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

Abstract

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 mitochondrial 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 mitochondrial efficiency. Herein, we focus on the association between mitochondrial haplotype and risk of late onset Alzheimer’s disease (LOAD). Evidence for the association of mitochondrial genetic variances/haplotypes and the risk of developing LOAD are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondrial haplotypes and two demonstrated risk factors for Alzheimer’s disease (AD), apolipoprotein E (APOE) genotype and chromosomal sex. We posit herein that mitochondrial 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 mitochondrial haplotype would advance precision medicine for AD and other age related neurodegenerative diseases.

Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts

“…Wang and Brinton specifically considered the possibility of APOE ‐mtDNA haplogroup interactions 46 . The cohorts we studied were probably only large enough to detect robust additive or epistatic interactions, and data shown in Figures 1 and 2 suggest it is perhaps premature to rule out this possibility.…”

Mitochondria, Cybrids, Aging, and Alzheimer's Disease

“…Association studies have variably reported particular mtDNA haplogroups are statistically over or under-represented in AD cohorts, and that particular mtDNA single nucleotide polymorphisms (SNPs) are statistically over or under-represented in AD cohorts [100–113]. Results across different mtDNA association studies in AD have not been consistent across studies, though, which has led to some concern about the reliability of individual reports [114–118].…”

“…Currently, the nature of such potential inherited mtDNA changes, if they in fact exist, is not clear. MtDNA sequence studies performed on AD thus far have not identified a single mutation or variant that distinguishes AD-affected from AD-unaffected individuals, although various studies have claimed common inherited mtDNA signatures, such as those defined by the different mtDNA haplogroups, influence AD risk [113]. No mtDNA study to date has definitively addressed the question of whether rare mtDNA mutations or sequence variants associate with AD; such studies would require extensive mtDNA sequence data from large numbers of AD and control subjects.…”

Insulin and the Brain

“…Following cytosolic reactions, energy fuels are mainly metabolised in the mitochondria. Pyruvate metabolised glucose can be actively transported into the mitochondria where it is converted to acetyl coenzyme A, which in turn is complexed with citrate produces nicotinamide adenine dinucleotides (NADH) and flavin adenine dinucleotides (FADH2) [5]. In order to maintain an effective and prompt mitochondrial network, the cell has adaptive control mechanisms for environmental changes [6].…”