Genetics of Alzheimer's disease: recent advances

Alzheimer's disease (AD), first described by Alois Alzheimer in 1907 [1], is a neurodegenerative disorder progressing from memory loss to profound dementia and death within an average of eight years. Although clinical diagnosis is reliable in more than 90% of cases, the definite diagnosis is assigned post mortem based on brain atrophy and the characteristic neuropathologic findings, which involve intracellular neurofibrillary tangles containing hyperphosphorylated tau protein and extracellular amyloid plaques containing deposits of beta amyloid (Aβ). AD is recognized today as the most common cause of dementia in the elderly.In the 1930s a number of reports described familial cases of AD with multiple affected individuals in each generation, consistent with an autosomal dominant mode of inheritance [2-4]. Like Alzheimer's first patient, the age of onset of the familial cases was most often below 65 years, which led physicians to identify AD as pre-senile dementia, distinguishing it from senile dementia. By 1980, however, it had become evident that the two types of dementia are essentially identical, named by Terry and Davies [5] as dementia of the Alzheimer type.Not surprisingly, the genes involved in the familial, auto-somal dominant AD (FAD) were quickly discovered during the golden years of gene mapping in the 1990s. Despite initial confusion and controversy due to the genetic heterogeneity of AD [6,7], extending even to the small subset of FAD, a combination of functional evidence, linkage analyses and sequence comparisons led to the identification of the three genes accounting for most FAD cases: APP [8], PSEN1 [9] and PSEN2 [10].The majority (95%) of AD cases, however, are of later onset and do not follow Mendelian inheritance, despite showing significant heritability [11,12]. Like most other psychiatric disorders, the genetics of the late-onset disease appear to be complex. AD is the first complex disorder for which a gene was identified through an association