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However, pathogenic links between these 2 disorders are yet to be identified. Therefore we used Taqman genotyping, exome and RNA sequencing to investigate Alzheimer\u2019s disease known pathogenic variants and pathways: <jats:italic>APOE<\/jats:italic> \u03b54 allele, APP-A\u03b2 metabolism and late-onset Alzheimer\u2019s\u00a0disease main genome-wide association loci (<jats:italic>APOE<\/jats:italic>, <jats:italic>BIN1<\/jats:italic>, <jats:italic>CD33<\/jats:italic>, <jats:italic>MS4A6A<\/jats:italic>, <jats:italic>CD2AP<\/jats:italic>, <jats:italic>PICALM<\/jats:italic>, <jats:italic>CLU<\/jats:italic>, <jats:italic>CR1<\/jats:italic>, <jats:italic>EPHA1<\/jats:italic>, <jats:italic>ABCA7)<\/jats:italic> in 96 early-onset small vessel ischemic disease Caucasian patients and 368 elderly neuropathologically proven controls (HEX database) and in a mouse model of cerebral hypoperfusion. Only a minority of patients (29%) carried <jats:italic>APOE<\/jats:italic> \u03b54 allele. We did not detect any pathogenic mutation in <jats:italic>APP<\/jats:italic>, <jats:italic>PSEN1<\/jats:italic> and <jats:italic>PSEN2<\/jats:italic> and report a burden of truncating mutations in APP-A\u00df degradation genes. The single-variant association test identified 3 common variants with a likely protective effect on small vessel ischemic disease (0.54&gt;OR\u2009&gt;\u20090.32, adj. p-value &lt;0.05) (<jats:italic>EPHA1<\/jats:italic> p.M900V and p.V160A\u00a0and <jats:italic>CD33<\/jats:italic> p.A14V). Moreover, 5\/17 APP-A\u00df catabolism genes were significantly upregulated (LogFC\u2009&gt;\u20091, adj. p-val&lt;0.05) together with <jats:italic>Apoe<\/jats:italic>, <jats:italic>Ms4a<\/jats:italic> cluster and <jats:italic>Cd33<\/jats:italic> during brain hypoperfusion and their overexpression correlated with the ischemic lesion size. Finally, the detection of A\u03b2 oligomers in the hypoperfused hippocampus supported the link between brain ischemia and Alzheimer\u2019s disease pathology.<\/jats:p>","DOI":"10.1038\/s41598-020-63183-5","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T10:04:11Z","timestamp":1588068251000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Investigating APOE, APP-A\u03b2 metabolism genes and Alzheimer\u2019s disease GWAS hits in brain small vessel ischemic disease"],"prefix":"10.1038","volume":"10","author":[{"given":"Sonja","family":"Blumenau","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Foddis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Holtgrewe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kajetan","family":"Bentele","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Berchtold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Beule","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Dirnagl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celeste","family":"Sassi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,4,28]]},"reference":[{"key":"63183_CR1","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1111\/j.1532-5415.1999.tb02571.x","volume":"47","author":"A Lim","year":"1999","unstructured":"Lim, A. et al. 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