**7. Alzheimer's disease and glaucoma**

Currently, RNFL, RGC and inner layers of the retina are considered indirect biomarkers of the CNS, enabling the prediction of brain pathology in patients suffering from different neuro‐ logical diseases [184, 308]. Since the development of OCT, this tool has been used to measure the thickness of the RNFL in different neurodegenerative pathologies. Despite that OCT was first developed in 1991 and commercially distributed in 1995, it was not until 2001 when a

During those first years, many studies appeared focusing on the peripapillary RNFL thickness in AD patients. In every study, a significant decrease in RNFL thickness was objectified in AD patients and compared with age‐matched controls. These analyses were carried out by segmenting the measures of the peripapillary thickness according to the area (superior, inferior, nasal and temporal). Several studies showed a decrease in the peripapillary RNFL thickness in all areas [10, 14, 16, 18, 42, 309]; others found that the thinning occurred in the inferior and superior regions [17, 307, 310], while in still other studies this significant decrease appeared only in the superior peripapillary region [15, 213, 311–313]. Some studies reported a certain thinning in the RNFL associated with the progressive cognitive decline [203, 312, 314]. Some authors even suggest that the inferior peripapillary quadrants might be the area with most specificity and sensitivity regarding the detection of the cognitive decline in the initial stages of the AD [17]. However, Salobrar‐García et al. [20] reported that their group of patients with mild AD showed no significant difference with respect to control subjects in terms of RNFL thickness of the peripapillary region (**Figure 3A**). These authors postulated that although no statistically significant differences in peripapillary RNFL were found between control and AD eyes, the increase in peripapillary thickness observed in mild‐AD patients could be secondary to an inflammatory process that may represent an early stage of degener‐ ation and could lead to progressive peripapillary fibre damage. The variability in peripapillary RNFL thickness reported in AD might be due to differences in disease progression among patients studied, since patients with greater involvement of the peripapillary region were those

**Figure 3.** Mean data of RNFL thickness against eye quadrants assessed with optical coherence tomography (OCT). (**a**) Peripapillary segmentation retinal nerve fibre layer, (**b**) central macular ring (1 mm away from the fovea). \**p* value <

study was first published on the thickness of the RNFL in patients with AD [42].

with a more advanced stage of AD.

400 Update on Dementia

0.01 (modified from **Figure 2** [20] with permission).

In the last decade, several studies have been made on some AD patients and experimental models of glaucoma. These studies have shown some significant similarities between the two pathologies [318–320]. Furthermore, in some clinical studies where the prevalence of primary open‐angle glaucoma (POAG) in AD patients was studied, an increase was observed in the incidence rate of POAG in AD patients [321, 322]. Tamura et al. identified an increase in the prevalence of the ε 4 allele of the APOE in POAG patients, similar to those that occur in patients suffering from AD. This suggests that common mechanisms could contribute to both pathol‐ ogies [322]. Lipton et al. [323] have postulated that treatment with memantine, a NMDA receptor blocker used in AD could help to slow the advance of glaucomatous neurodegener‐ ation. This hypothesis is based on the fact that the apoptosis, mediated by excitotoxic cell death, is a factor in the physiopathology of many neurodegenerative diseases, including glaucoma. This kind of excitotoxicity is caused by the excessive activation of NMDA glutamate receptors, at least partially. This excessive activity in the NMDA receptor entails an abnormally high influx of calcium ions in the neurons, which triggers multiple outcomes resulting in apoptosis. Thus, pharmacological blockage of NMDA receptor activity would prevent apoptosis related to excitotoxicity. However, the use of a neuroprotective drug (memantine) in patients with POAG gave discouraging results [324]. On the other hand, in a recent 12.7‐year longitudinal study, no direct link was found between normotensive glaucoma and increase risk of devel‐ oping dementia or AD, compared with the general population [325].

Whether or not glaucomatous optic neuropathy can be considered an ocular extension during Alzheimer's progression deserves further investigation.
