Evaluation of Amyloid Protective Factors and Alzheimer Disease Neurodegeneration Protective Factors in Elderly Individuals

Abstract

Importance: While amyloid and neurodegeneration are viewed together as Alzheimer disease pathophysiology (ADP), the factors that influence amyloid and AD-pattern neurodegeneration may be considerably different. Protection from these ADP factors may be important for aging without significant ADP.

Objective: To identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration in a population-based sample and to test the hypothesis that "exceptional agers" with advanced ages do not have significant ADP because they have protective factors for amyloid and neurodegeneration.

Design, setting, and participants: This cohort study conducted a prospective analysis of 942 elderly individuals (70-≥90 years) with magnetic resonance imaging and Pittsburgh compound B-positron emission tomography scans enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota. We operationalized "exceptional aging" without ADP by considering individuals 85 years or older to be without significant evidence of ADP.

Main outcomes and measures: We evaluated predictors including demographics, APOE, intellectual enrichment, midlife risk factors (physical inactivity, obesity, smoking, diabetes, hypertension, and dyslipidemia), and the total number of late-life cardiac and metabolic conditions. We used multivariate linear regression models to identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration. Using a subsample of the cohort 85 years of age or older, we computed Cohen d-based effect size estimations to compare the quantitative strength of each predictor variable in their contribution with exceptional aging without ADP.

Results: The study participants included 423 (45%) women and the average age of participants was 79.7 (5.9) years. Apart from demographics and the APOE genotype, only midlife dyslipidemia was associated with amyloid deposition. Obesity, smoking, diabetes, hypertension, and cardiac and metabolic conditions, but not intellectual enrichment, were associated with greater AD-pattern neurodegeneration. In the 85 years or older cohort, the Cohen d results showed small to moderate effects (effect sizes > 0.2) of several variables except job score and midlife hypertension in predicting exceptional aging without ADP.

Conclusions and relevance: The protective factors that influence amyloid and AD-pattern neurodegeneration are different. "Exceptional aging" without ADP may be possible with a greater number of protective factors across the lifespan but warrants further investigation.

Figure 1.. Summary of the Study Findings

The outcome variables (amyloid deposition and neurodegeneration in Alzheimer disease [AD] signature regions) are shown in the boxes. Solid arrows are shown from the significant predictor variables to the outcomes based on the study data. The dashed line indicates the widely accepted relationship between the 2 outcome variables.

Figure 2.. Trajectory Models for Amyloid and Neurodegeneration in Alzheimer Disease Signature Regions

A, Average trajectories for Alzheimer disease pathophysiology without protective factors. The horizontal line indicates biomarker positivity. B, High protection against amyloid and average/low/high protection against neurodegeneration in Alzheimer disease signature regions. The horizontal line indicates biomarker positivity.