AMD Supplementation: High Zinc vs Low Zinc

By Damon Dierker, OD, FAAO

Age-related macular degeneration (AMD) is the leading cause of adult blindness in the United States.[1] Although there is no cure for AMD, actions such as ceasing smoking [2], making dietary changes [3], and adding nutritional supplementation with macular carotenoids have proven benefits, even in early AMD.[4] Additionally, the AREDS2 study confirmed that risk of progression to choroidal neovascularization (CNV) can be reduced with a combination of antioxidants, carotenoids, and zinc in patients with bilateral intermediate AMD or late AMD in one eye.[5]

Could Zinc Be Making Patients Worse?

Practitioners continue to show concern that zinc supplementation may have negative effects on AMD patients. Genetic analysis of the AREDS dataset found that a subgroup of patients receiving zinc supplements showed negative outcomes (i.e. they were more likely to progress to CNV) associated with certain polymorphisms.6,7 However, these findings could not be replicated by AREDS investigators.8 Importantly, independent analyses of the AREDS dataset by Seddon [9] and Vavvas [10] concluded that the effectiveness of AREDS supplements appears to differ by genotype.

Although not proven, high doses of dietary and supplemental zinc have been associated with prostate hypertrophy [11], prostate cancer [12,13], and genitourinary-caused hospitalizations.[14] AREDS2 investigated whether a lower dose of zinc (25mg compared to 80mg) would be comparable in reducing risk of progression to advanced disease. Lowering the zinc dosage revealed no statistically significant effect. Additionally, recent genetic analysis of AREDS2 subgroups showed no difference in efficacy of low doses versus high doses of zinc [15] between groups.

A recently published study using an entirely new, real-world dataset found that long-term use of AREDS supplements significantly increases the risk of CNV in some patients due to their genetic makeup.[16] Patients taking only a half-dose of AREDS supplements (40mg of zinc) for at least 5 years were included in this analysis.

When Considering Zinc

So, what is a medically minded optometrist to do when considering recommending zinc supplements in AMD patients? I see two reasonable choices:

  1. Obtain in-office genetic testing (Macula Risk, ArcticDx) to determine if your patient may be potentially harmed by zinc supplements. If so, avoid prescribing a supplement containing zinc. I recommend MacuHealth once daily for these patients.

  2. If you choose not to offer genetic testing, recommend an AREDS2 based supplement with 25mg dose of zinc instead of 80mg, as this appears to be equally efficacious. MacuHealth PLUS+ is an excellent choice.

Nutritional supplementation in AMD cases is critical, as is the need to be mindful of recommending any treatment that may result in a negative outcome.


  1. Congdon N, O’Colmain B, Eye Diseases Prevalence Research Group, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122(4):477–485.

  2. Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective study of cigarette smoking and age-related macular degeneration in women. JAMA. 1996;276(14):1141-1146.

  3. Chiu C-J, Klein R, Milton RC, Gensler G, Taylor A. Does eating particular diets alter the risk of age-related macular degeneration in users of the Age-Related Eye Disease Study supplements? Br J Opthamol. 2009;93(9):1241-1246.

  4. Akuffo KO, Nolan JM, Howard AN, et al. Sustained supplementation and monitored response with differing carotenoid formulations in early age-related macular degeneration. Eye. 2015;29(7):902-912.

  5. Age Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005–2015.

  6. Awh CC, Lane AM, Hawken S, et al. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120(11):2317e2323.

  7. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study. Ophthalmology. 2015;122(1):162e169

  8. Chew EY, Klein ML, Clemons TE, et al. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology. 2014;121(11):2173e2180.

  9. Seddon JM, Silver RE, Rosner B. Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis. Br J Ophthalmol. 2016;100(12):1731e1737.

  10. Vavvas DG, Small KW, Awh CC, et al. CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation. Proc Natl Acad Sci USA. 2018;115(4):E696eE704.

  11. Lagiou P, Wuu J, Trichopoulou A, Hsieh CC, Adami HO, et al. Diet and benign prostatic hyperplasia: a study in Greece. Urology. 1999;54(2):284-290.

  12. Gallus S, Foschi R, Negri E, Talamini R, Franceschi S, et al. Dietaryzinc and prostate cancer risk: a case-control study from Italy. Eur Urol. 2007;52(4):1052-1056.

  13. Leitzmann MF, Stampfer MJ, Wu K, Colditz GA, Willett WC, et al. Zinc supplement use and risk of prostate cancer. J Natl Cancer Inst. 2003;95(13):1004-1007.

  14. Johnson AR, Munoz A, Gottlieb JL, Jarrard DF. High dose zinc increases hospital admissions due to genitourinary complications. J Urol. 2007;177:639-643.

  15. van Asten F, Chiu CY, Agrón E, Clemons TE, Ratnapriya R, Swaroop A, Klein ML, Fan R, Chew EY; Age-Related Eye Disease Study 2 Research Group. No CFH or ARMS2 interaction with omega-3 fatty acids, low versus high zinc, or β-carotene versus lutein and zeaxanthin on progression of age-related macular degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report No. 18. Ophthalmology. 2019;126(11):1541-1548.

  16. Kaufman SR, Yoganathan P, Small KW, et al. Genetics and age-related eye disease study formulation interaction in neovascular age-related macular degeneration. Journal of VitreoRetinal Diseases. August 2020.