In 1906, the German physician Dr. Alois Alzheimer was the

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2 With a new class of medication about to debut, an expert explains the rationale supporting the amyloid hypothesis. By Daniel D. Christensen, MD In 1906, the German physician Dr. Alois Alzheimer was the first to describe post-mortem observations of miliary plaques and neurofibrillary tangles the distinguishing features of the progressive neurodegenerative disease that would later bear his name in the brain of his patient who died from a severe, progressive dementia. 1 Alzheimer s disease is the most common of the dementing illnesses, and approximately five million Americans now have Alzheimer s disease. 2 With the burgeoning growth of the elderly population, estimates project that there will more than 13 million Americans with Alzheimer s disease by the year Since Dr. Alzheimer s seminal report, great strides have been achieved in our understanding of the natural course and pathogenesis of Alzheimer s disease. In contrast, advances in treatment during this time have not been as significant. Symptomatic treatments, which have been in widespread use for over 10 years, are generally well-tolerated, but offer only short-lived improvement or relative stability in cognitive, functional and behavioral symptoms. The underlying disease process is not appreciably altered by currently available symptomatic treatments. Mapping of the molecular events underlying the pathogenesis of Alzheimer s disease has enabled a deeper understanding of the disease process and facilitated the identification of potential biological targets for disease-modifying drug therapy. Treating Symptoms or Modifying Disease? Development of new therapies for Alzheimer s disease is advancing at a rapid pace and with a different emphasis than in the past. Rather than solely attempting to develop drugs that treat the symptoms of Alzheimer s, the research community is also turning its attention toward disease-modifying therapies that alter its natural course. Indeed, the preponderance of current drug development efforts are focusing on underlying pathologic events that begin many years before the onset of clinically-apparent symptoms. 4,5 The concept of disease modification in Alzheimer s disease encompasses a spectrum of potential outcomes that range from delay or slowing of disease progression at one end to complete restoration of cognitive abilities at the other. The current treatment armamentarium for Alzheimer s disease consists of the cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the non-cholinergic NMDA-receptor antagonist memantine. These treatments have been shown in randomized, placebo-controlled trials to alleviate symptoms and defer disease progression for six to 12 months. Thereafter, the rate of decline returns to levels similar to pre-treatment baseline (see Figure 1). 6-9 While the preponderance of data suggests that the clinical benefit from symptomatic treatment is temporary, findings from several randomized controlled trials and openlabel studies suggest that some patients may have a more durable clinical benefit Also, the cholinesterase inhibitors in some trials have reduced caregiver distress and improved patients activities of daily living scores. 13,14 The tolerability and short-term symptom improvement associated with the cholinesterase inhibitors and memantine contributes to their widespread use. However, currently available drugs do not alter the eventual rate of cognitive and functional deterioration, and the initial clinical response is not sustained October 2007 Practical Neurology 29

3 Amyloid Hypothesis Figure 1. Change from baseline scores on the 11-item Alzheimer s Disease Assessment Scale (ADAS) Cognitive Subscale in patients with mild to moderate Alzheimer s disease in a placebo-controlled trial of galantamine demonstrating transient symptom improvement for galantamine-treated patients followed by deterioration at roughly the same rate as in placebo-treated patients (reproduced with permission from Wilcock et al. 2000). over the long-term. This is not surprising, given that by the time symptoms emerge, neuronal damage is extensive. Disease-modifying treatments that address underlying pathology and prevent Alzheimer s disease from occurring represent the ultimate therapeutic objective. However, preventive medicine is a goal that is not immediately in sight. Rather, treatments that delay onset or slow the rate of