From prevention to the etiopathogenetic and pathophysiological mechanisms of dementia: a paradigm shift in the biological continuum of cognitive decline. The PREV-ITA-DEM study

Alzheimer's disease and other dementias were the leading cause of Disability-adjusted life years among chronic non communicable diseases and affect 57.4 millions people worldwide, with very high economic and social costs. The Lancet Commission reports 12 modifiable risk factors for dementia: low education, hypertension, hearing impairment, smoking, midlife obesity, depression, physical inactivity, diabetes, social isolation, excessive alcohol consumption, head injury, and air pollution that account for around 40% of cases worldwide. This study proposes a paradigm shift by trying to identify new neurodegenerative mechanisms in the relationship between risk factors and brain aging. The hypothesis of this study is that the modifiable risk factors of the onset of dementia act first on aging associated biological elements like microglia and mitochondria dysfunction. Four national partners will be involved being representative of the national health care system and of South Italy, i.e. Istituto Superiore di Sanità (Roma), Fondazione Golgi Cenci (Abbiategrasso, Milano), Neuroepinet network (Palermo), Università del Salento (Lecce).
This project will have three relevant aims: From the epidemiological and clinical point of view, a) to characterize the frequency of the 12 modifiable risk factors recognized for dementia in the Italian population and the investigation of new factors proposed in the literature such as the Mediterranean diet, sleep disorders, vision impairment and COVID-19; b) to investigate the association between exposure (the selected known and new risk factors) and outcome (MCI or dementia), in the twins¿ paradigm c) to elaborate a cognitive risk score for the onset of MCI or dementia at an individual level d) to characterize the natural history of the mild cognitive impairment and dementia in relation to the modifiable risk factors. 2) From the experimental research point of view a) to use animal models, such as the murine model characterized by the overexpression of the human MutT homologue (hMTH1) and mice treated by b-amyloid peptide 42 to evaluate the possible interactions between risk factors and mechanisms of neurodegeneration b) to use cellular model of skin fibroblasts and plasma samples in order to analyze cellular pathways, organelle functionality and extracellular vesicles c) to use blood samples, collecting in "InveCe.Ab" (Brain Aging in Abbiategrasso) longitudinal population-based study, for the characterization of hallmarks of aging, through the analysis of genome instability, oxidative stress biomarkers, inflammation, and AD blood-based biomarkers, d) to use the bio-informatics approach to investigate possible new therapeutic intervention strategies 3) From the neuropathological point of view to analyze brains coming from clinically well-documented donors provided by Abbiategrasso Brain Bank; to assess the hypothesis that microglial changes may be a possible prerequisite for the development of tau deposition and synaptic dysfunction.
We believe that our project will allow to a) define targeted prevention strategies of dementia, b) elaborate a cognitive risk score at individual level c) identify patients who will have a more rapid progression of the disease compared to those with slower progression. The findings will allow to characterize new etiopathogenetic hypotheses useful for the development of new drugs in the treatment of dementia.