Presenilin Mutations Linked to Age of Onset in Alzheimer's

Researchers studying the genetics of Alzheimer's disease (AD) have found a presenilin gene mutation associated with variable age of onset AD (from 35 to 85 years old) in one family and two presenilin gene mutations associated with early onset AD (from 49 to 54 years old) in two other unrelated families.

Familial Alzheimer disease (FAD) accounts for approximately 5-10% of all cases of AD. This disorder is genetically heterogeneous and can be categorized according to age-of-onset using 60 years as a cut-off. The early-onset FAD genes include the amyloid protein precursor (APP) gene on chromosome 21, the presenilin 1 (PS1) gene on chromosome 14, and the presenilin 2 (PS2) gene on chromosome 1. Approximately 50% of early-onset FAD is accounted for by defects in these genes, with the majority occurring in the PS1 gene.

Investigators at the University of Florence (Italy; www.unifi.it) used polymerase chain reaction (PCR) single-strand conformation polymorphism and DNA sequencing to analyze samples from 45 individuals from Italian families with members suffering from FAD.

They report in the November 2003 issue of the Archives of Neurology that they had found one novel PS2 mutation associated with highly penetrant but variable age at onset (35-85 years) and two novel PS1 missense mutations associated with early-onset Alzheimer disease at age 49 to 54 years.

The authors stated, "Results of this study confirm and extend the concept that the clinical manifestation of PS1 and PS2 mutations may be typical for AD and more similar to other dementias. In addition, the identification of new mutations is important, particularly for developing diagnostic testing programs based on the frequency of mutations in specific populations and for further enlarging out understanding of the great variability of FAD.”



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