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I.R.F. / Aging news / Diseases / 03101301

Predictive Therapies to Treat Alzheimer's Disease?
Posted on: October 13, 2003

In the not too distant future, clinical management of Alzheimer disease (AD) is likely to resemble the present management of atherosclerotic disease. Sometime before an individual reaches age 50, an internist will initiate a screening program to determine that person's risk for developing AD. This assessment will include a comprehensive genetic screen for AD-risk loci, determination of plasma amyloid β peptide (Aβ) levels, family history of AD, and, perhaps, potential environmental risks. Depending on the risk prediction, a follow-up visit with an Alzheimer specialist may be scheduled. During this visit, an amyloid-binding agent will be injected and used to evaluate the extent of amyloid deposition in the brain. Based on the amount of deposition present and the initial risk assessment, the specialist will then develop a personalized therapeutic regimen. This regimen might consist of an Aβ vaccination, an amyloid-lowering drug, an anti-inflammatory agent, a neuronal growth factor, an antioxidant, or a combination of these approaches. The efficacy of therapy will be monitored by measurement of plasma Aβ levels, imaging of amyloid in the brain, and volumetric scanning of the brain. Primary screening, along with monitoring of the presymptomatic indicators of disease, and appropriate intervention will significantly reduce one's risk for developing AD.

Although proposal of such a scenario might seem highly speculative, recent and expected advances in (a) understanding the pathogenesis of AD, (b) identifying the genetic factors that confer risk for AD, (c) validating potential biomarkers for AD, and (d) developing therapeutic agents that target both Aβ and downstream pathological changes greatly increase the likelihood that AD will be managed successfully in the future.

AD is the leading cause of dementia in the elderly. Estimates of prevalence vary, but 1-5% of the population over age 65, and 20-40% of the population over age 85, may be affected by AD. Given the increasing number of elderly individuals in industrialized societies, AD represents a burgeoning epidemic that exacts a tremendous toll on the individuals it affects, along with their families and caregivers. Moreover, AD has a tremendous negative economic impact amounting to over $100 billion a year. Treatment of AD in the US reportedly costs more per patient than management of other major age-associated diseases. Beginning with short-term memory loss, and continuing with more widespread cognitive and emotional dysfunction, typical late-onset AD (LOAD) occurs after age 65 and follows an insidious 5- to 15-year course. Although AD usually presents without motor or sensory alterations, rare variants (such as spastic paraparesis) with atypical clinical presentations are occasionally recognized. Even today, definitive diagnosis of AD is only possible through postmortem analysis of the brain. This histopathological analysis of the brain demonstrates the classic triad of AD pathology: (a) senile plaques containing Aβ, (b) neurofibrillary tangles (NFTs) containing tau, and (c) widespread neuronal loss in the hippocampus and select cortical and subcortical areas.

Aβ accumulation is the initiating factor in AD pathogenesis. Much of the Aβ that accumulates in the AD brain is deposited as amyloid within senile plaques and cerebral vessels. Although numerous proteins are associated with the amyloid deposits in AD, the principal proteinaceous component of AD amyloid is the approximately 4-kDa Aβ. Aβ is produced from the amyloid β protein precursor (APP) through two sequential proteolytic cleavages made by enzymes referred to as secretases (Figure 1). APP is first cleaved at the amino-terminus of Aβ by a membrane-bound aspartyl protease (referred to as β-secretase). This cleavage generates a large secreted derivative (sAPPβ) and a membrane-bound APP carboxy-terminal fragment (CTFβ). Cleavage of CTFβ by γ-secretase results in the production of Aβ peptides of varying length. The two species of most interest are a 40-amino acid Aβ peptide (Aβ40) and a 42-amino acid Aβ peptide (Aβ42). At the same time, a cognate CTFγ is produced. Two homologous polytopic membrane proteases, referred to as presenilins 1 and 2 (PS1 and PS2), are likely γ-secretases. If they are not γ-secretases, PSs are at least essential cofactors for this cleavage.

