Presenilin-1 mutations in Alzheimer's disease: an update on genotype-phenotype relationships

Presenilin 1 (PSEN1) gene mutations deterministic for Alzheimer's disease (AD) are associated with marked heterogeneity in clinical phenotype, with behavioral and psychiatric features, parkinsonism, myoclonus, epileptic seizures, spastic paraparesis, frontal behavioral changes suggestive of the phenotype of frontotemporal dementia, aphasia, and cerebellar ataxia being described as well as cognitive decline. This article reviews publications on the clinical neurological phenotype of PSEN1 mutations published between October 2008 and April 2013 and integrates this information with previous reviews to produce tabular summaries of phenotype and genotype. With the possible exception of "variant AD" (familial AD with spastic paraparesis), no clinical genotype-phenotype correlations are obvious. The mechanisms underpinning the clinical heterogeneity associated with PSEN1 mutations remain unclear. The "presenilin hypothesis" posits a loss of essential presenilin protein functions as a consequence of gene mutation, which might be one factor influencing disease phenotype.