02389nas a2200289   4500008004100000245013800041210006900179260000800248300000800256490000700264520153800271100001301809700001201822700002001834700001701854700001901871700002601890700001701916700001701933700002501950700001901975700001601994700002002010700001902030700001402049856003602063       2024                        eng d00a{Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites0 aBloodderived mitochondrial DNA copy number is associated with Al  cOct  a2340 v163 aBlood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear.\ We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer's Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer's Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites.\ 0.005).\ Our study indicates that mtDNA-CN measured in blood is predictive of AD and is associated with AD biomarkers including plasma NFL particularly in females. Further, we illustrate that decreased mtDNA-CN possibly increases AD risk through dysregulation of mitochondrial lipid metabolism and inflammation.1 aTong, T.1 aZhu, C.1 aFarrell, J., J.1 aKhurshid, Z.1 aMartin, E., R.1 aPericak-Vance, M., A.1 aWang, L., S.1 aBush, W., S.1 aSchellenberg, G., D.1 aHaines, J., L.1 aQiu, W., Q.1 aLunetta, K., L.1 aFarrer, L., A.1 aZhang, X.  uhttps://chs-nhlbi.org/node/9789