Genetic propensity for cerebral amyloidosis and risk of mild cognitive impairment and Alzheimer's disease within a cognitive reserve framework

Abstract

INTRODUCTIONWe constructed a polygenic risk score (PRS) for β‐amyloid (PRSAβ42) to proxy AD pathology and investigated its association with incident Alzheimer's disease (AD)/amnestic mild cognitive impairment (aMCI) and the influence of cognitive reserve (CR), proxied by educational years, on the relationship between PRSAβ42 and AD/aMCI risk.METHODSA total of 618 cognitive‐normal participants were followed‐up for 2.92 years. The association of PRSAβ42 and CR with AD/aMCI incidence was examined with COX models. Then we examined the additive interaction between PRSAβ42 and CR and the CR effect across participants with different PRSAβ42 levels.RESULTSHigher PRSAβ42 and CR were associated with a 33.9% higher risk and 8.3% less risk for AD/aMCI, respectively. An additive interaction between PRSAβ42 and CR was observed. High CR was associated with 62.6% less risk of AD/aMCI incidence only in the high‐PRSAβ42 group.DISCUSSIONA super‐additive effect of PRSAβ42 and CR on AD/aMCI risk was observed. CR influence was evident in participants with high PRSAβ42.

Cognitive resilience/reserve: Myth or reality? A review of definitions and measurement methods

“…Additionally, an additive interaction was observed between PRSAβ42 and CR, whereby individuals with high levels of CR and PRSAβ42 showed a 62.6% reduction in the risk of developing aMCI/AD compared to those with high levels of PRSAβ42 alone. 33 These findings provide support for the CR hypothesis, indicating that early-life education may lessen the impact of genetically mediated amyloid accumulation on the development of aMCI/AD.…”

“…Additionally, an additive interaction was observed between PRSAβ42 and CR, whereby individuals with high levels of CR and PRSAβ42 showed a 62.6% reduction in the risk of developing aMCI/AD compared to those with high levels of PRSAβ42 alone. 33 These findings provide support for the CR hypothesis, indicating that early‐life education may lessen the impact of genetically mediated amyloid accumulation on the development of aMCI/AD. These results have significant clinical implications, as they suggest that interventions designed to enhance CR, whether implemented early or later in life, could potentially delay cognitive decline and prevent AD, even in individuals at high genetic risk for amyloid brain pathology.…”

“…However, there is a contrasting finding where functional connectivity within the Default Mode Network decreases with increasing CR. In a recent study, the polygenic risk score for β‐amyloid (PRSAβ42) was utilized as a proxy for AD pathology 33 . The study aimed to explore the relationship between PRSAβ42 and the incidence of amnestic mild cognitive impairment (aMCI)/AD and examine the impact of CR (measured as education) on this association.…”

“…In a recent study, the polygenic risk score for β‐amyloid (PRSAβ42) was utilized as a proxy for AD pathology. 33 The study aimed to explore the relationship between PRSAβ42 and the incidence of amnestic mild cognitive impairment (aMCI)/AD and examine the impact of CR (measured as education) on this association. Educational years were used as a proxy for CR.…”

Genetic Predisposition for White Matter Hyperintensities and Risk of Mild Cognitive Impairment and Alzheimer’s Disease: Results from the HELIAD Study

“…Calling was generated by the 'Centre National de Recherche en Génétique Humaine' (Evry, France) using the data generated by the centers involved in genotyping (Life & Brain, Bonn, Germany, CNRGH, Evry, France and Erasmus Medical Center, Rotterdam, Netherlands) [29]. Further information regarding the genotyping and imputation in the HELIAD study have been described in a previously published work [30] and can be found in the Supplementary Materials.…”