cognitive and functional decline in persons with mild Alzheimer s disease are much more within reach. The Amyloid Hypothesis The hallmark features of Alzheimer s disease are amyloid plaques (formerly referred to as senile plaques) and neurofibrillary tangles. Amyloid plaque formation, which is widely considered to be the primary pathologic event in Alzheimer s disease, 15 is followed by development of neurofibrillary tangles. Amyloid plaques are extracellular cerebral deposits that consist primarily of insoluble, fibrillar β-amyloid (Aβ) and, to a lesser extent, activated microglia, dystrophic neurites and reactive astrocytes. In Alzheimer s disease, amyloid is deposited in brain regions that control memory and cognition: the frontal, temporal and parietal lobes; hippocampus; entorhinal cortex; and amygdala. 16 Neurofibrillary tangles disrupt neuronal communication, are located intracellularly and consist of paired helical filaments of the hyperphosphorylated microtubule-associated tau protein. 15,17,18 The leading theory of the pathogenesis of Alzheimer s disease is the amyloid hypothesis (see Table 1), which outlines a series of events leading to amyloid plaque production and subsequent pathology. Elucidation of the amyloid pathway has enabled the identification of a number of distinct biologic targets for diseasemodifying treatments. As such, the amyloid pathway forms the basis of robust efforts at drug discovery and development. In addition to the amyloid hypothesis, there are alternative, albeit less mature, theories that are likely complementary to the amyloid hypothesis. These hypotheses largely describe events that may increase the risk of developing Alzheimer s disease or factors associated with downstream events in the amyloid cascade. For example, vascular diseases such as diabetes mellitus, atherosclerosis and hypertension are associated with increased risk of Alzheimer s disease. However, it is not known with certainty whether vascular disease influences amyloid pathology or simply adds to overall symptoms of dementia in persons with Alzheimer s disease Findings of large population studies suggest that persons treated with cholesterol-lowering statins have a lower risk of developing Alzheimer s disease, 21,22 possibly due to interference with amyloid deposition. 5,23 One randomized clinical trial found that atorvastatin slowed the rate of cognitive decline in patients with mild to moderate Alzheimer s disease. 24 Insulin resistance may increase the risk of Alzheimer s disease, 25 and newer generation oral hypoglycemics are being studied for their effect on amyloid accumulation. 26 Elevated levels of copper, zinc, aluminum or iron in the brain may be an etiologic factor for Alzheimer s disease or speed its progression. 27 Several of the proposed alternative pathologic hypotheses are listed in Table 2. While the amyloid cascade is believed to be the triggering process in Alzheimer s disease, other factors come into play as the disease advances. Pathological events in Alzheimer s disease are complex, particularly as the disease progresses. Hyperphosphorylation of tau proteins and formation of intraneuronal tangles correlate with neurodegeneration in AD. However, according to the amyloid hypothesis, tau pathology occurs secondary to amyloid deposition. Thus, tau is a viable biological target for disease-modifying therapies, but such therapeutic approaches may be less desirable as preventive strategies or in patients with mild Alzheimer s disease. Beyond amyloid deposition and formation of neurofibrillary tangles, chronic inflammation and oxidative stress are additional processes that may 30 Practical Neurology October 2007

4 contribute to progression in advanced disease via independent pathways. 15 The amyloid hypothesis posits that accumulation of Aβ in the cerebral cortex and frontotemporal regions initiates a cascade of pathological events that lead to neurofibrillary tangle formation and ultimately, neurodegeneration, dementia and death. Aβ is constitutively produced during normal cell metabolism and as such is not considered to be a pathological entity. Accumulation of Aβ is the result of increased pro- Figure 2. Biological targets on the amyloid pathway for potential anti-amyloid disease-modifying therapies in Alzheimer s disease (with permission from Golde 2006). duction, decreased clearance, or a combination of both. 19,28 The Aβ component of the amyloid plaque consists primarily of aggregated Aβ42 (i.e., a highly neurotoxic 42-amino acid peptide subspecies of Aβ). Shorter non-neurotoxic peptide fragments, Aβ38-40, are also found in amyloid plaques but they do not appear to initiate or foster plaque deposition. 