Early macrostructural and microstructural cortical changes in Alzheimer's disease: longitudinal and cross-sectional studies of early change

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Alzheimer's disease is the commonest cause of dementia. Not only is Alzheimer's disease devastating for individuals and families but also represents a growing public health problem. Dementia research is therefore a key national and global priority. Alzheimer's disease is associated with the build up of abnormal proteins in the brain and loss of brain cells, both of which precede the onset of memory problems, probably by many years. Once loss of brain cells occurs, the damage is irreversible. Therefore, when drugs that can stop or slow the progression of Alzheimer's disease become available, ideally we would want to be able to identify and treat individuals at risk of developing dementia before symptoms had started. However, exactly how early this irreversible damage begins to occur is currently unclear, and detecting these early changes is difficult. Better techniques are urgently needed for identifying individuals at risk of Alzheimer's, for staging their disease, and for monitoring its progression.The cerebral cortex is the thin outermost layer of neural tissue (grey matter) on the brain's surface. The cerebral cortex plays a key role in our thought processes, from language and calculation to planning and attention. Abnormalities within the cerebral cortex occur very early in Alzheimer's disease. A number of new brain scanning techniques which may be able to detect very early changes in both the thickness and structure of the cortex, and its connections with other brain areas, have been developed. In addition to these brain scanning techniques, new memory tests have been developed which may be able to detect very early changes as the brain structures starts to become impaired. Taken together, these brain imaging techniques and memory tests may provide important information about the brain changes in Alzheimer's disease. Familial Alzheimer's disease is a rare form of the disease (accounting for less than 1% of cases) where the disease is inherited - usually at a young age - due to a genetic defect. Individuals from families with known genetic mutations have generously agreed to take part in longitudinal studies, which we have been running at the Dementia Research Centre for many years.We propose to evaluate the techniques described above to study individuals from families affected by familial Alzheimer's who are well, but who are at high risk of developing Alzheimer's disease. We will also assess people who already have symptomatic Alzheimer's disease and some healthy individuals for comparison. We will do this by acquiring detailed (MRI) brain scans, including the new techniques, in conjunction with detailed clinical and psychological assessments. We will examine how well each of these techniques can detect the earliest features of Alzheimer's disease, and how good each is at measuring change over time. We will also aim to improve our understanding of how early and where in the brain the first damage begins to occur. This information will be used to determine how best to run clinical trials in individuals at risk of developing Alzheimer's disease, which will ultimately increase our chances of finding an effective treatment.