The relationship between open angle glaucoma, optic disc morphology and Alzheimer’s Disease: a Mendelian randomization study
Year: 2020
Type: preprint
Study design: Observational Study
Abstract: Background Alzheimer’s disease (AD) and open angle glaucoma (OAG) are common age-related neurodegenerative disorders with shared pathological features, leading to the hypothesis that glaucoma may represent a type of “ocular Alzheimer’s disease”. However, no causal relationship has yet been established. Methods To test for a causal relationship, bi-directional two-sample Mendelian randomization analyses were performed using summary data from the largest available genome-wide association studies of AD and OAG. The effect on AD risk from exposure to genetically predicted OAG was measured using 24 single nucleotide polymorphisms (SNPs). In the reverse direction, the effect on glaucoma risk from exposure to genetically predicted AD was measured using 25 SNPs. Additionally, the relationship between AD and measurements of optic disc morphology (vertical cup:disc ratio (VCDR), optic cup area, optic disc area) and intraocular pressure (IOP) were investigated. Results People with congenitally larger optic discs, a phenotype not regarded to be related to glaucoma, had a lower risk of AD (OR=0.80 per mm 2 increase in disc area; 95%CI=0.66,0.97; P =0.02) and people with genetically predicted AD had smaller optic disc sizes (−0.03 standard deviation change in mm 2 optic disc area per doubling odds of AD, 95%CI=-0.05,0.00; P -value=0.03). However, there was little evidence that exposure to genetically predicted OAG affected AD risk (OR=1.00 per doubling odds of OAG, 95%CI=0.98,1.03; P =0.83). Nor did genetically predicted IOP, VCDR or optic cup area influence AD risk. In the reverse direction, there was little evidence that genetically predicted AD had a causal effect on risk of OAG, IOP, VCDR or optic cup area. Interpretation Genetic analyses show that congenital optic disc area influences AD risk but provide little support for a causal relationship between OAG and AD, suggesting that previous observed associations between OAG and AD may be due to reverse causation, confounding or other forms of bias. Panel 1 What is glaucoma? Debunking the jargon Glaucoma refers to a heterogenous group of neurodegenerative conditions characterised by progressive optic nerve head cupping and visual field loss. Primary open-angle glaucoma (POAG) is the commonest age-related glaucoma, accounting for 2/3 of all glaucoma cases. Elevated intraocular pressure (defined as IOP>21mmHg), age, myopia (negative refractive error), and family history are the main risk factors for POAG. Indeed, POAG is usually diagnosed on the basis of elevated IOP or diurnal spikes in IOP combined with progressive optic nerve head cupping and visual field loss. Furthermore, normal neuroretinal rim width (Figure 1) follows the ISNT rule (inferior > superior > nasal> temporal) and so vertical optic cup:disc ratio (VCDR) is used clinically to distinguish pathological glaucomatous cupping from physiological cupping. The caveat is that congenitally larger optic discs tend to have larger physiological optic cups, and so optic cup area needs to be adjusted for optic disc area (Figure 1). While glaucoma is characterised by progressive increases in optic cup size, optic disc area does not change over a lifetime. IOP is the only modifiable risk factor for glaucoma; and surgical, laser and medical interventions which lower IOP have been proven to slow down the progression of glaucomatous optic disc cupping and visual field loss. In contrast, elevated IOP without glaucomatous optic disc cupping or visual field loss is defined as ocular hypertension, not glaucoma. Measurements of IOP by applanation tonometry can be influenced by central corneal thickness, resistance, and hysteresis, and need to be corrected for these factors, e.g. by using the Ocular Response Analyzer. Nevertheless, the probability of converting from untreated ocular hypertension to POAG is ~2-3% per year. Some people develop progressive optic nerve head cupping and visual field loss despite IOP<21mmHg): so-called normal tension glaucoma (NTG). POAG and NTG are widely considered to represent a continuum in open angle glaucoma (OAG), and they are strongly correlated genetically (Figure 9). Nonetheless, risk factors other than IOP appear to be more important to the pathogenesis of NTG. For example, migraine, vasospasm, systemic hypotension and primary vascular dysregulation have all been associated with NTG (Figure 1). Many have also been linked to Alzheimer’s dementia. Many GWAS do not distinguish between POAG and NTG; yet, this may be important to studies conducted in different populations since the prevalence of NTG varies widely depending on ethnicity. For example, ~30% of open angle glaucoma cases of European-descent have normal IOP, whereas >90% of open angle glaucoma cases in Japan have normal IOP. Furthermore, several GWAS have identified new risk loci for glaucoma from related phenotypes: IOP, corneal thickness, resistance and hysteresis, VCDR, and optic cup area (Figure 1). These phenotypes make powerful quantitative traits in GWAS and they are highly heritable across populations, but they are not sufficient individually to meet the diagnostic definition of glaucoma. The importance is that some of these phenotypes, e.g. optic disc cupping, are not specific to glaucoma. Indeed, the differential diagnosis for optic disc cupping includes compressive lesions (e.g. pituitary macroadenoma), ischaemic, demyelinating, inflammatory, infiltrative, infectious, congenital and inherited disorders of the optic nerve. Therefore, signs of neurodegeneration in the eye, like optic disc cupping, can arise from a variety of aetiologies and not just glaucoma (Figure 1). Research in context Evidence before this study Several epidemiological studies from the US, France, Germany, Australia, South Korea, Taiwan, and Japan have reported that open angle glaucoma (OAG) is more prevalent among people with Alzheimer’s disease (AD) or that AD is more prevalent among people with OAG. However, other studies have reported no association. We searched PubMed for studies published between database inception and 28 January 2020 that had investigated the relationship between Alzheimer’s disease and glaucoma using the search terms (“Alzheimer” or “Alzheimer’s” and glaucoma”). Papers in English and other languages were included, if there was an English abstract for assessment. We found the putative relationship between AD and glaucoma was the subject of several reviews and two meta-analyses. The first meta-analysis of 8 observational studies (6870 AD cases) concluded people with OAG have an increased risk of AD (RR=1.52; 95% CI: 1.41-1.63; I 2 =97%, p<0.001). A positive association was found when analyses were restricted to Asia (RR=2.03; 95%CI: 1.02-4.07) but not when they were restricted to America (RR=0.91; 95%CI: 0.89-0.94). The second systematic review of 10 studies found that people with AD (RR=0.92; 95% 95%CI:0.89-0.94; I 2 =89%, p<0.001) or dementia (RR=0.94; 95%CI: 0.92-0.96; I 2 = 89.4%, p<0.001) had a lower risk of OAG. The studies cited in both reviews differed in case definition, ascertainment and population ethnicity, and were highly heterogenous in study design: results varied from large positive associations in small studies to negative or null estimates in cohort and record-linkage studies. Mechanistically, many authors have suggested that OAG is linked to intracranial pressure (ICP). It is reported that ICP is lower in people with OAG than healthy controls and ICP is lower in people with normal tension glaucoma (NTG) than people with OAG associated with elevated intraocular pressure (IOP). Turnover of cerebrospinal fluid (CSF) halves from birth to old age and is significantly reduced in people with AD and normal pressure hydrocephalus (NPH). In addition, people with NPH who receive ventriculoperitoneal shunts have increased risk of NTG. Hence, some authors have hypothesised that raised
Source: medRxiv
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3093683284