Editorial Current Alzheimer Research, 2009, Vol. 6, No. 5 407

Editorial

A Multi-Targeted Approach for a Complex Multifaceted Disease

Alzheimer’s disease (AD), as with other late life dis-eases, is undoubtedly caused by a multitude of factors that are influenced by stochastic events, an individual’s genetic makeup and environmental exposures. Combination therapy; including preventative treatments, disease modifying thera-pies, symptomatic agents and lifestyle changes may be our best hope at eradicating Alzheimer’s disease from our soci-ety. To this end, the Alzheimer’s Drug Discovery Founda-tion (ADDF) has funded diverse and novel programs, some of which are highlighted in these proceedings from the 9

th

International Conference on Alzheimer’s Disease Drug Dis-covery, that seek to intervene at various stages of the disease process. A similar effort by ADDF was previously high-lighted [1]. It is important to consider these independent studies as a joint effort to discover and develop treatments that complement each other as a means to improve the lives of Alzheimer’s disease patients and their families.

Studies with human post-mortem brain tissue have given us an invaluable window into the pathological state at the end-stage of the disease. From these studies, scientists have identified the major hallmarks of late stage disease, includ-ing amyloid plaques, neurofibrillary tangles, neuronal cell loss and gliosis. However, to this day, we do not fully under-stand the initiating triggers of the disease or what may be a cause verses a consequence of disease progression. While many valuable studies have been performed in in vitro and in vivo models of AD, our ability to monitor disease progres-sion or analyze pathological changes at early disease stages in humans has been quite limited. Therefore, advances in neuroimaging technology and biomarker assays are crucial for early detection, monitoring of disease progression and response to novel treatments. These efforts can reduce the cost and time of clinical trials, allowing new drugs to reach the market faster. If AD is detected early, before significant symptoms occur, preventative treatments (both pharmacol-ogical as well as lifestyle changes) can be initiated at the stage where they can have the most benefit. To this end, Jeff Kuret is working to develop small molecules that would spe-cifically detect neurofibrillary tangles in living human pa-tients as well as inhibit tangle formation (page 409-414). Neurofibrillary tangles, as a marker of neuronal injury and death, closely correlate with cognitive deterioration and clinical disease severity [2, 3]. Therefore, reliable measure-ments of the quantity and the distribution of tangles in living patients could serve as a valuable surrogate marker for clini-cal disease progression and aid in treatment development.

Understanding genetic risk factors for AD is another method to facilitate early detection of high risk individuals, while also providing insight into disease mechanisms which can lead to the discovery of novel targets and enhance drug discovery efforts. For example, individuals with the apolipo-protein E4 allele (ApoE4) have a significantly greater risk of developing Alzheimer’s disease and often exhibit an earlier age of onset and a more aggressive form of the disease [4]. While ApoE4 is a known risk factor for AD, we still do not fully understand the mechanism of how it influences AD

pathogenesis. To address this issue, Ning Zhong and Karl Weisgraber are working to correlate structural differences in the ApoE isoforms to the functional changes in AD risk (page 415-418). The more we understand about how these isoforms influence AD progression, the more insight we gain into mechanisms behind the variation seen in these genetic pools of AD patients. Identifying genetic subtypes of AD could allow for the development of more individualized therapies as well as aid in the clinical trial design of novel drug therapies. In fact, in the Phase II Bapineuzumab trial initiated by Wyeth and Elan, ApoE4 carriers were separated from non-carriers in the analysis. Only non-carriers demon-strated a significant benefit from the treatment, which would not have been detected had the population been analyzed as a whole [5].