Fig. 1. Aβ generation, aggregation, and sites for therapeutic intervention. APP is a type I transmembrane protein that is processed in several different pathways. The Aβ generation pathway is shown. Generation of Aβ in the β-secretase pathway requires two proteolytic events, a proteolytic cleavage at the amino-terminus of the Aβ sequence, referred to as β-secretase cleavage, and a cleavage at the carboxy-terminus, known as γ-secretase cleavage, which results in another carboxy-terminal fragment CTFγ. Although many Aβ peptides of various lengths can be produced in this fashion, the two of most interest are Aβ40, which is the predominant Aβ peptide, and Aβ42, which is typically produced at much lower levels than Aβ40. Although both peptides can aggregate, Aβ42 is thought to aggregate much more rapidly and to seed the aggregation of Aβ40. Sites for anti-Aβ intervention are indicated. Scissors indicate proteolytic cleavages. "sAPPβ" refers to the large secreted derivative generated by β-secretase cleavage of APP.

Anti-Aβ therapies under development

Secretase inhibitors.
Research clarifying the metabolic pathways that regulate Aβ production has revealed that the secretases that produce the Aβ may be good therapeutic targets since inhibition of either β- or γ-secretase decreases Aβ production. More progress has been made in developing γ-secretase inhibitors, because high throughput screens carried out in the pharmaceutical industry have identified numerous γ-secretase inhibitors. Multiple classes of potent γ-secretase inhibitors have now been described, and several of these have been shown to target both PS1 and PS2. At least one γ-secretase inhibitor is in clinical trials. Moreover, treatment of mice with a γ-secretase inhibitor reduces Aβ levels in the brain and attenuates Aβ deposition. However, despite these advances, numerous concerns over the use of γ-secretase inhibitors as AD therapeutics remain. These concerns center on target-mediated toxicity caused by interference with γ-secretase-mediated Notch signaling; inhibition of signaling mediated by newly recognized γ-secretase substrates (such as the epidermal growth factor receptor ErbB4) or unrecognized substrates; or accumulation of potentially neurotoxic APP CTFβ, which invariably occurs when γ-secretase is inhibited. Although the development of β-secretase inhibitors has lagged behind the development of γ-secretase inhibitors, many believe that β-secretase is likely to be a better therapeutic target.

Very recently, several Food and Drug Administration -approved (FDA-approved) ibuprofen, sulindac, and indomethacin, have been shown to be selective Aβ42-lowering agents. Moreover, long-term treatment of APP transgenic mice with ibuprofen attenuates Aβ deposition.

Fig. 2. Aβ aggregation as the cause of AD. A modified version of the amyloid cascade hypothesis is shown. This version takes into account the possibility that Aβ aggregates other than those found in classic amyloid deposits initiate the pathological cascade. It is possible that Aβ-induced toxicity in turn results in alterations in the brain, such as increased APP and apoE expression, that enhance Aβ deposition, although this is not shown in the figure. Besides known genetic pathways, a pathway in which normal Aβ levels in the context of normal aging may lead to Aβ accumulation is shown. "APPSw" refers to the APP Swedish mutant linked to familial AD; this mutation alters the lysine-methionine sequence immediately preceding Aβ to asparagine-leucine. Trisomy 21 is also known as Down syndrome.

Cholesterol-altering drugs.
Epidemiological data and data from model systems indicate that cholesterol-altering drugs may have an impact on the development of AD, and that this effect could be attributed to effects on Aβ accumulation. Cholesterol's role in Aβ metabolism appears to be quite complex and is the subject of recent reviews. Cholesterol-modulating drugs could influence Aβ deposition by (a) directly influencing Aβ production through alterations in secretase activity, (b) directly altering Aβ deposition, or (c) indirectly influencing Aβ deposition by altering levels of factors such as apoE. Alternatively, it is possible that the beneficial effect of cholesterol-lowering drugs on AD is related not to effects on Aβ, but rather to the fact that a CNS ischemic event can convert preclinical AD to clinically diagnosable dementia. It is worth noting that in a prospective population-based study, high systolic blood pressure was associated with a higher relative risk for AD than elevated serum cholesterol levels were. Nevertheless, regardless of the mechanism, treatment with statins or other cholesterol-altering agents may have a significant clinical benefit in the prevention of AD. The complex interaction of cholesterol with Aβ indicates, that there are many potential ways to alter Aβ metabolism. Other examples of the complex effects of drugs on Aβ metabolism include the action of the PI3K inhibitor wortmannin. Wortmannin inhibits Aβ production, both in cells and in vivo, apparently by altering APP trafficking. Although such drugs do not selectively target Aβ, if these compounds are relatively nontoxic (which is not the case for wortmannin), they are reasonable candidates for anti- Aβ therapy.

