# Brain network dynamics determine tau presence while regional vulnerability governs tau load in Alzheimer’s disease

## TL;DR

This study explores how tau spreads in Alzheimer's disease, finding that brain networks determine where tau appears, while individual factors affect how much tau accumulates.

## Contribution

The study introduces a multi-scale simulation framework to distinguish mechanisms governing tau presence and load in Alzheimer's disease.

## Key findings

- Tau presence is explained by synaptic spread and excitatory-inhibitory dynamics in brain networks.
- Tau load is influenced by regional factors like β-amyloid load, MAPT gene expression, and blood flow.
- Distinct brain networks and neurotransmitter systems are linked to different tau subtypes in Alzheimer's disease.

## Abstract

In Alzheimer’s disease (AD), tau pathology accumulates gradually throughout the brain, with clinical decline reflecting tau progression. A comprehensive understanding of, first, whether tau propagation is predominantly governed by connectome-based diffusion, regional vulnerability, or an interplay of both, and second, which types of brain connectivity or regional factors best explain tau propagation, remains crucial for advancing our understanding of AD progression. Here, we apply multi-scale, biologically informed disease progression simulations to human data, to disentangle the influence of local mechanisms on global tau progression patterns in AD. We find that whether tau reaches a brain region (presence) and how much tau accumulates there (load) are governed by different mechanisms. Tau presence patterns are highly consistent across the population, and can be largely explained through synaptic spread through white-matter networks and excitatory-inhibitory dynamics. Meanwhile tau load differs across people, and is driven by a combination of synaptic spread and intrinsic or extrinsic regional properties, including regional β-amyloid load, MAPT gene expression and regional blood flow. Finally, while distinct tau patterns in the population could each be explained by established AD mechanisms, our models highlight a role of distinct brain networks (parietal networks in MTL-sparing AD tau subtype) and neurotransmitter systems (cholinergic system in posterior subtype). Together, this work suggests that network dynamics likely determine the sequence of regional tau progression, while individual-specific tissue-vulnerability factors influence regional tau load.