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

## TL;DR

This study examines whether plasma amyloid-beta levels cause changes in total tau in a sample of older men.

## Contribution

The study uses twin modeling to test causal relationships between plasma amyloid and tau biomarkers.

## Key findings

- No direct causal impact of Aβ40 or Aβ42 on t-Tau was observed.
- Aβ biomarkers showed a causal impact on neurofilament light chain (NFL).
- Reciprocal causation was found between t-Tau and NFL.

## 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.