Precision Medicine Interventions in Alzheimer’s Disease (PMI-AD)

Alzheimer's disease (AD) is a devastating and incurable brain disorder causing the majority of dementia cases. AD slowly destroys memory, thinking and practical skills leading to complete dependency and deadth. AD is defined by common biological criteria and develops on a biological continuum where larger parts of the disease course runs before dementia including pre-clinical periods. Genetic risks and early disease pathways (mechanisms and cellular responses) differ between AD subgroups and likely will require precision-medicine (PM) approaches for successful interventions. PMI-AD exploits our world-leading technologies and competences to stratify early-stage AD patients employing a novel mechnistic pathway-to-therapeutic algorithm, resulting in cost-effective pathway-adapted diagnostics and therapeutics. PM can be delivered based on optimized diagnotic tools utilizing innovatieve pathways and prediction modelling.

Goal

AIM of this study was to identify the different subtypes of AD. The project aims to define the subtypes by cerebrospinal fluid (CSF) proteomics with Mass spectrometry analyses. Proteins in CSF are in a close contact to the brain and reflect disease processes related to Alzheimer's disease. 

Approach

Interestingly, inflammation and synapse loss are linked to premorbid genetic predispositions, and proteomic changes in cerebrospinal fluid and blood, and imaging changes, as seen e.g. with brain magnetic resonance techniques. Thus, PMI-AD will profile each patient for these types of changes, as a starting point for precision therapies. In parallel, the changes will be modelled in AD patient-derived (stem cell) immune- and nerve cell cultures, where effects of putative therapeutic interventions will be tested. The most promising therapies will be further tested in AD transgenic animal models, and adapted to therapeutic trials in patient cohorts stratified and targeted for stage, immune activation and synaptic affection. Lastly, impacts on societal health- and care costs will be calculated based on diagnostic and intervention-strategies needed for clinical implementation.

Results

In the project 1800 CSF samples are measured in individuals with AD, other types of dementia and in controls. We found 5 different subtypes: The subtypes had abnormalities in: 1. Outgrowth nerve cells, 2. Ignition, 3. Protein production, 4. Choroid plexus and 5. blood-brain barrier. By measuring the proteins, a better picture can be obtained of the disease changes in Alzheimer's disease. One finding is that each subtype may need a different treatment. We found that the subtypes were related to hereditary predisposition and the rate of deterioration of the disease. The differences in genetic factors suggest that the subtypes do not reflect disease severity but a specific underlying disease mechanism. This means that each subtype may need a different treatment . The differences in clinical markers show that the rate of decline and mortality differ between the subtypes.