Archives of Medical Research 43 (2012) 694e698

REVIEW ARTICLE

Pathogenesis and Disease-modifying Therapy in Alzheimers Disease: The Flat Line of Progress
Rudy J. Castellania and George Perryb
a

Division of Neuropathology, University of Maryland School of Medicine, Baltimore, Maryland b College of Sciences, University of Texas, San Antonio, San Antonio, Texas

Received for publication August 29, 2012; accepted September 18, 2012 (ARCMED-D-12-00460).

The lack of progress in the development of disease-modifying therapy in Alzheimers disease (AD) was highlighted recently by the cessation of a phase 3 clinical trial studying the effects of bapineuzumab on mild to moderate disease. No treatment benet was apparent, whereas several serious side effects occurred more commonly in the treatment group compared to placebo. This is the latest failure in a now long list of trials targeting lesional proteins believed to be fundamental drivers of the disease process. As the focus of the trial is directly tied to ostensible disease pathogenesis, objectivity compels us yet again to re-examine the amyloid cascade hypothesis as even a marginally signicant pathogenic mediator of disease and to perhaps revert back to traditional science where repeated negative data leads one to consider other ideas. In the case of AD, amyloid-b metabolism and tau phosphorylation have been exhaustively studied, both to no avail. Oxidative stress has similarly been examined in detail by multiple mechanisms and targeted for treatment with a similar result. An appeal to the scientic community may be made to consider lesions in a different light. Have we been seduced by so-called hallmark lesions into believing that they are responsible for disease when in fact the reverse is true, and will we genuinely consider a systems biology approach to AD or instead continue on the path of the lesion, which has so far followed a at line of progress? 2012 IMSS. Published by Elsevier Inc.
Key Words: Alzheimer disease, Amyloid-b, Tau, Oxidative stress, Mitochondria, Therapy.

Introduction The absence of even minimally effective disease-modifying therapy in Alzheimers disease (AD) after the exponential expansion of molecular technology in the latter half of the 20th century up to the present day, and more than 100 years after the identication of hallmark lesions, is direct testimony to what may be an absence of, or fundamentally erroneous understanding of, AD pathogenesis (1e3). Indeed, if we are true to the precept of objectivity in scientic investigation, we are compelled to accept that modern science has provided a catalog of downstream changes in AD, but the same has yet to address etiology, and therefore pathogenesis, in any tangible way. The recent failure of the phase 3 bapineuzumab trial is only the latest in a long list of reminders that we need to cure ourselves, as it were, of a priori bias
Address reprint requests to: Rudy J. Castellani, MD, 22 South Greene Street, Baltimore, MD 21201; Phone: 410-328-5422; FAX: 410-328-5508; E-mail: rcastellani@som.umaryland.edu

before we have any hope of curing patients of this devastating disease. Within the catalog of downstream changes is a list that includes amyloidosis, tau phosphorylation, oxidative stress including RNA modication and heavy metal toxicity (4,5), neurotrophic and neurogenesis failure (6), disordered energy metabolism (7), synaptic alteration (8), autophagy (9), and endosomal propagation, among other changes. Each is compelling in its own right, and the subject of voluminous literature. Each may be touted with great enthusiasm in the lay media and elsewhere. Yet the dismal fact remains: the diagnosis of AD, if rendered accurately today and in the foreseeable future, comes with it a disease course that is inalterable and with no hope of cure. Pathogenic Theories Amyloidosis Amyloidosis or altered Ab metabolism is perhaps the most prominent of the downstream changes of AD. The amyloid

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cascade hypothesis initially attributed pathogenesis to a conformational change, i.e., increased b-sheet secondary structure, and therefore decreased solubility, brillization, and nucleation of a toxic protein substance, amyloid, within the brain (10). The hypothesis had compelling genetic evidence in favor of its importance, most notably germline mutation in amyloid b protein precursor (AbPP) and cofactors inuencing AbPP cleavage, both leading to familial early onset disease. In addition, Down syndrome, in which increased copy number of the AbPP per se leads to amyloid deposits, neurobrillary pathology, and early-onset cognitive decline relative to baseline, is a compelling genetic link between Ab metabolism and neurodegeneration. On the other hand, hampering this hypothesis (in addition to now the repeated failures of immunotherapy and vaccine trials in humans) is the poor correlation between cerebral Ab deposits and cognitive function (11e16) which, in turn, has raised questions about the legitimacy of equating rare familial cerebral amyloidoses with the all-too-common sporadic disease. The oligomer concept, which suggests that soluble low-n protein aggregates are more proximally related to cognitive function, has been suggested as an explanation for the lack of a direct relationship of brillar Ab deposits and cognition. The concept, however, including a putative attack on the synapse, is still highly experimental and unproven and suffers from a number of issues surrounding relevance including, among others, poor reproducibility between investigators and inability to study, or even validate, in vivo in any direct way (1,17,18). Nevertheless, the amyloid cascade hypothesis is both remarkable and elegant in appeal, not only in terms of insight in illuminating the disease but its role in the diligent and exhaustive genetic investigation required for its elaboration (18). Tau Phosphorylation Tau phosphorylation has traditionally been a thorn in the side of the primacy of Ab metabolism in AD pathogenesis principally because of a i) superior relationship between protein deposition and cognition; ii) much greater eloquence in terms of brain region affected and neurological function associated with those brain regions, and iii) much greater diagnostic specicity (2,12,14e16). Moreover, should tau phosphorylation represent a rate-limiting factor in disease, this opens up new avenues in terms of intervention via kinase and phosphatase mechanisms, among others. Recent studies raising the possibility of tau-dependent prion-like activity of amyloid beta (19), cell to cell propagation of phosphorylated tau (20), have had some additional, recent impact in favor of tau pathology and disease. Clinical trials in this respect, however, although garnering enthusiasm in some cases (21), have been equally disappointing. From a genetic standpoint, tau metabolism also suffers from genotype-phenotype correlations, which indicate a close relationship between

