A genome-wide association study of non-pathological cognitive ageing

There are growing proportions of older people in Western societies, and people are living longer. Therefore, the changes to the body that occur as people grow older have become a research priority. The changes that worry older people most are the changes to the brain. Cognitive decline--changes to thinking skills like memory, reasoning, and speed of thinking--is the most feared aspect of ageing. Cognitive decline is a major contribution to lower quality of life and lost independence in old age. In the United Kingdom, cognitive failure as the critical reason is the cause for 40% of admissions to institutional care. Cognitive impairment is a major personal and social burden both currently and in the future. Retaining cognitive functions must be a priority for older people and good research is needed to inform how this can be done. Cognitive ageing is far more than the medical conditions of dementia and mild cognitive impairment. The greater part of cognitive ageing occurs among otherwise healthy old people. This is known as 'normal, 'usual' and 'non-pathological' cognitive ageing. One of the more remarkable features of normal cognitive ageing is the range of effects. Some people decline quite markedly in thinking skills. whereas others retain these powers very well as they grow older. The aim of this project will be to try to find some of the clues to successful cognitive ageing, to why some people appear to have more cognitive reserve than others. There are a number of hints as to why some people's cognitive abilities show differences in ageing. There are physiological, lifestyle, and social contributions to the ageing of cognitive functions. The emphasis of the present project is on possible genetic contributions to the ageing of cognitive functions. It is important to appreciate that, to conduct such an investigation, it is important to have cognitive functions assessed on at least two occasions, many years apart. It is this aspect of the design that properly allows actual cognitive change to be studied. Few human studies have such data. For this project there will be two of the largest cohorts in the world with the correct cognitive information for such a study. There are about 2000 DNA samples from the University of Edinburgh. Among the subjects who provided these are those that have valid mental test data from the Scottish Mental Surveys of 1932 and 1947, at age 11, and have been tested on cognitive functions in old age. There are about 2000 DNA samples from the University of Manchester's Dyne Steele DNA bank. Again, these subjects are rare in having cognitive function data decades apart. In addition to these rare cognitive data, the cohorts have additional information on health, lifestyle, personality and brain imaging. There are 6000 replication samples available. Since 1998 over twenty genetic variants have been associated with cognitive ability. Unfortunately, a combination of small genetic effects and study populations have resulted in inconsistencies within the literature and confusion as to the whether or not a particular gentic variation is genuinely associated with cognitive ability. Far fewer studies, still, have information on genetic contributions to cognitive change within old age. The project will combine two of the largest and most informative elderly cognitive ageing cohorts in the world. A whole genome screen of their DNA will be conducted using the most up to date genetic testing platform to allow the most detailed screening of an elderly cohort for genes that influence cognitive ability and decline ever attempted. This data may provide invaluable information that could be used in the screening and treatment of cognitive impairment in the elderly. Genetic contributions to cognitive ageing do not imply something untreateable: genetic discoveries lead to understanding of mechanisms, which can lead to intervention. The study will provide definitive and therefore cost effective research.

Cognitive ageing is the most feared aspect of growing old. It leads to lowered quality of life and loss of indendence. It is a huge financial burden to the nation. This involves not just the medical conditions of dementia and mild cognitive impairment but also the range of cognitive change that is referred to as normal, usual or nonpathological cognitive ageing. Understanding the contributions to variance in cognitive ageing is a research priority. The putative influences include medical conditions, fitness, lifestyle and psychosocial and demographic factors. There are also genetic contributions to individual differences in normal cognitive ageing, with variation in APOE among the best replicated. Although there is much interest in discovering the genetic contributions to cognitive ageing there are few appropriate data sets. That is, such a study requires large-enough samples with a rare phenotype: information on how cognition has changed across a sufficiently long period of time. In the present study we shall combine two of the largest cognitive ageing cohorts in the world with such data. There will be DNA and cognitive phenotypes from 2000 samples each at the University of Edinburgh and the University of Manchester. The University of Edinburgh has DNA and cognitive function data from people who took part in the Scottish Mental Survey of 1932 and 1947, at age 11, and were tested again 55-70 years later. The University of Manchester has DNA and cognitive function data in the Dyne Steele bank, with cognitive testing occurring over about 20 years. 4000 subjects' DNA will be subjected to whole genome screening using the Illumina Human370CNV chip. The top 30 SNPs (based on the association with cognitive ageing) will be tested on a further 6000 subjects in replication samples that are available in Scotland. The information from the replicated associations will provide unique information on the causes of cognitive ageing and may indicate paths to intervention.