A novel approach to resilience and its links with education and Alzheimer's disease genetics
Maria Carrigan (Swammerdam Institute for Life Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam)
Diana I. Bocancea (Vrije Universiteit Amsterdam, Amsterdam UMC)
Jacob Vogel (Lund University)
Anna C. van Loenhoud (Vrije Universiteit Amsterdam)
N. Tesi (Vrije Universiteit Amsterdam, TU Delft - Pattern Recognition and Bioinformatics)
F. Barkhof (Vrije Universiteit Amsterdam, University College London)
Paul J. Lucassen (Swammerdam Institute for Life Sciences)
S.J. van der Lee (Vrije Universiteit Amsterdam, TU Delft - Pattern Recognition and Bioinformatics, Alzheimer Center Amsterdam)
Rik Ossenkoppele (Lund University, Vrije Universiteit Amsterdam)
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Abstract
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 (βmeta-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.
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