Ging-Yuek Robin Hsiung, MD, MHSc, FRCPC and Howard Feldman, MD, FRCPC, Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC.

In the past decade, there have been numerous advances in our understanding of the molecular biology and pathogenesis of Alzheimer disease (AD). Although to date no pharmacological treatments have been shown to alter the pathology of AD, several medications have been proven to offer symptomatic improvement and to delay the progression of cognitive, behavioural and functional deficits. This article reviews the currently available medications for management of cognitive symptoms in AD, as well as other promising drugs that are under investigation.

Key words: Alzheimer disease, management, cholinesterase inhibitors, donepezil, memantine.

Introduction
An estimated 8% of the Canadian population over age 65 suffers from dementia, of which 60–70% is caused by Alzheimer disease (AD). The incidence of dementia doubles for every five years of increased age between 65 and 85 years.¹ The management of dementia is a significant burden to our health care system, with an estimated annual cost of $3.9 billion in 1991.² Epidemiologic studies suggest that if the symptoms of dementia can be delayed by just two years, prevalence will decrease by 25%, with significant savings to the long-term care of these individuals.

John Wherrett, MD, FRCPC, PhD, Division of Neurology, Toronto Western Hospital and the University of Toronto, Toronto, ON.

This commentary addresses current views about the interaction of vascular disorders and Alzheimer disease, including vascular pathologies that may be intrinsic to the Alzheimer process as identified through demonstration of amyloid plaques and neurofibrillary tangles. The common cerebrovascular pathologies accompanying aging, mainly atherosclerosis and arteriosclerosis, will coincide in varying proportions with the Alzheimer pathology, also a concomitant to aging. Because interventions are available to modify both risks and complications of these vasculopathies, an important goal of dementia research is to develop means to characterize the contribution of cerebrovascular disease in Alzheimer and other dementias. Realization of this goal is confounded by the recognition that Alzheimer pathology, usually considered a parenchymal process, involves important vascular changes.
Key words: Alzheimer disease, dementia, cerebrovascular, pathology, imaging.

Milita Crisby, MD, PhD, Neurotec Department, Division of Geriatric Medicine, Stockholm, Sweden.

The interaction of genetic and multiple environmental factors contributes to the development of Alzheimer disease (AD). Hypertension and hypercholesterolemia have been identified as risk factors for ischemic heart disease (IHD). Recent epidemiological data also have revealed an association between hypercholesterolemia and AD. Experimental models of AD and in vitro studies have shown that cholesterol modulates the amyloidogenic pathway in favour of production and deposition of amyloid in the brain. Dysregulation of the lipid metabolism in the brain due to apolipoprotein E4 or 24-hydroxylase polymorphisms has been observed in patients with AD and related dementias. Furthermore, observational studies have revealed that statin use could have a potential role in the prevention of AD.
Key words: cholesterol, statins, lipid-lowering, Alzheimer disease, neurodegeneration.

While pharmacologic therapies for mild-to-moderate stage Alzheimer disease (AD) are currently available, agents for the treatment of more severe AD have yet to be approved. Glutamate, the primary excitatory brain neurotransmitter, normally regulates cell signaling by binding various postsynaptic receptors. However, glutamatergic overstimulation of the N-methyl-D-aspartate (NMDA) receptor may cause excitotoxicity, and has been implicated in the pathogenesis of neurodegenerative dosorders. If interception of this pathway can slow cell death, then introduction of an NMDA-receptor antagonist should be of therapeutic benefit. Based on this rationale, memantine, an uncompetitive NMDA receptor antagonist, was investigated for its treatment efficacy of late-stage AD.

In a double-blind, parallel-group study, 252 patients with moderate-to-severe AD were randomised to receive memantine 20mg daily or placebo for 28 weeks. Of these, 181 patients completed the study and were assessed at baseline, at mid-study and at the end of treatment (week 28). The primary efficacy variables were the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADLsev). The CIBIC-Plus quantifies overall changes in cognition, function and behaviour relative to baseline (increasing score signifies worsening disease). The ADCS-ADLsev is a questionnaire designed to determine a patient's ability to perform various activities of daily living,with lower scores indicating declining abilities.

Based on ADCS-ADLsev scores, at week 28 significantly less deterioration was observed in the treatment arm than in the placebo group (score decreases of 2.5 and 5.9 points, respectively). Bolstering this trend, the CIBIC-Plus ratings at week 28 were 4.4 for the memantine group, versus 4.7 for placebo. Subgroup analysis indicated that both patients with moderate and severe AD benefited from memantine over placebo for all outcome measures.

