Genetic resilience to amyloid related cognitive decline

Abstract

Preclinical Alzheimer's disease (AD) is characterized by amyloid deposition in the absence of overt clinical impairment. There is substantial heterogeneity in the long-term clinical outcomes among amyloid positive individuals, yet limited work has focused on identifying molecular factors driving resilience from amyloid-related cognitive impairment. We apply a recently developed predicted gene expression analysis (PrediXcan) to identify genes that modify the association between baseline amyloid deposition and longitudinal cognitive changes. Participants free of clinical AD (n = 631) were selected from the AD Neuroimaging Initiative (ADNI) who had a baseline positron emission tomography measure of amyloid deposition (quantified as a standard uptake value ratio), longitudinal neuropsychological data, and genetic data. PrediXcan was used to impute gene expression levels across 15 heart and brain tissues. Mixed effect regression models assessed the interaction between predicted gene expression levels and amyloid deposition on longitudinal cognitive outcomes. The predicted gene expression levels for two genes in the coronary artery (CNTLN, PROK1) and two genes in the atrial appendage (PRSS50, PROK1) interacted with amyloid deposition on episodic memory performance. The predicted gene expression levels for two additional genes (TMC4 in the basal ganglia and HMBS in the aorta) interacted with amyloid deposition on executive function performance. Post-hoc analyses provide additional validation of the HMBS and PROK1 effects across two independent subsets of ADNI using two additional metrics of amyloid deposition. These results highlight a subset of unique candidate genes of resilience and provide evidence that cell-cycle regulation, angiogenesis, and heme biosynthesis likely play a role in AD progression.

Keywords: Amyloid; Cognition; Genetics; PET; PrediXcan; Resilience.

Figure 1. Predicted Levels of PRSS50 in the Atrial Appendage Interact with Amyloid Levels in the Brain on Age-Related Change in Memory Performance

Age in years is along the x-axis, composite memory performance is along the y-axis. Individual lines represent fitted trajectories from the mixed-effects regression model. Amyloid positivity and PRSS50 expression groups were for illustration purposes only. Amyloid positivity was defined based on the established cut-point of 1.11 and PRSS50 expression was divided into tertiles. Panel A includes amyloid negative individuals and panel B includes amyloid positive individuals.

Figure 2. Predicted Levels of HMBS in the Aorta Interact with Amyloid Levels in the Brain on Age-Related Change in Executive Function

Age in years is along the x-axis, composite executive function performance is along the y-axis. Individual lines represent fitted trajectories from the mixed-effects regression model. Amyloid positivity and HMBS Expression Groups were for illustration purposes only. Amyloid positive was defined based on the established cut-point of 1.11 and HMBS expression was divided into tertiles. Panel A includes amyloid negative individuals and panel B includes amyloid positive individuals.