The APOE E4 Allele Is Associated with Faster Rates of Neuroretinal Thinning in a Prospective Cohort Study of Suspect and Early Glaucoma

Sean Mullany; Henry Marshall; Santiago Diaz-Torres; Ella C Berry; Joshua M Schmidt; Daniel Thomson; Ayub Qassim; Minh-Son To; David Dimasi; Abraham Kuot; Lachlan S W Knight; Georgina Hollitt; Antonia Kolovos; Angela Schulz; Stewart Lake; Richard A Mills; Ashish Agar; Anna Galanopoulos; John Landers; Paul Mitchell; Paul R Healey; Stuart L Graham; Alex W Hewitt; Emmanuelle Souzeau; Mark M Hassall; Sonja Klebe; Stuart MacGregor; Puya Gharahkhani; Robert J Casson; Owen M Siggs; Jamie E Craig

doi:10.1016/j.xops.2022.100159

The APOE E4 Allele Is Associated with Faster Rates of Neuroretinal Thinning in a Prospective Cohort Study of Suspect and Early Glaucoma

Ophthalmol Sci. 2022 Apr 19;2(2):100159. doi: 10.1016/j.xops.2022.100159. eCollection 2022 Jun.

Authors

Sean Mullany¹, Henry Marshall¹, Santiago Diaz-Torres², Ella C Berry¹, Joshua M Schmidt¹, Daniel Thomson¹, Ayub Qassim¹, Minh-Son To¹, David Dimasi¹, Abraham Kuot¹, Lachlan S W Knight¹, Georgina Hollitt¹, Antonia Kolovos¹, Angela Schulz³, Stewart Lake¹, Richard A Mills¹, Ashish Agar⁴, Anna Galanopoulos⁵, John Landers¹, Paul Mitchell⁶, Paul R Healey⁶, Stuart L Graham³, Alex W Hewitt⁷, Emmanuelle Souzeau¹, Mark M Hassall¹, Sonja Klebe⁸, Stuart MacGregor², Puya Gharahkhani², Robert J Casson⁵, Owen M Siggs^{1

9}, Jamie E Craig¹

Affiliations

¹ Department of Ophthalmology, Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia.
² QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³ Faculty of Health and Medical Sciences, Macquarie University, Sydney, Australia.
⁴ Department of Ophthalmology, University of New South Wales, Sydney, Australia.
⁵ Discipline of Ophthalmology and Visual Sciences, University of Adelaide, Adelaide, Australia.
⁶ Centre for Vision Research, University of Sydney, Sydney, Australia.
⁷ Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
⁸ Department of Pathology, Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia.
⁹ Garvan Institute of Medical Research, Darlinghurst, Australia.

Abstract

Purpose: To investigate the association between the apolipoprotein E (APOE) E4 dementia-risk allele and prospective longitudinal retinal thinning in a cohort study of suspect and early manifest glaucoma.

Design: Retrospective analysis of prospective cohort data.

Participants: This study included all available eyes from participants recruited to the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study with genotyping data from which APOE genotypes could be determined.

Methods: Apolipoprotein E alleles and genotypes were determined in PROGRESSA, and their distributions were compared with an age-matched and ancestrally matched normative cohort, the Blue Mountains Eye Study. Structural parameters of neuroretinal atrophy measured using spectral-domain OCT were compared within the PROGRESSA cohort on the basis of APOE E4 allele status.

Main outcome measures: Longitudinal rates of thinning in the macular ganglion cell-inner plexiform layer (mGCIPL) complex and the peripapillary retinal nerve fiber layer (pRNFL).

Results: Rates of mGCIPL complex thinning were faster in participants harboring ≥1 copies of the APOE E4 allele (β = -0.13 μm/year; P ≤0.001). This finding was strongest in eyes affected by normal-tension glaucoma (NTG; β = -0.20 μm/year; P = 0.003). Apolipoprotein E E4 allele carriers were also more likely to be lost to follow-up (P = 0.01) and to demonstrate a thinner average mGCIPL complex (70.9 μm vs. 71.9 μm; P = 0.011) and pRNFL (77.6 μm vs. 79.2 μm; P = 0.045) after a minimum of 3 years of monitoring.

Conclusions: The APOE E4 allele was associated with faster rates of mCGIPL complex thinning, particularly in eyes with NTG. These results suggest that the APOE E4 allele may be a risk factor for retinal ganglion cell degeneration in glaucoma.

Keywords: APOE; APOE, apolipoprotein E; Apolipoprotein E; BMES, Blue Mountains Eye Study; Dementia; HTG, high-tension glaucoma; HVF, Humphrey visual field; IOP, intraocular pressure; NTG, normal-tension glaucoma; POAG; POAG, primary open-angle glaucoma; PROGRESSA, Progression Risk of Glaucoma: Relevant SNPs with Significant Association; Retinal Neurodegeneration; SD OCT, spectral-domain OCT; SE, standard error; SNP, single nucleotide polymorphism; mGCIPL, macular ganglion cell–inner plexiform layer; pRNFL, peripapillary retinal nerve fiber layer.