Precision Medicine Interventions in Alzheimer’s Disease

The project has compiled a comprehensive database of pre-dementia cases with cognitive impairment (memory impairment, other thought-processes) based on existing studies from Norway, the Netherlands and Slovenia where more than 2000 patients have been followed for up to 6 years, with information on many types of examinations (clinical, neuropsychological, genetic, proteomic, imaging examinations). Based on these, an etiological diagnosis is prepared (disease diagnoses that give reasons for symptoms and disease). Clinical methodology is used, as well as traditional and new biomarkers, genetics and machine learning. In addition to disease diagnostics, the focus is on interactions with the immune system (innate immunity), synapse-related mechanisms and cerebrovascular mechanisms) as well as machine learning applied to large amounts of data to understand disease progression within the Alzheimer's group. Indicators are modeled in cell models to elucidate disease mechanisms, and clarify the selection of patient groups for targeted clinical studies based on identified disease mechanisms within the Alzheimer's spectrum. Clinical trials based on these mechanisms are delayed, mainly due to the COVID situation in Slovenia and Romania where this is to be implemented.

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AD is a devastating and incurable brain disorder causing the majority of dementia cases. AD is defined by common biological criteria and develops on a biological continuum where the disease course includes preclinical periods and starts long before dementia appears. Genetic risks and disease pathways differ between AD subgroups and precision-medicine (PM) approaches are required to develop successful interventions. The PMI-AD consortium will exploit our world-leading technologies and competences to stratify early-stage AD patients using novel mechanistic pathway-to-therapeutic algorithm to develop cost-effective, pathway-adapted diagnostics and early interventions to delay disease onset. We hypothesize that PM can be delivered based on optimized diagnostic tools utilizing innovative pathways and prediction modelling. PMI-AD will focus on Innate Immune (Ii)- and Synapse (S)-related genetics that are tightly coupled to AD risk and are frequently manifested as distinct phenotypes early in the disease. We will employ integrated clinical scores, Ii and S polygenic scores, fluid (blood, cerebrospinal) and MRI biomarkers in advanced statistical modelling using machine learning and deep-learning techniques for Ii and S pathway- and stage -stratification. Furthermore, we will test candidate substances in established experimental models (incl. patient-derived neuron-microglia cultures), to stratify patient groups and perform early therapeutic interventions. Early-stage and pre-clinical trials require use of focused medical nutrition and repurposed drugs with established safety profiles. We will perform cost assessments of health and care-impacts, and trans-European implementation. PMI-AD partners are world-leaders in genetics, biomarker development, machine learning, clinical trials and health economy. PMI-AD will cooperate closely with user-representatives and patient advocate groups to ensure maximal AD prevention effects at a European level.