The relationship between open angle glaucoma, optic disc morphology and Alzheimer’s Disease: a Mendelian randomization study
Authors: Budu-Aggrey Ashley , Hysi Pirro , Kehoe Patrick G. , Igo Robert P. , Wiggs Janey L. , Bailey Jessica Cooke , Haines Jonathan , Pasquale Louis R. , MacGregor Stuart ,   NEIGHBORHOOD consortium,   International Glaucoma Genetics Consortium,   UK Biobank, Smith George Davey , Davies Neil M , Atan Denize 
Published: September 2020

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 mm2increase 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 mm2optic 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 anincreasedrisk of AD (RR=1.52; 95% CI: 1.41-1.63; I2=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; I2=89%, p<0.001) or dementia (RR=0.94; 95%CI: 0.92-0.96; I2= 89.4%, p<0.001) had alowerrisk 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 translaminar pressure gradient (the difference between IOP and ICP across the laminar cribrosa of the optic nerve head) may be responsible for the pathogenesis of glaucoma because this hypothesis would explain why it is both possible for some people to develop progressive optic nerve head cupping and visual field loss despite IOPs in the normal range, while raised IOP alone is insufficient to cause glaucoma in others (i.e. glaucoma is caused by low ICP). As low ICP is associated with AD, low ICP may be the mechanistic link between AD and OAG (Figure 2).

An alternative hypothesis is that the production, circulation and absorption of intraocular fluid shares similar mechanisms to that of cerebrospinal fluid, and the failure of these mechanisms leads to the build-up of neurotoxins in OAG and AD. This hypothesis might explain why Aβ proteins and tau are detected in the retina of people affected by OAG and AD. In support of this hypothesis, there is substantial overlap in gene expression in the ciliary body compared with the choroid plexus, e.g. ion and water channels and transporters, and the renin-angiotensin system. There may also be a role for the glymphatic system, which provides a mechanism for the clearance of soluble waste products, e.g. Aβ protein in ocular fluid or CSF. The influx and efflux of CSF into the glymphatic system occurs via periarterial and perivenous spaces respectively, which finally drain into dural and cervical lymphatic vessels. The optic nerve is surrounded by CSF and is thought to have its own specialised glymphatic network. Here, the lamina cribrosa provides an additional barrier to fluid transport from inside the eye to the optic nerve in a manner that is dependent on translaminar pressure gradient. In models of glaucoma, defects in the lamina cribrosa are associated with the redirection of potentially harmful solutes, e.g. Aβ protein, from the intra-axonal compartment and glymphatic system of the optic nerve to its extracellular spaces. This leads to the build-up of potentially harmful solutes within the optic nerve and the degeneration of retinal ganglion cell axons. Though not well understood, it is possible that similar abnormalities in the glymphatic system of the brain might exist in AD leading to the accumulation of neurotoxins.

There is also evidence that trans-synaptic neurodegeneration in the eye, e.g. from glaucoma, causes secondary neurodegeneration in functionally connected subcortical and cortical structures in the brain. Likewise, neurodegenerative processes in the brain, e.g. from dementia, can cause secondary neurodegeneration of the optic nerve. Tau pathology in AD is known to spread over time and could conceivably cause secondary neurodegeneration in the eye. Furthermore, amyloid microangiopathy can affect retinal and choroidal vasculature as well as cerebral blood flow in AD. Although amyloid microangiopathy has not been investigated in glaucoma, vascular dysfunction and genes involved in vascular endothelial morphology and genesis are consistently implicated in glaucoma. Hence, the neurodegenerative processes and vascular abnormalities common to both disorders might explain why they are both associated with visual field defects and the degeneration of retinal ganglion cells (RGCs). Studies using optical coherence tomography (OCT) imaging of the fundus have shown that thinning of the retinal nerve fibre layer (RNFL: the layer composed of RGC axons) and ganglion cell-inner plexiform layer (GC-IPL: composed of RGC bodies and dendrites) associate with future cognitive decline and dementia diagnosis. People with known glaucoma diagnoses were excluded from these analyses. However, the optic nerve is composed of RGC axons, which means that thinning of the RNFL and/or GC-IPL are signs of optic neuropathy from any cause, not just OAG. Hence, signs of neurodegeneration have been detected in the eye using OCT that are associated with future cognitive decline, but previous studies have not been designed to show whether these changes represent early OAG or whether they result from other unrelated neurogenerative processes affecting RGCs that are causally related to AD.

Added value of this study

Prior to this study, it was not clear whether there was a causal relationship between OAG and AD, whether their shared pathological features were merely non-specific signs of neurodegeneration, or whether some people were coincidentally affected by both disorders because of their high prevalence in older adults.

Using the largest available population cohorts to maximize our statistical power (International Genomics of Alzheimer’s Project (IGAP), Alzheimer’s disease working group of the Psychiatric Genomics Consortium (PGC-ALZ), Alzheimer’s Disease Sequencing Project (ADSP), National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD) consortium and UK Biobank) we compared the results of observational epidemiological studies with causal estimates from Mendelian Randomization (MR) analyses to make causal inferences about the biological relationship between AD and OAG.

In contrast to previous observational reports of an association between OAG and AD, we found weak evidence of a causal relationship between AD and OAG in either direction. Nor did we find strong evidence of a causal relationship between intraocular pressure (IOP), vertical cup:disc ratio (VCDR), and optic cup area with AD. Our data did, however, suggest that larger congenital optic disc size has a protective effect on AD risk.

Implications of all the available evidence

The genetic evidence in this study does not provide support for a causal relationship between AD and OAG or any related glaucoma phenotype, suggesting that the observed associations in previous studies were due to reverse causation, confounding and other types of bias. One possible source is collider bias, which occurs when two variables, e.g. AD and raised IOP, can independently cause a third collider variable, e.g. optic disc cupping and/or other signs of RGC degeneration: signs that are generally used to diagnose OAG. Collider bias is also an issue in studies of phenotypes related to glaucoma that are also used to define case-control status in the same cohort, e.g. IOP. In other words, conditioning on phenotypes which are also used to ascertain case-control status will bias the analyses.

An additional source of bias may be caused by methods of ascertainment. GWAS generally define OAG based on a threshold for optic disc cupping +/-raised IOP, but non-progressive optic disc cupping is not glaucoma. Moreover, other possible causes of optic disc cupping, e.g. compressive or congenital (Panel), would not be excluded by a single anterior segment examination, but would require further investigation, e.g. MRI head scan, and serial measurements over time.

Evidence that larger optic disc area is protective against AD or that people born with smaller optic discs have a greater risk of AD in future might support the idea of “cognitive reserve”, i.e. people with larger optic nerves and other correlated neuronal structures may be more resilient to age-related neurodegenerative processes. The links between specific genetic variants, e.g.APOE, optic disc size and educational attainment with AD suggest there may be several biological pathways that are causally related to AD (Figure 10).

In summary, clinicians and scientists should be aware there is little evidence for a causal relationship between AD and OAG. OAG is widely considered to be an IOP-driven disease; indeed, IOP>21mmHg is often used to diagnose POAG. However, this definition of glaucoma can lead to bias. Neurodegenerative changes affecting the eye can arise from multiple aetiologies and it is possible that IOP, AD and other unknown factors are independent risk factors that cause a similar pattern of RGC degeneration. Without strong evidence of a causal relationship, we predict little benefit in repurposing drugs developed for AD in clinical trials for OAG, except where they target common downstream pathways of neurodegeneration.