Alzheimer’s disease (AD) is a progressive, fatal disorder without cure. The mechanism(s) of the disease is not entirely understood, impeding development of effective therapy. Current treatments provide short-term alleviation of some symptoms, but generally have poor efficacy and can be accompanied by moderate to severe side-effects.
The “amyloid cascade hypothesis” posits that self-assembly of Aβ initiates a cascade of events leading to changes in cell membrane conductivity, production of ROS, tau hyperphosphorylation, glutamatergic excitotoxicity, deficits in neurotransmitters, including acetylcholine, norepinephrine and serotonin, inflammation, and apoptosis. These events cause impairment of neuronal function and neuron death, producing the symptoms of AD. Other hypotheses ascribe etiologic primacy to oxidative stress or related metabolic changes resulting from aging and argue that Aβ-mediated effects occur secondarily to these initial insults.
Wide acceptance of the amyloid cascade hypothesis has focused therapeutic efforts on inhibiting formation, or facilitating elimination, of neurotoxic Aβ assemblies. Leading approaches are Aβ immunization, inhibition of Aβ production, enhancement of Aβ clearance by specific proteases or general proteolytic mechanisms and prevention of Aβ assembly using a wide variety of chemicals. Other approaches include the use of neuroprotective agents, antioxidants, anti-inflammatory agents, hormone replacement therapy, cholinesterase inhibitors and NMDA receptor antagonists.
AChE Inhibitors (AChEIs)
The most commonly used drugs for treatment of AD are cholinesterase inhibitors. During the disease, degeneration of cholinergic nuclei localized in the basal forebrain occurs. Impairment of the cholinergic system, which projects into large areas of the limbic system and the neocortex, is followed by disturbance of attentional processes and cognitive decline. In the absence of better therapeutic alternatives, treatment of AD-induced cholinergic deficiency was considered an attractive and reasonable strategy in the 1980s. By 1993, execution of the strategy resulted in FDA approval of the AChEI Tacrine, the first drug specifically approved for the treatment of AD. Tacrine provides modest symptomatic relief in mild to moderate cases of AD, but like other AChEIs, it can cause severe side-effects, including nausea, vomiting, diarrhea, constipation, headache, dizziness and sleep disturbance. New AChEIs that cause less severe side-effects have been developed in the last decade, including Donepezil, Galantamine, Rivastigmine and Metrifonate.
Memantine is a low-to-moderate affinity, uncompetitive NMDA receptor antagonist that appears to block pathological, but not physiological, activation of NMDA receptors. The drug may interfere with glutamatergic excitotoxicity and provide temporary relief to AD patients with moderate-to-severe disease. Memantine has been shown to cause modest improvement in clinical symptoms in severe stages of AD and may retard disease progression. Side-effects of memantine are minimal. Strong voltage dependency and rapid blocking/unblocking kinetics are thought to be the basis for memantine’s clinical tolerability. Clinical studies demonstrate positive effects of memantine in AD both as a monotherapy and in combination with AChEI treatment. Memantine offers a complementary therapeutic approach to AChEI, which may slow down the progress of AD, but like AChEI it is not curative.
Antioxidants
Excessive accumulation of ROS contributes to neuronal loss and dysfunction, and has been implicated in many studies as one pathological mechanism of AD. Based on these observations, vitamin E, a potent antioxidant and neuroprotective agent, is often prescribed as a treatment for AD. A clinical trial of vitamin E in patients with moderately advanced AD was conducted by the
Alzheimer’s Disease Cooperative Study. The results indicated that vitamin E may slow functional brain deterioration, confirming results of previous trials. The selective monoamine oxidase inhibitor selegiline also slowed down AD progression, but its combination with vitamin E did not improve the outcome relative to each drug alone.
