Amyloid, Vascular, and Resilience Pathways Associated with Cognitive Aging

Abstract

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.

Figure 1

(Top panel) Two‐panel model showing the impact of worsening white matter microstructural changes as measured by genu fractional anisotropy (FA) on future neurodegeneration. The values shown by the arrows indicating significance refer to the estimate, standard error in parentheses, and p value. (Bottom panel) Plot of baseline genu FA versus thickness at first follow‐up after adjusting for baseline thickness.

Figure 2

Final model with significant associations at p < 0.05 shown by the arrows. Whereas arrows originating from age, sex, APOE4 status, and cycle number are shown in gray, the solid black arrows show the impact of the primary predictors. The amyloid pathway is shown by the red box, the resilience and vascular pathway are shown by the blue boxes, and the purple boxes show the variables where the pathways converge. FA = fractional anisotropy.

Figure 3

Resilience and vascular health pathways showing the impact of age, sex, education/occupation, and systemic vascular health on white matter microstructure as measured by genu fractional anisotropy (FA). The values shown by the arrows indicating significance refer to the estimate, standard error in parentheses, and p value.

Figure 4

The cognition trajectories for a 75‐year‐old male APOE4 carrier with mean education/occupation at high and low levels of genu fractional anisotropy (FA) and amyloid deposition defined by 20th and 80th percentiles.

Figure 5

Complex process of cognitive aging. Red curves show worse values for all predictors (low education/occupation, high amyloid burden, low genu fractional anisotropy [FA]), and blue curves show the better values for all predictors (high education/occupation, low amyloid burden, high genu FA). Plots are shown for males versus females as well as APOE4 carriers versus APOE4 noncarriers. SUVR = standardized uptake value ratio. [Correction added on 25 October 2019, after first online publication: There was an error in the table portion at the bottom of Figure 5. The age range in the 3rd column has been changed from 60‐60 to 60‐69.]