Next Generation Therapeutics for Alzheimer's disease

This section is compiled by Frank M. Painter, D.C.
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FROM:   EMBO Mol Med. 2013 (Jun); 5 (6): 795798 ~ FULL TEXT

Dale E. Bredesen, Varghese John

Buck Institute for Research on Aging,
Novato, CA, USA.

To date, no truly effective therapy has been developed for Alzheimer's disease or mild cognitive impairment. In searching for new approaches that may succeed where previous ones have failed, it may be instructive to consider the successful therapeutic developments for other chronic illnesses such as cancer and human immunodeficiency virus.

Keywords:   aging, Alzheimer's disease, chronic illnesses, dementia, multitherapy

From the FULL TEXT Article:

The current status

Dementia is one of the most significant global healthcare problems, with over 30 million symptomatic individuals, and many more likely to be in the decades-long pre-symptomatic phases (World Alzheimer Report, 2009, In the United States alone, over five million people suffer from Alzheimer's disease (AD), at an estimated annual cost of $200 billion, and a projection for 13 million patients by 2050. The high prevalence of AD is of particular concern because of the lack of success in developing effective therapeutics: in comparison to most classes of disease from neoplasia to cardiovascular and cerebrovascular disease to osteoporosis to diabetes to mental illness therapeutic development for AD has been, to date, a failure. Why?

The answer to this critical question is likely to be multi-faceted, and at least two of the more obvious facets relate to the similarities between AD and other chronic illnesses. First, there may be lessons to be learned from the successful development of therapeutics for other chronic illnesses, such as AIDS (acquired immunodeficiency syndrome), cancer, multiple sclerosis, type II diabetes mellitus and cardiovascular disease. HIV (human immunodeficiency virus) infection was transformed from a minimally treatable disease similar to the current state of AD treatments to a clearly treatable and chronically manageable disease with the introduction of combination therapy (HAART, highly active anti-retroviral therapy), in preference to monotherapy. Similarly, a major advance in oncology occurred with the introduction of combination chemotherapy (Frei et al, 1965), which has become the standard of care for numerous types of cancer. It is therefore noteworthy that, of the over 40 ongoing Phase 1, Phase 2 and Phase 3 clinical trials for Alzheimer's disease, virtually all involve monotherapeutic approaches (Mangialasche et al, 2010; Piau et al, 2011; Potter, 2010; Kushwah et al, 2012). Given the historical precedents, perhaps such an approach will not turn out to be the optimal one for the treatment of AD.

Is it possible that a comparison of the common features of the most frequent age-associated chronic illnesses may help provide insight into AD pathogenesis, and suggest novel therapeutic directions?

Feasibility of approvals

However, if the optimal therapeutic approach to AD does indeed turn out to involve a multi-component cocktail, an obvious consideration relates to the development and approval processes required for a cocktail approach: in the case of HIV treatment, each of the cocktail's constituents exerts a significant, albeit modest, effect on HIV infection. However, considering the numerous mechanisms identified as underlying AD pathogenesis, it is conceivable that many more than three different therapeutic agents will be required for optimal treatment of AD. Of even greater concern is the possibility that none of the components of the optimal therapeutic cocktail will turn out to exert a significant therapeutic effect when administered alone. How, then, would the optimal combination be identified, and ultimately approved for clinical use? Significant modernization of the current translational approach, clinical trial methodology and approval process may be required to render the optimization and approval of such a therapeutic cocktail feasible.

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