Summary
In patients with familial Alzheimer's disease (FAD) with early onset, mutations have been identified in three genes: Presenilin 1 (PS1), Presenilin 2 (PS2) and amyloid protein precursor (APP). Although many different mutations have been recorded for each gene, in most cases the clinical picture is typical of AD, with earlier onset than in sporadic AD. The question of whether mutations in these genes invariably predict AD pathology is the subject of this review. Almost all mutations in APP, PS1 and PS2 promote the development of neuropathological findings of AD, with deposition of amyloid beta protein (Aβ) to form prominent amyloid pathology. Progress has been made in correlating the effects of mutations on species of Aβ with vascular versus parenchymal deposition of Aβ. There are some exceptions to what appears to be an otherwise inevitable relationship. First, a few innocent mutations in APP and PS1 have been described. Second, in rare families with PS1 mutations, there are mutation-bearing individuals who may have escaped clinical disease. Third, some APP mutations alter the sequence of Aβ and lead to severe angiopathy with hemorrhage, rather than the plaques and tangles of AD. Finally, some families with fronto-temporal dementia (FTD) have shown PS1 mutations. Although neuropathologic studies are limited at present, the FTD association raises questions about whether amyloidogenic disease pathways are the only mechanisms that lead to neuropathological changes in early onset AD with presinilin (PS) mutations.
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Galasko, D. (2005). Early Onset Familial Alzheimer's Disease: Is a Mutation Predictive of Pathology?. In: Cummings, J.L., Poncet, M., Hardy, J., Christen, Y. (eds) Genotype — Proteotype — Phenotype Relationships in Neurodegenerative Diseases. Research and Perspectives in Alzheimer's Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26522-8_5
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