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Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps

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Abstract

Rationale

Over 30 years ago, we began to develop a nonhuman primate model to study cognitive deficits of age-related neurodegenerative diseases and their neuroanatomical–neurochemical underpinnings for purposes of translating this work toward first pharmacotherapies. This effort produced several notable findings that eventually received consensus support, which we have been asked to review.

Objectives

A discussion of these findings, in the context of issues and obstacles confronted and principles applied, might facilitate the development of even more effective models and treatments, not only for Alzheimer’s disease (AD) but for many other disorders involving cognitive deficits.

Results

Collectively, our research provided first evidence of the following: aged primates can be used as ‘models’ for human age-related neurodegenerative diseases; key cognitive deficits in early AD share important conceptual similarities to deficits in both aged monkeys as well as non-demented humans (e.g., age-associated memory impairment and mild cognitive impairment); pharmacological intervention can reduce age-related cognitive impairments in animals that are conceptually similar to those seen in human diseases, including AD; cholinergics would likely be the first approved therapeutics for AD; and that many other classes of drugs would not likely succeed.

Conclusions

Despite the early promise shown by behavioral/functional approaches to develop treatment strategies, the dramatic shift in focus away from behavioral outcomes in animal neurodegenerative research that began 20 years ago has compromised further progress and continues to impede our ability to understand how these diseases impair human cognition and what pathways might lead to effective therapies. Principles applied successfully in the past should provide guidance for facilitating efforts in the future.

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Acknowledgments

The vast majority of the authors’ studies reviewed here were performed while they were employees of either Warner-Lambert/Parke-Davis (now part of Pfizer) or Lederle Laboratories of American Cyanamid (now part of Wyeth). We are grateful for the support we received conducting this research and in particular for the encouragement of Dr. Duncan McCarthy (of Warner-Lambert/Parke-Davis) whose vision and passion was responsible for the initiation the first formal pharmaceutical program to search for drugs to treat learning and memory deficits (in 1973). We gratefully acknowledge the input, influence, and contributions of many friends and colleagues who, over the years, participated in many of the studies and thinking described in this review, and thus shared co-authorship in many of the published papers cited. We also appreciate the support of several journal and book editors involved in some of our earliest papers, who listened to our arguments and then supported our efforts to promote certain concepts and interpretations, often over the objection of some of their reviewers. Finally, we appreciate the helpful comments on earlier drafts by Drs. Steven Ferris, Mark Tuszynski, Jeffrey Kordower, and Trevor Robbins and the very helpful assistance of Anna Kovalchuk in preparing this manuscript and its tables.

Conflict of interest statement

The authors declare no conflicts of interest, except for brief mention of a possible treatment approach using AAV-NGF, for which Ceregene has an active clinical program. RTB (but not RLD) is an officer of Ceregene, receiving both salary and stock options.

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  1. Ceregene, Inc., 9381 Judicial Dr., Suite 130, San Diego, CA, 92121, USA

    Raymond T. Bartus

  2. Alkermes, Inc., 88 Sidney Street, Cambridge, MA, 02139, USA

    Reginald L. Dean III

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Correspondence to Raymond T. Bartus.

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Bartus, R.T., Dean, R.L. Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps. Psychopharmacology 202, 15–36 (2009). https://doi.org/10.1007/s00213-008-1365-7

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