Testing the causal impact of plasma amyloid on total Tau using a genetically informative sample of adult male twins

Nathan A Gillespie; Michael C Neale; Matthew S Panizzon; Ruth E McKenzie; Xin M Tu; Hong Xian; Chandra A Reynolds; Michael J Lyons; Robert A Rissman; Jeremy A Elman; Carol Franz; William S Kremen

doi:10.1016/j.nbas.2025.100139

Testing the causal impact of plasma amyloid on total Tau using a genetically informative sample of adult male twins

Aging Brain. 2025 May 17:7:100139. doi: 10.1016/j.nbas.2025.100139. eCollection 2025.

Authors

Nathan A Gillespie^{1

2}, Michael C Neale¹, Matthew S Panizzon^{3

4}, Ruth E McKenzie^{5

6}, Xin M Tu^{4

7}, Hong Xian^{8

9}, Chandra A Reynolds¹⁰, Michael J Lyons¹¹, Robert A Rissman^{3

4}, Jeremy A Elman^{3

4}, Carol Franz^{3

4}, William S Kremen^{3

4}

Affiliations

¹ Virginia Institute for Psychiatric and Behaviour Genetics, Department of Psychiatry, Virginia Commonwealth University, Box 980126, Richmond, VA 23298-0126, USA.
² QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4006, Australia.
³ Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
⁴ Department of Psychology, Boston University, 64 Cummington Mall, Boston, MA 02215, USA.
⁵ Winston School of Education and Social Policy at Merrimack College, 315 Turnpike Street, North Andover, MA 01845, USA.
⁶ Department of Family Medicine and Public Health, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
⁷ Department of Epidemiology and Biostatistics, Saint Louis University, 3545 Lafayette Ave, St. Louis, MO 63104, USA.
⁸ Research Service, VA St. Louis Healthcare System, 1 Jefferson Barracks Drive, St. Louis, MO 63125, USA.
⁹ Institute for Behavioral Genetics and Department of Psychology and Neuroscience, University of Colorado, Boulder, 1480 30th Street, Boulder, CO 80309, USA.
¹⁰ Department of Psychological and Brain Sciences, Boston University, 64 Cummington Mall, Boston, MA 02215, USA.
¹¹ Sam and Rose Stein Institute for Research on Aging, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Abstract

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.

Keywords: Amyloid-beta; Cascade hypothesis; Direction of causation; Gene; Plasma; Tau; Twin.

Abstract

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