Genetic Risk Factors of Imaging Measures Associated with Late-Onset Alzheimer’s Disease

Abstract

Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia and the fifth leading cause of death in Americans older than 65 years.1 Although other major causes of death have decreased, deaths due to LOAD have been rising dramatically over the past two decades, between 2000 and 2006 they increased by 46.1%.1 Clinically, LOAD is characterized by progressive cognitive decline in particular in the memory domain. Neuropathologically it is characterized by the aggregation and deposition of misfolded proteins, in particular aggregated ┚-amyloid (A┚) peptide in the form of extracellular senile (or neuritic) “plaques,” and hyperphosphorlylated tau (τ) protein in the form of intracellular neurofibrillary “tangles” (NFTs). These changes are often accompanied by microvascular damage, vascular amyloid deposits, inflammation, microgliosis, and loss of neurons and synapses. Although twin studies suggest that 37% to 78% of the variance in the age-at-onset of LOAD can be attributed to additive genetic effects,2 few genes have been identified and validated, and these genes likely explain less than 50% of the genetic contribution to LOAD. This is the upper bound of explained heritability in other complex diseases for which—unlike LOAD— significant association has been demonstrated for several common loci of large effect (i.e., ORs > 2 to > 3), such as age-related macular degeneration. Thus, a substantial proportion of the heritability for LOAD remains unexplained by the currently known susceptibility genes. A likely explanation for the difficulty in gene identification is that LOAD is a multifactorial complex disorder with both genetic and environmental components, and that multiple genes with small effects are likely to contribute. Several neuroimaging measures correlate with LOAD risk and progression, in particular the volumes of the hippocampus, parahippocampus and entorhinal cortex, and the cerebral grey matter. Also these measures appear to have a substantial genetic contribution reflected