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Published on: June 14, 2020
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Basic Science and Pathogenesis
1Department of Neurology, Columbia University, New York, NY, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 23, 2025
Summary
Aging immune dysfunction (immunosenescence) impacts Alzheimer's disease (AD) risk. This study links immune cell changes to brain health, revealing potential targets for early AD intervention.
Area of Science:
- Neuroimmunology
- Gerontology
- Alzheimer's Disease Research
Background:
- Aging is the primary risk factor for Alzheimer's disease (AD), with immunosenescence (age-related immune decline) significantly increasing susceptibility.
- Functional changes in microglia and circulating immune cells during aging impair their response to pathology, potentially worsening neuroinflammation and AD progression.
- Current interventions do not specifically address immunosenescence in preclinical AD, highlighting a need to profile age-related immune changes for early therapeutic strategies.
Purpose of the Study:
- To identify immune mechanisms associated with preclinical Alzheimer's disease (AD).
- To investigate the correlation between immune cell phenotypes, gene expression, and AD biomarkers.
- To explore the impact of immunosenescence on adaptive immune function and neurodegenerative risk.
Main Methods:
- Single-cell RNA and T/B cell receptor sequencing of over 439,000 transcriptomes from 205 participants (ages 29-81).
- Plasma proteomics analysis from 86 participants.
- Correlation of immune cell phenotypes and gene expression with AD biomarkers (plasma proteins, cortical thickness, cognitive performance, parental AD diagnosis).
Main Results:
- Distinct immune signatures correlate with cortical integrity: B cells positively associated with left hemisphere cortical thickness, CD8+ T cells inversely associated.
- Naïve and mucosal-associated invariant T (MAIT) cells enriched in preserved cortical structure; effector memory cells reduced.
- Age-associated decline in T cell receptor diversity and MAIT cell proportion observed, alongside downregulation of T cell cytotoxicity and antigen presentation pathways in those with better cognitive function.
Conclusions:
- Aging-related immunosenescence significantly influences neuroimmune interactions relevant to Alzheimer's disease (AD) risk.
- Age-driven immune dysregulation is a critical factor in AD susceptibility.
- Findings suggest potential targets for immune-based therapies to mitigate AD progression, particularly during early disease stages.
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