Therapies targeting Aβ aggregation or removal.
Because Aβ aggregation appears essential for the initiation of the AD pathogenic cascade, it may also be possible to prevent AD by altering Aβ aggregation or removing aggregates that are already formed. A number of research groups are currently exploring the development of direct Aβ aggregation inhibitors. While some encouraging results have been reported in animal models, these compounds are peptide-like and unlikely to make good drugs. One of the most surprising developments in anti- Aβ therapy is Aβ immunization. Direct immunization with aggregated Aβ42 was originally shown to attenuate Aβ deposition significantly in APP transgenic mice. Aβ immunization now appears to be effective in reducing amyloid deposition in multiple mouse models when mice are immunized, either actively with Aβ, or passively with intact anti-Aβ antibodies. However, it appears that there are some limits to the ability of immunization to clear existing plaques. Immunization of mice with large initial amyloid loads does not have a significant impact on amyloid deposition. Whether this lack of clearance can be attributed to an inherent limitation of the immunization approach or to the lack of production of sufficient amounts of anti-Aβ to clear large amounts of Aβ is unknown. In the latter case, one would postulate that simply increasing the amount of anti-Aβ would cause more Aβ to be cleared. Nevertheless, even in the apparent absence of any effect on Aβ load in the brain, Aβ immunization can ameliorate a cognitive deficit in reference memory and working spatial memory in APP transgenic mice. This suggests that, even in the absence of Aβ reduction, immunization may have some therapeutic effect.

Studies of Aβ metabolism reveal a number of potential therapeutic strategies that may alter Aβ accumulation in the AD brain. Agents targeting Aβ-induced cascades are also being evaluated; however, it is much more difficult to determine the potential efficacy of these, since the APP mouse models do not demonstrate all of the pathological features apparent in the AD brain. Moreover, because of the lack of clarity regarding how Aβ leads to neuronal dysfunction and death, most therapeutic modalities targeting downstream effects of Aβ are not necessarily specific to AD. Thus, agents such as antioxidants, neurotrophic factors, apoptosis inhibitors, and other neuroprotective agents may all be of benefit in the treatment of AD. They are also likely to be of general utility in other neurodegenerative conditions.

Any disease-modifying therapy must show clinical efficacy in order to be approved for the treatment or prevention of AD. This means that the rate of cognitive decline must be decreased or halted. Until that hurdle is overcome, ancillary studies examining effects of any therapy on Aβ or other biomarker levels in the plasma or CSF, on amyloid load in the brain, or on brain atrophy are largely meaningless. Once a convincing link is established between changes in any of these biomarkers and a clinically appreciable disease-modifying effect, approval of future drugs, which work through a similar mechanism, may require only that they modify linked biomarkers. For this reason, it is extremely important to monitor these parameters in current and future clinical trials. Studies with novel agents that assess both biomarkers and cognitive outcomes may be much more informative than studies that only assess clinical outcomes.

Cognitive enhancers that target acetylcholinesterase remain the only FDA-approved therapies for the treatment of the cognitive decline in AD. Such therapy is unlikely to modify the course of the disease to any significant extent. In contrast, therapies currently being developed that are based on an increased understanding of the pathogeneses of AD are likely to have disease-modifying effects. Given the plethora of potential targets, it is likely that successful anti- Aβ therapies will emerge. The major challenge that remains is to show that such therapies actually alter cognitive decline in humans. The medical community should be cautious in evaluating the efficacy of anti- Aβ drugs, as they may not show such disease-modifying effects when given in therapeutic trials. To restate the analogy to atherosclerotic disease, by the time a patient is experiencing angina, the patient needs a bypass or angioplasty, not a cholesterol-lowering agent (although after intervention such an agent would be appropriate). Similarly, in AD, by the time a patient is symptomatic, Aβ -lowering therapies may not be effective. We must hope that advances in diagnostic prediction and monitoring of disease progression proceed with a pace that equals the advances currently being made in developing AD therapeutics that target Aβ. If they do, then it is likely that AD will become manageable through a combination of presymptomatic screening, early therapeutic intervention, and vigilant monitoring of the effectiveness of treatment.

Source: Todd E. Golde. Alzheimer disease therapy: Can the amyloid cascade be halted? J. Clin. Invest. 111:11-18 (2003). doi:10.1172/JCI200317527.
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