Triad of Risk for Late Onset Alzheimer's: Mitochondrial Haplotype, APOE Genotype and Chromosomal Sex

Brain is the most energetically demanding organ of the body, and is thus vulnerable to even modest decline in ATP generation. Multiple neurodegenerative diseases are associated with decline in mitochondria' function, e.g., Alzheimer's, Parkinson's, multiple sclerosis and multiple neuropathies. Genetic variances in the mitochondrial genome can modify bioenergetic and respiratory phenotypes, at both the cellular and system biology levels. Mitochondrial haplotype can be a key driver of mitochondria' efficiency. Herein, we focus on the association between mitochondria' haplotype and risk of late onset Alzheimer's disease (LOAD). Evidence for the association of mitochondria' genetic variances/haplotypes and the risk of developing LOAD are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondria' haplotypes and two demonstrated risk factors for Alzheimer's disease (AD), apolipoprotein E (APOE) genotype and chromosomal sex. We posit herein that mitochondria' haplotype, and hence respiratory capacity, plays a key role in determining risk of LOAD and other age-associated neurodegenerative diseases. Further, therapeutic design and targeting that involve mitochondria' haplotype would advance precision medicine for AD and other age related neurodegenerative diseases.