One of the first symposia of the conference was dedicated to an overview of the current and future treatments for AD. Six presenters gave their perspectives on many treatment issues ranging from management of behavioral disturbances to new drug targets under development. On the whole there was a tone of optimism tinged with the reality of the limitations of current therapies.
Jeffrey Cummings considered the topic of behavioral management, noting that there are no current FDA-approved therapies for the treatment of AD-related behavioral disturbances. However, a number of medications used for the treatment of psychotic symptoms have been shown to be effective in AD, e.g., olanzapine and risperidone. A more common behavioral problem is agitation (up to 70 percent of cases) and increases with severity of disease. Haloperidol does not appear to be very effective, but risperidone does have efficacy. Major depression is infrequent but symptoms are present in 40 percent of patients. A number of common antidepressants appear to be effective, e.g., citalopram but there also appears to be a placebo response in many patients. Aricept and Exelon, which are used to treat mnemonic deficits, may also have signficant psychotropic properties.
Rachelle Doody provided an overview of cholinesterase inhibitors, several of which are already approved or currently in development. All appear to enhance cognition in at least certain patients. Side effects are mainly gastrointestinal complications. Dr. Doody reviewed the evidence for efficacy of these agents. Maximum effects depend on the measures used. None appeaer to show more than a 10 percent improvement on a variety of scores when mean group differences are used. However, she noted that efficacy can be quite dramatic in some patients, including those with severe dementia. There is little information available on efficacy for MCI patients (mild cognitively impaired) and for profound AD or other types of dementia. She noted that discontinuation of treatment carries a risk of not regaining baseline status after treatment is resumed but that benefits are of long duration if treatment is not interrupted. She also pointed out that the available evidence does not appear to converge on the original cholinergic hypothesis, which is now considered to be incomplete at best.
Kenneth Rockwood provided an overview of noncholinergic therapies, including recent disappointments of several drugs that have failed in initial trials, e.g., estrogen, prednisone, celecoxib, propentofylline. Specific disease-modifying drugs are some time in the future. In the meantime, there is a focus on prevention, combination therapies and some adjustment of expectations of current treatments. New strategies may include reducing Aβ production, reducing tangles, promoting repair, slowing neuronal death, and mitigating inciting events. Promising leads may come from anti-hypertensives. Another point Rockwood made was that some reports of ineffectiveness may be due to off-setting changes that are reported as no change, e.g., memory may not improve but other symptoms may. Ultimately combination therapies will probably be required.
Steve DeKosky gave an overview of anti-amyloid strategies noting that some drugs may have a nonspecific impact on amyloid. The goal is to develop agents that will act more specifically, such as β-secretase inhibitors, gamma secretase inhibitors, α-secretase enhancers, or agents that accelerate clearance of Aβ, or block amyloid aggregation. Since it is still not clear what the normal function of APP is, these strategies may involve undesired effects. Triggers for Aβ production include normal aging, APP mutations, PS-1 and PS-2, and altered second messenger systems. Other novel approaches include immunization to clear amyloid (through macrophage activity) or to prevent further deposition.
Steve Paul reviewed the evidence collected from transgenic mice on the role of ApoE. ApoE has been suggested to work through neurotrophic effects (E4 being less effective), as an antioxidant, or through effects on tau binding or amyloid deposition. The latter is supported by epidemiological data as well as the results from transgenic mice (APP V717F +/+ x apoE -/-) in which amyloid deposition is largely prevented by the lack of ApoE. ApoE appears to be involved in promoting fibrillization of Aβ as well as the formation of neuritic plaques. There is also reduced astrogliosis in the absence of ApoE.
Collectively the results are interpreted as indicating that ApoE contributes to disease risk by enhancing amyloid deposition. Dr. Paul also reported recent data in which infusion of LPS into the lateral ventricle of the APP mice resulted in three and fourfold acceleration of amyloid deposition in the presence of ApoE whereas the ApoE -/- mice still show no plaques. Current work is focused on strategies to reduce ApoE synthesis through manipulations of intracellular signaling pathways that implicate NFkB.
The symposium was rounded out by a review of cholinesterase inhibitors by Dr. Giacobini. He noted that the original assumptions underlying the cholinergic hypothesis do not appear to hold up in terms of understanding the effects of these inhibitors. He noted that there may be some effects that are not limited to the anticholinesterase activity of these agents in light of the fact that AChE also has binding sites for other molecules implicated in AD, such as amyloid and the fact that there is some evidence for cholinergic regulation of APP synthesis, possibly mediated through muscarinic receptors. This emphasizes the complexity of the establishing an effective treatment. All of the presenters agreed on the difficulty of developing a single treatment based on a single mechanism of disease pathology. The task is not easy but the ground that has been gained so far suggests that the next few years may well provide encouraging news on the eventual development of drugs that not only reduce negative symptoms but intervene in the insidious course of the disease. The challenge remains.—Keith Crutcher
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