Alzheimer's disease -- Current trends and future advances in therapeutic management

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Current trends and future advances in therapeutic management

by Serge Gauthier, MD

When considering our aging population and the public's awareness of the availability of treatments, it's very likely that the prevalence of Alzheimer's disease will increase in the coming years. Moreover, individuals concerned about their own genetic risks are motivated into getting older relatives properly diagnosed early on. New population-based figures will be required, however, to compare with data collected during the Canadian Study of Health and Aging in 1991, which was the first country-wide prevalence study for Alzheimer's disease and vascular dementia — 8% of people over age 65 had one or the other. The big revelation was that 16.8% of individuals over age 65 were cognitively impaired without reaching the threshold for dementia. A follow-up study five years later showed an incidence of 21.8 for women and 19.1 for men per 1,000 non-demented persons per year (60,150 new cases of dementia, the majority being from Alzheimer's disease, per year). There's hope that control of vascular risk factors, such as arterial hypertension in mid-life (age 40-60 years), combined with higher education levels and better diet (i.e. fish and red wine) will decrease the incidence of Alzheimer's disease in one generation.

Does an early diagnosis matter?

Earlier diagnosis of Alzheimer's disease is possible through higher sensitivity of physicians to memory complaints, particularly if brought up by family members or friends. The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA, available through www.mocatest.org) allow for measurement of cognitive changes over time, and are increasingly considered the best screening tests for persons with cognitive complaints. Direct observations by occupational therapists may further be required to assess executive abilities and functional autonomy at home — and behind the wheel of a car!

There are currently no biologic tests (i.e. blood work, cerebrospinal fluid or brain scans) specific enough for detection of Alzheimer's disease that can be used in daily clinical practice. It's possible, however, that a combination of cerebrospinal fluid markers such as amyloid-beta 42 protein (Aβ42) and tau (a protein found in brain plaques), along with brain positron emission tomography for glucose or amyloid, will make it possible to establish a very early diagnosis — perhaps before any symptoms begin to manifest.

There is ongoing debate, though, as to whether mild cognitive impairment can be considered a diagnosis of very early Alzheimer's or a syndrome of memory complaints (usually subjective), but which doesn't impact on daily life, is often reversible, and has multiple etiologies (i.e. depression, hypothyroidism, substance abuse or sleep apnea). A prudent approach is to rule out systemic and psychiatric causes of mild cognitive impairment, and to reassess the patient at least once a year for the possibility of "conversion" to early dementia, one of the clinical milestones of Alzheimer's disease (see Table 1).

____
Table 1. Clinical milestones in Alzheimer's

* emergence of cognitive symptoms
* conversion from mild cognitive impairment to dementia
* loss of instrumental activities of daily living
* emergence of neuropsychiatric symptoms (such as hallucinations, apathy, aggressiveness, agitation)
* nursing home placement
* loss of self-care activities of daily living
* death
___

Once mild dementia of the Alzheimer's disease type has been diagnosed, a number of issues need to be dealt with. For one, explain the diagnosis to the patient and family, taking into account the risk of depression, and educate them about the natural history of the disease. Advise them to keep legal documents updated, such as a will, power of attorney and a mandate (in case of incapacity). Encourage patients and their families to join support groups through local Alzheimer's disease societies or other community resources. Pharmacotherapy, such as antidepressants (when required) and cholinesterase inhibitors can be offered. Retirement issues will need to be worked out for individuals who are still working and in addition, these patients' ability to drive should be monitored regularly.

Do existing therapies work?

Realistic expectations are key to successful treatment when using cholinesterase inhibitors (donepezil, rivastigmine and galantamine) in mild to moderate stages of Alzheimer's disease. Once labelled as "cognitive enhancers," these drugs act through potentialization of cholinergic activity. Through many randomized placebo-controlled studies of 3-12 months duration, they've been shown to improve cognitive abilities and initiative for activities of daily living in the first 2-3 months of treatment, followed by a slower progression of symptoms, but not of disease. There's also evidence for improvement of apathy and hallucinations, which can re-emerge when cholinesterase inhibitors are stopped. This "discontinuation syndrome" can occur within two weeks of stopping treatment and is partly reversible when the drugs are restarted at a lower dose and titrated up. Switching between cholinesterase inhibitors has been done when there's an apparent loss of benefit over time, though it's better to avoid using two of these agents simultaneously, unless employing a lower dose of the first drug while building up the dose of the second one. The efficacy of the cholinesterase inhibitors is considered equivalent for Alzheimer's disease, at least during the first year of use. Tolerability may vary and some patients need to try two, or even three, cholinesterase inhibitors to find the one that is most appropriate for them.

