PURPOSE: To assess the longitudinal relationship between age-related macular degeneration (AMD) and allostatic load (AL), an established framework for quantifying the physiologic effects of chronic stress through measurements of systemic biomarkers. DESIGN: Retrospective case-control study. METHODS: Participants of the National Institutes of Health All of Us (AoU) Research Program with complete AL biomarker data between February 1985 to May 2022 and with (cases) or without (controls) AMD were identified. AL scores were calculated using the adapted Seeman AL scale consisting of 10 systemic biomarkers: body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, glomerular filtration rate, albumin, C-reactive protein, and homocysteine. AL score was defined as the number of biomarkers with measurements in the highest risk quartiles. Age was calculated as the median age at time of earliest or latest biomarker measurements. The main outcome was AMD status (AMD or non-AMD). Logistic regression models assessed the association between AL score and AMD after standardization of age and sex and adjustment for race/ethnicity and pack-years of cigarette smoking. Mediation analysis estimated the relationship between race/ethnicity and AMD as mediated by AL score. RESULTS: Among 1530 participants (221 cases, 1309 controls) with complete biomarker data, there were 44.6% males, 76.1% non-Hispanic Whites (NHWs), 18.6% other specified race/ethnicity (Asian, Black, or Hispanic race/ethnicity), and 5.3% unspecified race/ethnicity. AL scores measured a median of 9.0 (IQR=5.0-14.0) years prior to diagnosis were higher among cases compared to controls (Median [IQR] = 2 [2-4] versus 2 [1-3]
P = .02). On multivariable analysis, higher baseline AL score (OR=1.11) and greater pack-years (OR=1.15 per 10 pack-years) conferred higher risk of AMD (P ≤ .02). Mediation analysis revealed a significant indirect effect that increased risk of AMD among other specified race/ethnicity participants compared to NHW participants through higher AL score (OR=1.07 per unit [1.01-1.15]). CONCLUSION: All of Us participants diagnosed with AMD had greater AL score 9.0 years prior to AMD diagnosis. Chronic stress appears to increase risk for AMD and may contribute to racial/ethnic differences in disease prevalence.