Alzheimer's disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation: A clinicopathological study.

We describe 21 affected individuals from a kindred with early-onset autosomal dominant familial Alzheimer's disease caused by an intronic presenilin-1 mutation (in intron 4). Mean age at onset of symptoms was 37.4 years [95% confidence interval (CI): 36.6-38.2 years], mean age at death was 44.7 years (95% CI: 43.1-46.3 years) and mean duration of illness was 7.3 years (95% CI: 5.9-8.7 years). Myoclonus and seizures were prominent features of this pedigree. In the four cases for whom neuropsychometric data were available, verbal memory impairment preceded visual memory deficits; naming was relatively preserved until late in the disease. One of these four cases underwent serial volumetric MRI scans demonstrating in vivo brain tissue loss of 3.9% (38.9 ml, annualized rate of atrophy: 1. 7%) over 22 months of follow-up. The four individuals who had necropsies demonstrated the neuropathological hallmarks of Alzheimer's disease. Apolipoprotein E (APOE) status was assessed in five individuals: the case with the youngest age at onset at 33 years of age was found to be homozygous epsilon4/epsilon4, > 1 SD below the mean age of onset for those of known APOE genotype (36.4 +/- 2.3 years, mean +/- SD), and > 2 SDs below the mean age of onset for the pedigree as a whole (37.4 +/- 1.7 years, mean +/- SD). APOE genotype may therefore modulate age at onset in this pedigree.