In moderate to severe Alzheimer's disease, the partial antagonist of N-methyl-D-aspartate (NMDA) receptor, memantine, can be used alone or combined with a cholinesterase inhibitor. Memantine acts by reducing the noise to signal ratio in neurotransmission. Randomized placebo-controlled studies lasting 3-6 months have demonstrated a slower decline for cognition and loss of activities of daily living, and improvement or reduction of emergence of troublesome behaviours such as agitation and aggressiveness. A randomized placebo-controlled study is currently underway in Canada to establish whether the use of memantine, with or without a cholinesterase inhibitor decreases the need for neuroleptics and improves quality of life for both patients and caregivers. If it's necessary to stop a cholinesterase inhibitor in order to start memantine, it's better to overlap the two drugs for one month while titrating up the doses of memantine (see Table 2 below)


TABLE 2. Recommended titration schedules for cholinesterase inhibitors and memantine

Drugs Starting doses Titration schedules

donepezil
(Aricept) 5 mg q.d.*¶ increase to 10 mg after 4-6 weeks

rivastigmine
(Exelon) 1.5 mg b.i.d. increase to 3 mg b.i.d.** after 4 weeks,
then 4.5 mg b.i.d.§

galantamine
(Reminyl ER) 8 mg q.d.¶ increase to 12 mg q.d. after 4 weeks§§

memantine
(Ebixa) 5 mg q.d.¶ increase 5 mg weekly up to 20 mg/day in
one or two doses


* could be 2.5 mg q.d. for 2 weeks, then 5 mg q.d. in frail individuals, or in the presence of sinus bradycardia (rule out sick sinus syndrome which is a contra-indication for the cholinesterase inhibitors)

** could be 1.5 mg q. am and 3 mg at dinner for 2 weeks, then 3 mg b.i.d. in frail patients

§ a higher dose of 6 mg b.i.d. is available, but usually given after 6-12 months

§§ a higher dose of 24 mg q.d. is available, but usually given after 6-12 months

¶ breakfast time is preferable


Can we modify the progression of AD?

There is uncertainty as to why Alzheimer's disease can appear in young individuals (the youngest patient I've encountered was 33 years old), as well as in the very old with seemingly the same pathology in the brain (beta-amyloid deposits in neuritic plaques and small arterioles, neurofibrillary tangles, neuronal cell loss, inflammation). What is clear is that genetic factors weigh heavily in the younger patients, whereas atherosclerotic factors are more predominant later in life.

Many randomized studies are underway in Canada and other countries, which are attempting to modify some of these pathogenic factors, including amyloid-suppressing drugs, neuronal repair enhancing agents and statins. Immunotherapy using monoclonal antibodies against beta-amyloid will soon be available for testing. These studies are being done by randomization to new treatment or to placebo in addition to standard symptomatic therapy with a cholinesterase inhibitor and/or memantine. Clinical observations are done over 12-18 months and supplemented by measurement of brain volume using magnetic resonance imaging.

What about future therapies?

The question should be: will future disease-modifying drugs work for all individuals at risk and all patients with Alzheimer's disease?

It's likely that different patterns of genetic predisposition will require different classes of drug treatments. For instance, carriers of the recently identified mutation in presenilin 1 (PSEN 1), which is linked to Alzheimer's disease in individuals as young as age 40, would require an early and sustained anti-amyloid therapy. Alternatively, patients homozygous (carrying two copies) of apolipoprotein E4 (apoE), with a risk of Alzheimer's disease emerging in their 60s, would need a more aggressive treatment for mid-life vascular risk factors. They'd also possibly require an anti-amyloid drug as soon as abnormalities are detected in their amyloid brain scan (under development as the Pittsburgh compound and positron emission tomography), or if a decline in their working memory is documented on annual testing.

For patients already diagnosed with Alzheimer's disease, pharmacogenomic profiling will likely become standard for apoE and butyrylcholinesterase polymorphisms, as well as for other genes that still need to be identified so that the most appropriate long-term treatment is selected for each individual. Currently, genetic testing outside of research protocols isn't recommended.

Are we making progress?

The answer to that question is a definite yes! The natural history of Alzheimer's is better understood. Moreover, the mild cognitive impairment stage of this devastating disease may become part of revised diagnostic criteria to allow for earlier disease-modifying treatments in pre-dementia stages of Alzheimer's disease. Furthermore, the milestones associated with this disease spectrum (Table 1) can be planned for with the patient more easily and through advance directives specific to Alzheimer's disease and the family. For the population as a whole, better knowledge of the risk and protective factors for AD may well change the number of individuals that are affected in one generation.

On a negative note, there is still debate in some parts of Canada about whether patients with Alzheimer's disease should have access to and be reimbursed for drugs that have a proven efficacy and safety profile. Even if the benefits appear modest, these individuals have as much rights as any other younger patient to receive the best available care. This may be facilitated by improvements in the transfer of knowledge from clinical trials to clinical practice, and the availability of clear practice guidelines that should include how to assess response to treatment and when to stop a treatment when it's not effective.

References:

Feldman HH, Gauthier S, Chertkow H et al. Canadian guidelines for the development of anti-dementia therapies: a conceptual summary. Can J Neurol Sci 2006;33: 6-26.

Gauthier S, Reisberg B, Zaudig M et al. Mild cognitive impairment. The Lancet 2006;367:1262-70.

Patterson JS, Gauthier S, Bergman H et al. The recognition, assessment and management of dementing disorders: conclusions from the Canadian Consensus Conference on Dementia. CMAJ 1999;160 (Suppl 12). [Being updated this year].
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Vol.14, No.05, May 2006