High frequency of open-angle glaucoma in Japanese patients with Alzheimer's disease

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Abstract

The clinical and genetic relationships between Alzheimer's disease (AD) and glaucoma remain obscure. The aim of this study was to determine the prevalence of open-angle glaucoma (OAG) in patients with AD and whether the apolipoprotein E (APOE) 4 allele is associated with AD, with or without OAG, in Japanese. The groups consisted of 172 patients with the diagnostic criteria of AD and 176 age-matched controls. Ophthalmic examinations were conducted, and genomic analysis was performed by PCR and digestion of products with an enzyme. OAG was found in 41 (23.8%) of the AD patients, which was a significantly (p = 0.0002) higher prevalence than that in the controls (9.9%). Furthermore, there was no significant difference between intraocular pressures (IOPs) in AD patients with OAG and without OAG. The percentage of AD patients who carried an APOE ε4 allele (29.5%) was significantly (p = 0.0007) higher than that of the controls (9.1%). However, the percentage of AD patients with OAG who carried an APOE ε4 allele (35.7%) was not significantly different than that of AD patients without OAG (27.7%, p = 0.42). In summary, the prevalence of OAG is high in Japanese patients with AD, suggesting that common factors other than APOE may contribute to the two diseases.

Introduction

Alzheimer's disease (AD) is a neurodegenerative disease that is the most common cause of dementia in the elderly. AD is characterized neuropathologically by large extracellular beta-amyloid plaques and tau-containing intraneuroral neurofibrillary tangles. Early-onset AD may be explained by highly penetrate mutations in the genes encoding amyloid precursor protein, presenilin 1 and presenilin 2, and the majority of cases (90–95%) are late-onset AD (LOAD) in which several factors have been implicated. The ε4 allele of the gene encoding apolipoprotein E (APOE) is a major risk factor for LOAD in the general population [1], [2], [3], [4].

Glaucoma is the second or third leading cause of visual loss worldwide. Open-angle glaucoma (OAG) is the most common type of glaucoma in many populations [5], [6], [7], [8]. The pathogenesis of OAG is not yet known, but there are several known risk factors [9], [10], [11], one of which is elevated intraocular pressure (IOP). Lowering IOP is the current standard therapy for many kinds of glaucoma and effectively slows down disease progression [12]. However, even after pressure reduction, many patients have ongoing visual loss. In addition, 30%  50% of OAG patients suffer from ‘normal-tension’ glaucoma (NTG) in which there is optic nerve degeneration without elevation in IOP [8], [12], [13].

AD and glaucoma have common features. Both become more severe with advance of age, and they both occur more frequently in women than in men [5], [14]. Neurons are affected in the brain of AD patients and the eye of glaucoma patients. In addition, it has been reported that patients with AD demonstrate widespread axonal degeneration of the optic nerves and loss of retinal cells, especially ganglion cells [7], [15], [16], [17]. Moreover, the ε4 allele of APOE has been established as a genetic risk factor of AD. Some studies have shown that ε4 is a genetic risk factor of OAG, though the contribution of the ε4 allele remains controversial [18], [19], [20], [21]. Therefore, AD and glaucoma might have some common risk factors, mechanisms, or pathways.

To clarify the relationship between AD and glaucoma, we investigated the frequency of OAG in AD patients and we evaluated APOE as a common risk factor for AD and OAG in Japanese.

Section snippets

Prevalence of open-angle glaucoma in patients with AD

A total of 172 patients with sporadic AD (age: mean ± S.D. = 80.9 ± 8.4 years; 35 men, 137 women) who were institutionalized residents in four Japanese hospitals or who visited those hospitals for treatment of AD were recruited into this study. The diagnosis of probable AD was based on clinical findings according to the National Institute of Neurological and Communicative Disorders Association (NINCDS–ADRDA) criteria. A total of 176 individuals (age: mean ± S.D. = 81.9 ± 8.8 years; 42 men, 134 women) who

Results

Clinical characteristics of the AD patients and control subjects are shown in Table 3. Among the 172 patients with AD, 41 (23.8%) had OAG. In the control group, 16 subjects (9.9%) had OAG. The percentage of AD patients with OAG (23.8%) was significantly higher than the percentage of control subjects with OAG (9.9%; p = 0.0002). There was no variation between the study group and control group as the difference between slit-lamp biomicroscopy and indirect ophthalmoscopy which could represent a

Discussion

The prevalence of OAG in the AD patients was 23.8%, which was significantly higher than that of the control subjects (9.9%). In the Tajimi study [24] (a study carried out to assess a population-based prevalence of glaucoma among residents aged 40 years or older in Tajimi City, located in central Japan, by simple random sampling without stratification, which was used to select 4000 subjects from the 54 165 residents in Tajimi City), the prevalence of OAG increased with age from 2.0% for subjects

Acknowledgements

The authors thank Nobuhiro Yoshitani and Masataka Nomura of the Department of Ophthalmology and Visual Science, Graduate School of Biomedical Sciences, Hiroshima University, Shuhei Nishimura of Mitsugi Public General Hospital and Tatsuji Tamura and Akihiro Kishi of Kake Kenko-Hoken General Hospital, who contributed genomic DNA samples. All authors have no competing interests.

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