A novel approach to resilience and its links with education and Alzheimer's disease genetics

Introduction: Cognitive resilience refers to maintaining cognitive function despite Alzheimer's disease (AD) pathophysiology.
Methods: We analyzed amyloid-positive individuals across clinical stages of AD in two cohorts: the Amsterdam Dementia Cohort (ADC, N = 1036) and Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 685). Cognitive resilience was conceptualized from a canonical correlation analysis of magnetic resonance imaging and neuropsychological data in each cohort separately. Model validation involved education as a resilience proxy and key genetic factors (apolipoprotein E [APOE] ε4 and APOE ε2) of AD. We explored associations between 83 AD risk loci and cognitive resilience.
Results: Resilience was correlated with education (ADC: β = 0.144, p < 0.001; ADNI: β = 0.149, p < 0.001) and APOE ε4 (β_{meta-analysis} = –0.052, p = 0.014). Exploratory single nucleotide polymorphism meta-analysis identified potential involvement of genetic variants around genes UNC5CL, USP6NL, and TPCN1 in lower, and genes COX7C and MINDY2 in higher resilience.
Discussion: Our novel resilience approach showed conceptual validity and potential for future discovery of resilience-related genetic variants.
Highlights
We define a novel approach to resilience using canonical      correlation analysis (CCA).
Apolipoprotein E ε4 is linked to lower resilience, suggesting increased vulnerability.
Genetic loci around COX7C and MINDY2 are potentially involved in higher resilience
This novel approach may be used for multi-cohort studies such as genome-wide association studies in the future.