Approximately 30% of older adults exhibit the neuropathological features of Alzheimer’s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer’s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10−20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10−4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer’s disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10−8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10−13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer’s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

Background Cognitive and brain reserve theories suggest that aspects of neural architecture or cognitive processes modify the impact of neuropathological processes on cognitive outcomes. While frequently studied in the context of dementia, reserve in delirium is relatively understudied. Methods We examined the association of three markers of brain reserve (head circumference, MRI-derived brain volume, and leisure time physical activity) and five markers of cognitive reserve (education, vocabulary, cognitive activities, cognitive demand of lifetime occupation, and interpersonal demand of lifetime occupation) and the risk of postoperative delirium in a prospective observational study of 566 older adults free of dementia undergoing scheduled surgery. Findings Twenty four percent of patients (135/566) developed delirium during the postoperative hospitalization period. Of the reserve markers examined, only the Wechsler Test of Adult Reading (WTAR) was significantly associated with the risk of delirium. A one-half standard deviation better performance on the WTAR was associated with a 38% reduction in delirium risk (P = 0·01); adjusted relative risk of 0·62, 95% confidence interval 0·45–0·85. Interpretation In this relatively large and well-designed study, most markers of reserve fail to predict delirium risk. The exception to this is the WTAR. Our findings suggest that the reserve markers that are important for delirium may be different from those considered to be important for dementia.

Background/Objectives To examine the baseline (preoperative) neuropsychological test performance in a cohort of elderly individuals undergoing elective surgery and the association between specific neuropsychological domains and post-operative delirium. Design/Setting/Participants An ongoing prospective cohort study of elderly patients (n=300) scheduled for elective (non-cardiac) surgery. Measurements Neuropsychological testing, including standardized assessments of memory, divided and sustained attention, speed of mental processing, verbal fluency, working memory, language, and an overall measure of premorbid cognitive functioning, was obtained 2-4 weeks prior to surgery. The relationship of the individual neuropsychological tests and delirium status was examined using linear regression, adjusting for age, gender and education. Results After adjustment, patients who developed post-operative delirium performed significantly lower pre-operatively on measures of speed of mental processing and divided attention (Trails Making Test B, mean difference=17.55, p=0.02), category fluency (animal naming, -1.94, p=0.01), sustained visual attention (Visual Search and ATtention, -3.19, p <0.001) and working memory with new learning and recall, (HVLT-R Total, -0.53 to -0.79, p <0.01). Conclusion Lower performance scores on tests evaluating the areas of complex attention, executive functioning, and rapid access to verbal knowledge or semantic networks are seen at baseline in patients who later develop delirium. Future studies to better understand how the identified cognitive profiles may predispose individuals towards developing delirium may help pave the way to greater understanding of the mechanisms of delirium.