Association of Resilience-Related Life Experiences on Variability on Age of Onset in Dominantly Inherited Alzheimer Disease

Abstract

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 CSF_p-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, CSF_p-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 CSF_p-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 CSF_p-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.

Figure 1. Study Profile

AAO = age at symptom onset; DIAN = Dominantly Inherited Alzheimer Network; EYO = estimated years from expected symptom onset.

Figure 2. Determination of the Analytical Population in Cohort 1 (A and B) and Cohort 2 (C and D)

(A) Cohort 1. Interindividual variability in longitudinal CSF_p-tau181 levels plotted against estimated years from expected symptom onset (EYO) in 194 asymptomatic carriers (shown in red, 386 visits), 21 converters (shown in orange, 68 visits), and 64 symptomatic carriers (shown in blue, 161 visits) whose first visits were within 3 years from actual symptom onset and 202 asymptomatic noncarriers (shown in green, 406 visits). The vertical dashed line at 0 years represents the expected point of parental symptom onset. Negative EYO values represent the expected preclinical period. Positive values indicate the expected postclinical period. The vertical solid line at −20 years indicates the time point after which the SD of the distribution of CSF_p-tau181 levels at 2-year EYO intervals first started to be more than twice greater in pathogenic variation carriers than in noncarriers, according to the method described in (B). The horizontal dashed line indicates the CSF_p-tau181 pathology cutoff level (CSF_p-tau181 level of 51.52 pg/mL) at 2 SDs from the mean CSF_p-tau181 level in asymptomatic noncarriers across the entire EYO range. (B) Cohort 1. Interindividual variability in longitudinal CSF_p-tau181 levels, represented as the SD of the CSF_p-tau181 levels at 2-year EYO intervals, was plotted against the EYO for pathogenic variation carriers (194 asymptomatic carriers, 21 converters, and 64 symptomatic carriers) and 202 noncarriers. The vertical dashed line at −20 years indicates the time point from which the SD of the CSF_p-tau181 distribution at 2-year EYO intervals first started to be more than twice as high in pathogenic variation carriers than noncarriers. Because of the low number of participants with data points located at the extremes of the graph, the SDs of the CSF_p-tau181 levels for these participants in the time frame before the −30 EYO and after the +15 EYO were calculated as −35 EYO to −30 EYO (n = 3) and +15 EYO to +28 EYO (n = 15), respectively (additional data in eTable 4). (C) Cohort 2. The process of selecting the representative visit data for exposure and covariate (lifestyle, clinical, and pathology) variables among the multiple visits of individuals. The EYO range in which visits were most frequently and uniformly distributed before onset was −3.04 ± 3.21 EYO. Visit data from 2 outlier individuals (marked with an asterisk) were excluded from the subsequent analysis. (D) Cohort 2. The selected representative visits among multiple visits per participant included in the final analysis. After excluding visit data from 2 outlier participants (marked with an asterisk in Figure 2C), the EYO range in which visits were most frequently and uniformly distributed before onset was −2.45 ± 2.18 EYO. To minimize interindividual variance in EYO time points, we selected the 1 representative visit per participant nearest to the mean EYO (−2.45 EYO) among −2.45 ± 2.18 EYO; the mean of the chosen visits was −1.80 ± 1.08 EYO. The positive outcome group with 15 participants consisted of 11 asymptomatic carriers (purple dots) whose age at the last visit was equal to or greater than the parental age at symptom onset (AAO) and 4 converters (red dots) whose AAO was later than the parental AAO. The negative outcome group with 13 participants consisted of all converters (blue dots).

Figure 3. Three-Dimensional Visualization of Within-Individual Longitudinal Trajectories of Modifiable Life Experiences Over Estimated Years From EYO and CSF_p-tau181 Levels of the Entire DIAN Cohort According to the Disease Spectrum (A–D, F, G, and I–K) and the Resilience Status (E and H)

(A–E) Visualization of longitudinal collateral-reported conscientiousness over the estimated years from expected symptom onset (EYO) (A, C) and CSF_p-tau181 levels (B, D), with an overlaid least-squares best-fitting plane (C, D) of asymptomatic carriers (red) vs symptomatic carriers (blue). X: EYO, Y: CSF_p-tau181 levels, Z: collateral-reported conscientiousness. (E) Visualization of longitudinal collateral-reported conscientiousness over CSF_p-tau181 levels and EYO in the high-pathology subset (CSF_p-tau181 level ≥51.52 pg/mL) according to the resilience status. (F–H) Three-dimensional (3D) visualization of within-individual longitudinal trajectories of collateral-reported openness to experience over EYO (F) and CSF_p-tau181 levels (G), with an overlaid least-squares best-fitting plane, according to the disease spectrum and the resilience status (H). In the entire cohort and the subset of participants with high pathology, asymptomatic carriers showed greater overall longitudinal trends of collateral-reported conscientiousness and openness to experience than symptomatic carriers, during the expected preclinical period, as grossly estimated from a higher least-squares best-fitting plane in the conscientiousness or openness to lifestyle-axis direction. (I–K) Three-dimensional (3D) visualization of within-individual longitudinal trajectories of physical activity over CSF_p-tau181 levels and EYO of the entire DIAN cohort according to the disease spectrum. (I) Moderate-intensity (MET 3.0–5.9) exercise volume. (J) Total physical activity volume. (K) High-intensity (MET ≥6.0) exercise volume. For moderate-intensity exercise, asymptomatic carriers showed greater overall longitudinal trends in exercise volume than symptomatic carriers, and among asymptomatic carriers, participants with greater moderate-intensity exercise volume trended toward a lower degree of CSF_p-tau181 pathology. By contrast, for high-intensity exercise, because some symptomatic carriers had a high volume of high-intensity exercise that was comparable to or even greater than in asymptomatic carriers, there was no significant difference in exercise volume between asymptomatic and symptomatic carriers, as observed for moderate-intensity exercise. Model fitting was performed using the “Best-fit Surfaces for 3-Dimensional Data” code generating least-squared best-fit planes for 3-dimensional data using linear regression techniques (1st-order polynomials), provided by Patrick J. Wright from Inversion Labs (LLC, Wilson, WY; inversionlabs.com/2016/03/21/best-fit-surfaces-for-3-dimensional-data.html). In the 3D plane where the X-axis is the EYO, the Y-axis is the CSF p-tau level, and the Z-axis is the lifestyle data, the mesh grid surface (X_mg, Y_mg) with a 20*20 matrix size was extracted: $\mathrm{f}\left(\mathrm{x},\mathrm{y}\right)=\text{aX}\_\text{mg}+\text{bY}\_\text{mg}+\mathrm{c}$. Model fitting to estimate the constants (a, b, c) satisfying the least-squares solution for f(x,y) = Z was performed using the scipy.linalg.lstsq function in Python 3.9.12 and consequently produced surface plots with the estimated X_mg, Y_mg, and Z_linear: $\mathrm{Z}\_\text{linear}=\text{aX}\_\text{mg}+\text{bY}\_\text{mg}+\mathrm{c}$.