Senile dementia of the Alzheimer type continues to be a frustrating and frightening disease in elderly patients. But the secret remains locked away and awaits discovery, as scientists learn more about the disease but fail to find the breakthrough treatment.
In a year when the 25th anniversary of President Richard M. Nixon's declaration of a War on Cancer serves only to remind Americans of how long that battle will continue, senile dementia of the Alzheimer type presents another cluster of diseases that have frustrated medical science. SDAT has emerged as the fourth leading cause of death among the elderly, and it remains difficult to treat or even manage, despite the billions of dollars spent on research and the attention brought by high-profile victims such as President Ronald Reagan.
In this article, I review recent clinical literature detailing advances in understanding of SDAT and track progress toward successful preventive and therapeutic measures.
Not One Disease, But Several
Confirmed in the past couple of years is one fact that many have long suspected: SDAT is not a single disease with a single etiology. Rather, patients diagnosed today with SDAT have a cluster of symptoms with any of several different genetic, environmental, and combination factors.1
Even among those with clearly genetic disorders, many different genotypes and phenotypes have been identified.1 Possible roles have been studied for loci on chromosomes 6, 14, 17, 19, and 21.2 Chromosome 21, involved in Down's syndrome, has long been a prime suspect in SDAT and is associated with familial SDAT and the protein precursor to the beta-amyloid found in abundance in the brains of patients who have died following SDAT.
Genetics has provided one clear, major distinction in subtypes of patients with SDAT. Harvey and Rosser3 reported last year: "Recent advances in the molecular genetics of familial Alzheimer disease (FAD) and the discovery of defined genetic abnormalities have provided a robust approach to distinguishing between early- and late-onset cases within the group of autosomal dominant FAD." These and other authors have recommended that future studies should distinguish between early-onset familial versus late-onset familial disease and between early-onset familial versus early onset-sporadic conditions.3-6
A potential environmental factor studied frequently is nutrition. Zinc is a prime suspect, because altered concentrations of the mineral are associated with several states of altered mentation. These included SDAT, as well as Down's syndrome, epilepsy, and amyotrophic lateral sclerosis.7
Cobalamin deficiency is another nutritional possibility. McCadden et al.8 hypothesized that a common pathogenic mechanism involving protease inhibition might explain the link between cobalamin deficiency and amyloidogenesis; the authors noted that AIDS patients also have cobalamin deficiency and a dementia complex.
Heterogeneity in Neurochemistry
Thus, combinations of genetic and environmental factors combine in certain patients to produce SDAT, especially in patients with late onset or chromosome 21 abnormalities. For instance, patients can be categorized according to their responses to cholinergic therapy, which is a key point when treating with drugs such as tacrine.9 The possibility of using screening tests-such as pupillary dilation, electroencephalogram, CSF neurochemistry, or imaging studies-for cholinergic responsivity is being studied.9
Apolipoprotein E genotype is an important risk factor for SDAT, as it is for cardiovascular disease.10-12 The apoE gene has three common alleles-epsilon 2, 3, and 4-and the presence of the epsilon 4 allele is increased among people with both cardiovascular disease and SDAT. Population differences have been found in studying the incidence of the epsilon 4 allele-for example, with only percent of Taiwanese people carry the allele but 40 percent of Papua New Guineans carry it.10
The epsilon 4 allele is associated with late onset SDAT, acting as a dose-dependent, age-of-onset modifier. The epsilon 2 allele may serve a protective role.13
However, experts are not recommending routine screening for the epsilon 4 allele of apoE because other factors seem to determine how it is expressed. Two national genetics groups reached this conclusion in an article published in the Journal of the American Medical Association late last year14: "Studies to date indicate that the apoE genotype alone does not provide sufficient sensitivity to allow genotyping to be used as a diagnostic test. Because SDAT develops in the absence of apoE epsilon 4 and because many with apoE epsilon 4 seem to escape disease, genotyping is also not recommended for use as a predictive genetic test.… Whether apoE genotypes have other uses in the management of SDAT will become apparent over the next few years."
Heterogeneity in Neuroanatomy
The variations in neuroanatomy among SDAT patients have long intrigued, confused, and frustrated researchers in this area. From senile plaques to neurofibrillary tangles, postmortem findings in SDAT patients make clear the degree to which the neuroanatomy system is overwhelmed by this devastating condition.
Neurofibrillary tangles comprised at least 20 identifiable substances, which can be categorized into five groups15:
A major component of these tangles is microtubule-associated protein tau.15 Beta/A4-amyloid protein is the major component of the amyloid found in senile plaques.7 Various kinases, proteases, and inhibitors-several of which are coded for on chromosome 21-are involved in the production of tau and beta-AP.
While this type of information has not proven useful in screening patients and determining prognosis, it may be critical in aiding drug-development efforts. New agents will build on clinical experiences with tacrine, the first and only approved agent for SDAT. Let's look at how it is doing.
Clinical Results with Existing Therapies: Tacrine
Tacrine, a mixed, reversible cholinesterase inhibitor, has definite mechanisms by which it improves cognition in healthy people as well as those with SDAT. However, not all SDAT patients respond to the agent,16 and modest effects are observed in, at best, 20 to 50 percent of SDAT patients.9
Some reports indicate that those with early-onset SDAT-which is more likely to be genetically controlled-respond better to drug therapy, and delineation of response to tacrine and other agents according to age at onset is thus important.6 Also important in tacrine evaluations are clinical features of prognosis identified through the Predictors Study, which has developed a model of progression of SDAT to predict disease course in specific patients.17
Clinical literature indicates that tacrine delays deterioration by about five to six months during two to three months of therapy. In reviewing this observation, Giacobini made this hypothesis: "If treatment with tacrine will be extended to a longer period, the drug effect may not be only a symptomatic improvement but a slow-down of the disease course."18
As better screening and predictive models become available, the place of tacrine in treatment of SDAT patients should become clearer.
For now, two facts are obvious: Many SDAT patients will not respond to the drug and those with early-onset disease are better candidates for therapy.
Promises of Future Drugs
Table 1 lists some of the many new drugs under study for SDAT. The promise of a cure appears remote, given the nature of this list; the best odds to be in the interplay between molecular biology, gene therapy, and technological breakthroughs in the future.
SDAT: Where Is the Cure?
In a field with as much ongoing research as is devoted today to Alzheimer's disease, the myths, misinformation, and reality will continue to be confused for years to come. But looking back at the hard data available in peer-reviewed publications and evaluating its reliability, consultant pharmacists can be well-informed about the emerging understanding of the causes, pathophysiology, and treatments of SDAT and the several diseases it represents.
References
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15. Yen SH, Liu WK, Hall FL, Yan SD, Stern D, Dickson DW. Alzheimer neurofibrillary lesions: molecular nature and potential roles of different components. Neurobiol Aging 1995; 16(3): 381-7.
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