|1) Target validation||
Demonstrate necessary or sufficient factors for developing AD pathology and disease (e.g. ApoE, TREM2, mutations in PSEN1, PSEN2, APP)|
Discover human variations that negate risk for AD (e.g. Icelandic and ApoE mutations)
Determine the atomic models of AD pathology for amyloid plaques and other associated pathologies (e.g. synapse and neuron loss, alpha-synuclein, TDP-43) as has been accomplished for tau tangles.
Identify the relationships between biological changes and consequences of amyloid, tau, and neurodegeneration changes as it relates to AD and clinical manifestation.
Diversified testing of tau targets and mechanisms are essential to addressing target validation.
|2) Animal and in vitro model development||
Simulate and model the different forms of tauopathies (AD vs. 4R tauopathies) to emulate the molecular and structural pathology present in each disease. Both in vitro and animal in vivo preclinical model studies need to match the disease to inform clinical trial design.|
Simulate and model Aβ amyloid plaque and other isoform changes with human AD stages. Implement standardization protocols for testing Aβ therapies by stage of disease to include primary prevention (pre-plaque), secondary prevention (plaque growth stage before tangles), symptomatic (fully established amyloid plaque load with downstream consequences in tau aggregation and neurodegeneration) in transgenic or other related in vivo models.
Create greater fidelity of AD in animal models: amyloid and tau co-pathology; specific ultrastructural conformation of AD tau and better recapitulate the sequence of stages, for example, soluble tau and p-tau changes in CSF and blood.
Develop models of AD inflammation and microglial activity that mimics the specific AD related inflammation and neurodegeneration.
Develop standard assays and techniques to measure drug effects on pathology, pharmacodynamics, and pharmacokinetics in animal and cellular models that are most directly translatable to human clinical studies.
Accelerate studies and programs of preclinical models that can test rational combinations with a focus on translating these to prevention trials. For example, removing amyloid while preventing the spread of tau pathology.
|3) Biomarker development||
Develop novel biomarkers that can track pre-clinical biological changes and distinguish stages of pre-clinical AD and predict future biological and clinical changes.|
Understand the relationship between currently available biomarkers and the pathophysiology of the AD process and how this relates to pathology and current and future clinical measures. For example, how do different phosphorylated tau species related to tau aggregation in the brain and to clinical onset and progression?
Improve understanding of biomarkers relation to clinical symptoms and age at onset. For example, track the longitudinal changes in amyloid-beta, soluble tau species vs. aggregated tau changes
|4) Prevention trial design||
Improve prevention trial screening accuracy through the development and implementation of cost-effective non-invasive biomarkers. What combination of biomarkers are optimal for identifying stage of disease, years to clinical onset and decline and prognostic of rates of decline?|
Identify stages of asymptomatic disease that match the pathophysiology with the intervention target. For example, intervening in tau spread during rapid tau aggregation growth, or blocking the amyloid-tau link before tau pathology becomes autonomous.
Develop sensitive cognitive measures aimed at demonstrating efficacy in the very earliest detectable stages of AD. Novel approaches may need to include rapid and frequent sampling and significantly complex cognitive tasks to accurately track asymptomatic cognitive dysfunction.