The results of this trial are promising and point towards therapeutic alternatives to anticholinergics. If memantine is, in fact, effective in lessening the severity of AD, there is reason to hope that it might be similarly capable of alleviating the pathogenesis of other neurological disorders in which NMDA receptor overstimulation has been implicated.

Source

1. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348:1333-41.

André Tanguay, MD, Chief Physician, Pavillon Hubert-Maisonneuve, CHSLD Drapeau-Deschambault, Rosemère, QC.

A common theme in dementia is misunderstanding--patients with dementia are confused in their thoughts, about the people around them, and by their environment. Furthermore, the patient's family should not be astounded by the seemingly different viewpoints of professionals. In dementia, understanding is of the utmost importance between professionals and family caregivers, and delivering the facts in a clear manner is essential. Striving for this goal, the training tool presented in this article allows the factual understanding of the natural progression of Alzheimer disease. Clinical data and 13 grades are charted within a single table to allow optimal understanding of this disease.
Key words: Alzheimer disease, caregivers, GDS-FAST, training table, MMSE.

A novel brain mapping technique has provided the first quantitative, dynamic visualization of the spreading wave of cortical atrophy in the brains of living patients with Alzheimer disease (J Neurosci 2003;23:994-1005).

Using this unique mapping method, Australian neuroscientists were able to visualize dynamic patterns of atrophy in 52 high-resolution MRI scans of 12 patients with AD and 14 elderly matched controls. Based on these scans, dramatic time-lapse videos were created, showing sequential loss of gray matter in four dimensions as it spread over time from temporal and limbic cortices into frontal and occipital brain regions, while sparing sensori-motor areas. The visualized patterns of cortical atrophy correlated with the AD patients' progressively declining cognitive ability and mirrored the sequence of neurofibrillary tangle accumulation observed at autopsy. AD patients were found to lose an average of 5.3% grey matter per year compared to a loss of only 0.9% in the healthy volunteers.

In the future, such images may offer researchers a potent tool for assessing the impact of therapies on dementia as well as for evaluating the spread of the disease.

Previously, apolipoprotein E (ApoE) was the only gene unequivocally linked to a propensity for late-onset Alzheimer disease (LOAD) development, but a step was recently made towards further elucidation of the genetics involved in the disease.

24S-hydroxylase, the neuronal protein encoded by the gene CYP46, catalyses the conversion of brain cholesterol to 24-hydroxycholesterol, thereby facilitating the export of cholesterol from brain tissue via the blood-brain barrier. Brain cholesterol accumulation has been tentatively linked to the generation of beta-amyloids (Ab), the peptides implicated in Alzheimer disease (AD) pathogenesis. It is therefore reasonable to propose that defects in the CYP46 gene may contribute to an increased genetic risk of disease development.

To further assess the contribution of 24S-hydroxylase to effective brain cholesterol metabolism and to LOAD risk, European researchers screened the CYP46 genomic region for single nucleotide polymorphisms (SNPs). rs754203, a TT polymorphism located between exons 2 and 3 on chromosome 14q, was polymorphic in 100 chromosomes and was thus deemed a candidate for genotyping. ApoE genotyping was also performed.

To determine genetic associations, studies were conducted on a hypothesis testing sample of 76 control subjects and 107 AD patients, followed by a confirming sample of 172 controls and 94 demented patients. In the two samples, CYP46*TT frequency was higher in AD subjects than in the controls (60.7% vs. 46.1%; 58.5% vs. 43.0%, respectively). Importantly, the odds ratio (OR) for the risk of AD in carriers of CYP46*TT and ApoE4 was 9.63 compared to an OR of 2.03 for carriers of only the former and an OR of 4.06 for carriers of only the latter. These results suggest a synergistic mechanism between CYP46 and ApoE on AD risk.

The relationship between CYP46 and ApoE polymorphisms and Ab and 24S-hydroxycholesterol levels was examined by analysing brain tissue and cerebrospinal fluid (CSF) samples. Brain Ab load was significantly higher in CYP46*TT-positive subjects than in CYP46*TT-negative subjects, and was highest in carriers of both the CYP46*TT genotype and the ApoE4 allele. The same trend was noted in CSF samples. However, while CSF levels of 24S-hydroxycholesterol were higher in AD patients than in controls, no difference in CSF 24S-hydroxycholesterol levels was noted between CYP46*TT-positive and -negative subjects. This suggests a possible alternate pathway by which the CYP46*TT genotype is contributing to Ab accumulation.

