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.

TNFRSF1B Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer's Disease

“…It is possible, therefore, that sTNFR2 and TNFRSF1B SNPs play a modulating role in regard to clinical outcomes in AD, rather than serving as an AD risk gene that have been the focus of prior genome-wide association studies in AD. This is consistent with prior reports of gene variants related to resilience in AD which suggest that genetic architecture of resilience appears to be distinct from that of clinical AD (Dumitrescu et al, 2020 ).…”

Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer’s pathophysiology

“…In examining published results from the largest available AD case–control GWAS [ 36 ], we cannot find evidence supporting an association of rs12056505 with lower risk of clinically diagnosed probable AD dementia ( p = 0.90, β = 0.997). Clinical diagnosis of AD dementia is by no means a proxy for resilience to AD pathology, and our data more broadly mirrors conclusions from a recent study on resilience in suggesting that the genetic architectures underlying these outcomes are likely to be meaningfully different [ 16 ]. Nevertheless, the lack of clear protective relationship of rs12056505 on clinical AD dementia diagnosis in published data is a limitation.…”

“…Although TOMM40 rs2075650 displayed nominal association within a basic model not accounting for APOE ɛ4 ( p = 0.001, β = -0.14), this association was attenuated in the GWAS which included APOE ɛ4 as a covariate ( p = 0.07, β = -0.11). Replication signal was not identified for SNPs reported in prior work to have associations with resilience proxy measures, including RAB10 (RAS oncogene family Rab10) rs142787485 ( p = 0.50, β = 0.03) [ 53 ], BDNF rs6265 ( p = 0.59, β = 0.02) [ 19 ], KL rs9536314 ( p = 0.44, β = 0.03) [ 6 ], and ATP8B1 (ATPase phospholipid transporting 8B1) rs2571244 ( p = 0.28, β = 0.05) [ 16 ].…”

“…Our findings nominate new targets which warrant further study of the underlying molecular processes which impact brain structure and metabolism, functional network connectivity, and neuronal and synaptic health, to ultimately account for differential coping with amyloid pathology well-validated AD biomarker (amyloid PET) and linear regression to model cognitive trajectories, approaches that can be straightforwardly applied to other datasets. However, the optimal approach to modeling resilience is still an active question, and alternative methods based on latent variables (estimating cognitive dysfunction in cross-sectional data over and above that expected from pathology) [16], gene expression data [21], and longitudinal linear mixed models [8] may provide complementary information. In addition, we assessed differential cognitive resilience through the lens of a continuous measure of rate of decline, and acknowledge that our findings may not be applicable to a paradigm whereby cognitive resilience is operationalized as a marker of clinical status (i.e., coping without impairment).…”

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

“…As in many other chronic diseases, AD risk can be influenced by multiple factors, such as age, gender, family history, brain injury, environment, and lifestyle. Notably, results from postmortem autopsy showed that about 30% of cognitively normal people present various signs of AD pathology in the brain ( Arenaza-Urquijo and Vemuri, 2018 ; Dumitrescu et al, 2020 ), raising the question of why some people have AD-like pathology but remain cognitively intact. Individual differences in overcoming adverse factors and thus maintaining a better performance can be a reason.…”