Imagine a puzzle with thousands of tiny pieces, each representing a different aspect of cognitive impairment in older adults. In a groundbreaking study, scientists set out to solve this challenging puzzle and shed light on the causes of this debilitating condition. By examining a group of long-living adults aged 90+, the researchers used advanced techniques to uncover key genetic factors that contribute to cognitive decline. These factors were identified through a genome-wide association study, which explored the relationship between specific gene variations and cognitive status. The study revealed a well-known marker of dementia, a polymorphism called rs429358 in the APOE gene. Further investigations using molecular modeling showed how this genetic variation affects the structure of an important protein called APOE, potentially playing a role in cognitive impairment development. However, it’s not just this single genetic variation alone that determines cognitive decline. The study also introduced the concept of polygenic risk scores (PRS) – a collection of multiple genetic variations that collectively contribute to an individual’s susceptibility to cognitive impairment. This comprehensive approach highlights the multifactorial nature of cognitive decline and paves the way for future early detection strategies. To dive deeper into this intriguing research, check out the full article!

BackgroundCognitive impairment is an irreversible, aging-associated condition that robs people of their independence. The purpose of this study was to investigate possible causes of this condition and propose preventive options.MethodsWe assessed cognitive status in long-living adults aged 90+ (n = 2,559) and performed a genome wide association study using two sets of variables: Mini-Mental State Examination scores as a continuous variable (linear regression) and cognitive status as a binary variable (> 24, no cognitive impairment; <10, impairment) (logistic regression).ResultsBoth variations yielded the same polymorphisms, including a well-known marker of dementia, rs429358in the APOE gene. Molecular dynamics simulations showed that this polymorphism leads to changes in the structure of alpha helices and the mobility of the lipid-binding domain in the APOE protein.ConclusionThese changes, along with higher LDL and total cholesterol levels, could be the mechanism underlying the development of cognitive impairment in older adults. However, this polymorphism is not the only determining factor in cognitive impairment. The polygenic risk score model included 45 polymorphisms (ROC AUC 69%), further confirming the multifactorial nature of this condition. Our findings, particularly the results of PRS modeling, could contribute to the development of early detection strategies for predisposition to cognitive impairment in older adults.

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