Alzheimer’s disease (AD) is a complex disorder and is the most common form of dementia 
. After age, family history is the single greatest risk factor for AD. AD can be classified into early and late onset forms. Mutations in three genes: PSEN1/2 and APP are known to cause early onset AD in an autosomal dominant manner 
. The majority of AD cases, however, are late onset (LOAD) and the APOE e4 allele is the strongest known genetic risk factor. Many additional genetic polymorphisms have been identified, though with substantially lower risk estimates 
. LOAD appears to be inherited and/or sporadic and there is evidence of a maternal inheritance pattern 
. Current estimates suggest that more than 20% of inherited LOAD cases are maternally inherited 
Analyses of families with inherited LOAD have repeatedly reported a greater incidence of AD in children with affected mothers than with affected fathers. Among individuals affected with AD who have one affected parent, the mother is 1.8 to 3.8 times more likely to be affected than the father 
. When extended to families with multiple affected siblings and a single affected parent, the ratio of affected mothers to fathers increased to 9
. While no biological mechanisms for maternal inheritance were demonstrated, results of these studies, observed in multiple datasets, strongly suggest maternal inheritance.
Imaging studies provide additional evidence of maternal inheritance of AD. These studies have identified decreased glucose metabolism and atrophy in brain regions affected in AD. Similar to the studies cited above, individuals with a paternal, maternal, or no family history of AD were compared. First, progressive gray matter atrophy was only observed in people with a maternal family history of AD. These same individuals had greater atrophy in the precuneus and parahippocampal gyrus (regions known to be affected in AD) than those with a paternal or no family history of AD 
. Next, other studies compared reductions in glucose metabolism in the brain for each of the three groups listed above. Subjects with a paternal family history of LOAD had decreased glucose metabolism similar to those with no family history; however, individuals with a maternal family history of LOAD had significantly decreased glucose metabolism compared to the other groups 
. Additionally, similar to the atrophy studies, lowered glucose metabolism was concentrated in the same brain regions known to have impaired glucose metabolism in AD (posterior cingulate cortex/precuneus, parieto-temporal, and medial temporal cortices) 
. The increased incidence of AD or risk for AD-related phenotypes among individuals with a maternal family history of AD, compared to people with no family history or a paternal family history of AD, strongly support a maternal inheritance pattern for LOAD.
Maternal inheritance occurs by several mechanisms including disease susceptibility genes on the X-chromosome, maternal specific genetic imprinting, or by mitochondrial genetic effects. We investigated the role of mitochondrial sequence variants in maternal transmission of LOAD. Mitochondrial malfunction is a plausible explanation for a number of AD phenotypes, including the decreased glucose metabolism in specific brain regions discussed above. Numerous mitochondrial modifications in patients with AD have been reported; these include morphological changes 
, alterations in the enzymes of the electron transport chain, including cytochrome c oxidase 
, changes in the mitochondrial proteome 
, and reduced numbers of mitochondria 
. Beta-amyloid plaques aggregate within mitochondria 
and it has been hypothesized that changes in mitochondrial function facilitate Aβ deposition and tau phosphorylation 
. These observations have led investigators to ask whether mitochondrial dysfunction is a cause or effect of plaque aggregation.
The mitochondrial cascade hypothesis 
posits that a decline in mitochondrial number and function is a cause of neurodegeneration. Briefly, it is known that mitochondrial function declines with age and in conjunction with certain morphological changes 
. As mitochondrial function declines with age, hypothesized consequences are increased tau phosphorylation and beta-amyloid amyloidosis in brain tissue. In contrast, in familial forms of AD, Aβ aggregation and tau phosphorylation are hypothesized to occur before mitochondrial malfunction and lead to the mitochondrial dysmorphology and dysfunction characteristic of AD 
. Other evidence suggests that Aβ aggregation directly causes mitochondrial malfunction 
or that Aβ and tau interact to increase oxidative stress and impede mitochondrial function 
Mitochondrial malfunction can be caused by numerous factors, one of which is inherited sequence variation in the mitochondrial genome. To date, many studies have been published analyzing the association between mitochondrial haplogroups or specific mitochondrial sequence variants, and AD. The results have been mixed, confusing, and at times contradictory. The majority of studies have not identified any associations 
, but some have reported significant associations. Haplogroups H and U (or sub-haplogroups of H and U) have been associated with both increased and decreased risk of AD 
and different effects for men and women. The UK and HV clusters, as well as haplogroups J, G2A, B4C1, and N9B1, have been associated with increased risk for AD 
, while haplogroups K and T are thought to be protective 
. No consensus has been reached and no previous studies have reported on large population-based samples with complete mtDNA genome sequence data. Here we present the largest analysis to date of mitochondrial haplotypes and associated risks for LOAD based on fully sequenced mitochondrial genomes.