Treating Alzheimer’s Disease:A New Era Begins
By Dennis J. Selkoe, MD, Professor of Neurology and Neuroscience, Harvard Medical School and Codirector of the Center for Neurological Diseases, Brigham and Women’s Hospital, Boston, Mass.
Few consultations in neurology are more dispiriting than conveying a diagnosis of Alzheimer’s disease (AD) to patient and family. Providing this diagnosis is accompanied by the knowledge of an impending, inexorable decline in the patient’s most human qualities, with little or no hope for meaningful therapeutic intervention. But recent dramatic progress in deciphering the fundamental mechanism of AD has brought us to the verge of testing novel treatments that offer the first real hope of slowing the course of this devastating disorder. Neurologists need to become increasingly aware of these emerging therapeutic opportunities so that they can participate in their evaluation and explain how they work to anxious patients and their families.
At the outset, it is important to emphasize that useful symptomatic treatments for some of the features of AD are presently available. These include psychotropic medications that temporarily ameliorate one or another debilitating symptom of the disease, such as anxiety, agitation, depression, or psychotic behavior. The choice and dosage of psychotropic agents must be considered carefully, and the array of possibilities in this area has recently been reviewed (Mayeux R, Sano M. N Engl J Med 2000;341: 1670-1679). A second group of available agents comprises the acetylcholinesterase inhibitors. Beginning with tetrahydroaminoacridine (Cognex), then donepezil (Aricept), and, recently, rivastigmine (Exelon), the pharmaceutical industry has developed inhibitors to enhance the level of acetylcholine in the synaptic cleft and thereby attempt to decrease, at least temporarily, those symptoms of the disease principally related to cholinergic deficiency. To date, these inhibitors have provided modest and temporary benefit at most to the majority of patients in whom they have been tried. Nevertheless, they represent a potentially helpful modality for patients newly diagnosed with AD, and the more recent compounds have relatively few side effects.
Cholinesterase inhibitors are not expected to address the underlying mechanism of cholinergic cell loss, which is one of numerous neurotransmitter deficiencies occurring in AD. Indeed, no drugs proven to significantly retard the progression of AD are currently available. But this sense of therapeutic nihilism may soon change. To understand the nature of the new compounds that are now entering clinical trials and will come on line in the next few years, we need to review briefly what is currently understood about the causes and mechanism of AD.
Some have said that studying the senile (amyloid) plaques and neurofibrillary tangles that Alois Alzheimer described would be unlikely to provide important insights into the etiology of AD, since these lesions appeared to represent tombstones of the pathogenic process in the brain. The application of biochemistry and molecular genetics to the problem has shown this concern to be unfounded.
Beginning in the mid-1980s, scientists isolated and analyzed the vascular and plaque amyloid deposits and neurofibrillary tangles purified from postmortem brain tissue. These studies led to the conclusion that the extracellular amyloid deposits in vessels and plaques were composed of the 40- and 42-amino acid amyloid ß-peptides (Aß), whereas the intraneuronal neurofibrillary tangles were composed of highly phosphorylated forms of the microtubule-associated protein, tau. Subsequent studies led to an increasingly detailed understanding of the origins of these protein deposits and the mechanisms of processing of their precursors, particularly the ß-amyloid precursor protein (APP). This elucidation of the molecular pathology was accompanied by great progress in identifying genetic alterations that could predispose individuals to AD. At least four genes have been unequivocally implicated to date: the APP gene itself, presenilins 1 and 2, and the E-4 allele of the apolipoprotein E gene (reviewed in Selkoe DJ. Nature 1999;399:A23-A31).
The next step in research proved to be especially important for developing therapies (i.e., establishing the genotype-to-phenotype relationships for each of the implicated genes). This work led to the conclusion that each of the four gene products that can underlie familial forms of the disease increases the cerebral accumulation and deposition of Aß. Because excessive levels of Aß occur in all "sporadic" cases of AD as well, the link of these causative genes to Aß accumulation is believed to be directly relevant to the pathogenesis of all forms of AD. By mechanisms that are largely distinct at the molecular level, the four genetic factors augment the steady-state levels of Aß peptides in the brain, particularly that of the highly amyloidogenic Aß42 species.
The many subsequent steps in the different evolutions of neuronal/synaptic dysfunction, microgliosis, and astrocytosis in the Alzheimer brain are not fully understood. A growing consensus, however, believes that an imbalance between Aß production and Aß clearance leads gradually to a buildup of Aß in diffusible and, later, particulate (plaque-like) forms. The result has stimulated a strong interest in identifying compounds that chronically lower Aß levels in the brain. The ability to identify such molecules flowed from the discovery that Aß is normally produced by cells throughout life and is a natural metabolic product that circulates in the plasma and cerebrospinal fluid (CSF). As a result, scientists used cultured cells that secrete Aß to screen large libraries of compounds and detect "hits" that lower Aß levels in the cell medium without noticeably injuring the cells. Through a laborious iterative process carried out by several pharmaceutical companies, such compounds have been analyzed and then chemically modified in an attempt to achieve Aß inhibitors with drug-like properties that can be administered to humans. In general, this process has gone well, and several companies are apparently at advanced stages of preclinical development. In one case, human trials of an Aß-lowering compound have recently begun.
Most of the compounds currently emerging from pharmaceutical screening appear to act as inhibitors of the enzyme called g-secretase. This protease is one of two (the other is called ß-secretase) that sequentially cleave APP to release the Aß peptides. It is not currently clear why drug screening has yielded few inhibitors of ß-secretase; perhaps these lead to some general cellular toxicity or cannot penetrate cells and therefore do not emerge from these cellular screens. In any event, Aß-lowering drugs that appear to act by inhibiting g-secretase represent one hopeful therapeutic approach that has recently entered phase I clinical trials. The testing of such drugs will now take several years, assuming that there are no major untoward effects in the early safety trials.
A separate and novel approach to lowering Aß levels in the brain has come from the observation that immunizing APP transgenic mice that display the early features of Alzheimer pathology leads to a high anti-Aß antibody titer and a subsequent clearing of Aß deposits from the brain. The exact mechanism of this immunological effect is under study. Nonetheless, the results in the mouse model have been sufficiently robust to lead to initiation of phase I trials of this "Aß vaccination" approach. Again, one will not know whether this will constitute a useful therapy until several years of trials conclude.
While the Aß-lowering strategies described here will require extensive clinical evaluation, they offer the first hope of slowing and perhaps even preventing the progression of AD. The currently planned trials are therapeutic (i.e., they attempt to treat diagnosed patients with mild to moderate cognitive symptoms). Later on, if such trials have some success, there may well be an attempt to prevent the disease in subjects predisposed to AD, genetically or otherwise. One important subgroup of symptomatic patients will be those diagnosed with "minimal cognitive impairment" (MCI), many of whom gradually convert from a subtle, early memory disturbance to frank progressive dementia.
While much hard work in the clinic lies ahead, the rate of progress in elucidating AD and moving toward potentially disease-altering drugs has been impressive. One can only hope that the emerging trials will achieve at least a modicum of success sufficient to allow us to offer our patients a way of slowing this tragic disorder. —djs