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.http://repub.eur.nl/res/pub/19462/100512_Schuur%2C%20Maaike.pdf
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