WIDE-RANGE OF DISEASE ONSET IN A FAMILY WITH ALZHEIMER-DISEASE AND A HIS163TYR MUTATION IN THE PRESENILIN-1 GENE

Objectives: To describe clinical and genealogical data of a Swedish fa mily with a His163Tyr mutation in the presenilin-1 gene (PSI) and to s tudy the Alzheimer disease (AD) penetrance in this family. Design: Int erviews with relatives, studies of medical records, analysis of pedigr ee, physician examination of the affected individuals, and comparison with other families affected by AD with PS1 mutations. Setting: Large university-affiliated hospital. Patients and Other Participants: Indiv iduals with a His163Tyr mutation in PSI and their relatives. Results: A study of this family with a history of very early AD onset (mean age , 47 years) has been previously published, but an investigation of the extended family revealed a new pattern of onset, with a mean age at o nset of 54 years (range, 44-65 years). In general, families with AD sh ow a tight cluster of age at onset with high penetrance of the disease . However, in this family, an individual whose child carries the PSI m utation died at age 67 years free from cognitive symptoms, indicating a very late age at onset or nonpenetration of the disease. No associat ion between age at onset and disease duration was found. Furthermore, the disease duration did not differ between those having an early onse t compared with those having a late onset. The earliest clinical manif estations were deficits in memory function and disorientation in time and place. Myoclonic jerks and epileptic seizures were common symptoms later in the disease. Conclusion: The large range in age at onset in this family with a uniform genetic basis for the disease, a His163Tyr mutation in PSI, supports the existence of other unknown genetic or en vironmental factors of importance for the expression of the AD phenoty pe.