Genotype-phenotype relationships of presenilin-1 mutations in Alzheimer's disease: an update

It is now more than ten years since pathogenic mutations were first described in the gene encoding presenilin 1 (PSEN1) on chromosome 14. Although PSEN1 mutations are "deterministic" for Alzheimer's disease, they are associated with marked heterogeneity in the clinical expression of neurological features. We review recent publications on the clinical neurological phenotype of PSEN1 mutations, many of which now appear only in abstracts or brief communications, perhaps because PSEN1 mutations are no longer regarded as "novel". However, the clinical heterogeneity associated with these mutations prompts important questions about possible genetic and epigenetic factors which may modify disease phenotype. This area, which may also be relevant to neurodegenerative disorders resulting from other genetic mutations, such as those in the tau gene, currently remains ill-understood.