Testing the causal impact of plasma amyloid on total Tau using a genetically informative sample of adult male twins
The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. Plasma Aβ40, Aβ42, 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 Aβs and t-Tau. No clear evidence that Aβ40 or Aβ42 directly causes t-Tau was observed. Instead, the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau, though our use of total rather than phosphorylated tau was a limitation. In contrast, Aβ biomarkers appeared to causally impact NFL in cognitively unimpaired men in their late 60 s.
Authors
- Jeremy A. Elman (ORCID: https://orcid.org/0000-0002-5840-1769)
- Robert A. Rissman (ORCID: https://orcid.org/0000-0001-9245-8278)
- William S. Kremen (ORCID: https://orcid.org/0000-0002-8629-5609)
- Xin Tu (ORCID: https://orcid.org/0000-0001-6470-980X)
- Michael C. Neale (ORCID: https://orcid.org/0000-0003-4887-659X)
- Chandra A. Reynolds (ORCID: https://orcid.org/0000-0001-6502-7173)
- Nathan A. Gillespie (ORCID: https://orcid.org/0000-0001-8655-2823)
- Ruth McKenzie (ORCID: https://orcid.org/0000-0001-6973-4174)
- Michael J. Lyons (ORCID: https://orcid.org/0000-0001-6516-9219)
- Hong Xian (ORCID: https://orcid.org/0000-0002-7549-4880)
- Carol E. Franz (ORCID: https://orcid.org/0000-0002-8987-1755)
- Matthew S. Panizzon
Institutions
- Boston University (US)
- Virginia Commonwealth University (US)
- University of Colorado Boulder (US)
- QIMR Berghofer Medical Research Institute (AU)
- University of California San Diego (US)
- Merrimack College (US)
- Institute on Aging (US)
- VA St. Louis Health Care System (US)
- Saint Louis University (US)
Publication Details
- Journal
- Aging Brain
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.nbas.2025.100139
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- National Institute on Aging