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Basic Science and Pathogenesis
Aivi T Nguyen1, Vijay K Ramanan2, Scott A Przybelski3
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
Microglial activation, specifically an MS4A6A SNP, plays a key role in cognitive resilience, even with high Alzheimer's disease neuropathologic change. Increased microglial activation markers were linked to better cognitive performance.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Cognitive resilience is the ability to maintain normal cognition despite significant Alzheimer's disease neuropathologic change (ADNC).
- The role of microglial activation in cognitive resilience remains understudied.
Purpose of the Study:
- To investigate the association between microglial activation and cognitive resilience in individuals with intermediate to high ADNC.
- To explore the impact of specific microglial-associated genes, such as MS4A gene cluster SNPs, on cognitive function.
Main Methods:
- Identified cognitively resilient (CR) individuals from a high-cognitively unimpaired cohort based on ADNC levels.
- Utilized regression models to assess the relationship between global cognition, ADNC, and microglial-specific genes (MS4A SNPs).
- Performed postmortem analysis of microglial activation markers (ARM) and beta-amyloid in the dorsolateral prefrontal cortex, correlating with antemortem cognitive and imaging data.
Main Results:
- A third of high-cognitively unimpaired individuals met criteria for cognitive resilience (intermediate/high ADNC).
- An MS4A6A SNP was found in 28% of CR individuals, showing a protective cognitive effect.
- Cognitively resilient individuals exhibited higher ARM:amyloid ratios and fewer neuritic plaques compared to controls.
Conclusions:
- Microglial activation, modulated by MS4A6A SNPs, is present in a significant portion of cognitively resilient individuals.
- Increased microglial activation (ARM:amyloid) is associated with better antemortem cognitive performance in resilient individuals.
- These findings highlight microglial activation as a crucial component of cognitive resilience, warranting further investigation into protective mechanisms and vascular links.
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