Alzheimer's Disease: Mechanisms and Prospects for Treatment

Alzheimer's Disease (AD) is the leading cause of dementia in the elderly. The Alzheimer’s Association estimates that there are currently over 5 million AD patients in the US, and this number is expected to climb to 16 million by 2050. In 2011, the cost of care for AD patients will total an estimated $183 billion dollars, and by 2050 this cost will rise to $1.1 trillion in today’s dollars. Given these statistics, it is clear that AD represents a looming epidemic that will threaten to bankrupt our health care system. In addition, the cost in human suffering to patients and care-givers is incalculable. The currently available AD therapies include acetylcholinesterase inhibitors, which provide only modest temporary palliative alleviation of memory symptoms. However, no disease-modifying treatments for AD yet exist. Clearly, the need for therapies that can inhibit the underlying pathophysiological mechanisms of AD is enormous. In this lecture, I will review the putative mechanisms of AD and discuss the prospects for future disease-modifying therapies. Two defining lesions are found in AD brain, the amyloid plaques and the neurofibrillary tangles. Much current evidence suggests that the major component of the amyloid plaques, the beta-amyloid peptide, plays a critical early role in AD pathogenesis. The beta-amyloid peptide is generated through the action of two enzymes, the beta- and gamma-secretases, and intense efforts are underway to develop secretase inhibitors to block beta-amyloid generation. Anti-amyloid immunotherapies are also being developed. Neurofibrillary tangles seem to appear later in the disease, but are likely to play a major role in subsequent neuronal degeneration and death. Treatments that block abnormal modifications of the tau protein that comprises neurofibrillary tangles are possible in principle but are far less developed than anti-amyloid strategies. Other potential AD therapies will also be mentioned. Despite recent clinical trial failures, progress continues toward understanding pathogenic mechanisms and developing therapeutic strategies for this devastating neurodegenerative disorder.