Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations.

Three genes have been implicated in the etiology of early-onset autosomal-dominant Alzheimer disease (AD): the amyloid precursor protein, the presenilin-1, and presenilin-2 genes. Approximately half of autosomal-dominant AD cases are associated with mutations in the presenilin-1 (PS-1) gene on the long arm of Chromosome 14. Marked allelic heterogeneity characterizes families with PS-1 gene mutations; more than 100 different mutations have been found in independent families thus far. With the exception of age at onset, the clinical phenotype is similar to late-onset AD, although some rare specific phenotypes have been described. These mutations lead to enhanced deposition of total Abeta and Abeta42 (but not Abeta40) in the brain, compared with sporadic AD. There is a considerable heterogeneity in the histological profiles among brains from patients with different mutations, and although some lead to predominantly parenchymal deposition of Abeta in the form of diffuse and cored plaques, others show predominantly vascular deposition, with severe amyloid angiopathy. Only some mutations are associated with enhanced neurofibrillary tangle formation and increased neuronal loss compared with sporadic AD. However, there is an important clinical and pathological variability even among family members with the same mutation, which suggests the involvement of other genetic or environmental factors that modulate the clinical expression of the disease. This represents a valuable model for identifying such factors and has potential implications for the development of new therapeutic strategies for delaying disease onset.