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IntroductionFindings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent.MethodsWe developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene-based tests were performed using SKAT-O.ResultsAnalysis of 4220 mtDNA variants revealed study-wide significant association of AD with a rare MT-ND4L missense variant (rs28709356; minor allele frequency = 0.002; P = 7.3 × 10-5 ) as well as with MT-ND4L in a gene-based test (P = 6.71 × 10-5 ). Significant association was also observed with a MT-related nuclear gene, TAMM41, in a gene-based test (P = 2.7 × 10-5 ). The expression of TAMM41 was lower in AD cases than controls (P = .00046) or mild cognitive impairment cases (P = .03).DiscussionSignificant findings in MT-ND4L and TAMM41 provide evidence for a role of mitochondria in AD.

Original publication




Journal article


Alzheimer's & dementia : the journal of the Alzheimer's Association

Publication Date



Department of Medicine (Biomedical Genetics), Boston University School of Medicine, 72 East Concord Street, Boston, Massachusetts, 02118, USA.


Alzheimer's Disease Sequencing Project