The impact of different presenilin 1 and presenilin 2 mutations on amyloiddeposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain - Evidence for other phenotype-modifying factors

To assess the influence of the presenilin 1 (PS1) and 2 (PS2) mutations on amyloid deposition, neurofibrillary tangle (NFT) formation and neuronal los s, we performed stereologically based counts in a high-order association co rtex, the superior temporal sulcus, of 30 familial Alzheimer's disease case s carrying 10 different PSI and PSZ mutations, 51 sporadic Alzheimer's dise ase cases and 33 non-demented control subjects. All the PS1 and PS2 mutatio ns assessed in this series led to enhanced deposition of total A beta and A beta(x-42/43) but not A beta(x-40) senile plaques in the superior temporal sulcus when compared with brains from sporadic Alzheimer's disease patient s. Some of the PS1 mutations studied (M139V, I143F, G209V, R269H, E280A), b ut not others, were also associated with faster rates of NFT formation and accelerated neuronal loss in the majority of the patients who harboured the m when compared with sporadic Alzheimer's disease patients. In addition, ou r analysis showed that dramatic quantitative differences in clinical and ne uropathological features can exist even among family members with the ident ical PS mutation, This suggests that further individual or pedigree genetic or epigenetic factors are likely to modulate PS phenotypes strongly.