The study was conducted on a small scale, but produced results sufficiently significant to warrant further, larger tests and to extend the hypothesis to encompass other CYP46 polymorphisms. The study supports a model of LOAD whereby CYP46 loss of function increases brain cholesterol, causing Ab aggregation and ultimately leading to neurodegeneration. However, the data gathered to date do not rule out the possibility that the CYP46*TT genotype increases rather than decreases CYP46 activity, thus contributing to LOAD by way of an alternate mechanism. A more detailed understanding of the manner in which 24S-hydroxycholesterol is exported from the brain may indicate that other loci are involved in influencing AD susceptibility.

Source

1. Papassotiropoulos A, Streffer JR, Tsolaki M, et al. Increased brain b-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol 2003;60:29-35.

Kunin-Lunenfeld Applied Research Unit 2nd Annual Conference at Baycrest Centre for Geriatric Care, October 18, 2002

Joanna Goldberg, MSc, Associate Editor, Geriatrics & Aging.

Speakers

1. The Role of Anti-inflammatories and the Inflammatory Hypothesis in the Prevention of Alzheimer Disease
   Presented by Patrick McGeer, MD, Vancouver, BC.
2. Decreasing Dementia Risk and Minimizing Cognitive Decline with Participation in Engaging Activities and Memory Rehabilitation
   Presented by Angela Troyer, PhD, CPsych, Baycrest Centre for Geriatric Care, Toronto, ON.
3. Pharmacological Strategies for Prevention of Alzheimer Disease
   Presented by Serge Gauthier, MD, FRCPC, McGill Centre for Studies in Aging, Montreal, QC.

The goal of research at the Baycrest Centre for Geriatric Care is to provide a scientifically based understanding of diseases and disorders of the elderly. Through various educational methods, staff are trained to implement new practices in assessment, management and rehabilitation. The ultimate goal is to find preventative measures to delay or eliminate the onset of disease. Three of the eight lectures at this conference that touched on how future research, clinicians and care providers may help to achieve these goals in patients with dementia are presented in this report.

I.

Women appear to be at greater risk of developing Alzheimer disease (AD) than men, and the postmenopausal depletion of estrogens may be one of the contributing factors to this trend. Although many studies have sought to establish whether hormone replacement therapy (HRT) may help reduce the risk of AD, results have been mixed. The Cache County Study, a longitudinal investigation of the incidence of AD relative to genetic and environmental risk factors, recruited 1,357 men (mean age 73 years) and 1,889 women (mean age 75 years). Subjects were screened with the Modified Mini-Mental State examination, followed by the Dementia Questionnaire. If cognitive disturbance was suggested, a clinical assessment was performed. For females, a history of current and former use of HRT was also taken.

Within the three year follow-up, 2.6% of men and 4.7% of women developed AD, and the incidence among women increased after age 80 and exceeded the risk among men of the same age. Women who used HRT were found to have a reduced risk of developing AD compared to women who did not use HRT. However, the risk varied with the duration of HRT use: women using hormone replacement for more than 10 years experienced a 2.5-fold lower incidence of AD--comparable to the risk seen among the male participants. Nearly all of the HRT-related reduction in incidence was due to former use of HRT, whereas current use had no effect unless duration of treatment exceeded 10 years.

Although these findings suggest that prior HRT use is associated with reduced risk of AD, the authors acknowledge several limitations in their study. For example, the participants from Cache County, Utah were well educated and homogenous in their sociodemographics, thus suggesting a lack of generalizability to other populations. The researchers suggest awaiting further results from ongoing large, randomized prevention trials before making any firm conclusions.

Source

1. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women. JAMA 2002;288:2123-9.

K. Farcnik, MD, FRCP(C), Psychiatrist, Division of Geriatric Psychiatry, University of Toronto, Toronto, ON.
M. Persyko, PsyD, CPsych, Division of Geriatric Psychiatry, University of Toronto, Toronto, ON.

Significant work has been done in the treatment of Alzheimer disease (AD) since cholinesterase inhibitors (CI) were approved in Canada five years ago. This has led to a better understanding of these drugs in terms of their different properties, therapeutic efficacy and indications for switching, and their use has since been extended to the treatment of AD with vascular pathology. Other treatments for AD, such as estrogens and non-steroidal anti-inflammatory drugs (NSAIDs), have also been evaluated further, while newer treatments, including a vaccine for AD, are currently in development. Although research outcomes have not always been positive, a significant effort is being made to achieve greater impact in a disease that is becoming ever more prevalent.

Cholinesterase Inhibitors
Currently, the CIs are the only class of drugs that have been proven efficacious in the symptomatic treatment of AD.¹ There are two types of CIs: acetyl and butyryl. Butyrylcholinesterase levels in the brain increase with the progression of AD, whereas levels of the enzyme acetylcholinesterase decrease.² The CIs approved in Canada that have demonstrated efficacy as well as a favourable safety profile are donepezil, rivastigmine and galantamine.