Centenarians and oldest olds in Liguria – COOL: A multidisciplinary cohort study to investigate the genetic determinants of cognitive well-being in Genoa, Italy. Rationale, study protocol and baseline cohort profile

BACKGROUND: Despite the body of literature on genetic risk factors for dementia, little is known on protective genetic factors associated with favourable cognitive ageing in the oldest population. In Europe, Italy has a leading position with a swelling population of centenarians, and the urban area of Genoa in the Liguria region has one of the highest prevalences of centenarians. The COOL study is aimed at the identification of genomic biomarkers associated with cognition in the oldest old population. Here we report the development of the study protocol and the interim descriptive analysis of the cohort. METHODS: The COOL study is a not-for-profit, multicentric, real-world cohort study on centenarians living in the Genoa area. Inclusion criteria are being aged >99 and having the capacity to give informed consent (with their legally authorised representative if appropriate). Participants underwent a semi-structured interview on personal, disease and family history, and a neuropsychological assessment of the main cognitive domains. The primary outcome measure is the cognitive profile, as assessed by MMSE or CDR. Recruitment started in June 2021. RESULTS: As of July 2025, we enrolled 88 centenarians (age range: 99-108, median 100.56) with and without cognitive impairment; 32 subjects were followed up. All participants were of Italian ancestry; 80.7% were female. The subset of individuals who could be ascertained for cognitive profile (n = 84) showed a wide range of cognitive health measures: CDR varied from 0 to 5 (median = 1; n = 64), MMSE interval 3-30 (median = 24; n = 52). Whole peripheral blood and DNA samples from 67 participants were stored. CONCLUSIONS: We showed that the protocol is feasible and agreeable to participants and their families. A comprehensive phenotype dataset was established, and DNA samples were stored for subsequent genomic analysis. Centenarians exhibited a broad spectrum of cognitive profiles, from preserved cognition to severe dementia. Some data were unavailable, which should be considered in light of the study design and the characteristics of the cohort. These findings will eventually allow investigation of the profiles of genomic variants associated with variability in cognitive performance in centenarians.