tau mutation and the frontotemporal dementia phenotype. To date, no association has been demonstrated between tau mutation and AD phenotype (22). A number of experimental studies demonstrating tau-phosphorylation as clearly downstream of Ab accumulation are in a sense not surprising (23). In the human brain, it generally seems to be the case that tau phosphorylation in the cerebral neocortex is always preceded by an Ab aggregation (24), whereas neurobrillary pathology in the entorhinal cortex and locus coeruleus (25), which can and does occur in the absence of Ab deposits, is increasingly regarded as an incidental change more closely aligned with aging per se than AD pathogenesis (26). Oxidative Stress Substantial evidence demonstrating oxidative stress in AD, as well as its presence in preclinical disease and prepathological neurons, indicates yet another potentially important pathogenic mechanism and one with still further potential avenues for disease-modifying therapy (27). Hampering the oxidative stress hypothesis, however, is its complexity in biological systems and its universality. The idea of an orbiting, unpaired electron diffusing in a biological system is nebulous at the outset and suggests that oxidative stress is impossible to study directly in vivo. Crude downstream measures such as urinary excretion of oxidative by-products such as isoprostanes are certainly obtainable (28), but their relationship is separated from cell biology within neurons by several degrees. Adduct formation such as advanced glycation end products (29e32), advanced lipid peroxidation end products (33), and free carbonyls, may present novel epitopes (e.g., pentosidine, pyrraline, hydroxynonenal, malondialdehyde) which, in turn, can be exploited immunologically, offers a more direct assessment of oxidative stress in situ. Indeed, many advances in our understanding of oxidative stress in neurodegenerative and other diseases have been via this approach, whereas alterations in morphologically normal neurons and clinically normal individuals suggest an important, early change. Of more recent import is the nding of RNA oxidation, which may be particularly deleterious in that RNA is single stranded, such that RNA oxidation may induce sublethal changes within the cell that result in aberrant translation and exacerbation of chronic disease (4,5). Unfortunately, such changes are not disease specic, either in theory or empirically, and RNA and other macromolecules that are targeted are present in all cell types and all tissues. The obligatory hand-waving about vulnerability and anti-oxidant defenses thus ensues, but unfortunately brings us no closer to disease-modifying therapy. Not surprisingly, oxidative stress has pathogenic implications in a broad spectrum of disease states, in both acute and chronic settings and, in particular, age-associated processes such as

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atherosclerosis, and carcinogenesis in neurodegeneration (34). Such broad application necessarily runs counter to discussions of etiology. Redox biology is further complicated by the chemical-state-dependent property in that a given molecule may be either a pro- or anti-oxidant depending on the chemistry of the biological system, which may explain, at least in part, the disappointing results of anti-oxidants in AD clinical trials (35). Our knowledge of the chemistry as it relates to biology may presently be too primitive for brain-targeted therapy. Mitochondria and Energy Metabolism Energy metabolism, which is as old as life itself, is yet another attractive biological process implicated in neurodegeneration and AD (7). Mitochondrial alterations in particular, such as ssion-fusion abnormalities (36,37), defects in electron transport chain proteins (7), and cytoskeletal abnormalities that may impair mitochondrial movement and therefore biology (38), have all been shown to be altered in AD (38). Moreover, the biology of mitochondria brings into the equation calcium metabolism, intrinsic apoptosis pathways and activation of caspases, and generation of free radicals. Mitochondria thus represent a more systems biology-oriented model for neurodegeneration, less dependent on reductionism, or the idea of single small molecules such as Ab that may be pathophysiologically (or physiologically) altered in the face of thousands of proteins being transcribed at any given time within the neuron (1). Mitochondrial biology remains a fertile area of investigation for the above reasons, but with still much data being necessary before ascribing potential alterations in disease to etiology. Et Cetera Many other areas of investigation have yielded a wide array of interesting and even promising results. Among these are neurotrophic factors (6), dietary inuences (39), heavy metals (40), autophagy (9), and other environmental risk factors, blood brain barrier alterations and RAGE (41), and targeting of the synapse (8). Yet as promising as these areas of investigation may seem, each suffers from lack of specicity, lack of compelling evidence for etiology, and lack of demonstrable diseasemodifying treatment based on the given construct. In the end, we again seem to be faced with an encyclopedia of changes involving virtually every molecular mechanism described in human disease and the inability to alter the process. The Ab cascade showed the most promise and was easily the most studied, but has yielded results no different than placebo and sometimes worse. Examination of the eld, understanding of chronic disease, and the way we do business as scientists may be the most important next step.

