Association of Resilience-Related Life Experiences on Variability on Age of Onset in Dominantly Inherited Alzheimer
Hye Joo Son1, Jae Seung Kim1, Randall J Bateman1
1From the Department of Nuclear Medicine (H.J.S., Jai-Hyuen Lee), Dankook University College of Medicine, Cheonan, Chung Nam; Department of Nuclear Medicine (J.S.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; Department of Neurology (R.J.B., J.J.L.-G., J.C.M., A.D.), Washington University School of Medicine, St. Louis, MO; Department of Clinical Epidemiology and Biostatistics (S.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; Department of Neurology (G.S.D.), Mayo Clinic College of Medicine and Science, Jacksonville, FL; Department of Neurology (J.P.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Neurology (S.B.B.), University of Pittsburgh School of Medicine, PA; Neuroscience Research Australia (P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales, Sydney, Australia; Department of Cellular Neurology (M.J.), Hertie Institute for Clinical Brain Research, University of Tübingen; German Center for Neurodegenerative Diseases (M.J.), Tübingen; Department of Neurology (J.L.), Ludwig-Maximilians-Universität München; German Center for Neurodegenerative Diseases (J.L.), Munich; Munich Cluster for Systems Neurology (SyNergy) (J.L.), Germany; Department of Neurology (Jae-Hong Lee), University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; Department of Pathology and Immunology (R.J.P.), Knight Alzheimer's Disease Research Center (R.J.P., J.H.), and Department of Neurology (R.J.P., J.H.), Washington University in St. Louis; Department of Psychiatry (C.C.), Washington University School of Medicine; Department of Psychological and Brain Sciences (J.H.), Washington University, St. Louis, MO; and Department of Neurology (S.P.S.), The Warren Alpert Medical School of Brown University, Butler Hospital, Providence, RI.
Background And Objectives:
It remains unknown whether the associations between protective lifestyles and sporadic dementia risk reported in observational studies also affect age at symptom onset (AAO) in autosomal dominant Alzheimer disease (ADAD) with predominant genetic influences. We investigated the associations between resilience-related life experiences and interindividual AAO variability in ADAD.
Methods:
We performed a longitudinal and confirmatory analysis of the Dominantly Inherited Alzheimer Network prospective observational cohort (January 2009-June 2018, follow-up duration 2.13 ± 2.22 years), involving clinical, CSF, and lifestyle/behavioral assessments. We performed a 2-pronged comprehensive resilience assessment in each cohort. Cohort 1, incorporating the general resilience definition (cognitive maintenance [Clinical Dementia Rating = 0] despite high pathology), included carriers during the periods of significant CSFp-tau181 variability and grouped into resilience/resistance outcome bins according to the dichotomous pathologic and cognitive statuses, subcategorized by the estimated years from expected symptom onset (EYO). Cohort 2, focused on ADAD-specific genetically determined time frame characterizing the onset predictability, included asymptomatic participants with available preclinical lifestyle data and AAO outcomes and grouped into delayed or earlier AAO relative to the parental AAO. Associations of cognitive, CSFp-tau181, and lifestyle/behavioral predictors with binary outcomes were investigated using logistic regression.
Results:
Of 320 carriers (age 38.19 ± 10.94 years, female 56.25%), cohort 1 included 218 participants (39.00 ± 9.37 years, 57.34%) and cohort 2 included 28 participants (43.34 ± 7.40 years, 71.43%). In cohort 1, 218 carriers after -20 EYO, when the interindividual variability (SD) of CSFp-tau181 first became more than twice greater in carriers than in noncarriers, were grouped into low-risk control (asymptomatic, low pathology, n = 103), high-resilience (asymptomatic despite high pathology, n = 60), low-resilience (symptomatic despite low pathology, n = 15), and susceptible control (symptomatic, high pathology, n = 40) groups. Multivariable predictors of high resilience, controlling for age and depression, included higher conscientiousness (odds ratio 1.051 [95% CI 1.016-1.086], p = 0.004), openness to experience (1.068 [1.005-1.135], p = 0.03) (vs. susceptible controls), and agreeableness (1.082 [1.015-1.153], p = 0.02) (vs. low resilience). From 1 to 3 years before parental AAO (cohort 2), the multivariable predictor of delayed AAO, controlling for CSFp-tau181, was higher conscientiousness (0.916 [0.845-0.994], p = 0.036).
Discussion:
Among the cognitively and socially integrated life experiences associated with resilience, measures of conscientiousness were useful indicators for evaluating resilience and predicting future dementia onset in late preclinical ADAD.
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