A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer’s Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE ɛ4 Carriers

Abstract

Background Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk. Objective We organize three possible combinations into a “network” of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer’s disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: (1) Apolipoprotein E (APOE), (2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and (3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein). Method We use an accelerated longitudinal design (n = 634; age range = 55–95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (ε4+ versus ε4-). Results APOE ε4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOE ε4 carriers with low AD-GRS. Conclusions APOE ε4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differential predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.

A Multiomics Approach to Heterogeneity in Alzheimer’s Disease: Focused Review and Roadmap

“…was not certified by peer review) (which The copyright holder for this preprint this version posted October 10, 2019. . https://doi.org/10.1101/19008615 doi: medRxiv preprint prediction of cognitive trajectories and clinical outcomes have also been reported (Sapkota and Dixon, 2018).…”

From Polygenic Scores to Precision Medicine in Alzheimer’s Disease: A Systematic Review

“…Most studies were in healthy older adults, although two studies included participants with established AD/MCI [11,26], two studies had young adult participants [51,57], one study had adolescent participants [40] and one included longitudinal data from children aged 11 [59]. There were some cross-sectional studies that only reported associations with AD polygenic risk and cognition at one timepoint [40, 50-52, 54, 55, 57, 68], whereas longitudinal studies were able to report the correlations with change in cognition over time [11,26,31,33,36,44,45,56,60,[62][63][64]. As expected, most studies reported that the effects attenuated or were no longer significant when APOE was excluded from the PRS.…”

“…Of these, cognition has been the most widely investigated. While the methodology and samples were diverse, the vast majority of studies reported significant associations [11,26,31,33,36,40,44,45,50,52,54,56,60,63,64,68,69]. Of the negative studies, one used a threshold-based PRS [59] and another used a PRS including 15 Bonferronisignificant risk SNPs [39] but both excluded APOE entirely.…”

Impacts of CR1 genetic variants on cerebrospinal fluid and neuroimaging biomarkers in alzheimer’s disease

“…However, in spite of the progress in understanding risk factors related to AD development, the underlying mechanisms involved in this disease have not been completely understood till now, and to date there is no curative treatment for AD [5,6]. Now many genes are proved to significantly influence AD risk, among which the complement component (3b/4b) receptor 1 gene (CR1) has been proved to affect AD susceptibility across different ethnic and districts groups [7][8][9][10][11][12]. Currently, CR1 has been postulated to be a key factor for AD pathogenesis because of its role in regulating complement activity by acting as a receptor of complement C3b protein [13].…”