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.

Elise J. Levinoff, BSc^1,2, Howard Chertkow, MD, FRCPC^1,2,3
1Bloomfield Centre for Studies in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University
²Department of Neurology and Neurosurgery, McGill University
³Division of Geriatric Medicine, Dept. of Medicine, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, PQ.

Alzheimer disease (AD) is a neurodegenerative disease of elderly patients, pathologically characterized by the presence of senile plaques and neurofibrillary tangles in the brain. This pathology occurs in the cerebral cortex, specifically within the temporal lobes, resulting in impairment in cognitive domains such as short-term memory, attention, semantics, as well as aphasia and apraxia.¹ Patients also show marked changes in behaviour and are impaired in activities of daily living (ADLs). The causes of AD are unknown, but age is a major risk factor. Women are at a higher risk of developing AD, although this may be due, in part, to increased longevity. Additionally, mechanisms of neuronal injury, such as the presence of cerebral infarcts and consequences of head trauma, increase the risk of developing AD. Expression of the APOE-e4 genotype has also been associated with an increase in the risk of developing AD.¹

Presently, there is no cure for AD.

Jerilynn C. Prior MD, FRCPC, Professor of Endocrinology/Metabolism, Department of Medicine, University of British Columbia and Vancouver Hospital, Vancouver,

Abstract
Estrogen and progesterone (so-called "hormone replacement") therapy was formerly considered essential for menopausal women. The purpose of this paper is to outline the shifts in concepts related to estrogen and progesterone therapy and to describe situations in which it remains a practical, effective therapy for older women.

Estrogen and progesterone are useful for women >65 years old who have osteoporosis diagnosed by bone mineral density or vasomotor symptoms (VMS) disturbing sleep, especially if either are combined with recurrent urinary tract infections or severe dysparunia. If a woman has had a fragility fracture (in a fall from a standing height or less), hormone therapy should be combined with a bisphosphonate such as etidronate for optimal fracture prevention.

Optimal hormone therapy for older women, ideally, is transdermal (patch or gel), rather than oral, to decrease thromboembolic risks. Several lines of evidence suggest that low estrogen doses (such as 25 µg Estraderm®‚ patch, one pump Estragel®) are adequate. Oral micronized progesterone (Prometrium®), given daily, avoids flow, is effective for VMS and increases bone formation. Optimal therapy is daily full or moderate dose progesterone (200 to 300 mg or 5-10 mg medroxyprogesterone).

Dr. Mary Tierney
Senior Scientist and Director of
Geriatric Research
Sunnybrook and Women's College Health Sciences Centre

Alzheimer's disease (AD) is the most common cause of dementia, accounting for more than 64% of dementia cases in Canada. It is a progressive neurodegenerative disorder that currently afflicts more than 161,000 Canadians and is expected to affect approximately 800,000 by the year 2030.

A recent accumulation of laboratory, epidemiological and small clinical-trial studies suggest that estradiol, the principal gonadal hormone in females, may delay or prevent the onset of AD, and may also improve cognition in women with the disease. These observations raise the possibility that women taking postmenopausal hormone replacement thera-py (HRT) may be at significantly lower risk for AD. Thus, there is a compelling and urgent need for randomized, placebo-controlled clinical trials to determine whether estrogen replacement can prevent or delay the course of AD. This urgency is made greater by recent studies that have identified cognitive tests and genetic risk factors that enable earlier diagnosis of AD and enable the identification of those most at risk for the disease. For example, our previous research has shown that two neuropsychological tests and two demographic covariates (referred to below as the Alzheimer predictive index) predicted, over a two-year period, with 80% accuracy, the onset of AD in memory-impaired individuals without dementia.

Anna Liachenko, BSc, MSc

A large body of observational evidence suggested that estrogen replacement therapy (ERT) after menopause decreases a women's lifetime risk of death from myocardial infarction by 35 to 50 percent and increases life expectancy by 2 to 3 years. However, a recent major clinical trial concluded that estrogen plus progestin therapy did not decrease the overall risk of myocardial infarction and coronary death among postmenopausal women with previous heart disease. The main question raised by the results of the trial is whether doctors should change their prescribing patterns and which patient populations will be affected. While there is no simple answer, it is important to consider the issues involved such as, How serious were the limitations of the observational research? Did the trial look at the right group of patients? How far can we extrapolate the results? And what are the future implications?

The Heart and Estrogen/progestin Replacement Study (HERS) trial was a randomized, blinded, placebo-controlled trial designed to test the efficacy and safety of hormone replacement therapy (HRT, estrogen plus progestin) on secondary prevention of heart disease. The trial involved 2763 postmenopausal women with established coronary artery disease. In the HRT group, the rate of coronary events increased by 50% in the first year of the trial and subsequently decreased by 40% in the forth and fifth years, yielding no significant effect overall.

Andrea Sotirakopoulos, BSc

Gonadal steroids have wide and complex roles that reach beyond the regulation of gonadotrophin and prolactin secretion and the modulation of sexual behavior.¹ These hormones have several clinical effects on brain function throughout the life span, beginning during gestation and continuing into senescence. Estrogen is a female steroid hormone that is produced in the ovary and circulates in the blood stream. The specific proteins that bind to estrogen are distributed throughout the limbic brain, forebrain, hypothalamus, midbrain and anterior pituitary, and in organs such as the ovary and uterus. The widespread hormonal influence of estrogen on brain function could prove to be an important tool in the fight against Alzheimer's Disease (AD).

AD is characterized by neuropathologic features such as the accumulation of neurofibrillary tangles, neuritic plaques and amyloid deposits within regions of the cerebrum and brainstem² and by the progressive decline of mental function affecting long-term memory and other cognitive domains.³ A close relationship between neurofibrillary tangles and cell death exists within the brains of patients with AD. In the cholinergic basal forebrain and the hippocampus, these tangles are found inside neurons of cell groups that are progressively depopulated.