16,28-30 Amyloid plaque formation begins with the amyloid precursor protein (APP), which is a membrane-bound protein involved in normal cellular function, including synaptogenesis and neuronal plasticity. 30 Amyloid precursor protein is cleaved sequentially, first by β-secretase (i.e., BACE-1) and subsequently by γ-secretase, to produce either Aβ42 or other benign peptides of varying lengths (see Figure 2). An alternative, non-amyloidogenic pathway in the processing of APP involves α-secretase, which cleaves at a site that precludes Aβ42 formation and may protect against Aβ42 production and amyloid plaque formation. 28,31,32 Under normal circumstances, approximately 80 percent of Aβ consists of Aβ38-40; Aβ42 makes up a relatively small minority of the amino acid peptide fragments produced by the cleavage of APP. However, in Alzheimer s disease, the balance of APP processing shifts to increased production of Aβ42, which aggregates more readily than other subspecies of Aβ. 31 Evidence Supporting the Amyloid Hypothesis At present, Alzheimer s disease is a clinical diagnosis based on increasingly severe symptoms of memory loss, cognitive decline, functional impairment and behavioral disturbances. Definitive diagnosis requires autopsy confirmation of sufficient numbers of amyloid plaques and neurofibrillary tangles. Ongoing work in the field of neuroimaging is advancing our ability to make a diagnosis. One promising technique is positron emission tomography (PET) using amyloid-imaging agents that show amyloid plaque deposits prior to cognitive decline in persons with Alzheimer s disease. 33 However, until prospectively-conducted studies demonstrate the ability of neuroimaging techniques to make an early diagnosis, a differential diagnosis, or follow patients longitudinally and track disease progression and treatment response, it is not yet possible to truly study Alzheimer s disease in the living brain. Thus, several different avenues of preclinical and clinical investigation have been explored and provide support for the pivotal role of amyloid plaque and Aβ42 in the pathogenesis of Alzheimer s disease (see Table 1). Genetic transmission. Evidence from genetic studies offers a compelling argument for the primary role of Aβ42 in the pathogenesis of Alzheimer s disease. For example, approximately one percent of patients have the familial, early-onset (i.e., diagnosed in persons younger than 60), autosomal dominant form of Alzheimer s disease. Familial Alzheimer s disease is caused by mutations in genes that express APP, presenilin-1 [PS-1], or PS ,30 Most patients with Alzheimer s disease have the sporadic form, which can be associated with inheritance of the polymorphic apolipoprotein E (APOE) ε4 allele. 30 Persons with Down s October 2007 Practical Neurology 31

5 Amyloid Hypothesis Table 1. Research Supporting the Amyloid Hypothesis and the Pivotal Role of Ab42 See refences 15, 19, 36 Widespread accumulation of amyloid plaques in the brains of persons with Alzheimer s disease. Mutations of genes encoding for amyloid precursor protein (APP) and γ-secretase (i.e., presenilin-1 [PS-1] and PS-1) that promote overall Aβ production or selectively increase production of Aβ42 in familial Alzheimer s disease. Presence of the APOE (apolipoprotein E) ε4 allele (involved in Aβ deposition) increases the risk of sporadic (i.e., late-onset) Alzheimer s disease. Over-expression of APP, increased levels of Aβ42 in the brain, and high risk of early-onset Alzheimer s disease in persons with Down s syndrome. Mice genetically engineered to produce high levels of APP or to produce Ab42, but not other subspecies of Aβ, develop profound amyloid plaque burden and learning deficits in an age-dependent fashion. Positron emission tomography (PET) scans using amyloid-binding ligands demonstrate amyloid deposition prior to memory loss in persons with Alzheimer s disease. Aβ42, which aggregates more rapidly than other Aβ subspecies, is the predominant peptide in amyloid plaques. syndrome (Trisomy 21) are genetically predisposed to develop Alzheimer s disease as early as the third decade of life as a result of an extra APP gene that leads to over-production of APP. Further, elevated levels of Aβ42, but not Aβ40, are detected in both the fetal brain and in the brains of children and adults with Down s syndrome, suggesting an early and primary role for Aβ42 in the pathogenesis of Alzheimer s disease. 