Abstract
Studies of Alzheimer’s disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSAPOE) or excluding APOE (emPRSAPOE). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer’s cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSAPOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSAPOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development.
Highlights
An improved understanding of the extended preclinical phase of Alzheimer’s disease (AD), has seen an increased focus on early disease intervention (Sperling et al, 2014)
We have previously reported that while an AD risk weighted PRS was associated with cognitive decline (Porter et al, 2018b), the association was only observed in carriers of the apolipoprotein E (APOE) ε4 allele
A participant was classified by a clinical review panel (Ellis et al, 2009), blinded to Aβ-amyloid status, as cognitively normal (CN) if they did not meet the clinical criteria for diagnosis of mild cognitive impairment (MCI) (Winblad et al, 2004) or dementia (McKhann et al, 1984)
Summary
An improved understanding of the extended preclinical phase of Alzheimer’s disease (AD), has seen an increased focus on early disease intervention (Sperling et al, 2014). Importance has been placed on investigating potential factors that could underpin the significant variability in cognitive decline between individuals in this early stage of the disease. Levels of Aβ alone do not track well with progressive cognitive decline and there is strong convergent evidence that variable rates of decline in the preclinical stages of AD may be influenced by genetic factors (Lim et al, 2015a,b; Porter et al, 2018a,c). Identification of genetic factors that contribute to accelerated rates of cognitive decline in at risk individuals will be of significant importance, through an increased understanding of potential mechanisms of preclinical decline and the identification of individuals most suitable for intervention trials
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