Brain, Vol. 123, No. 5, 894-907,
May 2000
© 2000 Oxford University Press
Alzheimer's disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation
A clinicopathological study
1 Dementia Research Group, Institute of Neurology and Division of Neurosciences, 2 MRC Prion Unit, Department of Neurogenetics, Imperial College School of Medicine, 3 Department of Neuropathology, Institute of Psychiatry and 4 Departments of Clinical Neuropsychology and 5 Radiology, National Hospital for Neurology and Neurosurgery, London, UK
Correspondence to:
Professor M. N. Rossor, Dementia Research Group, Institute of Neurology, Queen Square, London WC1N 3BG, UK
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 
4/4, > 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.
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