34,35 Transgenic mice. Data from animal models that mimic many characteristics of Alzheimer s disease are central in supporting the role of Aβ42 production and amyloid accumulation as primary pathological events. The findings from studies using genetically-engineered (i.e., transgenic) mice represent an important piece of the Alzheimer s disease puzzle. Many different transgenic mouse models of Alzheimer s disease are in use. Although transgenic mice that completely replicate Alzheimer s disease in humans have not yet been developed, these animal models are very useful in studying the age-related effects of excess APP production, selective expression of Aβ42 or other Aβ subspecies, learning deficits, tau pathology, and effects of investigational drugs. Transgenic mice are engineered by transplanting one or more genes for aberrant APP production or other elements of the amyloid pathway (e.g., selective production of Aβ42 or Aβ40) into embryos that are implanted in breeding females. Subsequent offspring express the target genes and associated features. 36 Transgenic mice engineered to express only Aβ42 develop high levels of amyloid plaque at an early age (see Figure 3). When mice that are engineered to over-express APP are bred with transgenic mice that selectively express Aβ42, the offspring have marked amyloid-related pathology exceeding that of either parent. Development of a triple transgenic model in which mice express mutant APP, PS-1, and tau genes demonstrated the temporal sequence of Alzheimer s disease pathology. In these triple transgenic mice, profound amyloid plaque development was apparent by the age of six months. However, tau pathology occurred secondarily in these mice, at 12 months of age. 37 Such findings provide further support for the primary role of amyloid and Aβ42 in the pathogenesis of Alzheimer s disease. Targets for Anti-amyloid Drug Development Translational research in Alzheimer s disease is beginning to bear fruit as findings from studies in basic science are being applied to drug development and clinical testing in patients. A better understanding of the underlying biological mechanisms responsible for the onset and progression of Alzheimer s disease is enabling the development of drugs that are targeted at specific points in the pathway. In theory, blocking the formation of Aβ42 and deposition of amyloid plaque or increasing its clearance will delay or prevent the onset of Alzheimer s disease and slow its course. Thus, the amyloid pathway is a logical target for disease-modifying treatments (see Figure 2). Interfering with the expression of APP is a possible intervention point for a disease-modifying therapy. Phenserine is a cholinesterase inhibitor that also blocks translation of APP, but clinical testing of this compound was halted because trial results were disappointing. 38 Some have speculated that APP is probably necessary for normal brain function so that blocking its production is not a desirable approach. Preventing the cleavage of 32 Practical Neurology October 2007

6 Figure 3. Amyloid plaque deposition increases in an age-dependent fashion at three months (panel A), six months (panel B), and 16.5 months (panel C) in transgenic mice engineered to selectively produce Aβ42 (reprinted with permission from McGowan et al. 2005). APP by β-secretase or g-secretase is another strategy for potential disease modification by prevention of Aβ42 and subsequent downstream pathology. Both β-secretase inhibitors and g-secretase inhibitors have been studied in clinical trials. However, developing safe and effective clinical compounds is a challenge which has not yet been fulfilled. The catalytic site on the b-secretase enzyme readily binds to large molecules. However, large molecules do not cross the blood-brain barrier, and successful development of a b-secretase inhibitor awaits identification and testing of a viable small-molecule compound. In contrast, g-secretase inhibitors achieve measurable concentrations in the brain. Safety concerns are a consideration with these agents because inhibition of g-secretase has untoward consequences on other biological systems, such as the gastrointestinal tract and hematopoietic cell lines. 