What are the relative contributions of different brain changes to the development of dementia?
Dementia Frontiers Fund Research Question
Context
Alzheimer’s disease and related dementias are now recognised as multifactorial disorders characterised by diverse and co-occurring pathologies, including Aβ, tau, TDP-43, Lewy bodies, neuroinflammation, and vascular changes. These interacting pathological processes influence symptom presentation, disease progression, and therapeutic response.
Challenges
Despite progress in biomarker development, characterising co-pathologies still relies heavily on post-mortem data. In vivo detection of non-AD pathologies like TDP-43 or vascular injury remains limited, and the mechanisms by which these co-pathologies interact and influence symptoms are poorly understood. Current tools and models do not adequately capture this complexity, and most treatments continue to target single pathological processes, limiting their effectiveness in real-world, mixed-pathology cases.
Opportunities & Expertise
New technologies - such as blood-based biomarkers, advanced imaging, and omics platforms - enable detection and characterisation of co-pathologies in living individuals. These approaches support patient stratification based on distinct pathological profiles and could guide the development of multi-targeted or combination therapies tailored to individual disease biology.
Tackling this question may benefit from an interdisciplinary team that brings together diverse areas of expertise, which could include neuropathology, neuroimmunology, and vascular biology to advanced neuroimaging, multi-omics, and fluid biomarker development. Contributions from fields such as pharmacology, medicinal chemistry, and computational modelling may also support the translation of insights into novel therapeutic strategies.
Impact
This topic will help uncover the role of multiple pathologies, how they interact and contribute to disease onset and progression. Based on this understanding, strategies targeting multiple disease mechanisms through combination therapies could be developed. This may also shift the field towards precision medicine, tailoring interventions to an individual’s unique pathological profile and using biomarker-stratification based on co-pathologies to reduce population heterogeneity and improve trial outcomes.
Plain English Summary
Dementia is more than just a build-up of proteins like amyloid and tau. Other changes like inflammation and blood vessel damage also play a role, but we don’t yet know how these changes interact, or which ones matter most. Without this knowledge, we risk creating treatments that only tackle part of the problem. By learning how these changes are linked, we can start to develop better treatments that target the whole disease rather than just one aspect of it, ultimately leading to more effective treatments for people affected by dementia.