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We thank Dr Liu et al for their correspondence and have performed new analyses to distinguish inner and outer segment (IS, OS) associations with aging and with incident AMD in response. Liu et al highlight the importance of distinguishing IS and OS in the association between photoreceptor thickness and age-related macular degeneration (AMD) by discussing a concept previously identified in the literature: that IS thickness is not linked to AMD, whereas OS thickness is associated with AMD.1Baraas R.C. Horjen A. Gilson S.J. et al.The relationship between perifoveal L-cone isolating visual acuity and cone photoreceptor spacing-understanding the transition between healthy aging and early AMD.Front Aging Neurosci. 2021; 13732287Crossref PubMed Scopus (3) Google Scholar Here, we replicate this association in the UK Biobank population cohort previously described.2Zekavat S.M. Sekimitsu S. Ye Y. et al.Photoreceptor layer thinning is an early biomarker for age-related macular degeneration development: epidemiological and genetic evidence from UK Biobank optical coherence tomography data.medRxiv. 2021; 2021.08.18.21262226PubMed Google Scholar First, we looked at the association of IS versus OS layers with age, stratified by AMD status. We show that OS thinning is, indeed, associated with aging and AMD. Although IS thinning is also observed with age, no clear pattern exists between IS thickness and AMD across lifespan. Second, we observed that OS thinning is specifically and independently associated with incident AMD in a multivariate model (independent of IS thickness, age2Zekavat S.M. Sekimitsu S. Ye Y. et al.Photoreceptor layer thinning is an early biomarker for age-related macular degeneration development: epidemiological and genetic evidence from UK Biobank optical coherence tomography data.medRxiv. 2021; 2021.08.18.21262226PubMed Google Scholar, sex, smoking status, and the first 10 principal components of AMD), with each standard deviation of OS thinning being associated with a 1.34× higher risk of future AMD (95% confidence interval, 1.24–1.45; P = 7.4 × 10–14), whereas no significant association was observed with IS thickness in the multivariate model (hazard ratio, 0.93 per standard deviation of IS thinning; 95% confidence interval, 0.86–1.01; P = 0.1). Overall, our result highlights that OS thinning is specifically and independently associated with future AMD risk. Although we are unable to distinguish between rods and cones given the nature of our analyses using retinal layer thicknesses from OCT imaging data, our results are consistent with other experimental analyses, and highlight the potential role of OS thinning in reduced cholesterol turnover, and thus drusen accumulation in the path toward AMD development.3Curcio C.A. Photoreceptor topography in ageing and age-related maculopathy.Eye (Lond). 2001; 15: 376-383Crossref PubMed Scopus (228) Google Scholar, 4Curcio C.A. Medeiros N.E. Millican C.L. Photoreceptor loss in age-related macular degeneration.Invest Ophthalmol Vis Sci. 1996; 37: 1236-1249PubMed Google Scholar, 5Zekavat S.M. Lu J. Maugeais C. et al.An in silico model of retinal cholesterol dynamics (RCD model): insights into the pathophysiology of dry AMD.J Lipid Res. 2017; 58: 1325-1337Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Re: Zekavat et al.: Photoreceptor layer thinning is an early biomarker for age-related macular degeneration: epidemiological and genetic evidence from UK Biobank OCT data (Ophthalmology. 2022;129:694–707)OphthalmologyVol. 130Issue 4PreviewZekavat et al1 conducted a cohort study in the UK and reported that 10 years of data proving photoreceptor segment thinning precedes retinal pigment epithelium and Bruch’s membrane complex thickening by decades, and is the retinal layer most strongly predictive of future age-related macular degeneration (AMD) risk. We congratulate the authors on a careful trial with important results. However, we would like to offer an alternative explanation. Full-Text PDF