4,15,39 Another approach to prevent the production of Aβ42 is to modulate the activity of γ-secretase. Shifting the γ-secretase cleavage site so that shorter, non-toxic Aβ fragments (i.e., not Aβ42) are produced is being studied in advanced stage clinical trials with the selective Aβ42-lowering agent (SALA) tarenflurbil. Modulation of γ-secretase avoids toxicity concerns because other biologically essential substrates of γ-secretase are not affected. 15 α-secretase cleavage is a pathway that cuts the APP within the Aβ42 domain so that Aβ42 is not produced. Agents, such as cholesterol-lowering statins and hormone replacement therapy, may activate a-secretase and in theory could be protective in Alzheimer s disease. Clinical trials are ongoing. 4,15 Increasing clearance of amyloid deposits from the brain is a concept being tested with active and passive antibodies against Aβ. Strategies designed to avoid the neurotoxicity that has been associated with active immunotherapy are under active investigation. Finally, preventing Aβ from aggregating and forming amyloid plaques and/or enabling clearance of soluble Aβ is a strategy under investigation with anti-aggregation agents. One such agent is tramiprosate, which binds to glycosaminoglycan receptors thereby blocking Ab aggregation. 15,40 The hyperphosphorylation of tau and development of intracellular neurofibrillary tangles represent other logical targets for disease modification. Studies of therapeutic agents designed to block tau pathology are far less advanced than anti-aβ strategies. Nonetheless, tau remains an important downstream target for drug therapy. Tauopathy in Alzheimer s disease appears to occur after Aβ deposition and is believed to be pivotal to the subsequent progressive neurodegeneration. Therapeutic strategies for targeting tau include decreasing tau production, inhibiting tau aggregation, altering tau phosphorylation via kinase inhibitors, and enhancing tau clearance. 15,19 Conclusions Tremendous advances have been gained in our understanding of the underlying pathology of Alzheimer s disease in the past 100 years. Currently available treatments, while widely used, offer transient improvement in symptoms, but do not appreciably alter underlying disease processes. Disease-modifying treatments that slow or stop the progression of Alzheimer s disease or possibly prevent its onset are now the goal for new drug development. A deeper understanding of the biological processes that initiate Alzheimer s disease has allowed the identification of poten- October 2007 Practical Neurology 33

7 Amyloid Hypothesis Table 2. Various Hypotheses of the Basic Pathology of Alzheimer s Disease Amyloid hypothesis Tau hypothesis Calcium hypothesis Metabolic hypothesis Energetics hypothesis Inflammation hypothesis Plasticity hypothesis Microglial dysfunction hypothesis Cell cycle hypothesis tial biological targets for disease-modifying drug therapy. According to the amyloid hypothesis, which is the leading theory underlying the pathophysiology of Alzheimer s disease, accumulation of amyloid β (Aβ) plaques initiates a cascade of events leading to neurodegeneration and dementia. Amyloid plaque formation begins with sequential cleavage of the amyloid precursor protein (APP) first by b-secretase and subsequently by g-secretase. When this process favors the production of Aβ42 over shorter species (i.e., Aβ38-40) plaque deposition becomes more likely. Aβ42 is highly neurotoxic, and its production appears to be a central event that triggers the downstream pathology of Alzheimer s disease. A large body of preclinical and clinical evidence supports the amyloid hypothesis of Alzheimer s disease. Based on the amyloid hypothesis, a broad array of investigational disease-modifying treatments has entered and will continue to enter clinical trial testing. PN Daniel D. Christensen, MD is Clinical Professor of Psychiatry, Clinical Professor of Neurology, and Adjunct Professor of Pharmacology at the University of Utah Neuropsychiatric Institute in Salt Lake City, Utah. Dr. Christensen wishes to thank Karen Fullmer for clerical and administrative assistance and Sally Laden for assistance with literature review and manuscript editing. 1. Maurer K, Volk S & Gerbaldo H (1997) Auguste D and Alzheimer's disease. Lancet. 349: Alzheimer s Association. What is Alzheimer s? 2007; available at eimers.asp; accessed September 18, Hebert LE, Scherr PA, Scherr JL, Bienias JL, Bennett DA & Evans DA (2003) Alzheimer disease in the US population: prevalence estimates using the 2000 census. 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