Lesion Seduction In retrospect, the scientic community appears to have been seduced by pathological lesions into believing that they, the lesions, speak to etiology. Ironically, such lesion seduction increased dramatically, not with descriptions by Alzheimer, Fisher, or Bielschowskyindeed, these individuals were remarkably circumspect in their interpretation of the pathogenic signicance of what they were seeingbut rather with the purication of pathological lesions. Breakthroughs in molecular biology and the assignment of lesions to specic proteins and specic genetic loci led to the irresistible temptation to equate lesion with toxicity. This may be the fundamental misadventure that has resulted in so little progress. Pathologists may be particularly to blame for this, as it is they who are the most moved by new morphological ndings, and it is the pathologist more than other practitioners who are given to presume the importance of those ndings, albeit with relatively limited insight into clinical disease (42). Such is borne out in the most recent iteration of consensus criteria for AD (43) in which clinical ndings are now regarded as immaterial to the tally of pathological lesions, which are in turn renamed AD neuropathological changes, the nosology retaining the palpable sense of importance of that change to the disease process. Neurologists, for their part, in adherence to the time-honored but oversimplied principle of Occams razor, apply supercial understanding of the pathologic basis of disease to copious clinical expertise in order to narrow the etiological possibilities, which is a set-up for the co-mingling of an overly simplied pathogenesis and a highly complex disease. Neuroscientists, being molecular- and cell biologyoriented, may be given to apply singular pathways to explain overall disease, which is a blueprint for a level of reductionism that is inapplicable to the aged human brain. Systems biology is a relatively recent construct that attempts to address these human deciencies. Moreover, all of the above classes of investigator understand what is meant by systems biology and all recognize its importance, especially in the abstract. Yet, even a casual perusal of the literature, funded research, and clinical trials indicates that the lesion or its constituents are the elephant in the room; they continue to be studied and targeted with considerable compulsion in the hope of treating a primary or etiological process or cause rather than the more likely effect. Pathology and Pathogenesis in Chronic Disease It may be that the understanding of chronic disease pathology and its relationship to pathogenesis is turned upside down. Those changes that we have identied through the microscope or at the bench, to date, in chronic disease, may be an expression of survival, more closely aligned with Darwinian theory than with pathology/cause-clinical disease/effect theory, the latter being more true of acute disease processes. Experts in AD pathogenesis will often

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draw analogies with the process of atherosclerosis (44), i.e., plaques are the counterpart to atheromatous change, whereas tangles or other manifestations of toxicity are the counterpart to end-organ damage. Such analogies, although satisfying in their rhetoric, are probably irrelevant. Atheromatous change, including perhaps brous intimal hyperplasia, smooth muscle proliferation, macrophage inltrates, formation of necrotic cores, etc. indeed occurs over a period of years and may set up the environment for end-organ damage, e.g., myocardial infarct or ischemic stroke, but the latter takes place over a period of minutes or even seconds associated with plaque rupture or thromboembolism. Disease expression is thus dened by the acute changes rather than the chronic pathology, which was in actuality a decadeslong adaptation to the environment. In AD, there is no acute stage; it is slowly but steadily progressive loss of function. One could submit, therefore, that pathology of whatever type and by whatever detection modality, equals adaptation in neurodegenerative disease, and that targeting such changes is done with a very real risk of targeting a productive response and, therefore, accelerating the process. In this respect, enhancing something like amyloid deposition still dees sensibility to most clinicians and scientists. On the other hand, the heavy amyloid burden in many cognitively intact aged individuals, and decreased oxidative stress with increased pathology, may also be considered (27). Conclusion The above is a necessarily general discussion aimed more at appealing to a sense of objectivity among the many talented and achievement-oriented physicians and scientists among us because the problem we face, a lack of ability to modify age-related degenerative disease, is a general one, applicable to the spectrum of biological systems and all such systems studied to date. Indeed, we may be well served to keep in mind that the exponential slope of advances in molecular biology techniques, details of putative molecular-genetic pathways of disease, and the size of the arsenal of pharmacological agents at our disposal are accompanied by a at line in terms of disease modication, mathematically inseparable from the x-axis. The authors believe that a re-organization of the way we approach chronic disease is in order, that the possibility of confusing cause with effect be recognized in practice as well as in the abstract, and that a greater awareness of the possibility that pathology equals protection in neurodegenerative diseases be achieved and maintained. References
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