Brain, Vol. 122, No. 9, 1709-1719,
September 1999
© 1999 Oxford University Press
The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain
Evidence for other phenotype-modifying factors
1 Neurology Service, Massachusetts General Hospital, 2 Neurology Service, Brigham and Women's Hospital, Boston, 3 Department of Pathology (Neuropathology), University of Washington School of Medicine, 4 Neurology Service, VA Medical Center and University of Washington School of Medicine, Seattle, USA, 5 Department of Pathology, University of Antioquía, Medellín, Colombia and 6 Department of Neuropathology, Institute of Psychiatry, London, UK
Correspondence to:
Dr Teresa Gómez-Isla, Department of Neurology, 420 Delaware St SE, University of Minnesota, Box 295 FUMC, Minneapolis, MN 55455, USA E-mail: gomez010{at}tc.umn.edu
To assess the influence of the presenilin 1 (PS1) and 2 (PS2) mutations on amyloid deposition, neurofibrillary tangle (NFT) formation and neuronal loss, we performed stereologically based counts in a high-order association cortex, the superior temporal sulcus, of 30 familial Alzheimer's disease cases carrying 10 different PS1 and PS2 mutations, 51 sporadic Alzheimer's disease cases and 33 non-demented control subjects. All the PS1 and PS2 mutations assessed in this series led to enhanced deposition of total Aß and Aßx-42/43 but not Aßx-40 senile plaques in the superior temporal sulcus when compared with brains from sporadic Alzheimer's disease patients. Some of the PS1 mutations studied (M139V, I143F, G209V, R269H, E280A), but not others, were also associated with faster rates of NFT formation and accelerated neuronal loss in the majority of the patients who harboured them when compared with sporadic Alzheimer's disease patients. In addition, our analysis showed that dramatic quantitative differences in clinical and neuropathological features can exist even among family members with the identical PS mutation. This suggests that further individual or pedigree genetic or epigenetic factors are likely to modulate PS phenotypes strongly.
Aß plaques; neurofibrillary tangles; neuronal loss; presenilin; familial Alzheimer's disease
ANOVA = analysis of variance; APOE = apolipoprotein E; APP = amyloid-ß protein precursor; NFT = neurofibrillary tangles; PS1 = presenilin 1; PS2 = presenilin 2
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