Cited by 300Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Emerging roles of innate and adaptive immunity in Alzheimer’s disease

Open access
Chen, Xiaoying, Holtzman, David M.·2022·Immunity

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease, with characteristic extracellular amyloid-β (Aβ) deposition and intracellular accumulation of hyperphosphorylated, aggregated tau. Several key regulators of innate immune pathways are genetic risk factors for AD. While these genetic risk factors as well as in vivo data point to key roles for microglia, emerging evidence also points to a role of the adaptive immune response in disease pathogenesis. We review the roles of innate and adaptive immunity, their niches, their communication, and their contributions to AD development and progression. We also summarize the cellular compositions and physiological functions of immune cells in the parenchyma, together with those in the brain border structures that form a dynamic disease-related immune niche. We propose that both innate and adaptive immune responses in brain parenchyma and border structures could serve as important therapeutic targets for treating both the pre-symptomatic and the symptomatic stages of AD.

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Crossref · 10.1016/j.immuni.2022.10.016

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  • The connection between AD and T-cell function was reported for neuronal signaling and AD pathology.

    “The connection between AD and T-cell function was reported for neuronal signaling and AD pathology (4,47).”

    From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [4]

    The section on the adaptive niche in AD links T-cell accumulation with more severe pathology and neuronal damage. The section on interplay between innate and adaptive immunity discusses T-cell-derived IFN-γ, but says its signaling through receptors on neurons requires further study; it does not establish a T-cell connection to neuronal signaling. (LLM, conf=0.82)

    Experimental — accuracy not yet measured
  • The possible contribution of the adaptive immune system in AD patients to reducing cancer incidence has not been studied.

    “The possible contribution of the adaptive immune system in AD patients to reducing cancer incidence has not been studied (4,5).”

    From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [4]

    The ‘Reconstructed adaptive niche in the brain parenchyma in AD’ section identifies unanswered questions about adaptive immunity in AD, but none concerns cancer incidence. Searches for cancer incidence and reduced cancer risk in AD patients found no passage addressing whether adaptive immunity contributes to such a reduction or whether that possibility has been studied. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 2

  1. Alzheimer A (1907). Über eine eigenartige Erkrankung der Hirnrinde. Allg. Z. Psychiatr 64, 146. 8713166
  2. Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, Bales K, Ashe KH, Irizarry MC, and Hyman BT (2000). Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol 47, 739– 747. 10852539

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Authors
Chen, X., & Holtzman, D. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Holtzman, David M.
Venue
Immunity
Publisher
Elsevier BV
Published
2022-12
Volume
55
Issue
12
Pages
2236-2254
ISSN
1074-7613 (ISSN-L)
OpenAlex
W4308510589
Cited by
297
References
202
Citations by year
2026: 57 · 2025: 100 · 2024: 93 · 2023: 47
FWCI
6.26
Type
journal article
Language
en
Open access
Locations
  • Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (RF1AG047644)
  • National Institute of Neurological Disorders and Stroke (RF1NS090934)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, innate immunity, adaptive immunity, microglia, amyloid-beta, tau hyperphosphorylation, genetic risk factors, neuroinflammation, immune niches, immune cell composition, therapeutic target
MeSH terms
Alzheimer Disease, Humans, Immunity, Innate, Amyloid beta-Peptides, Microglia, Neurodegenerative Diseases, Adaptive Immunity

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