Perspective on a pathogenesis and treatment of Alzheimer’s disease

Abstract

Although Alzheimer’s disease (AD) was described nearly 100 years ago, systematic studies focusing on the neurobiology of the disease have a relatively short history. The number of theories on the etiology of the disease and hypothesis on putative therapeutic targets has mushroomed since the late 1970s with the increased funding of research by the National Institutes of Health (NIH), particularly the National Institute on Aging (NIA). Now, in contrast, as recently as 15 years ago when there were no treatments available, the field has a rich array of hotly contested “leads,” ideas, and theories on treatment(s) [1–3]. Yet, in spite of the scientific popularity and the enormous investment of research resources to pursue the therapeutic utility/ validity of these theories, none of these have yet yielded a safe and effective intervention for AD. To date, four cholinesterase inhibitors and one N-methyl-D-aspartate (NMDA) receptor antagonist are the only classes of drugs that have been approved for symptomatic treatment of AD [3]. These interventions only provide short-lived improvement, with no effect on the progression of the disease. In the arduous and highly unpredictable world of drug discovery and therapy development it is unknown whether, when, or which one of several therapeutic strategies, targets, or molecules may ever result in an effective drug. The pending public health crisis, owing to the projected dramatic increases in the number of aging “baby-boomers” at risk for some form of dementia, mandates an accelerated and efficient drug discovery and development process. The effort will require partnerships between academia, industry, and government with renewed commitment to enrich the drug testing pipelines by increasing the number and variety of ideas driving the therapy development machinery. With this goal in mind, the present “Perspective” report presents a drug discovery– development hypothesis based on the initial findings from a clinical trial [4]. The ultimate objective of this hypothesis report is to generate dialogue and further experimental studies with the hope of broadening the options for therapies. The hypothesis is based on the results of a 24-week randomized clinical trial of an unmarketed formulation of rosiglitazone maleate, an insulin sensitizer and peroxisome proliferator-activated receptor (PPARgamma, PPAR) agonist, in the treatment of AD [4]. Exploratory analyses of the data raised the possibility of an interaction between treatment efficacy and presence or absence of the APOE4 allele, a common AD susceptibility gene. Related to this interaction, APOE4 noncarriers showed significant clinical improvement (Figure 1). If subsequently confirmed, this interesting and potentially important preliminary finding would provide the first clinically relevant use of genomic information in the selection of candidates for an AD treatment, and it would provide support for the use of a new drug class in the treatment of these patients. Currently, studies are underway not only to confirm efficacy but also to determine whether there is a gradient of improvement that is observed in virtually all patients depending on their specific genotypes, or whether there are some patients who receive no benefit. It is unusual for a clinical trial based on a new hypothesis to be successful. However, when there are preliminary clinical data available, it becomes relevant to discuss the underlying hypotheses more fully. In fact, the proposed hypothesis can become a factor in understanding the cascades of pathology and clinical systems associated with AD.