Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites

Abstract

Background: 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.

Methods: 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.

Results: 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 (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-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 < 0.005).

Conclusions: 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.

Keywords: Alzheimer’s disease; Biomarkers; Causal mediation; Mendelian randomization; Mitochondria DNA copy number; Serum metabolites; Whole genome sequencing.

Fig. 1

Analysis design. mtDNA-CN = mitochondria DNA copy number; ADSP = Alzheimer’s Disease Sequencing Project; WGS = whole genome sequencing; AD = Alzheimer disease; EA = European Ancestry, AA = African American, CH = Caribbean Hispanic; ADNI = Alzheimer’s Disease Neuroimaging Initiative; MCI = mild cognitive impairment; GWAS = genome-wide association study; * Covariates include age, sex, genetic ancestry group, APOE ε2 and ε4 dosage, sequencing center, and PCR. ** Covariates include age, sex, and original study phase; *** Covariates include age, sex, original study phase, and AD diagnosis; # Cox proportional hazards regression model: $logh(t)\sim adjustedbloodmtDNA-CN+age+sex+originalstudyphase$

Fig. 2

Partial residuals plots showing the relationships between blood mtDNA-CN from ADNI and AD diagnosis (A), age (B), sex (C). Residuals were calculated after fitting a liner model where mtDNA-CN was the dependent variable and age, sex, cohort, and AD diagnosis were the independent variables. Kaplan-Meier plot to visualize the probability of (D) MCI participants at ADNI baseline free from converting to AD and (E) CN patients free from converting to MCI for low mtDNA-CN group and high mtDNA-CN group. mtDNA-CN was dichotomized by the median

Fig. 3

P-value and effect size plot to visualize the association between blood mtDNA-CN and classic AD biomarkers for all ADNI participants, each sex and AD diagnosis strata. * P < 0.05; ** P < 0.01. CN = cognitively normal; MCI = mild cognitive impairment; AD = Alzheimer disease

Fig. 4

Adjusted P-value and effect size plot to visualize the association between blood mtDNA-CN and serum metabolites for all ADNI participants, each sex and AD diagnosis strata. P _adj< 0.1; * P _adj < 0.05; ** P _adj <0.01