Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis.

A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.