AimsClinical trials in pre-symptomatic and prodromal AD are focused on pathology-biomarker positive (CSF/PET Amyloid-β) individuals. For therapeutic efficacy, individuals need to decline over the course of the trial on clinical endpoints (cognitive measures). Several genes have previously been associated with cognition, including APOE, KIBRA, KLOTHO, BDNF and COMT. The aim of this report is to elucidate if risk alleles within these genes can be suitably combined to predict cognitive decline in a pre-symptomatic population
Method174 biomarker positive (Aβ PET) pre-symptomatic AD participants from the Australian Imaging, Biomarker and Lifestyle (AIBL) study were evaluated. A decision tree was generated that combined genotypes from the aforementioned genes into a genetic risk profile. Cognitive decline was evaluated across six composites (Preclinical/Prodromal AD, Verbal/Visual Episodic Memory, Executive Function, Language) using linear mixed models to estimate the longitudinal trajectories.
ResultsA genetic risk profile encompassing four of the five genes (excluding COMT) elucidated four groups: ε4+ risk, ε4+ resilient, ε4- risk and ε4- resilient. The ε4+ risk group had significantly faster rates of cognitive decline than both ε4- groups for all composites and significantly faster rates than the ε4+ resilient group for all composites except Preclinical AD. The ε4- risk group declined faster than the ε4- resilient group on all composites.
ConclusionGenes previously associated with cognition grouped pre-symptomatic, biomarker positive AIBL participants into at-risk and resilient groups for cognitive decline. If validated this profile has potential utility in participant selection/stratification for pre-clinical AD trials where decline on clinical endpoints (cognition) is essential to determine therapeutic effectiveness.