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Project Topic
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Late onset Alzheimer’s disease (AD) may have a long natural history and the search for peripheral biomarkers that could be used for screening in the preclinical phase of the disease is a major challenge. Ageing is the major risk factor for AD and the most recent conceptualizations of ageing and age-related diseases, including neurodegeneration and AD, indicate that they share basic mechanisms, e.g. (neuro)- INFLAMMAGING. Thus, to better understand AD pathogenesis and to identify such early biomarkers capable of distinguishing AD from physiological ageing without dementia, it is mandatory to fully posit AD within the framework of ageing process and to study LONGITUDINAL COHORTS OF PRESYMPTOMATIC INDIVIDUALS. The main goal of ADAGE is to identify preclinical circulating biomarkers deviating from healthy ageing trajectories towards AD. To this aim the project will adopt the innovative strategy of comparing extreme phenotypes, i.e. blood samples from AD patients collected years before the clinical onset of the disease versus blood samples from DEMENTIA-FREE CENTENARIANS (100+) and their offspring (CO), and HEALTHY NONAGENARIAN SIBLINGS (90+ sibs) characterized by familial longevity, who maintain a good cognitive status despite their very advanced age. Accordingly, ADAGE will exploit unique, large and very informative EXISTING COHORTS where biomaterials (blood, plasma, serum and brains) are available and whole genome genetic and epigenetic studies (as well other omics investigations) have been recently performed: i) old TWINS OF THE SWEDISH TWIN REGISTRY (STR) FOLLOWED LONGITUDINALLY FOR >45 YEARS, assessed for lifestyle, cognitive status and exposure to toxicants. Here, incident and prevalent cases of AD DISCORDANT TWINS have been identified, blood/serum/plasma have been collected at different time points before AD clinical manifestation and post-mortem brains are available; ii) 100+ and their CO as well as 90+ sibs as gold standard of healthy ageing, who have never shown any signs of cognitive disability/decline and are fully characterized phenotypically and with a variety of omics, including genetics and epigenetics. In these cohorts, ADAGE will perform a metanalysis of existing omics data, an analysis of circulating proteome (several hundred proteins) and metabolome integrated by studies on circulating miRNA, advanced flow cytometry and an in depth neuropathological analysis of AD versus normal old brains, focused on markers of inflammation/cell senescence, to be correlated with cognitive status and omic data. In a consistent subgroup of AD patients and controls where both blood and CSF is available an in depth analysis (proteomics, metabolomics) of the two fluids will be performed. representing a. This approach will allow to validate the results obtained in peripheral specimens in the other cohorts but also to identify new combined CSF and blood AD signature(s). On the whole, ADAGE has the potential to identify new molecular biomarkers of cognitive aging as well new risk and protective factors for dementia on bench to bedside translational level (diagnostic and druggable targets).
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