APOE4, oxidative stress and decreased repair capacity - a no-brainer. Faulty lipid metabolism and increased levels of oxidative damage may be risk factors in the pathogenesis of late-onset dementia

Abstract

Keywords: Late-onset disease, dementia, APOE, mitochondrial DNA, individual repair capacity.Abbreviations: AD -Alzheimer's disease, APOE -apolipoprotein E, ATP -adenosine triphosphate, BER -base excision repair, CAA -cerebral amyloid angiopathy, CNS -central nervous system, FTD -frontotemporal dementia, HD -Huntington's disease, IMT -intimamedia thickness, IRC -individual repair capacity, MCI -mild cognitive impairment, MND -motor neuron disease, NER -nucleotide excision repair, NMDA -N-methyl-D-aspartate, PD -Parkinson's disease, PDAPP -PDGF promoter expressing amyloid precursor protein, ROS -reactive oxygen species; SOD -superoxide dismutase, VCI -vascular cognitive decline.* Corresponding Authors: Ashima Nayyar, email: a.nayyar@abertay.ac.uk Conflict of Interests:No potential conflict of interest was disclosed by any of the authors. AbstractDementia is very common in the elderly and its incidence increases in an age-dependent fashion. Alzheimer's disease and vascular cognitive decline are the most common cases of dementia in the elderly. Amyloid burden and increased levels of oxidative damage have been implicated to play significant roles in the pathogenesis of late-onset dementia. In this paper we propose that there are three major genetic factors that may modulate the risk for dementia in later life: carriership of APOE variant alleles, carriership of mitochondrial DNA of haplogroups associated with ineffective oxygen utilisation (specifically, haplogroup H) and carriership of genetic polymorphisms conferring subtly deficient DNA repair. All three factors are quite common in the European populations. Each of these three factors may not have significant effect on the phenotype when taken separately, but when combined in the same genotype, the effects may be cumulative. Further studies are needed in order to elucidate the genotype-phenotype relationships and provide a reliable basis for assessment of the genetic risk for sporadic late-onset dementia. Lifestyle alterations and therapies targeted at decreasing the oxidative burden to aging cells and tissues may decrease the risk for neurological decline in later life.

The success of stem cell transplantations and the potential post-transplantation complications may be dependent, among other factors, on the capacity of the recipient and the transplanted cells to repair DNA damage

“…This was only the beginning of the studies on the role of IRC in human health and disease. It had later become clear that the capacity for DNA repair and management of genomic integrity in humans could have significant effects on the risk for development of many common diseases with late onset, such as diabetes and cancer (Roy et al 2007, Petkova et al 2011b, Schiewer and Knudsen 2016, cardiovascular disease (Chelenkova et al 2014, Wu andRoks 2014), neurodegenerative disease (Coppedè and Migliore 2015, Nayyar et al 2015); and that it could potentially reflect on the susceptibility for disease in different individuals, and at different ages (Cherdyntseva et al 2010, Petkova et al 2013 and the outcomes of different genotoxic treatments (Kan and Zhang 2015, Velic et al 2015, Petkova et al 2014b. DNA damage repair pathways began to be regarded as useful therapeutic targets in cancer therapy, , Khalil et al 2012b, Khalil et al 2012c, Gavande et al 2016.…”

Reproductive outcomes in pregnant women aged 35 or older: the role of individual repair capacity

“…Thus, individual variance in IRC may become more pronounced and/or may determine the susceptibility to common diseases and conditions in later age [35,36], the outcomes of therapies (especially those based on genotoxic effects such as anticancer and immunosuppressive therapies) and the risk for development of therapy-associated adverse effects [36,37]. IRC is a key determinant of the capacity for cell and tissue renewal and plays a major role in the risk for development of cancer and degenerative disease [37][38][39][40]. Studies of individual repair capacity are currently part of the rapidly expanding field of individualised (personalised) medicine, dedicated to tailoring of therapies to meet the needs of a particular patient, assessment of eligibility for specific types of therapy, prognostication of outcomes from different therapies and anticipation of potential adverse effects.…”