Researchers map key Alzheimer's protein in 196 patient scans

Tau is a protein that helps stabilise neurons. However, in Alzheimer’s disease, it begins to misfold and tangle inside neurons, spreading across the brain and forming toxic clumps that impair neuronal function and ultimately lead to cell death. Some brain areas, such as the hippocampus and entorhinal cortex, succumb early to ‘tau tangles’, while other parts of the brain, such as the primary sensory cortices, remain resilient to the disease.

Published this week in Brain, researchers from University of California San Francisco (UCSF) have created what they describe as a “Google Maps” for how tau moves in the brain of Alzheimer’s patients.

The study

The researchers set out to better understand the selective vulnerability (SV) or resilience (SR) to Alzheimer’s disease, described above. To do this, they looked to gene association and transgenic studies to identify Alzheimer’s risk genes; however, extant research had not shown a clear link between the location of genetic risk factors and associated tau pathology.

So, the researchers combined advanced mathematical modelling, brain imaging and genetics into a new lens, which revealed multiple distinct pathways by which risk genes confer vulnerability or resilience in Alzheimer’s disease. A model of disease spread called the extended Network Diffusion Model was applied by the researchers to brain scans from 196 individuals at various stages of Alzheimer’s.

When the researchers subtracted what the model predicted from what they saw in the scans, the leftovers — called “residual tau” — pointed to areas where something else besides brain connections influences the build-up of tau (in this case, genes). The researchers then tested the degree to which Alzheimer’s risk genes explain the patterns of both actual and residual tau, using brain gene expression maps from the Allen Human Brain Atlas.

Doing so allowed the team to tease apart genetic effects that act with or independently of the brain’s wiring. “We think of our model as Google Maps for tau,” said Dr Ashish Raj, a UCSF professor of Radiology and Biomedical Imaging and senior study author. “It predicts where the protein will likely go next, using real-world brain connection data from healthy people.”

Key findings

Four distinct gene types were uncovered based on how much and in what manner they were predictive of tau:

1. Network-Aligned Vulnerability (SV-NA) — genes that boost tau spread along the brain’s wiring;
2. Network-Independent Vulnerability (SV-NI) — genes that promote tau build-up in ways unrelated to connectivity;
3. Network-Aligned Resilience (SR-NA) — genes that help protect regions that are otherwise tau hotspots;
4. Network-Independent Resilience (SR-NI) — genes that, like hidden shields in unlikely spots, offer protection outside of the network’s usual path.

“Vulnerability-aligned genes dealt with stress, metabolism and cell death; resilience-related ones were involved in immune response and the clean-up of amyloid-beta — another Alzheimer’s culprit,” said Dr Chaitali Anand, a UCSF post-doctoral researcher and study first author. “In essence, the genes that make parts of the brain more or less likely to be affected by Alzheimer’s are working through different jobs — some controlling how tau moves, others dealing with internal defences or clean-up systems.”

Part of a larger project

This study built on an earlier study, also by UCSF and published in May in Alzheimer’s & Dementia. In that earlier study, which was in mice, the researchers demonstrated that rather than travelling randomly or diffusing passively, tau follows the brain’s wiring pathways with a distinct directional preference. The researchers, using a system of differential equations called the Network Diffusion Model (NDM), were able to show the dynamics of tau spread between connected brain regions, challenging the traditional view that tau spreads simply by diffusing through extracellular space or leaking from dying neurons.

“Our research showed that tau propagates trans-synaptically, travelling along axonal projections driven by active transport processes rather than passive diffusion, and exploiting active neural pathways in the preferred retrograde direction,” said Dr Justin Torok, a post-doctoral researcher working in the Raj lab. The existing approaches for validating and identifying gene-based determinants of selective vulnerability and resilience were, therefore, able to be complemented in the Brain study — through network-based analyses.

Genes that respond independently of the network were found in the latest study to have different biological functions from those genes that respond in concert with the network. “This study offers a hopeful map forward: one that blends biology and brain maps into a smarter strategy for understanding and eventually stopping Alzheimer’s disease,” Raj said on the more recent study’s significance. “Our findings offer new insights into vulnerability signatures in Alzheimer’s disease and may prove helpful in identifying potential intervention targets.”

**************************************************

‘Selective vulnerability and resilience to Alzheimer’s disease tauopathy as a function of genes and the connectome’ has been published open access in the July 2025 edition of Brain and you can read it at doi.org/10.1093/brain/awaf179.

**************************************************

Image credit: iStock.com/allanswart