title: Mitochondrial transcription factor A (TFAM) rs1937 and AP endonuclease 1 (APE1) rs1130409 alleles are associated with reduced cognitive performance.
abstract: Mitochondrial dysfunction and DNA damage is intimately connected to ageing and neurodegeneration, including Alzheimer's disease (AD). A particular culprit in this context is oxidative stress, which is a result of increased reactive oxygen species (ROS) due to hyperactive or dysfunctional mitochondria and/or reduced DNA repair capacity. Base excision repair (BER) is the major pathway for repairing oxidative damage events in chromosomal and mitochondrial DNA. Defects in BER have been detected in ageing and neurodegeneration. Mitochondrial transcription factor A (TFAM) plays an important role in the maintenance of mitochondrial DNA integrity. The present study investigated single nucleotide polymorphisms (SNPs) in the genes encoding the BER components MutYH, OGG1, APE1, PolB and PolG and the gene encoding mitochondrial TFAM in a cohort of 161 AD patients, 96 non-AD patient controls (PC) and 192 healthy controls (HC). Notably, the minor allele carriers of APE1 rs1130409 and the common allele carriers of TFAM rs1937 were associated with reduced mini-mental state examination score in AD patients, PC and HC, with no distinction of SNP frequencies in either of these sub-groups. Collectively, the results suggest an association between DNA maintenance and decline in cognitive function. These studies enlighten the normal brain aging process and point to potential new biomarkers for cognitive function and impairment.
authors.affiliation: Department of Microbiology, Healthy Brain Aging Centre (HBAC), Oslo University Hospital, Postbox 4950 Nydalen, 0424 Oslo, Norway; Department of Microbiology, Healthy Brain Aging Centre (HBAC), University of Oslo, 1078 Blindern, PO 0316, Norway. Electronic address: m.s.lillenes@medisin.uio.no.
authors.forename: Meryl S
authors.initials: MS
authors.lastname: Lillenes
authors.affiliation: Department of Microbiology, Healthy Brain Aging Centre (HBAC), Oslo University Hospital, Postbox 4950 Nydalen, 0424 Oslo, Norway; Department of Microbiology, Healthy Brain Aging Centre (HBAC), University of Oslo, 1078 Blindern, PO 0316, Norway. Electronic address: Mari.Stoen@rr-research.no.
authors.forename: Mari
authors.initials: M
authors.lastname: Støen
authors.affiliation: Norwegian Computing Center, P.O. Box 114 Blindern, NO-0314 Oslo, Norway. Electronic address: clara-cecilie.gunther@nr.no.
authors.forename: Clara-Cecilie
authors.initials: CC
authors.lastname: Günther
authors.affiliation: Department of Neurology, Faculty Division, Akershus University Hospital, University of Oslo, Postboks 1000, 1478 Lørenskog, Norway. Electronic address: per.selnes@medisin.uio.no.
authors.forename: Per
authors.initials: P
authors.lastname: Selnes
authors.affiliation: Department of Neurology, Faculty Division, Akershus University Hospital, University of Oslo, Postboks 1000, 1478 Lørenskog, Norway. Electronic address: uxstvh@ous-hf.no.
authors.forename: Vidar T V
authors.initials: VT
authors.lastname: Stenset
authors.affiliation: Department of Psychology, University of Oslo, Postboks 1094, Blindern, 0317 Oslo, Norway. Electronic address: thomas.espeseth@medisin.uio.no.
authors.forename: Thomas
authors.initials: T
authors.lastname: Espeseth
authors.affiliation: Department of Psychology, University of Oslo, Postboks 1094, Blindern, 0317 Oslo, Norway. Electronic address: ivar.reinvang@psykologi.uio.no.
authors.forename: Ivar
authors.initials: I
authors.lastname: Reinvang
authors.affiliation: Department of Neurology, Faculty Division, Akershus University Hospital, University of Oslo, Postboks 1000, 1478 Lørenskog, Norway. Electronic address: tormod.fladby@medisin.uio.no.
authors.forename: Tormod
authors.initials: T
authors.lastname: Fladby
authors.affiliation: Department of Microbiology, Healthy Brain Aging Centre (HBAC), Oslo University Hospital, Postbox 4950 Nydalen, 0424 Oslo, Norway; Department of Microbiology, Healthy Brain Aging Centre (HBAC), University of Oslo, 1078 Blindern, PO 0316, Norway. Electronic address: tone.tonjum@medisin.uio.no.
authors.forename: Tone
authors.initials: T
authors.lastname: Tønjum
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000235:genetics* / Q000523:psychology; D004249:DNA Damage / Q000235:genetics; D000074002:DNA Polymerase gamma; D004260:DNA Repair / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C499631:TFAM protein, human; D014157:Transcription Factors; D016875:tau Proteins; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1; Alzheimer’s disease; Base excision repair; Cognition; MMSE; Mitochondria; Oxidative DNA damage; Single nucleotide polymorphisms; TFAM