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The Impact of Genetic Research on our Understanding of Normal Cognitive Ageing: 1995 to 2009

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Abstract

Identifying the risk factors for individual differences in age-related cognitive ability and decline is amongst the greatest challenges facing the healthcare of older people. Cognitive impairment caused by “normal ageing” is a major contributor towards overall cognitive deficit in the elderly and a process that exhibits substantial inter- and intra-individual differences. Both cognitive ability and its decline with age are influenced by genetic variation that may act independently or via epistasis/gene-environment interaction. Over the past fourteen years genetic research has aimed to identify the polymorphisms responsible for high cognitive functioning and successful cognitive ageing. Unfortunately, during this period a bewildering array of contrasting reports have appeared in the literature that have implicated over 50 genes with effect sizes ranging from 0.1 to 21%. This review will provide a comprehensive account of the studies performed on cognitively healthy individuals, from the first study conducted in 1995 to present. Based on current knowledge the strong and weak methodologies will be identified and suggestions for future study design will be presented.

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    Antony Payton

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Genetic glossary

Allele

One of a number of different polymorphic states. For example for an SNP where a T is replaced by a G, the T and G are the two alleles

Epigenetic

Describes something which influences the behaviour of a cell without directly affecting its DNA or other genetic machinery, such as an environmental effect

Exon

Coding regions of DNA that are transcribed and translated into protein

Genotype

The specific allele makeup of a polymorphism. For example, an SNP where an A is the common allele and a T is the minor allele can have three potential genotypes: homozygous AA or TT, or heterozygous AT

Haplotype

A set of polymorphisms from the same region which are usually inherited as a unit

Heterozygous

Occurs when alleles at the same chromosomal position are different. For example if a T is inherited from a specific genetic location from the mother and an A is inherited at the same position from the father then the genotype will be heterozygous (AT)

Homozygous

Occurs when alleles at the same chromosomal position are the same

Intron

Regions of DNA located between exons which do not translate into protein

Mutation

DNA variations that occur at a frequency of less than 1% within a population

Non-synonymous

A substitution of one nucleotide for another nucleotide within an exon of a gene that results in the production of a different amino acid

Polymorphism

DNA variations that occur at a frequency of greater than 1% within a population

Promoter site

Region of DNA that regulates the amount of protein produced

Single nucleotide polymorphism (SNP)

DNA sequence variation occurring at a single nucleotide. They are identified by an individual reference sequence (rs) number. For example rs6265 (an SNP within the BDNF gene)

Stochastic

Random or probabilistic event

TagSNP

Multiple SNPs can be inherited together on a single block of DNA (these SNPs are said to be in linkage disequilibrium). Therefore, it is possible to genotype a small number of SNPs on a block in order to identify a haplotype. The selected SNPs are called tagSNPs and they are a way of reducing genotyping costs while maintaining power to detect association.

Transcription

Transfer of genetic information from DNA to RNA

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Payton, A. The Impact of Genetic Research on our Understanding of Normal Cognitive Ageing: 1995 to 2009. Neuropsychol Rev 19, 451–477 (2009). https://doi.org/10.1007/s11065-009-9116-z

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