Basic Science and Pathogenesis

Area of Science:

• Immunology
• Neuroscience
• Genetics

Background:

• Immune responses in aging and Alzheimer's disease (AD) vary, influenced by genetics, socioeconomic status, race, and ethnicity.
• Understanding immune phenotypes linked to biological and cognitive aging can reveal AD risk factors and potential therapeutic targets.

Purpose of the Study:

• To investigate correlations between immune cell phenotypes and cognitive/brain aging markers in a multi-ethnic cohort.
• To identify immune processes that may influence Alzheimer's disease risk and progression.

Main Methods:

• Single-cell RNA and T/B cell receptor sequencing of over 439,000 immune cells from 205 participants (ages 29-81).
• Plasma proteomics data analyzed from 86 participants.
• Correlations assessed between immune cell proportions, T cell expansion, gene expression, cognitive scores, and cortical thickness, controlling for demographics.

Main Results:

• Higher cortical thickness associated with increased naive and mucosal-associated invariant T (MAIT) CD8+ T cells, and decreased effector memory cells.
• Greater cortical thickness linked to reduced T cell clonal expansion and lower expression of antigen presentation/cytotoxicity genes in T cell subtypes.
• Higher cognitive scores correlated with reduced expression of cytotoxicity, antigen presentation, and antimicrobial defense genes in gamma-delta T cells.

Conclusions:

• Higher naive CD8+ T cell proportions and reduced T cell cytotoxicity gene expression correlate with greater cortical thickness in AD-relevant brain regions, independent of age.
• Therapeutic strategies targeting naive T cell maintenance and T cell cytotoxicity/expansion may offer neuroprotection and cognitive benefits in aging and AD.