A PRESENILIN-1 TRUNCATING MUTATION IS PRESENT IN 2 CASES WITH AUTOPSY-CONFIRMED EARLY-ONSET ALZHEIMER-DISEASE

We have examined genomic DNA from 40 cases of autopsy-confirmed early- onset Alzheimer disease (EOAD) (age at onset less than or equal to 65 years) that were all unselected for family history. We have sequenced the 10 exons and flanking intronic sequences of the presenilin-1 (PS-1 ) gene for all 40 individuals. A single mutation, a deletion of a G fr om the intron 4 splice-donor consensus sequence, was detected in two i ndividuals in this study. The mutation was associated with two shorten ed transcripts, both with shifted reading frames resulting in prematur e-termination codons. All the PS-1 mutations described elsewhere have been missense or in-frame splice mutations, and recent data suggest th at these result in disease by gain-df-function or dominant-negative me chanisms. The mutation that we have identified is likely to result in haploinsufficiency and would be most consistent with other mutations a cting in a dominant-negative manner. However, we cannot exclude the po ssibility that the small amounts of truncated transcripts exert a gain of function. Since no other mutations or polymorphisms were detected in our patients, mutations in the coding regions and splice consensus sequences of PS-1 are likely to be rare in EOAD cases unselected for f amily history.