{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:17:47Z","timestamp":1768511867751,"version":"3.49.0"},"posted":{"date-parts":[[2024,7,26]]},"group-title":"Pathology","reference-count":18,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T00:00:00Z","timestamp":1721952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>INTRODUCTION<\/jats:title>\n                  <jats:p>The amyloid cascade hypothesis predicts that amyloid-beta (A\u03b2) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between A\u03b240 and A\u03b242 and total Tau (t-Tau) plasma biomarkers.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>Plasma A\u03b240, A\u03b242, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between A\u03b2s and t-Tau.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>No clear evidence that A\u03b240 or A\u03b242 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the A\u03b2 biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>DISCUSSION<\/jats:title>\n                  <jats:p>Plasma A\u03b240 or A\u03b242 do not appear to have a direct causal impact on t-Tau. In contrast, A\u03b2 aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.07.23.602498","type":"posted-content","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T10:05:24Z","timestamp":1721988324000},"source":"Crossref","is-referenced-by-count":0,"title":["Testing the causal impact of amyloidosis on total Tau using a genetically informative sample of adult male twins"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8655-2823","authenticated-orcid":false,"given":"Nathan A.","family":"Gillespie","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C.","family":"Neale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew S.","family":"Panizzon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth E.","family":"McKenzie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin M.","family":"Tu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Xian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chandra A.","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Lyons","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9245-8278","authenticated-orcid":false,"given":"Robert A.","family":"Rissman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy A.","family":"Elman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol","family":"Franz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William S.","family":"Kremen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024072905050747000_2024.07.23.602498v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1566067"},{"issue":"1","key":"2024072905050747000_2024.07.23.602498v1.2","first-page":"356","article-title":"The heritability of blood-based biomarkers related to risk of Alzheimer\u2019s Disease in a population-based sample of early old-age men","volume":"20","year":"2023","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2024072905050747000_2024.07.23.602498v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.1370110606"},{"key":"2024072905050747000_2024.07.23.602498v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/BF01067552"},{"key":"2024072905050747000_2024.07.23.602498v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.1370110607"},{"key":"2024072905050747000_2024.07.23.602498v1.6","doi-asserted-by":"publisher","DOI":"10.1023\/A:1025365325016"},{"key":"2024072905050747000_2024.07.23.602498v1.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2869.2012.01026.x"},{"key":"2024072905050747000_2024.07.23.602498v1.8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1017\/thg.2019.2","article-title":"umx: A library for Structural Equation and Twin Modelling in R","volume":"22","year":"2019","journal-title":"Twin Research and Human Genetics"},{"key":"2024072905050747000_2024.07.23.602498v1.9","unstructured":"R Development Core Team, R: A language and environment for statistical computing. 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