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P4‐344: Structural and biochemical analysis of the heparin‐induced E1 dimer of the amyloid precursor protein
Author(s) -
Dahms Sven,
Hoefgen Sandra,
Roeser Dirk,
Than Manuel
Publication year - 2011
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.2011.09.090
Subject(s) - proteolysis , dimer , chemistry , amyloid precursor protein , biophysics , function (biology) , amyloid (mycology) , protein structure , molecular replacement , biochemistry , microbiology and biotechnology , biology , alzheimer's disease , enzyme , medicine , inorganic chemistry , disease , organic chemistry , pathology
a widespread misperception that dominant mutations in amyloid precursor protein, presenilin 1, and presenilin 2 cause most cases of EOAD even though they explain less than 10% of all EOAD cases. Here we set out to determine the genetic contribution to the remainingw90% of EOAD cases. Methods: A liability threshold model of disease was used to estimate heritability of EOAD and late-onset AD (LOAD) using concordance for AD among parent-offspring pairs. Individuals with probable AD and detailed parental history (n 1⁄4 5,370) were identified in a research registry of 32 United States Alzheimer’s Disease Centers. Results: For LOAD (n 1⁄4 4,302), we found sex-specific parent-offspring concordance that ranged fromw10-30% resulting in a heritability of 69.8% (95% CI: 64.6-75.0%) and equal heritability for both sexes regardless of parental gender. For EOAD (n 1⁄4 702), we found that the parent-offspring concordance is 1⁄4 10% and EOAD heritability is 92-100% for all likely values of EOAD prevalence. Conclusions: We confirm LOAD is a highly polygenic disease. By contrast, the data for EOAD suggest it is an almost entirely genetically based disease, and the low rate of concordance and sex-specific pattern observed lead us to reject the hypotheses that EOAD is a purely dominant, mitochondrial, X-linked, or polygenic disorder. The most likely explanation of the data is thatw90% of EOAD cases are due to autosomal recessive causes.