Immunotherapy
Based on initial data from in vitro experiments followed by studies in rodents, immunization with Aβ has been a very active area of research. Active and passive immunization strategies have been shown to reduce AD-like pathology and restore cognitive deficits in transgenic mice, rabbits, guinea pigs and monkeys. These results evoked substantial optimism. Unfortunately, phase IIa clinical trials, in which patients with AD were immunized with Aβ(1-42) in adjuvant QS-21 (preparation AN-1792) were halted because a small but significant number of patients developed meningoencephalitis. Post-mortem examination of two treated patients revealed few plaques in the neocortex and no dystrophic neurites or reactive astrocytes (as compared with unimmunized controls). Reactive microglia associated with areas devoid of plaques were not observed. These results suggest that an effective immune response was generated in these patients, resulting in clearance of Aβ plaques.In addition, patients who produced antibodies in response to immunization with AN-1792 exhibited slower rates of cognitive decline. Additional studies now must be performed to understand the mechanistic basis of the iatrogenic problems and to develop safer vaccines for future use.
Statins
Statins are molecules that lower plasma levels of LDL and cholesterol, and increase HDL levels. Statins have been in use for many years in the treatment of cardiovascular and other diseases, and are considered safe medications. Recent studies now suggest that statins may be of use for the prevention of AD. It should be noted that these studies involved relatively small numbers of subjects and therefore that the data extant are insufficient to justify the use of statins in the general, non-demented population without hyperlipidemia. Large-scale, placebo-controlled clinical trials will be required to establish the efficacy and safety of statins in prevention and treatment of AD.
Chelation Therapy
In vitro and in vivo data have suggested that formation of neurotoxic assemblies of Aβ is mediated by interaction of A with ions of transition metals such as copper and zinc. This hypothesis led to in vitro studies of the effects of chelators on Aβ fibril formation and dissociation. These studies showed that chelators could block fibril formation in vitro, dissociate ex vivo amyloid and inhibit A accumulation in vivo. Based on these results, clinical trials were initiated to determine if chelators could be used to treat AD. The chelator chosen for study was clioquinol, a copper and zinc-chelating agent that had been in use for more than 70 years in the treatment of amoebic dysentery. The drug had been in disfavor since the 1970s because many patients developed blindness and paralysis following treatment. Further investigation revealed that these severe adverse effects resulted from deficiency in vitamin B12 and could be prevented by vitamin B12 supplementation. Recently, a phase II clinical trial of clioquinol with vitamin B12 supplementation showed that the cognitive abilities of treated patients stabilized and their plasma Aβ (1-42) levels were reduced relative to a placebo group. These results suggest that clioquinol, or other chelators, may hold promise as therapeutic agents for AD.
Hormone Replacement Therapy
Epidemiologic studies have shown a higher prevalence of AD in women than in men, suggesting a link between gonadal hormone levels and AD. In view of these studies, and of evidence supporting a role for estrogen in brain regions involved in learning and memory and in the protection and regulation of cholinergic neurons, hormone replacement therapy has been studied with respect to its ability to decrease the risk for, or delay the onset of, AD in post-menopausal women. Unfortunately, recent trials have suggested that estrogen treatment has no significant effect on the clinical course of AD in elderly women with the disease. Moreover, the Women’s Health Initiative study of estrogen plus medroxyprogesterone acetate showed an increased risk of dementia among post-menopausal women who showed no cognitive deficits before entering the trial and were in the active-treatment group. Hormone replacement therapy thus does not appear to be a viable approach for the treatment or prevention of AD.
Interest in anti-inflammatory drugs has been driven by observations of inflammation in brain regions affected by AD and by studies showing that certain non-steroidal anti-inflammatory drugs (NSAIDs) reduce the likelihood of developing AD. One mechanism by which the NSAID effect is mediated has been suggested by the finding that a subset of NSAIDs specifically reduces Aβ42 levels, possibly through interaction with the γ-secretase complex and/or the small G-protein Rho. Long-term use of NSAIDs has been found to reduce AD risk and greater risk reduction was observed among patients with longer NSAID treatment histories. However, other studies have failed to show clear beneficial effects of NSAID treatment. These conflicting data suggest that simple anti-inflammatory treatment of AD patients may be ineffective and that better understanding of the mechanisms by which NSAIDs affect AβPP processing will be required if the approach is to be successful.
Reference:
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