A NOVEL PRESENILIN-1 MUTATION - INCREASED BETA-AMYLOID AND NEUROFIBRILLARY CHANGES

The prevalence of known mutations in presenilin genes (PS1 and PS2) ca using early-onset familial Alzheimer's disease (FAD) was assessed in a population of 98 singleton early-onset AD cases, 29 early-onset FAD c ases, and 15 late-onset FAD cases. None of the cases tested positive f or the eight mutations initially reported, and none of these mutations were observed in 60 age-matched controls. A novel mutation (R269H) in PS1 was found in a single case of early-onset AD but not in any other AD or control case. Thus, the PS mutations tested are quite rare in e arly-onset AD. Amyloid beta protein (AP) deposition was investigated i n the temporal cortex of the R269H mutation case using end-specific mo noclonal antibodies to detect the presence of A beta(x-40) and A beta( x-42) subspecies. Stereologically unbiased tangle and neuropil thread counts were obtained from the same region. R269H PS1 mutation was asso ciated with early age of dementia onset, higher amounts of total A bet a and A beta(x-42), and increased neuronal cytoskeletal changes. Thus, if the changes observed on this case prove to be typical of PS1 mutat ions, PS1 mutations may impact both amyloid deposition and neurofibril lary pathology.