Potential biological targets for vascular dementia

Caused by damage to blood vessels in the brain, there is currently no approved treatment for vascular dementia. Could genetics-led approaches offer pathways to future therapies?

Potential biological targets that could help guide future research into treatments for vascular dementia have been identified in a study by UNSW Sydney’s Centre for Healthy Brain Ageing (CHeBA) that was funded by the Dementia Australia Research Foundation (DARF) Royce Simmons Project Grant and published open access (doi.org/10.1002/trc2.70258) in a journal of the Alzheimer’s Association, Alzheimer’s & Dementia: Translational Research & Clinical Interventions.

Vascular dementia is the second most common form of dementia worldwide, accounting for around 15–20% of all cases, and is caused by damage to blood vessels in the brain. Despite its prevalence and impact, currently, the condition has no approved treatments in Australia.

“Vascular dementia is a major and growing public health problem. It affects memory, thinking and function, yet we have no effective treatments to stop or slow its progression. Our study provides an initial step by identifying biologically plausible targets that could inform future research into therapies,” said lead author of the study Dr Matthew Lennon.

Genetic approach Mendelian randomisation was used in the study to analyse more than 12,000 potentially ‘druggable’ genes. Along with the proteins they produce, these genes could be targeted by medications. The team identified genes that may play a causal role in vascular dementia by examining large-scale genetic datasets from hundreds of thousands of individuals.

Four such genes were identified and linked to vascular dementia risk in the study. These were APOE and TOMM40 — well-established genes already known to play roles in brain health and dementia — and ERAP and SAA1-4 — linked to inflammation and immune processes, these are newer, emerging targets.

APOE and TOMM40 were the two strongest signals and associated with brain imaging markers of small vessel disease, a major contributor to both vascular dementia and Alzheimer’s disease. The researchers said this strengthens the evidence that these genes are involved in underlying disease processes.

As to the importance of this study, the researchers said that vascular dementia research has lagged behind research into diseases like Alzheimer’s disease, where several treatments exist and many more are in development — something that has left patients with limited options.

“Managing risk factors like blood pressure and cholesterol helps, but it’s not enough,” Lennon said. “Even under ideal conditions, prevention strategies may only reduce dementia risk by less than half. We urgently need new avenues for research into targeted treatments.”

It is believed that this gene identification may help inform future research aimed at drug development targeting pathways relevant to vascular dementia; exploration of whether existing medications acting on these genes could be repurposed; and advancing understanding of how vascular and Alzheimer’s disease processes overlap.

Yet, many potential drug targets do not ultimately lead to successful therapies, the researchers emphasised, and translating genetic findings into safe and effective treatments is a complex and lengthy process.

“At a time when vascular dementia remains a major unmet medical need, this study highlights the potential of genetics-led research to uncover new treatment pathways and bring hope for future therapies,” CHeBA Co-director Professor Perminder Sachdev said.

Laboratory studies, additional genetic analyses and clinical trials are among the further work that is needed, the researchers acknowledge, yet they also believe that the study constitutes an important lead for future drug development. “This is an important first step,” Lennon said. “By identifying potential targets, we can begin to better understand where future research and drug development efforts might be directed.”

Image credit: iStock.com/Tonpor Kasa. Stock image used is for illustrative purposes only.