Why are some high-risk populations resilient to dementia?
Dementia Frontiers Fund Research Question
Context
The brains of some individuals have the capacity to maintain cognition and function with ageing and risk factors, or in the presence disease pathology (resilience). This suggests that there may be genetic, environmental, and lifestyle factors that protect against or delay cognitive decline, challenging the idea that pathology always leads to dementia.
Challenges
People with similar pathology can experience very different cognitive outcomes. While genes beyond APOE and lifestyle factors like education or activity levels appear to play a role, the biological mechanisms remain unclear. There are no reliable biomarkers to detect resilience in living individuals, and most insights come from post-mortem studies, limiting our understanding of how resilience develops or changes over time.
Opportunities & Expertise
Understanding the biology of resilience could lead to therapies that preserve cognitive function despite pathology. Existing drugs targeting inflammation, mitochondria, or protein clearance might be repurposed. Advances in genetics may improve risk prediction and personalise prevention. Developing resilience biomarkers would also enable earlier identification and tracking of protective mechanisms.
Addressing this question may benefit from an interdisciplinary team that brings together diverse areas of expertise including ageing biology, genetics, cognitive neuroscience, epidemiology, among others. Insights from biomarker development and drug discovery could also play an important role in uncovering protective mechanisms and exploring their therapeutic potential.
Impact
This topic will help uncover the underlying mechanisms that allow some individuals to avoid cognitive decline, despite ageing, risk factors, or even the presence of disease pathology in their brains. These findings could support early, targeted interventions to delay or prevent dementia, and inform future treatments that focus not only on reducing pathology, but also on enhancing the brain’s ability to cope with it - helping individuals maintain cognitive health even in the presence of disease.
Plain English Summary
Some people live to an advanced age without ever developing symptoms of dementia, despite having known risk factors - we have no idea why. If we can understand why certain individuals show hallmarks of dementia in the brain but never develop symptoms, it would open up entirely new avenues for treatment, potentially helping us prevent the disease before it ever begins.