Frontiers in the Pathogenesis of Alzheimer's Disease

Article excerpt

Byline: Kumar. Sambamurti, K. Jagannatha Rao, Miguel. Pappolla

Alzheimer's disease (AD) is characterized by progressive dementia and brain deposits of the amyloid [sz] protein (A[sz] ) as senile plaques and the microtubule-associated protein, Tau, as neurofibrillary tangles (NFT). The current treatment of AD is limited to drugs that attempt to correct deficits in the cholinergic pathway or glutamate toxicity. These drugs show some improvement over a short period of time but the disease ultimately requires treatment to prevent and stop the neurodegeneration that affects multiple pathways. The currently favored hypothesis is that A[sz] aggregates to toxic forms that induce neurodegeneration. Drugs that reduce A[sz] successfully treat transgenic mouse models of AD, but the most promising anti-A[sz] vaccination approach did not successfully treat AD in a clinical trial. These studies suggest that AD pathogenesis is a complex phenomenon and requires a more broad-based approach to identify mechanisms of neurodegeneration. Multiple hypotheses have been proposed and the field is ready for a new generation of ideas to develop early diagnostic approaches and develop successful treatment plans.

Introduction

Alzheimer's disease (AD) is the most common cause of dementia among the elderly. AD currently affects 12 million people worldwide (4.5 million in America) and this number is likely to triple with the aging of the baby-boom generation by 2050.[sup] [1],[2],[3] The prevalence rate for AD is about 7% for individuals aged 65 or more, and the risk doubles every 5 years after age 65.[sup] [4]

Clinical diagnosis of AD is carried out by establishing the existence of progressive dementia and then ruling out other conditions such as depression, vascular dementia, etc. The diagnosis is normally confirmed in the post-mortem brain by the presence of characteristic lesions -- senile plaques (SP) and neurofibrillary tangles (NFT). The National Institute on Aging (NIA) has listed seven early warning signs of AD that are paraphrased below (http://www.nia.nih.gov/Alzheimers/Publications/sevensigns.htm):

*Asking the same question over and over again. *Constantly repeating the same story, word for word. *Forgetting activities that were routine, such as cooking or playing cards. *Losing one's ability to manage critical activities such as managing finances and paying bills. *Getting lost in familiar surroundings, or misplacing household objects. *Neglecting personal hygiene while insisting that they were clean. *Relying on someone else to decide and respond on issues they normally handled themselves.

In early stages, the disease is characterized by amnesia (memory loss), visuospatial deficits, and slurred speech patterns. As AD progresses, patients display a number of abnormal and socially inappropriate behavior traits that lead to considerable embarrassment. Eventually, the disease leads to extensive disruption of activities of daily living and the patient becomes confined to nursing home care and often needs to be restrained. The patient forgets the caregiver even when they have been close for very long periods of time and ultimately even loses the sense of self. Although AD ultimately leads to death, the process is extremely slow and can last as long as 10 years. In general, early cognitive symptoms can last for up to 3 years and progress to functional dependence and behavior deficits between 1.5 and 4 years and death between 3 and 10 years.[sup] [5]

AD was initially described in the early 1900s by Alois Alzheimer as an unusual psychiatric disorder in a 51 yr old woman admitted to an asylum with cognitive and language deficits, auditory hallucinations, delusions, paranoia, and aggressive behavior. He went on to characterize the brain at the microscopic level using a number of histochemical stains that were newly developed during this period. The lesions -SP and NFT- continue to remain the main landmarks of the disease named after its discoverer. …