Objectives: To characterize clinical features of a very large pedigree with early-onset Alzheimer disease (AD) in which all affected individuals carry the identical glutamic acid-to-alanine mutation at codon 280 in the presenilin-1 gene.
Design: Clinical histories were obtained by patient and family interviews and through medical or civil records. Using standard diagnostic criteria, a case series of 128 individuals was identified, of which 6 have definitive (autopsy-proven) early-onset AD, 93 have probable early-onset AD, and 29 have possible early-onset AD.
Setting: Community based in Antioquia, Colombia.
Patients: A population-based sample in which all members of 5 extended families (nearly 3000 individuals) were surveyed. Criteria for inclusion required obtaining sufficient information to categorize the individual as affected.
Main outcome measures: Age at onset, neuropsychological profile, neurologic history, and examination.
Results: The patients had a mean age at onset of 46.8 years (range, 34-62 years). The average interval until death was 8 years. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentation was memory loss followed by behavior and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent.
Conclusions: Other than the early onset, this clinical phenotype is indistinguishable from sporadic AD except that affected individuals frequently complained of headache preceding and during the disease. Despite the uniform genetic basis for the disease, there was significant variability in the age at onset, suggesting an important role for environmental factors or genetic modifiers in determining the age at onset.