Late-onset Alzheimer's disease is associated with mitochondrial DNA 7028C/haplogroup H and D310 poly-C tract heteroplasmy

Coto, Eliécer; Gómez, Juan; Alonso, Belén; Corao, Ana I.; Díaz, Marta; Menéndez, Manuel; Martı́nez, Carmen; Calatayud, María Teresa Reyna; Morís, Germán; Álvarez, Victoria

doi:10.1007/s10048-011-0295-4

Cited by 36 publications

(28 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…APOE genotype and female chromosomal sex are two known risk modulators for late onset Alzheimer's disease (LOAD), where APOE4 carriers [1][2][3][4][5][6][7][8] and females [9][10][11][12][13][14] exhibit a higher life-time risk of Alzheimer's disease. An early indicator of LOAD risk is decline in brain glucose metabolism, a key phenotype observed during the prodromal phase of LOAD, and a hallmark of the disease [15][16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice

et al. 2020

View full text Add to dashboard Cite

Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.

show abstract

Section: Introductionmentioning

confidence: 99%

Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In brief, these studies vary in regards to the sample size analyzed, the techniques employed, and the type of mtDNA variants genotyped or sequenced. With only a few exceptions [Elson et al, ; Clark et al, ; Coto et al, ; Hudson et al, ], most of mtDNA case‐control association studies in AD, PD, and migraine did not employ replication cohorts, most of them lacked estimates on statistical power [Pardo‐Seco et al, ], and ignored cofounding factors such as population stratification. In addition, with a few exceptions, and despite evaluating a moderate to high number of mtSNPs and/or haplogroups, no corrections for multiple testing were performed (Text S1; see also below).…”

Section: Introductionmentioning

confidence: 99%

No evidence of association between common European mitochondrial DNA variants in Alzheimer, Parkinson, and migraine in the Spanish population

Fachal

Mosquera-Miguel

Pástor

et al. 2014

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Certain mitochondrial DNA (mtDNA) variants and haplogroups have been found to be associated with neurological disorders. Several studies have suggested that mtDNA variation could have an etiologic role in these disorders by affecting the ATP production on high-energy demanding organs, such as the brain. We have analyzed 15 mtDNA SNPs (mtSNPs) in five cohorts of cases presenting Alzheimer disease (AD), Parkinson disease (PD), and migraine, and in controls, to evaluate the role mtDNA variation in disease risk. Association tests were undertaken both for mtSNPs and mitochondrial haplogroups. No significant association was detected for any mtSNP or haplogroup in AD and PD cohorts. Two mtSNPs were associated with one migraine cohort after correcting for multiple tests, namely, T4216C and G13708A and haplogroup J (FDR q-value = 0.02; Santiago's cohort). However, this association was not confirmed in a second replication migraine series. A review of the literature reveals the existence of inconsistent findings and methodological shortcomings affecting a large proportion of mtDNA association studies on AD, PD, and migraine. A detailed inspection of the literature highlights the need for performing more rigorous methodological and statistical standards in mtDNA genetic association studies aimed to avoid false positive results of association between mtDNA variants and neurological diseases.

show abstract

“…In APOE ε 4 carriers MT-hg K and U were observed to have neutralizing effect (Carrieri et al, 2001;Maruszak et al, 2011) on AD risk. Conversely, SNP mt7028C, a defining SNP for MT-hg H, and MT-hg H5a had acted synergistically with APOE ε 4 to increased risk of AD (Coto et al, 2011;Maruszak et al, 2011). Finally, SNP mt4336C which defines MT-hg H5a was associated with an increased risk of AD only in APOE ε 4 carriers (Edland et al, 2002).…”

Section: Discussionmentioning

confidence: 96%

Mitonuclear interactions influence Alzheimer’s disease risk

Andrews

Fulton‐Howard

Patterson

et al. 2019

Preprint

View full text Add to dashboard Cite

We examined the associations between mitochondrial DNA haplogroups (MT-hg) and their interactions with a polygenic risk score based on nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset of dementia (AOO). Logistic regression was used to determine the effect of MT-hgs and nMT-PRS on dementia at baseline (332 controls / 204 cases). Cox proportional hazards models were used to model dementia AOO (n=1047; 433 incident cases). Additionally, we tested for interactions between MT-hg and nMT-PRS in the logistic and Cox models. MT-hg K and a one SD larger nMT-PRS were associated with elevated odds of dementia. Significant antagonistic interactions between the nMT-PRS and MT-hg K and T were observed. Individual MT-hg were not associated with AOO; however, a significant antagonistic interactions was observed between the nMT-PRS and MT-hg T and a synergistic interaction between the nMT-PRS and MT-hg V. These results suggest that MT-hgs influence dementia risk, and that variants in the nuclear and mitochondrial genome interact to influence the age of onset of dementia.• Mitochondrial dysfunction has been proposed to influence dementia risk • MT-hg K and T interacted with a genetic risk score to reduce dementia risk • MT-hg T and V interacted with a genetic risk score to influence dementia age of onset

show abstract

Late-onset Alzheimer's disease is associated with mitochondrial DNA 7028C/haplogroup H and D310 poly-C tract heteroplasmy

Cited by 36 publications

References 6 publications

Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice

Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice

No evidence of association between common European mitochondrial DNA variants in Alzheimer, Parkinson, and migraine in the Spanish population

Mitonuclear interactions influence Alzheimer’s disease risk

Contact Info

Product

Resources

About