Supplement Formulations for Age-Related Macular Degeneration (AMD)

Jerry Rapp, PhD

Eye doctors should be aware of two as yet unresolved issues concerning the PreserVision supplement formulation designed to slow the progression of AMD.

The first issue is the amount of zinc (Zn++) being ingested on a daily basis. AREDS2 investigators, concerned that the 80 mg daily amount of zinc in the original AREDS ”could cause minor side effects, such as stomach upset, in some people”, compared the beneficial effects of 80 vs. 25 mg. (The RDA, recommended dietary allowance, for daily intake of zinc for adults is 8 mg for females and 11 mg for males.) They found that ”…. lowering zinc to the AREDS formulation …. had no effect on AMD progression”. And they concluded that “ …. based on evidence from AREDS2 it is unclear how much zinc is necessary”.1

High levels of zinc intake have been associated with potentially serious (not “minor”) adverse situations, especially in an elderly population.2-8 Despite all the statistical brouhaha raised in the AREDS2 report 9, it seems that the lesser 25 mg. daily dose of zinc is as efficacious as the 80 mg. dose and is a safer and more prudent recommendation for patients. And there is, in fact, a supplement available “based on the clinically effective formula tested by the National Eye Institute in its 2013 AREDS 2 study”, which contains 25 mg. of zinc.10 And let us not forget the warning of Paracelsus, the medieval alchemist and physician, who, centuries ago, noted that it is the dose of a substance that renders it a remedy or a poison.

The second, many would argue, more serious issue, involves whether one’s genetic profile should be taken into consideration when recommending a supplement formulation. This controversy began with a paper in 201311 which, based on data from the original AREDS, argued that individuals with 2 CFH risk alleles and no ARMS2 risk alleles should be taking a supplement that does not contain zinc because zinc increased the rate of progression of AMD compared to placebo. And patients with 2 ARMS2 risk alleles and no CFH risk alleles should be taking a supplement that does not contain antioxidants because antioxidants increased the rate of progression of AMD compared to placebo. (CFH stands for complement factor H, a gene that regulates the alternative complement pathway. Activation of the complement pathway destroys bacteria, regulates immune reactions and produces inflammation. CFH inactivates components of the pathway, thereby limiting the inflammatory response. ARMS stands for age-related maculopathy susceptibility; its exact function is unknown.) This has been followed by a number of publications, some supporting using one’s genetic profile when recommending a supplement concoction12-14 ; others arguing against.15-17 It is worth noting that one of the papers (ref. 13), which showed a strong interaction of genetics (CFH and ARMS2) with AREDS formulation treatment on the development of neovascular AMD, was published in Proceedings of the National Academy of Sciences, one of the most prestigious scientific journals on the planet.

About 4 1/2 years ago, I posted the following e-letter in the journal Science18:

“Jerry Rapp, Professor, Department of Biological and Vision Sciences, SUNY College of Optometry (3 July 2016)

There is at present a monumental statistical battle taking place on the very important clinical question of whether one’s genetic profile should be taken into account when recommending a supplement formulation to deal with age-related related macular degeneration (AMD). This conflict will never be resolved by two opposing groups, each with a vested interest in the outcome, shooting statistical arrows at each other. The raw data should be released and given without context (just columns of numbers labeled x, y, z or whatever) to three reputable statisticians (or groups), not necessarily in the world of science — for example, business, political or the sports world, or maybe one from each — and let them crunch the numbers and tell us what they mean.

With an ever-increasing number of elderly patients relying on these supplements to help decrease the progression of this devastating disease, this situation represents a prime example of data sharing as an ethical and scientific imperative.”

So far, to the best of my knowledge, no one has taken me up on this simple suggestion that might provide a competent, critical analysis of the data and quite possibly help resolve this crucial controversy.

  2. Bush AI. The metal theory of Alzheimer’s disease. J Alzheimers Dis. 2013;33:S277-S281.
  3. Kawahara M, Mizuno D, Koyama H, et al. Disruption of zinc homeostasis and the pathogenesis of senile dementia. Metallomics. 2014;6:209-219.
  4. Faller P, Hureau C, Berthoumieu 0. Role of metal ions in the self-assembly of the Alzheimer’s amyloid l3 peptide. Inorg Chem. 2013;52:12193-12206.
  5. Morris DR, Levenson CW. Ion channels and zinc: Mechanisms of neurotoxicity and neurodegeneration. J Toxicol. 2012; doi:10.1155/2012/785647.
  6. Yao F, Zhang R, Tian H, Li X. Studies on the interactions of copper and zinc ions with beta-amyloid peptides by a surface plasmon resonance biosensor. Int J Mol Sci. 2012;13:11832-11843.
  7. Tougu V, Tiiman A, Palumaa P. Interactions of Zn(II) and Cu(II) ions with Alzheimer’s amyloid-beta peptide. Metal ion binding, contribution to fibrillization and toxicity. Metallomics. 2011;3:250-261.
  8. Faller P. Copper and zinc binding to amyloid-beta: coordination, dynamics, aggregation, reactivity and metal-ion transfer. Chembiochem. 2009;10:2837-2845.
  9. 2013;309(19):2005-2015. doi:10.1001/jama.2013.4997
  11. Awh CC, Lane AM, Hawken S, Zanke B, Kim IK. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120(11):2317-2323.
  12. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in theAge-Related Eye Disease Study. Ophthalmology. 2015;122(1):162-169.
  13. CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation. Demetrios G. Vavvas (ΔημήτριoςΓ . Βάββας), Kent W. Smallb, Carl C. Awh, Brent W. Zanke, Robert J. Tibshiranie, and Rafal Kustra;
  14. Genetics and Age-Related Eye Disease Study Formulation Interaction in Neovascular Age-Related Macular Degeneration. Stephen R. Kaufman, MD, Pradeepa Yoganathan, MD, Kent W. Small, MD, Deepam Rusia, MD, Sophia I. Pachydaki, MD, Stephen M. Conti, MD, Robert E. Wenz, MD, Mark A. Gersman, MD, Fadi S. Shaya, BS, and Rafal Kustra, PhD. Journal of VitreoRetinal Diseases; DOI: 10.1177/2474126420941713
  15. Chew EY, Klein ML, Clemons TE, et al; Age-Related Eye Disease Study Research Group. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology. 2014;121(11):2173-2180.
  16. Chew EY, Klein ML, Clemons TE, Agrón E, Abecasis GR. Genetic testing in persons with age-related macular degeneration and the use of AREDS supplements: to test or not to test? Ophthalmology. 2015;122(1):212-215.
  17. Genetic Polymorphisms of CFH and ARMS2 Do Not Predict Response to Antioxidants and Zinc in Patients with Age-Related Macular Degeneration Independent Statistical Evaluations of Data from the Age-Related Eye Disease Study. Melissa J. Assel, MS, Fan Li, MS, Ying Wang, PhD, Andrew S. Allen, PhD, Keith A. Baggerly, PhD, Andrew J. Vickers, PhD. Ophthalmology;

About the Author:

Jerry Rapp, PhDDr. Rapp joined the faculty of SUNY, College of Optometry, in 1973, and is presently Professor, Department of Biological and Vision Sciences. He served as Chairperson of the Department of Biological Sciences for 15 years (1973-88) and is a Founding Member of the college-affiliated Schnurmacher Institute for Vision Research. He is also a member of the Graduate Faculty in Vision Science.