Association of Anticholinergic Drug Use With Risk for Late Age-Related Macular Degeneration

Abstract

IMPORTANCE Amyloid-β is a major component of retinal drusen, the primary lesions of age-related macular degeneration (AMD), and autopsy and animal models suggested that anticholinergic drug (ACD) use increased brain amyloid-β deposition. OBJECTIVE To investigate the association between exposure to ACDs and late AMD (features of neovascular AMD or geographic atrophy of the retinal pigment epithelium in at least 1 eye). DESIGN, SETTING AND PARTICIPANTS A multicenter case-control study in 4 French ophthalmologic centers comprising 200 cases with late AMD and 200 controls enrolled from July 2016 to June 2017. EXPOSURES Exposure to at least 3 months of ACDs started before AMD diagnosis was recorded during a specific interview. A dose-effect association with cumulative exposure duration and Anticholinergic Burden Score was explored. The association between ACD exposure and AMD was assessed by multivariate logistic regression analysis adjusted for age, sex, smoking status, family history of AMD, alcohol consumption, and use of anticoagulant and anti-inflammatory drugs. Odds ratios (ORs) and 95% confidence intervals were estimated. MAIN OUTCOMES AND MEASURES Association between exposure to ACDs and late AMD. RESULTS Among case participants, the mean (SD) age was 74.8 (9.2) years, 129 (64.5%) were women, 192 (96%) were white, 65 (32.5%) had geographic atrophy, 135 (67.5%) had neovascular AMD, 116 (58%) had unilateral AMD, and 84 (42%) had bilateral AMD. Among control participants, the mean (SD) age was 75.5 (7.2) years, with 116 (58%) women and 187 (93.5%) white participants. Twenty-six cases (13%) and 10 controls (5%) were exposed to ACDs throughout life for at least 3 months before AMD onset. Risk of AMD was increased with ever exposure to ACDs (adjusted OR [aOR], 2.84; 95% CI, 1.33-6.06; P = .007), high Anticholinergic Burden Score (Ն3) (aOR, 6.42; 95% CI, 1.38-29.92; P = .02), and longest cumulative exposure to ACD (Ն15 years) (aOR, 5.88; 95% CI, 1.22-28.31; P = .03). CONCLUSIONS AND RELEVANCE Risk of late AMD may be increased with at least 3 months' use of ACDs. A dose-effect association was suggested by a greater association with prolonged use and high Anticholinergic Burden Score. Further studies, in particular those with longitudinal design, are needed to confirm this association.

Quality of anticholinergic burden scales and their impact on clinical outcomes: a systematic review

“…The 104 validation studies consisted of 1 RCT (good quality) [ 98 ], 74 cohort studies (50 good and 24 poor quality) [ 33 – 36 , 41 , 44 , 54 , 55 , 57 , 59 , 61 – 66 , 70 – 75 , 77 , 78 , 80 , 81 , 83 – 97 , 100 , 103 – 108 , 112 – 115 , 117 , 119 , 120 , 123 , 124 , 129 , 131 – 137 , 139 , 141 – 146 , 148 , 149 ], 9 case-control studies (6 good, 1 fair and 2 poor quality) [ 56 , 67 – 69 , 102 , 110 , 118 , 130 , 147 ] and 20 cross-sectional studies (2 good and 18 poor quality) [ 39 , 53 , 58 , 60 , 76 , 79 , 82 , 99 , 101 , 109 , 111 , 116 , 121 , 122 , 125 – 128 , 138 , 140 ] (Appendix 6 ). More than half of the studies were judged to be of good quality (60 out of 104).…”

Dose-response association of metformin use and risk of age-related macular degeneration among patients with type 2 diabetes mellitus: a population-based study

“…Our findings showed that T2DM patients treated with metformin, older patients, and having a higher DCSI score linked to an increased risk of AMD. Previous studies have identified several risk factors for AMD, including aging, ocular disorders, systemic diseases, smoking, diet, genetic susceptibility, and environmental risk factors ( Lim et al, 2012 ), with aging being the strongest risk factor ( Aldebert et al, 2018 ). In the general population, vitamin B12 plasma levels decline with age, and thus, the prevalence of vitamin B12 deficiency increases with age.…”

Key Transcription Factors Linking Macular Degeneration and Alzheimer’s Disease

“…

The global prevalence of AMD in 2020 is projected to be 196 million people [1] and that of Alzheimer's disease was 50 million in 2017 [2]. Chronic oxidative stress and neuroinflammation from aging, injury, and individual risk factors (smoking, hypertension, arteriolosclerosis, obesity, dietary indiscretion, chronic anticholinergic use, and latent infection) in AMD and AD contribute to toxic protein deposits, loss of homeostatic protein clearance, and progressive neurodegeneration [3][4][5][6][7][8][9][10][11].Neuroinflammation also provokes persistent immune response, which participates in further brain and macular damage. However, studies using anti-inflammatory therapy in AD and in AMD have yielded small, mixed or inconclusive results [12][13][14][15].Toxic protein accumulation: in AMD, drusen, (lipoprotein deposits between the basal lamina and the retinal pigment epithelial layer, RPE) and lipofuscin (from inefficient protein clearance) [3,4,13] and in AD, extracellular and intracellular amyloid and complement and intracellular tau, (because of breakdown of the blood-brain barrier from reactive oxygen species, inflammation, or local or systemic infection), may be slow burners in chronic inflammation and its sequelae [5,6,16] However, cognitive issues, (memory and learning) in AD may precede amyloid plaque and tau fibrillar aggregates by months or longer [5].

…”

“…The global prevalence of AMD in 2020 is projected to be 196 million people [1] and that of Alzheimer's disease was 50 million in 2017 [2]. Chronic oxidative stress and neuroinflammation from aging, injury, and individual risk factors (smoking, hypertension, arteriolosclerosis, obesity, dietary indiscretion, chronic anticholinergic use, and latent infection) in AMD and AD contribute to toxic protein deposits, loss of homeostatic protein clearance, and progressive neurodegeneration [3][4][5][6][7][8][9][10][11].…”