{"id":3148,"date":"2024-11-21T07:23:40","date_gmt":"2024-11-21T12:23:40","guid":{"rendered":"https:\/\/www.bumc.bu.edu\/fhs-bap\/?p=3148"},"modified":"2024-11-21T07:23:53","modified_gmt":"2024-11-21T12:23:53","slug":"3148","status":"publish","type":"post","link":"https:\/\/www.bumc.bu.edu\/fhs-bap\/2024\/11\/21\/3148\/","title":{"rendered":"Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites"},"content":{"rendered":"<h2 class=\"title\">Abstract<\/h2>\n<div class=\"abstract-content selected\" id=\"eng-abstract\">\n<p><strong class=\"sub-title\">Background:<span>\u00a0<\/span><\/strong>Blood-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.<\/p>\n<p><strong class=\"sub-title\">Methods:<span>\u00a0<\/span><\/strong>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&#8217;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&#8217;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.<\/p>\n<p><strong class=\"sub-title\">Results:<span>\u00a0<\/span><\/strong>MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (\u03b2 = 0.103; P = 0.022), amyloid-PET (\u03b2 = 0.117; P = 0.034), CSF amyloid-\u03b2 (A\u03b2) 42\/40 (\u03b2=-0.124; P = 0.017), CSF t-Tau (\u03b2 = 0.128; P = 0.015), p-Tau (\u03b2 = 0.140; P = 0.008), and plasma NFL (\u03b2=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P &lt; 0.005).<\/p>\n<p><strong class=\"sub-title\">Conclusions:<span>\u00a0<\/span><\/strong>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.<\/p>\n<p><a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/39444005\/\">Read More<\/a><\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Abstract Background:\u00a0Blood-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. Methods:\u00a0We performed [&hellip;]<\/p>\n","protected":false},"author":22858,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[12],"tags":[15,22,35,36,37,38,39],"_links":{"self":[{"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/posts\/3148"}],"collection":[{"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/users\/22858"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/comments?post=3148"}],"version-history":[{"count":2,"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/posts\/3148\/revisions"}],"predecessor-version":[{"id":3150,"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/posts\/3148\/revisions\/3150"}],"wp:attachment":[{"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/media?parent=3148"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/categories?post=3148"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bumc.bu.edu\/fhs-bap\/wp-json\/wp\/v2\/tags?post=3148"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}