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To detect vulnerable connections, we devised a multiscale, hierarchical method for spatial clustering of the whole brain tractogram and examined the impact of age and APOE allelic variation on cognitive abilities and bundle properties including texture e.g., mean fractional anisotropy, variability, and geometric properties including streamline length, volume, and shape, as well as asymmetry. We found that the third level subdivision in the bundle hierarchy provided the most sensitive ability to detect age and genotype differences associated with risk factors. Our results indicate that frontal bundles were a major age predictor, while the occipital cortex and cerebellar connections were important risk predictors that were heavily genotype dependent, and showed accelerated decline in fractional anisotropy, shape similarity, and increased asymmetry. Cognitive metrics related to olfactory memory were mapped to bundles, providing possible early markers of neurodegeneration. In addition, physiological metrics such as diastolic blood pressure were associated with changes in white matter tracts. Our novel method for a data driven analysis of sensitive changes in tractography may differentiate populations at risk for AD and isolate specific vulnerable networks.<\/jats:p>","DOI":"10.1101\/2024.06.24.599407","type":"posted-content","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T22:25:14Z","timestamp":1719613514000},"source":"Crossref","is-referenced-by-count":1,"title":["Mapping the impact of age and APOE risk factors for late onset Alzheimer\u2019s disease on long range brain connections through multiscale bundle analysis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9680-8386","authenticated-orcid":false,"given":"Jacques","family":"Stout","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3021-9797","authenticated-orcid":false,"given":"Robert J","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2252-4529","authenticated-orcid":false,"given":"Ali","family":"Mahzarnia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zay","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate","family":"Beck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8573-7073","authenticated-orcid":false,"given":"Jeffrey","family":"Browndyke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8793-2489","authenticated-orcid":false,"given":"Kim","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J","family":"O\u2019Brien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6621-4560","authenticated-orcid":false,"given":"Alexandra","family":"Badea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024070118401030000_2024.06.24.599407v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26251"},{"key":"2024070118401030000_2024.06.24.599407v1.2","doi-asserted-by":"publisher","DOI":"10.3171\/2013.12.JNS131537"},{"key":"2024070118401030000_2024.06.24.599407v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2007.01378.x"},{"key":"2024070118401030000_2024.06.24.599407v1.4","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.nicl.2017.01.003","article-title":"Automated tractography in patients with temporal lobe epilepsy using TRActs Constrained by UnderLying Anatomy (TRACULA)","volume":"14","year":"2017","journal-title":"NeuroImage: Clinical"},{"key":"2024070118401030000_2024.06.24.599407v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2008.09.021"},{"key":"2024070118401030000_2024.06.24.599407v1.6","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0b013e3283546264"},{"key":"2024070118401030000_2024.06.24.599407v1.7","doi-asserted-by":"crossref","first-page":"48","DOI":"10.3389\/fnagi.2015.00048","article-title":"Comparison of nine tractography algorithms for detecting abnormal structural brain networks in Alzheimer\u2019s disease","volume":"7","year":"2015","journal-title":"Frontiers in aging neuroscience"},{"key":"2024070118401030000_2024.06.24.599407v1.8","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhac419"},{"key":"2024070118401030000_2024.06.24.599407v1.9","doi-asserted-by":"crossref","unstructured":"Prasad, G. , et al. 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