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P1‐267: Alzheimer Risk Variant Clusterin (CLU) and Brain Function During Aging
Author(s) -
Thambisetty Madhav,
BeasonHeld Lori,
Kraut Michael,
Nalls Michael,
Hernandez Dena,
Singleton Andrew,
Ferrucci Luigi,
Lovestone Simon,
Resnick Susan
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.547
Subject(s) - clusterin , single nucleotide polymorphism , cerebral blood flow , longitudinal study , medicine , apolipoprotein e , cognitive decline , oncology , genotype , biology , dementia , pathology , disease , genetics , gene , apoptosis
of Alzheimer’s disease (AD). Mitochondria (mt) are the principal source of intracellular energy in the form of adenosine triphosphate (ATP), which is produced by the respiratory chain through oxidative phosporylation. The respiratory chain is a potent source of reactive oxygen species (ROS), both a defect of ATP synthesis and increased ROS production could contribute to the pathophysiology of AD. Progressive mitochondrial dysfunction has been reported in the post-mortem AD brain and non-neural tissue implicating a systemic defect of oxidative phosphorylation. This suggests that polymorphic variation of mtDNA contributes to the genetic risk of developing sporadic AD. Being uniparentally inherited, mtDNA undergoes negligible recombination at the population level, and mutations acquired over time have sub-divided the human population into a number of discrete haplogroups. Several studies have reported the association of different mtDNA haplogroups or specific mtDNA SNPs with the AD, with both concordant and conflicting results. To resolve this issue, we performed a meta-analysis of summary statistics from publically available data and data from our previously reported (ICAD 2010) genome-wide association study of the mitochondrial genome. Haplogroups that showed some evidence of association (PMethods:Meta-analyses were performed using summary statistics from publically available data identified through literature searches and the alzgene website. The replication sample comprised 2,987 AD cases and 3,213 controls. All AD cases met criteria for either probable (NINCDSAARDA, DSM-IV) or definite (CERAD) AD. Controls were aged 60 years or over and were screened for cognitive decline or neuropathological signs of AD. SNPs were genotyped on the Sequenom platform. All statistical analyses were carried out in PLINK (v 2.050) using an allele-based model. Results: Results will be presented at ICAD 2011. Conclusions: Considerable evidence suggests that intervention at the mitochondrial level could ameliorate Aß triggered dysfunction and degeneration, and reduce or alleviate defects in glucose utilization and oxidative phosphorylation in the brains of AD patients. This study aims to access the contribution of variationwithin themitochondrial genome to the aetiology of AD by utilising a powerful AD case-control dataset.