PREADAPT: Identification of personalized inflammatory profiles of aging and senescence which are modified specifically by risk factors of dementia

Age represents by far the largest risk factor for dementia, including Alzheimer's disease (AD) dementia. However, not every person will develop dementia during aging. This indicates that age-related processes may not inescapably lead to dementia. Understanding the fundamental processes that occur during aging will likely offer new options to prevent or postpone the development of dementia. One such key mechanism is cellular senescence in which cells normally stop diving and also release of a senescence-associated secretory phenotype (SASP) profile of mediators which causes chronic inflammation. Several of the molecules included in SASP have been detected in fluids which are in direct contact with the brain raising the hypothesis that senescence and SASP is also occurring in brain cells during aging. PREADAPT will build on the hypothesis that chronic inflammation affects the path towards cell death, particularly in the brain. We will measure and quantified levels of SASP mediators, and will use information collected from this measurement to predict future cognitive decline and dementia. The levels and changes of these molecules are also affected by different genetic and environmental factors, which we will also use to generate a personalized risk profile for progressing to dementia. Members of the PREADAPT team have already conducted preliminary work to define a set of molecules believed to be important in this process. We will use a large number of pre-existing samples collected from older adults, and will integrate information about these molecules with known biological markers of Alzheimer's disease, and comorbidities to generate combined risk profiles. To achieve these goals, PREADAPT has gathered a team of leading experts in the field of neuroinflammation, epidemiology, genetics, epidemiological genetics, neuropsychology, and clinical research. The PREADAPT team has access to state-of-the-art methodology and to large studies where participants were observed over time, and studies that involved an intervention. A substantial amount of information was collected during these studies, which include brain imaging, genetic and other biological details. This unique configuration will enable PREADAPT to identify, before someone develops dementia, age-related profiles to inform their personalized future risk of progressing to dementia. PREADAPT will also provide the first evidence showing whether this personalized risk profile is altered by specific interventions by including several intervention cohorts.

Age is the largest risk for dementia, including Alzheimer's disease (AD). However, not every person develops dementia, indicating that age-related processes may not inescapably lead to dementia. The elucidation of the processes occurring in aging will likely offer new options to prevent or postpone development of dementia. One key mechanism is cellular senescence, which causes chronic inflammation through the release of a senescence-associated secretory phenotype (SASP) profile of mediators. PREADAPT builds on the hypothesis that chronic systemic inflammation and neuroinflammation, quantified through a set of SASP mediators, affects the trajectory of senescence occurring in the aging brain, thus allowing prediction of future cognitive decline and dementia. The levels and changes of SASP mediators during aging are modulated by different genetic and environmental factors, thus defining a personalized risk for dementia. By leveraging the individual variability of large existing aged samples, we aim to integrate SASP, genetics, known AD biomarkers, and comorbidities to generate combined risk profiles which will provide personalized information on risk of dementia. To achieve these goals, PREADAPT includes a team of experts in the field of neuroinflammation, epidemiology, genetics, epigenetics, neuropsychology, and clinical research. PREADAPT has access to state-of-the-art methodology and knowhow on inflammatory markers to define a set of SASP mediators derived from preliminary research done by PREADAPT members. PREADAPT also has access to large epidemiological and clinical follow-up studies that are characterized using neuroimaging, genomics, and proteomics. This unique configuration will enable PREADAPT to identify age-related profiles to inform the personalized future risk of cognitive decline and dementia. From a translational perspective, PREADAPT will also provide first evidence showing that a SASP personalized risk profile responds to specific intervention.

The dissemination channels outlined in the Communication Plan and Pathways to Impact will be used to share PREADAPT with our key stakeholders and beneficiaries which include:
Clinicians: Through our research on intervention cohorts, we will provide information to what extent such interventions lower the risk of dementia by modulating the risk profile of a patients and/or modulate delay the onset age. This information will include: a) relevant immune markers which could be analysed in peripheral blood to help identify patients who might be at-risk of dementia; b) how to improve the immune risk profile by non-pharmacological intervention such as nutrition, life style, control of comorbidities. This will be a starting point for planning future specific preventive and treatment trials evaluating efficacy and cost benefits.
Clinical chemists and immunologists: Our findings will be starting point for further studies optimizing diagnostic tests directed to peripheral pathways (blood) and to central pathways (CSF and imaging).
Pharmaceutical companies: Existing partnerships of PREADAPT partners with pharmaceutical companies will allow rapid dissemination and implementation of findings in the pharmaceutical industry.
Patients, patient organizations, and the general public: One main objective of PREADAPT is to explore whether specific interventions targeting pathways involved in AD and other dementia forms, modify the identified immune risk profiles. Thus, PREADAPT results have clear translational applications in regular clinical setups. In addition, several of the interventions are non-pharmacological involving lifestyle and nutritional changes which can be shared directly with patients, patient organizations and the general public.