Alzheimer's disease and glaucoma: is there a causal relationship?

Evidence of a link between Alzheimer's disease (AD) and glaucoma has emerged from studies showing that patients with AD may have a significantly increased rate of glaucoma occurrence. In addition, it has been reported that patients with AD exhibit optic nerve degeneration and loss of retinal ganglion cells. In spite of intensive research, the clinical and genetic relationships between AD and glaucoma remain obscure. It is unclear whether the clinical correlation between the two diseases might be due to shared risk factors or the influence of one disorder on the other. Interestingly, certain observations may provide a clue towards a better understanding of the high rate of comorbidity reported between AD and glaucoma. In this article, we hypothesise that there may be a causal relationship between AD and glaucoma that may be explained by decreased cerebrospinal fluid pressure (CSFP) in patients with AD. A very recent study reported the intriguing new observation that mean CSFP was 33% lower in subjects with primary open-angle glaucoma than that of non-glaucomatous controls. It was noted that this observation supports the concept that an abnormal high trans-lamina cribrosa pressure difference, whether the result of elevated intraocular pressure, reduced CSFP, or both, plays an important role in glaucomatous optic nerve damage. Interestingly, it was also reported that a substantial proportion of AD patients have very low CSFP. Therefore, we hypothesise that an abnormal high trans-lamina cribrosa pressure difference may explain why patients with AD have a greater risk for developing glaucoma.

Can chronic increased intracranial pressure or exposure to repetitive intermittent intracranial pressure elevations raise your risk for Alzheimer's disease?

Over a decade ago, I formulated the hypothesis that cumulative effects of exposure to high intracranial pressure (ICP) may contribute to the development of Alzheimer's disease (AD), though not necessarily in an exclusive way. In addition to individual ICP characteristics (high 'physiological' ICP) and diseases causing ICP elevation, various activities with significant Valsalva effort, such as weightlifting and wind instrument playing, can generate very high ICPs. Recent studies of normal-pressure hydrocephalus (NPH), glaucoma and Alzheimer's disease provide supportive evidence for this hypothesis. A number of studies have shown a high incidence of AD related lesions in patients with NPH, which is known to be associated with prolonged elevation of ICP in a majority of cases. In both NPH and AD, an important decrease in cerebrospinal fluid (CSF) production was calculated. According to researchers in the US, the resulting CSF stagnation with impaired clearance and accumulation of neurotoxic substances may play an important role in the onset and progression of AD. They tested the hypothesis that improving CSF turnover by means of an investigational low-flow ventriculoperitoneal shunt will delay the progression of dementia in patients with Alzheimer's disease. With regard to the observed decrease in CSF production in patients suffering from NPH, it was postulated that chronic increased ICP causes downregulation of CSF production. It is hypothesized here that repetitive intermittent ICP elevations also may lead to downregulation of CSF production due to long-term cumulative effects. If the latter proves to be true, then both chronic increased ICP and repeated exposures to increased ICP (e.g., repetitive Valsalva maneuvers) may cause a similar cascade of CSF circulatory failure events leading to AD over time. Furthermore, AD may be causally related to increased ICP through other pathomechanisms. Additional supportive evidence for the role of a pressure factor in the pathogenesis of AD comes from studies concerning glaucoma. Elevated intraocular pressure (IOP) is a hallmark of glaucoma. Recently, similarities in pathophysiology between glaucoma and AD have been noted, with increased processing of amyloid precursor protein (APP) and up-regulation of beta-amyloid protein expression in retinal ganglion cells (RGCs). Given this link between AD and glaucoma, evidence for a causal relationship between repetitive intermittent ICP elevations and AD is gained from research indicating that high resistance wind instrument playing raises IOP and may result in glaucomatous damage. To test the validity of the hypothesis that exposure to repetitive but nonsustained ICP elevations may predispose to AD a non-invasive, epidemiological study is proposed in this paper.

Intracranial pressure and Alzheimer's disease: a hypothesis.

Several neuropathological and epidemiological data on Alzheimer's disease (AD) are considered in relation to data from other scientific sources. The correlation between all these data provides support for the hypothesis that high intracranial pressure (ICP) could play a role in the pathogenesis of AD.

The prevalence of dementia in Belgium: a population-based door-to-door survey in a rural community.

The project Epidemiology Research on Dementia in Antwerp (ERDA) estimated the prevalence of dementia in a random, population-based sample, stratified for age and sex. The sample of 1,736 elderly was screened at home with the Mini-Mental State Examination. All elderly under the cutoff of 23-24/30 got a diagnostic examination with the Cambridge Mental Disorders of the Elderly Examination and the DSM-IIIR criteria. The prevalence of dementia in the population above 65 years was estimated at 9%. The following age-specific prevalences of dementia (included mild dementia) were found in the age-groups 65-69, 70-74, 75-79, 80-84, 85+: 0.6, 5.1, 7.6, 16.2 and 33.6%. The prevalence of at least moderate dementia was 0.3, 3.9, 4.0, 11.2 and 25.0%, respectively. The prevalence of dementia, vascular dementia and dementia of the Alzheimer type was markedly higher in women than in men.

Epidemiology research on dementia in Antwerp, Belgium.

Epidemiological research on dementia in Belgium started in 1990 with a prevalence study. In the first phase of the MMSE was used for screening a random sample, stratified by age, of 1,800 aged people. In the second phase the diagnostic work was done by a psychiatrist using the CAMDEX. An incidence study will start after 2 years. Potential risk factors will be examined in a case-control study.