|
Project Topic
|
Preventing dementia and Alzheimer disease (AD) is a global priority. Dementia pathogenesis is
complex and multifactorial, with abnormalities in multiple cellular and molecular pathways that result from multifaceted
interactions between several (non)modifiable risk factors. Currently available single-mode-of-action interventions are
little effective to trigger a sustained clinically relevant benefit. However, this can be improved via combinations of
interventions (i.e. multimodal approach) applied early in the disease process to address more targets simultaneously
and trigger a stronger response from individual targets. Given the progressive nature of AD/dementia, some targets
may be more effectively addressed in different stages of the disease continuum therefore timing and sustainability
is another key mechanistic factor to be analysed.
Multi-MeMo aligns experimental molecular, cellular, and animal models with a very strong array of unique multinational multimodal human trials which have already demonstrated multi-year cognitive and functional benefits
across the entire continuum from at-risk to prodromal disease stages. This will allow comprehensive in-depth
analysis of multiple relevant molecular and cellular mechanisms that cannot be clarified from human trials alone, as
well as to rapidly validate the identified mechanisms for clinical relevance using successful long-term (up to 11
years) human trial data and samples. We hypothesise that multimodal interventions may exert their effects via a
combination of synergistic mechanisms, possibly amyloid/A and tau-related, but likely also unrelated or only indirectly
related to classical AD mechanisms (e.g. synaptic plasticity, inflammatory-immune responses, glucose/lipid
homeostasis and bioenergetic metabolism, promotion of neurotrophic factors and insulin signalling, vascular function,
stress hormone level alteration, and oxidative stress). Key questions we will address are e.g. if lifestyle intervention
actually modifies the AD pathological process itself; or if responsiveness to intervention depends on baseline biomarker
status and psychosocial factors, once AD has already started. We aim to identify individual targets and pathways,
and their complex interaction. This will be done either for a given intervention or combination of interventions. Specific
aims are to: (1) Identify the mechanistic basis for multimodal preventive interventions with experimental molecular,
cellular and animal models, including 2 species and 3 different neurodegeneration models, mirroring the human nonpharmacological trial design and interventions; (2) Validate the mechanistic basis for multimodal preventive
interventions with our unique set of human randomised controlled trials (samples and clinical data); (3) Based on the
mechanistic findings, to investigate the effectiveness window for targets addressed by the interventions studied, and
(4) identify personalized predictors (markers) of short-term (<2 years) and sustainable (long-term, up to 11 years)
intervention response. Moreover, (5) Investigate patient-centred psychological and social mechanisms in shorterand longer-term multimodal preventive interventions, including patient and public involvement (PPI) activities
throughout the project; and (6) Develop an enhanced, mechanistically driven multimodal intervention model,
compatible for combinations of pharmacological and non-pharmacological modalities that enhance each other’s effects.
Project results will ultimately lead to timely, personalised interventions to effectively prevent or delay dementia onset.
|
