Genetic Determinants of Cognitive Function and Age-Related Brain Changes

The brain is by far the most complicated structure of the human being, and its malfunction is characterized by various degrees and types of morbidity. Several brain functions deteriorate with increasing age during life. Cognitive decline and age-related brain pathology are common in the elderly, but these changes may also become manifest early in life and preceding the onset of clinical symptoms of disease. The detection of early changes may be relevant for therapeutic interventions to prevent disease, and are therefore also increasingly targeted in genetic research as endophenotypes. Endophenotypes are defined as heritable phenotypes that are related to the disease of interest, and are typically approached as quantitative outcomes, i.e., instead of hypertension, the endophenotype of interest is systolic or diastolic blood pressure. In contrast to classical risk factors in epidemiology, an endophenotype is by definition not uniquely associated to a single disease. Blood pressure for example, is consistently associated to various clinically relevant outcomes such as stroke, myocardial infarction and heart failure. There is an increasing interest in the genetic research of endophenotypes, and genome-wide association studies of endophenotypes have been very successful. In this thesis I focus on cognitive function and age-related brain changes early in life as endophenotypes for late-life brain disease and as targets for early prevention. Cognitive deterioration can be seen in pre-clinical stages of neurodegenerative and neuropsychiatric disorders like dementia, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder (ADHD). Cognitive function is a broad concept referring to multiple cognitive domains, among which memory, language, executive function and visuospatial ability. Although the domains are highly correlated, it is known that specific domains are related to specific diseases. Cognitive function is in part determined by our genetic make-up. The heritability is estimated to around 40% and there have been various studies that have tried to identify genes explaining the heritability of cognitive functions. These included candidate gene studies, linkage studies and genome-wide association studies. The genes and chromosomal regions that have been found so far are partly explained by genes related to neuropsychiatric disease, and partly by genes related to dementia and Alzheimer’s disease (AD) with the Apolipoprotein E gene as genetic factor with one of the strongest effects. In the studies presented here, we will focus on a cognitive test battery targeting AD. Dementia is one of the most common causes of morbidity and mortality in the Western society (prevalence of 25 million cases worldwide), in which Alzheimer disease accounts for over 70% of cases. Regarding the high prevalence and major impact of these diseases, early diagnosis and treatment strategies have a high priority in neuroscience. Identifying risk factors for cognitive decline would benefit our increasingly elderly population.

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