A new French multi-centre case control study conducted in four French ophthalmologic centers in Montpellier and Nimes has reported an association of late AMD (age-related macular degeneration) with increasing exposure to anti-cholinergic drugs (ACDs) for at least 3 months before AMD diagnosis. As increased age is a significant risk factor for AMD, and the use of ACDs may increase with age, the observation is likely to be relevant to clinical management of the disease. ACDs refer to drugs that block the action of the neurotransmitter acetylcholine and include medications such as anti-depressants, anti-psychotics, anti-epileptics, anti-histamines, bladder anti-muscarinics and anti-Parkinson agents.
Several risk factors have been associated with AMD including age, smoking, BMI, cardiovascular risk factors, nutrition, sunlight exposure and family history. However, no specific drug appears to have been clearly associated with the disease, although certain beneficial claims exist for statins and anti-inflammatory drugs, while some suspicions of increasing risk for AMD have been published regarding aspirin and β-blockers. Regardless, no comprehensive or conclusive data appears to have been generated to date. In investigating such potential association, the French research group noted that while older adults may use certain medications with anticholinergic activity at a prevalence between 7.5% and 27%, there is an increasing awareness of the risks versus the benefits of ACDs. Some anticholinergic drug use has been associated with cognitive decline and dementia and it is additionally suspected that reduced cholinergic transmission may increase brain amyloid-β deposition.
The research included only ACDs with a clinical anti-muscarinic effect, which was achieved by using an independent anticholinergic drug scale to exclude all drugs with a measure below 1 on the scale. The research assessed a total of 200 cases and 200 controls comprising 129 (64.5%) and 116 (58%) women, respectively. The mean (SD) age was 74.8 (9.2) years and 75.5 (7.2) years, in the case and controls respectively. Results of the analysis showed that twenty-six cases (13%) and 10 controls (5%) were exposed to ACDs throughout life for at least 3 months prior to AMD onset. and the risk of AMD appeared to be increased with exposure to ACDs (adjusted OR [aOR], 2.84; 95%CI, 1.33-6.06; P = .007). While the research was not designed to uncover the exact mechanism of the association, the researchers hypothesized that retinal amyloid-β deposition, secondary to ACD use, may cause an increase in macular inflammation. Independent studies had indicated that anticholinergic drug use may increase brain amyloid-β deposition. In addition, research in animal models has shown that reduced cholinergic transmission may increase brain amyloid-β concentration, which itself can promote mitochondrial dysfunction followed by oxidative stress and local inflammation involving complement and microglial cell activation. In concluding their research, the French investigators commented that while there was a clear association of late AMD with ACD use for at least 3 months, and that “a dose-effect relation was suggested by a greater association with prolonged intake and high Anticholinergic Burden Score”, further research would be needed to figure out the specific pathways that may lie behind the observed association.