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

Gillespie, N.; Neale, M. C.; Panizzon, M. S.; McKenzie, R. E.; Tu, X. M.; Reynolds, C. M.; Lyons, M. J.; Rissman, R. A.; Elman, J. A.; Franz, C. E.; Kremen, W. S.

doi:10.1101/2024.07.23.602498

bioRxiv · 10.1101/2024.07.23.602498

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

Gillespie, N.·Neale, M. C.·Panizzon, M. S.·McKenzie, R. E.·Tu, X. M.·Reynolds, C. M.·Lyons, M. J.·Rissman, R. A.·Elman, J. A.·Franz, C. E.·Kremen, W. S.

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Abstract

INTRODUCTIONThe amyloid cascade hypothesis predicts that amyloid-beta (A{beta}) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between A{beta}40 and A{beta}42 and total Tau (t-Tau) plasma biomarkers. METHODSPlasma A{beta}40, A{beta}42, 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{beta}s and t-Tau. RESULTSNo clear evidence that A{beta}40 or A{beta}42 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{beta} biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. DISCUSSIONPlasma A{beta}40 or A{beta}42 do not appear to have a direct causal impact on t-Tau. In contrast, A{beta} aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

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Gillespie, N., Neale, M. C., Panizzon, M. S., McKenzie, R. E., Tu, X. M., Reynolds, C. M., Lyons, M. J., Rissman, R. A., Elman, J. A., Franz, C. E., Kremen, W. S.. 2024-07-26. Testing the causal impact of amyloidosis on total Tau using a genetically informative sample of adult male twins.. https://doi.org/10.1101/2024.07.23.602498

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