REDUCED MITOCHONDRIAL DNA COPY NUMBER IN THE ALZHEIMER’S HUMAN BRAIN IS ASSOCIATED WITH TAU BUT NOT AMYLOID-BETA PATHOLOGY AND HAS AN INDEPENDENT EFFECT ON COGNITION
- Hans-Ulrich Klein, United States of America
Abstract
Aims
Mitochondrial dysfunctions have been described in neurodegenerative diseases including Alzheimer’s disease (AD). Age-related accumulation of mitochondrial DNA (mtDNA) mutations and altered mtDNA copy number (mtDNAcn) can both disrupt mitochondrial energetics. Here, we disentangle how mtDNA quality and quantity are related to pathologies in different brain regions, and whether mtDNA alterations affect cognition independent of pathologies and neuronal loss.
Methods
We used whole genome sequencing data to estimate mtDNAcn and detect mtDNA heteroplasmies in n=1361 samples from 5 brain regions. Cognitive scores, (semi-)quantitative measurements of 10 neuropathologies, and neuronal proportions were available for n=454 dorsolateral prefrontal cortex (DLPFC) samples and n=242 cerebellum samples.
Results
The mtDNAcn was consistently decreased in AD in all four cortical regions but not in the cerebellum. In a multivariable regression with 10 different neuropathologies, only tau (p=0.004) remained significantly negatively associated with mtDNAcn in the DLPFC. Tau also remained significant when adjusting for neuronal proportion, which was positively associated with mtDNAcn (p=5.5×10-5). Age and gender were not associated with mtDNAcn. Interestingly, mtDNAcn had a significant effect on cognition (p=0.034) after adjustment for pathologies and neuronal proportion. In cortical regions, mtDNA heteroplasmies were more frequent than in the cerebellum and increased by 1.64% per year (p=2.8×10-5), but were not associated with pathologies or cognition.
Conclusions
MtDNA heteroplasmies in the cortex accumulate with age, but this process is unrelated to brain pathologies in our data. In contrast, mtDNAcn reduction is associated with tau burden and independently affects cognitive performance, indicating that maintaining mtDNAcn levels may attenuate tau-driven cognitive decline.