Genetic variants and functional pathways associated with resilience to Alzheimer's disease

Abstract

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.

Keywords: Alzheimer’s disease; GWAS; amyloid; reserve; resilience.

Figure 1

Quantification of resilience metrics. Residuals from linear regression models in which a cognitive score was regressed on age, sex, and amyloid levels were extracted and entered as indicator variables in a partial least squares path model using established procedures. Combined resilience was quantified as a second order latent trait in the model in which educational attainment was included as an additional indicator variable. PACC = Preclinical Alzheimer Cognitive Composite.

Figure 2

Workflow of analytical activities. CU = cognitively unimpaired.

Figure 3

Genome-wide genetic covariance results. Genetic covariances between combined resilience and 67 complex traits. Error bars represent 95% confidence intervals. FWE-P: corrected P-value based on the family-wise error rate. BMI = body mass index; HDL = high density lipoprotein; LDL = low density lipoprotein; pvRSA HF = peak-valley respiratory sinus arrhythmia, high frequency power; RMSSD = root mean square of successive differences; SDNN = standard deviation of the NN interval (NN interval is the interval between two heart beats).

Figure 4

Variant-level resilience GWAS results. (A) Manhattan plot of results from the GWAS analysis of combined resilience. GWAS significance (5 × 10⁻⁸) is indicated by the red line, while suggestive significance (1 × 10⁻⁵) is indicated by the blue line. (B) LocusZoom plot of the GWAS-significant locus on chromosome 18. Colours denote linkage disequilibrium with the most statistically significant SNP. (C) Forest plot for the top SNP on chromosome 18 is presented demonstrating consistent direction and magnitude of effect across the autopsy and PET datasets and within the component cohorts. The summary estimate at the bottom indicates the meta-analysis of the autopsy and PET combined datasets. CI = confidence interval.

Figure 5

Functional annotation of resilience GWAS results. The minor allele of rs2571244 (T) is associated with decreased methylation at the CpG site cg19596477.