The benefit of developing treatments for a disease as complicated and multifaceted as AD is that there are likely numerous points at which one can intervene. The 9

th Interna-

tional Conference on Alzheimer’s Disease Drug Discovery illustrated the diverse spectrum of programs that ADDF funded investigators are pursuing. Neuroprotective and syn-aptic enhancement strategies as well as anti-oxidant and anti-inflammatory strategies complement approaches that are more specifically targeted to disease-associated proteins. For example, H. Uri Saragovi is working on developing novel ligands to modulate neurotrophin receptors and confer neu-roprotection (page 419-423). In addition, Hyman Schipper is working on developing inhibitors of glial heme-oxygenase 1 in order to prevent oxidative injury to neurons (page 424-430), while Sergey Kalinin and Douglas Feinstein are testing PPARdelta agonists for their ability to decrease amyloid plaque load and inflammation (page 431-437). Since both plaques and tangles, as well as other neurodegenerative dis-ease pathologies, are composed of misfolded protein, ADDF funded investigators are also pursuing general strategies that promote normal protein folding or facilitate degradation of abnormally folded proteins. Along these lines, Ben Bahr is developing lysosomal modulatory drugs to increase mis-folded protein disposal (page 438-445).

Common pathways exist between many neurodegenera-tive diseases and efforts are underway to develop treatments that could be effective for multiple diseases. In an effort to promote knowledge sharing between these diseases, a ses-sion on Frontotemporal dementia (FTD) and neurofibrillary tangle-targeted therapies was added to the 9

th International

Conference on Alzheimer’s Disease Drug Discovery. While FTD and AD demonstrate different disease etiologies and are typically distinguishable in the clinic, the end-stage diseases share many similarities including cognitive and behavioral changes as well as neurofibrillary tangle accumulation and neuronal cell loss in the brain [6]. Studying these pathways provides new clues to general mechanisms of neurodegen-eration and allows for cross-fertilization of tangle-targeted drug discovery ideas that have the potential to benefit both diseases. To this end, Einar Sigurdsson is working to de-velop tau-targeted immunotherapy for AD (page 446-450);

408 Current Alzheimer Research, 2009, Vol. 6, No. 5 Editorial

while Scott Yuzwa and David Vocaldo are testing the con-cept of targeting O-GlycNAC modification of tau to decrease tau phosphorylation and tangle formation (page 451-454). Further, Illana Gozes is developing a nasally administered neuroprotective peptide for clinical testing (page 455-460). This peptide is thought to work by enhancing microtubule stability and would therefore protect against tangle-induced toxicity.

Philanthropy has the unique position of being able to take on increased risk to fund novel research areas, like the ap-proaches presented in these proceedings, and fill the funding gap between basic and clinical research, allowing for innova-tive ideas to be tested and brought forward into drug discov-ery platforms. ADDF focuses almost exclusively on transla-tional research and stimulates interdisciplinary interactions and collaborations to catalyze drug discovery and develop-ment studies [7]. These proceedings demonstrate diverse and complementary approaches to AD drug discovery research which could one day be mirrored in the clinic as an Alz-heimer’s disease treatment ‘cocktail’ of sorts, containing multiple treatments to target the many pathways influencing this complex, multifaceted disease.

In closing, we would like to thank all of the presenters and attendees at the 9

th International Conference on Alz-

heimer’s Disease Drug Discovery as well as the editors of Current Alzheimer Research. Finally, we are grateful for the support of our sponsors without which this conference would not have been possible: Allon Therapeutics, Elan Pharma-ceuticals, Inc., Forest, Wyeth Research, Bellus Health Inc., Genentech, Inc., JSW-Research Forschungslabor GmbH, Baxter BioSciences, Eisai Inc., and the Association for Fron-totemporal Dementia (AFTD).

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[1] Horton AR, Fillit HM. Drug discovery for Alzheimer's disease:

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[3] Mitchell TW, Mufson EJ, Schneider JA, Cochran EJ, Nissanov J, Han LY, et al. Parahippocampal tau pathology in healthy aging,

mild cognitive impairment, and early Alzheimer's disease. Ann Neurol 51: 182-189 (2002).

[4] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele

and the risk of Alzheimer's disease in late onset families. Science 261: 921-923 (1993).

[5] Elan and Wyeth Present Encouraging Results from Phase 2 Clinical Trial of Bapineuzumab at International Conference on Alzheimer's

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pathies. Annu Rev Neurosci 24: 1121-1159 (2001). [7] Refolo LM, Fillit HM. Partnerships between philanthropy, govern-

ment and industry are needed to advance drug discovery for neurodegenerative diseases. Curr Alzheimer Res 3: 175-176

(2006).

D.W. Shineman and H.M. Fillit Guest Editors

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