Alzheimer’s disease is characterized by the abnormal processing and accumulation of mutant or damaged intracellular and extracellular proteins, increasing neuronal vulnerability to dysfunction. Several studies have revealed a higher occurrence of both nuclear and mtDNA mutations in AD brains [
42,
43]. Genetic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), APP, tau, and APOE4 genes are strongly associated with Aβ aggregation and AD development [
28,
44]. Among these genes, mutations in APP (21q21), PSEN1 (14q24), and PSEN2 (1q42) are fully penetrant and follow an autosomal dominant inheritance pattern, resulting in aggressive forms of early-onset AD that account for approximately 5% of all AD cases [
45]. In addition, other susceptibility genes are believed to increase AD risk or drive pathogenesis through complex interactions with environmental factors. For instance, APOE (19q13) allele polymorphisms are associated with increased risk for late-onset AD, typically at 65 years or older [
46].
Mitochondria DNA is composed of complementary H- and L-strands in a circular form with an approximate length of 15.5 kb [
25]. Human mtDNA possesses 37 genes, of which 13 encode for respiratory and electron transport chain (ETC) components, 2 for ribosomal (r)RNAs, and 22 for transfer (t)RNAs necessary for mitochondrial protein synthesis [
47]. Among the 13 mtDNA genes associated with the respiratory system and ETC, seven encodes complex I (NADH dehydrogenase, ND) components ND1, ND2, ND3, ND4, ND4L, ND5, and ND6, one encodes the complex III (cytochrome reductase), three encode complex IV (cyt c oxidase or COX) components COX I, COX II, and COX III, and two encode complex V (ATP synthase) components ATPase6 and ATPase8. Other subunits of complex II are encoded by nuclear nDNA. While mtDNA is critical for the proper functioning of mitochondria, it is prone to oxidative damage due to proximity with free radical generation sites, the lack of DNA-protective histones, and less efficient DNA repair mechanisms; indeed, it is estimated that mtDNA is ten times more prone to mutations than nDNA [
48]. These mutations can occur at sites of known mtDNA transcription and replication regulatory elements, disrupting ETC component expression, and mitochondrial homeostasis. Moreover, mtDNA mutations (e.g., partial deletions, duplications, and point mutations) can be inherited maternally. These mutations then propagate through clonal expansion, eventually reaching a threshold for significant deleterious effects on mitochondrial function, resulting in cell death, and other age-related changes. Mitochondrial dysfunction is strongly associated with cognitive deficits and dementia due to high metabolic requirements, including for the synaptoplastic processes underlying higher-order cognitive functions [
49]. For instance, Tanaka et al. (2008) reported impaired retention and consolidation of memory traces in mice harboring mtDNA mutations (Mito-mice) [
50]. Hence, mutations in mtDNA, such as somatic mutations in OXPHOS genes, as well as several allelic polymorphisms (e.g., in APOE) are strongly associated with particular pathophysiological features of AD, including cognitive impairment and OS from excessive free radical generation [
51,
52,
53].