Almost 100 years ago, Alois Alzheimer described the case of Auguste D., a woman who developed delusions and memory impairment at 56 years of age. Alzheimer went on to detail the symptoms and neuropathology of the disease that came to carry his name. For most of the subsequent century, however, little more was learned: Alzheimer's disease remained an entity with a well-described syndromal presentation, clinical course, and a distinct neuropathology but little else appreciated. Only in the past 20 years have findings regarding the pathogenesis of AD and potential treatments emerged. The emergence of standardized criteria for both the clinical diagnosis of AD and its pathological definition; the mainstreaming of a pathogenetic theory; the development of animal models; the identification of specific gene risk factors; and the first round of approved treatments have recently come to light.

This wealth of discovery has been fueled by the development of new techniques and technologies. Equally important has been the shift in attitude regarding cognition in the elderly. The notion of “senility” has been largely supplanted by a growing appreciation that cognitive decline is not the rule and is indicative of a distinct disease process. This realization spurs the research to determine who declines, who does not, and the risks factors for decline. This paradigm shift has allowed a renewed focus on disease processes related to memory decline in aging, and particularly AD. This issue of CNS Spectrums focuses on the shift in thinking about AD. We are on the cusp of a dramatic change in our understanding of the risks for AD, the mechanisms for its genesis, and how it might be prevented and treated.

Hillel Grossman, MD, expands the paradigm shift by focusing on diabetes mellitus and its relationship to AD. Early epidemiologic studies saw a seeming protective effect from AD among patients with diabetes mellitus. More recent prospective studies note that diabetes mellitus and insulin resistance seem to heighten the risk for AD. This finding has moved to the laboratory, where observations related to insulin-degrading enzyme and its role in amyloid metabolism suggest a potential mechanism for this heightened risk.

Diabetes mellitus has long been considered a risk factor for the development of vascular dementia. Epidemiologic evidence has suggested that diabetes mellitus significantly increases risk for the development of Alzheimer's disease, independent of vascular risk factors. As insulin's role as a neuromodulator in the brain has been described, its significance for AD has also emerged. Insulin dysregulation may contribute to AD pathology through several mechanisms including decreased cortical glucose utilization particularly in the hippocampus and entorhinal cortex; increased oxidative stress through the formation of advanced glycation end-products; increased Tau phosphorylation and neurofibrillary tangle formation; increased β-amyloid aggregation through inhibition of insulin-degrading enzyme. Future treatment of AD might involve pharmacologic and dietary manipulations of insulin and glucose regulation.

The distinction between Alzheimer's disease and vascular dementia, the two most common types of dementia, has been undermined by recent advances in epidemiologic, clinical, imaging, and neuropathological studies. Cardiovascular risk factors, traditionally regarded as distinguishing criteria between the two entities, have been shown to be associated with both AD and vascular dementia. In this article, we propose mechanisms of action of cardiovascular risk factors in AD, suggest possible explanations for the overlap with vascular dementia and discuss the implications this might have on future differential diagnosis, research, and treatment strategies.

Emerging therapies for Alzheimer's disease offer hope to patients and their caregivers. Future treatments will probably include combination approaches with agents that modify amyloid processing, deposition, and clearance. One example, the AD vaccine, reduced amyloid burden and changed behavior in animal models of AD, but the human trial was halted when several subjects developed brain inflammation. Anti-inflammatory agents have epidemiologic support, but clinical trials have been disappointing, possibly related to inadequate study with anti-inflammatory agents that modify amyloid processing. Agents that target known cardiovascular risk factors, such as hypercholesterolemia, hypertension, and insulin resistance, have epidemiologic, preclinical, and clinical evidence to warrant further investigation. Heavymetal chelators, antioxidants, neurotrophic factors, glutaminergic modulators, and agents that modify hyper-phosphorylation of Tau are other approaches in research and development.

Alzheimer's disease represents a significant challenge to the aging population. Since most estimates suggest that AD has a multifactorial etiology, the challenge to find preventative approaches is particularly great. With the aging of the population and the very high incidence from the eighth decade on, the challenge is further enhanced by the need to think of relatively safe interventions given the relative frailty of this elderly population. The need to find safe treatments, or ones with well-understood safety profiles, has led to the examination of known agents for potential dementia-preventing properties. Data supporting these interventions comes from observational studies, laboratory analyses, and clinical trials. Potential mechanisms for prevention of AD include anti-inflammatory and antioxidant approaches. Modulation of risk factors associated with cardiac disease may also reduce the risk of AD. Known agents have been examined for their potential to modify amyloid pathology. Trial designs to address prevention of AD include both primary and secondary prevention studies as well designs to assess slowing disease progression. Information can also be gathered when dementia evaluation is added to ongoing studies. As results from these studies becoming available, we will be able to refine our approach to managing this disease.