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

ABSTRACT: Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer's disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10^-8, β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.

SUBMITTER: Ramanan VK

PROVIDER: S-EPMC7986461 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Twin studies indicate that genetic and environmental factors contribute to both psychological resilience and coping style, but estimates of their relative molecular and shared environmental contributions are limited. The degree of overlap in the genetic architectures of these traits is also unclear. Methods: Using data from a large population- and family-based cohort Generation Scotland (N = 8,734), we estimated the genetic and shared environmental variance components for resilience, task-, emotion-, and avoidance-oriented coping style in a linear mixed model (LMM). Bivariate LMM analyses were used to estimate the genetic correlations between these traits. Resilience and coping style were measured using the Brief Resilience Scale and Coping Inventory for Stressful Situations, respectively. Results: The greatest proportion of the phenotypic variance in resilience remained unexplained, although significant contributions from common genetic variants and family-shared environment were found. Both task- and avoidance-oriented coping had significant contributions from common genetic variants, sibling- and couple-shared environments, variance in emotion-oriented coping was attributable to common genetic variants, family- and couple-shared environments. The estimated correlation between resilience and emotion-oriented coping was high for both common-variant-associated genetic effects (r G = -0.79, se = 0.19), and for the additional genetic effects from the pedigree (r K = -0.94, se = 0.30). Genetic correlations between resilience and task- and avoidance-oriented coping did not meet statistical significance. Conclusions: Both genetics and shared environmental effects were major contributing factors to coping style, whilst the variance in resilience remains largely unexplained. Strong genetic overlap between resilience and emotion-oriented coping suggests a relationship whereby genetic factors that increase negative emotionality also lead to decreased resilience. We suggest that genome-wide family-based studies of resilience and coping may help to elucidate tractable methodologies to identify genetic architectures and modifiable environmental risk factors to protect against psychiatric illness, although further work with larger sample sizes is needed.

Project description:OBJECTIVE:To investigate the multifactorial processes underlying cognitive aging based on the hypothesis that multiple causal pathways and mechanisms (amyloid, vascular, and resilience) influence longitudinal cognitive decline in each individual through worsening brain health. METHODS:We identified 1,230 elderly subjects (aged ?50?years) with an average of 4.9?years of clinical follow-up and with amyloid positron emission tomography, diffusion tensor imaging, and structural magnetic resonance imaging scans from the population-based Mayo Clinic Study of Aging. We examined imaging markers of amyloid and brain health (white matter microstructural integrity and cortical thinning), systemic vascular health preceding the imaging markers, and early to midlife intellectual enrichment to predict longitudinal cognitive trajectories. We used latent growth curve models for modeling longitudinal cognitive decline. RESULTS:All the pathways (amyloid, vascular, resilience) converged through their effects on cortical thinning and worsening cognition and together explained patterns in cognitive decline. Resilience and vascular pathways (aging process, sex differences, education/occupation, and systemic vascular health) had significant impact on white matter microstructural integrity. Education/occupation levels contributed to white matter integrity through systemic vascular health. Worsening white matter integrity contributed to significant cortical thinning and subsequently longitudinal cognitive decline. Baseline amyloidosis contributed to a significant proportion of cognitive decline that accelerated with longer follow-up times, and its primary impact was through cortical thinning. INTERPRETATION:We developed an integrated framework to help explain the dynamic and complex process of cognitive aging by considering key causal pathways. Such an approach is important for both better comprehension of cognitive aging processes and will aid in the development of successful intervention strategies. ANN NEUROL 2019;86:866-877.

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

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