SOMATIC MUTATION ANALYSIS OF THE APP AND PRESENILIN-1 AND 2 GENES IN ALZHEIMERS-DISEASE BRAINS

The molecular basis for sporadic Alzheimer disease (AD) remains largel y unknown. We hypothesized that in some cases of sporadic AD, a somati c mutation in an embryonic cell committed to neuronal development with in the amyloid precursor protein (APP), the presenilin 1 (PS-1) or the presenilin 2 (PS-2) genes (genes known to be involved in familial AD) may result in AD phenotype. Using PCR, denaturing gradient gel electr ophoresis (DGGE), restriction enzyme digest and direct DNA sequencing, we analyzed these genes in 99 brain tissues from patients with histop athologically proven AD. One brain sample showed a mutation within the PS-1 gene, His163 Arg, later shown to be a germline mutation. No othe r migration abnormalities were demonstrated in any sample in exon 16 o r 17 of the APP gene or the coding exons of the PS-1 gene. Restriction digest pattern was normal with regard to the predominant PS-2 gene mu tation (N1411). A known mutation in the APP gene, as well as novel mut ations within the PS-1 gene were easily detected by DGGE (Reznick Wolf et al. manuscript submitted). We conclude that the genes that are inv olved in familial AD do not display somatic mutations in the brains of sporadic AD patients, and that other molecular mechanisms are probabl y involved in the pathogenesis of sporadic AD.