Prevention of cognitive decline with early diagnosis and multicomponent interventions

Dementia is a growing global public health challenge, but a substantial proportion of cases may be delayed or prevented by addressing modifiable risk factors across the life course. This PhD thesis focuses on dementia prevention through early diagnosis and tailored multidomain interventions, within the Age-It program funded by the Italian Piano Nazionale di Ripresa e Resilienza (PNRR), and specifically within Spoke 8, dedicated to multicomponent strategies to reduce age-related diseases and disabilities. The first part of the thesis addresses early diagnosis, investigating the role of plasma biomarkers of Alzheimer’s disease across different clinical settings. Using data from memory clinic cohorts and international studies in individuals with mild cognitive impairment, dementia, and subjective cognitive decline (SCD), we show that plasma biomarkers—particularly p-tau217—demonstrate good diagnostic performance. In MCI and dementia, they may support diagnostic confirmation, reserving cerebrospinal fluid testing for uncertain cases. In SCD, plasma biomarkers show high negative predictive value, supporting their use primarily to rule out Alzheimer’s disease. These findings also highlight the marked heterogeneity of SCD, with a substantial subset showing biological evidence of Alzheimer’s pathology and increased dementia risk. The second part focuses on preventive interventions. Results from a board-game–based cognitive and social intervention did not demonstrate significant cognitive benefits in individuals with MCI or SCD, although improvements in depressive symptoms were observed, likely reflecting social engagement. Finally, the thesis presents the protocols of two ongoing studies: MEMO, evaluating mnemonic techniques for cognitive enhancement in SCD, and In-TeMPO, a large multicenter multidomain intervention inspired by the FINGER trial. Overall, this work supports the integration of plasma biomarkers into preventive clinical pathways and contributes to the development of personalized multidomain strategies for dementia prevention.\