The Role of Mitochondrial genome abundance in Alzheimer's Disease

Abstract

Mitochondrial dysfunction is an early and prominent feature of Alzheimers disease (AD), with impaired energy metabolism preceding the onset of clinical symptoms. Here we propose an update to the mitochondrial dysfunction hypothesis of AD based on recent results examining the role of mitochondrial genome abundance in AD. In a large post-mortem study, we show that lower brain mitochondrial genome abundance is associated with a greater odds of AD neuropathological change and worse cognitive performance. We hypothesize that lower mitochondrial genome abundance impairs mitochondrial function by reducing mitochondrial bioenergetics, thereby impacting neuronal and glial cell function. However, it remains to be determined if mitochondrial dysfunction causes, mediates, or is a by-product of AD pathogenesis. Additional support for this hypothesis will be generated by linking peripheral blood mitochondrial genome abundance to AD and establishing clinical trials of compounds that upregulate total mitochondrial genome abundance or boost mitochondrial mass. RESEARCH IN CONTEXTO_ST_ABSSystematic ReviewC_ST_ABSThe authors used PubMed to review the literature on mitochondrial genomics in Alzheimers disease (AD) using the following search term: mitochondria* AND ("copy number" OR heteroplasmy OR haplogroup*) AND "Alzheimers disease". The accumulated evidence suggested that increased mitochondrial genome abundance is neuroprotective, but found conflicting evidence for the association of mitochondrial heteroplasmy or specific haplogroups with AD. InterpretationWe found that higher mtDNA abundance was robustly associated with reduced AD neuropathology burden and higher neurocognitive performance. Given these findings, we propose an updated hypothesis for mitochondrial dysfunction in AD: that mitochondrial genome abundance is a relevant mechanism in AD pathogenesis. We postulate that baseline mtDNA abundance itself contributes to baseline mitochondrial function and lifetime risk, and that propensity and sensitivity to mtDNA depletion further modulate risk, histopathology, and clinical decline. Future directionsUsing statistical genetics approaches, examining the association of peripheral mtDNA abundance with AD, and upregulating mtDNA abundance, would further strengthen the evidence of a causal role for mtDNA abundance and mitochondrial dysfunction in AD pathogenesis