Epidemiology and Genetics of Alzheimer Dementia

Alzheimer dementia (AD) affects over 650,000 people in Germany and is the most common form of aging-related dementia. Mutations in the presenilins (PS1, PS2) and amyloid precursor protein (APP) are causative in rare forms of autosomal dominant familial Alzheimer disease (FAD). These findings contributed significantly to the current concept of the pathogenesis of AD. Whereas FAD accounts for <1% of all AD, the vast majority of AD is sporadic, age-related and multifactorial, i.e., late-onset AD (LOAD) due to genetic and non-genetic risk factors contributing etiologically. The genetic association between APOE e4 and (LOAD) was discovered more than a decade ago. Cumulative data of epidemiological, family, twin, linkage, and theoretical studies allow us to conclude that there may exist risk alleles in several genes in order to fully explain the proportion of AD attributable to genetic factors. However, up to now none of the numerous studies involving more than 130 candidate genes revealed convincing evidence for any risk alleles in genes other than APOE. In the published literature there are more than 55 loci with positive association findings. Most of these findings (including those of our group) could not be confirmed. This raises the question of why and how APOE was found and whether there are strategies to be optimized for future association studies on LOAD and polymorphic candidate genes. The APOE hypothesis was supported by linkage, existence of intragenic functional polymorphisms, and biochemical data suggesting an interaction between ApoE and beta amyloid peptide. Besides the chromosome 19 region harboring APOE, genome scans and linkage analyses revealed genomic regions suggestive of linkage with AD on chromosomes 1, 5, 9, 10, 12, 21, and X, in addition to several loci with a possible linkage. Furthermore, molecular genetic, biochemical and neurobiological research has revealed several molecular mechanisms involved in the pathogenesis of AD. Based on the data available now, future association studies on AD could focus on candidate genes simultaneously fulfilling several criteria that also were essential for discovering APOE. Supported by DFG, grant FI 704/1–3.