The Visual Impairment/Cognitive Impairment Co-morbidity : Examining the Genotype-Structure-Function Relationship

Research reports a high co-occurrence of Age-related Macular Degeneration (AMD) and Alzheimer’s Disease (AD), suggesting that visual and cognitive impairments may be related. This is further supported by structural similarities in the retina and brain, shared disease risk factors, and histopathological evidence, including beta-amyloid. Due to this, it is hypothesized that AMD and AD may share genetic risk factors as well. The goal of this research was to replicate studies demonstrating a higher incidence of cognitive impairment among individuals with AMD, and to explore the relationship among genotype, structure, and function in this co-morbidity.  The results showed a greater number of individuals with AMD scored positive for mild cognitive impairment (MCI) compared to controls. Mean Montreal Cognitive Assessment score for the AMD group was lower than that of the control group, however this was not significant. Those scoring positive for MCI in the AMD and control groups did differ significantly on the cognitive domains with which they had difficulty. While controls had difficulty with only memory, those with AMD had difficulty with memory in addition to other cognitive domains, indicating a higher risk of progression to AD. The genetic results showed that the most common AMD single nucleotide polymorphisms (SNPs), CFHY402H and ARMS2A69S, occur in the expected frequencies within the Quebec population. FADS1 rs174547, which has a less significant contribution to AMD, was found to be overrepresented in the Quebec population, indicating a possible Founder Effect for this SNP. In terms of visual function, carriers of CFHY402H were found to have greater ecentricity compared to non-carriers while carriers of ARMSA69S had poorer visual acuity and contrast sensitivity. Analysis of retinal structure revealed CFHY402H was related to increased drusen area, mid reflectivity, and geographic atrophy, meanwhile ARMS2A69S had fewer correlations with characteristics of drusen. Taken together, these results suggest that the CFH SNP plays a role in the disruption of retinal architecture while the ARMS2 SNP is involved in photoreceptor dysfunction. This is further evidenced by the results of psychophysical measures, where carriers of ARMS2A69S had particular difficulty with first order stimuli which relies heavily on contrast sensitivity. Although no significant differences were found in cognitive performance based on CFH or ARMS2 carrier status, all those scoring positive for MCI were carriers of the FADS1 SNP with homozygotes having the lowest cognitive scores. These results have implications for the fields of genetics, biology, and low vision rehabilitation. Exploration of the AMD/cognitive impairment co-morbidity across the spectrum of genotype-structure-function increases communication across the sciences to better serve the growing proportion of the population facing this co-morbidity.

Keyphrases: Age-related Macular Degeneration (AMD), Alzheimer’s Disease (AD), Mild Cognitive Impairment (MCI), Complement Factor H (CFH), Age-related Maculopathy Susceptibility Gene 2 (ARMS2), Single nucleotide polymorphism (SNP), Drusen, Retina, Visual function