K. Y., & Ip, N. Y.
Affiliations
  • Hong Kong University of Science and Technology (HK)
  • Chinese Academy of Sciences (CN)
  • Queen Elizabeth Hospital (CN)
  • Chinese University of Hong Kong (HK)
Corresponding author
Ip, Nancy Y.
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2024-02-07
Volume
20
Issue
4
Pages
2469-2484
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
OpenAlex
W4391615814
Cited by
25
References
68
Citations by year
2026: 8 · 2025: 14 · 2024: 3
FWCI
7.35
Type
journal article
Language
en
Open access
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion, cc-by-nc)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • Eli Lilly and Company
  • National Natural Science Foundation of China (32061160472, 2018B030336001, 2019003, 2019B1515130004, 2019001)
  • University Grants Committee (AoE/M-604/16)
  • Innovation and Technology Commission (ITC PD/17-9, MRP/097/20X, MRP/042/18X, ITS/207/18FP)
  • Eisai
  • Hong Kong University of Science and Technology (ITCPD/17-9)
  • Shenzhen Virtual University Park
  • Shenzhen Fundamental Research Program (JCYJ20200109115631248, ZDSYS20200828154800001)
  • Shenzhen Knowledge Innovation Program (JCYJ20200109115631248, JCYJ20180507183642005)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, blood transcriptome
MeSH terms
Alzheimer Disease, Humans, Biomarkers, Gene Expression Profiling, Gene Regulatory Networks, Transcriptome

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