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P2‐434: EXAMINING THE MOLECULAR FACTORS INVOLVED IN THE PATHOGENESIS OF FAMILIAL ALZHEIMER'S DISEASE THROUGH A CORRELATION ANALYSIS OF CLINICAL AND CELLULAR DATA
Author(s) -
Bi Stephanie,
Li Bin
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.2841
Subject(s) - presenilin , correlation , disease , amyloid precursor protein , pathogenesis , amyloid (mycology) , computational biology , bioinformatics , biology , medicine , alzheimer's disease , genetics , pathology , geometry , mathematics
Background: Research on familial Alzheimer’s disease (fAD) has enabled the identification and study of molecular species implicated in disease, such as amyloid beta peptides and the tau protein. In turn, many theories, including the amyloid cascade, presenilin loss-of-function, and mitochondrial cascade hypothesis, have been proposed, focusing on the effects brought about by individual species. However, mounting evidence and failed clinical trials have shown that it is crucial to investigate the interplay and relationships between these various factors.Methods: We conducted a systematic literature search of the PubMed, HGMD, and Alzforum databases, and gathered clinical and cellular data of fAD cases caused by mutations of three genes: amyloid precursor protein, presenilin 1, and presenilin 2. We performed statistical analyses, including Pearson’s correlation tests, using the IBM SPSS software version 25. To classify mutations by gene based off our cellular data, we built and applied a decision tree (J48) machine learning model using WEKA. Results: Our analyses demonstrated that both the buildup of intracellular amyloid beta peptides and the Ab42/Ab40 peptide ratio exhibit a negative correlation with the age of onset (AAO) (coeff. 1⁄4 -0.539, p1⁄40.00, n1⁄443 and coeff. 1⁄4 -0.299, p1⁄40.00, n1⁄4132, respectively). Interestingly, a decrease in the Ab42/Ab40 ratio is also correlated with a lower AAO.We found that mutation physicochemical severity, as measured by the PredictSNP software, had a negative correlation with the age of onset (coeff. 1⁄4 -0.182, N1⁄4188, p1⁄40.012). These results were supported by our decision tree model, which also allowed us to identify factors that were shared by genes, like the intracellular amyloid beta peptide buildup, and others that differed between genes, like the deleteriousness of the individual mutations. Conclusions: Our results suggest that intracellular amyloid beta generation and changes of the the Ab42/Ab40 ratio are highly correlated with incidence of disease. We conclude that while there may be differences in the pathogenesis of fAD caused by mutations in different genes, certain aspects are shared and may be potential predictors of disease.