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Nien Yeh Daphne Yu¹, Shea J Andrews², Lifang Hou³

¹Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association

|December 23, 2025

Summary

This summary is machine-generated.

Mitochondrial DNA haplogroups, not heteroplasmy burden, were linked to mid-life cognitive function. Haplogroups in macro-haplogroup L were associated with worse cognition, while specific haplogroups showed varied effects across racial groups.

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Area of Science:

Genetics
Neuroscience
Aging Research

Background:

Mitochondrial dysfunction is linked to age-related diseases and neurodegeneration.
The role of mitochondrial DNA (mtDNA) mutations, including heteroplasmy (mtHz) and haplogroups (mtHg), in cognitive health is underexplored, especially in diverse populations.
This study investigates the impact of mtHz burden and mtHg on mid-life cognition.

Purpose of the Study:

To evaluate the association between mitochondrial heteroplasmy burden and cognitive performance in mid-life adults.
To assess the relationship between mitochondrial haplogroups and cognitive outcomes in a diverse mid-life cohort.
To explore race-specific effects of mitochondrial haplogroups on cognition.

Main Methods:

Analysis of 2308 participants from the Coronary Artery Risk Development in Young Adults study (mean age ~45 years).
Measurement of heteroplasmy burden using the Mitochondrial Local Constraint Score.
Determination of mitochondrial haplogroups using PhyloTree Build 17 and multivariate linear regression for cognitive outcome analysis, with race-stratified analyses.

Main Results:

No significant association was found between heteroplasmy burden and cognitive function.
Mitochondrial haplogroups within macro-haplogroup L were associated with worse cognitive outcomes, particularly in processing speed and global cognition.
Specific haplogroups showed race-associated cognitive effects (e.g., mtHg N with improved processing speed in White participants; better executive function, verbal memory, and global cognition in Black participants), though not significant after multiple comparisons adjustment.

Conclusions:

Mitochondrial haplogroups show potential associations with mid-life cognitive performance.
mtDNA variation may be a factor in mid-life cognitive health.
Race-stratified findings highlight the importance of considering haplogroup distribution across different racial groups and warrant further investigation into genetic, environmental, and social factors.