Alzheimer’s Disease and the Neuroscience of Aging

Alzheimer’s disease, the most common cause of dementia, is the result of abnormal changes in the brain that lead to a precipitous decline in intellectual abilities and changes in behavior and personality. As the primary Federal agency responsible for research on Alzheimer’s disease, the NIA leads national efforts to gain greater understanding of the biological mechanisms underlying Alzheimer’s disease and to develop preventive measures and treatments based on research findings. Tragically, as many as four million Americans now suffer from Alzheimer’s disease, 3 and the predicted explosive growth in the number of people living to 85 years and older, persons most at risk for dementia, lends an urgency to this research. Although the early signs of Alzheimer’s disease involve mild forgetfulness, the progressive dementia ultimately leaves patients incapable of caring for themselves. Behavior changes may cause patients to become agitated, sometimes to the point of causing harm to themselves or others. Alzheimer’s disease devastates its victims and profoundly affects the millions of family members and other loved ones who provide most of the care for people with this disease. Alzheimer’s disease also necessitates formal services at substantial cost to individuals and public programs, estimated at greater than $100 billion per year. 4 While much remains to be done, research progress has been accelerating rapidly, bringing the field to the threshold of prevention trials. Story of Discovery—Progress in Understanding Alzheimer’s Disease

In 1906, Dr. Alois Alzheimer described a patient, Auguste D., who experienced a four-year progressive decline into dementia and then died at age 55. Alzheimer’s postmortem study of Auguste D.’s brain revealed two striking pathological findings—neuritic plaques and neurofibrillary tangles. Decades later, these lesions, recognized as hallmarks of Alzheimer’s disease (AD), are the focus of a vigorous research effort to understand the underlying causes of dementia in late life and to develop compounds that will prevent the disease or block its progress.

For years, evidence has burgeoned about the protein fragment beta-amyloid in AD pathology. Beta-amyloid is the primary component of neuritic plaques, along with inflammatory cells and other insoluble filamentous proteins that can contribute to neuronal damage. An early and consistent feature in the AD brain, beta-amyloid surrounds brain cells (neurons) in regions of the brain involved in memory and cognition. Beta-amyloid peptide is derived from a much larger protein called the amyloid precursor protein (APP). The discovery in 1990 of a genetic mutation on chromosome 21 that ties APP to AD was the first real indication of a link between beta-amyloid production and the pathology of the disease. This mutation is associated with a rare form of early-onset, familial AD. Two other genes that cause early-onset AD were identified in 1995, presenilin-1 on chromosome 14 and presenilin-2 on chromosome 1. The proteins produced by the presenilin genes are tied to beta-amyloid by the discovery that the AD-linked mutations in these genes are associated with increased production of beta amyloid. A defect in any one of these three genes can cause AD, accounting for approximately 50% of the inherited early-onset cases, or as few as 10% of persons with AD.

For most individuals, however, susceptibility to AD is more complex, and its genetic component probably involves more than one gene. The only accepted risk factor for the common, late-onset form of AD is ApoE4, a variant of the ApoE gene on chromosome 19. ApoE4 accounts for approximately 50% of the genetic effect in the development of late-onset AD. Recent findings suggest that ApoE is critical for promoting beta-amyloid deposition in neuritic plaques. This and other evidence help define beta-amyloid as a prime target for intervention in the cascade of events that initiate neuronal degeneration.

An important recent advance in AD research was the generation of transgenic mice expressing the mutant forms of human beta-amyloid associated with early onset AD. These mice develop amyloid plaques with similarities to those observed in AD patients, providing for the first time a candidate mouse model of this disease. This year, scientists at the Elan Corporation immunized young beta-amyloid transgenic mice with a synthetic form of beta-amyloid found in plaques and succeeded in preventing almost entirely the deposition of beta-amyloid in mouse brains and reducing other features of disease compared with controls. Older transgenic mice vaccinated at 11 months also had a considerable reduction in amyloid deposition at 15 and 18 months when compared with controls. Although the relevance of this model to human disease remains uncertain, these results raise the possibility of immunization as a treatment or perhaps a prophylactic measure against AD.

The role of neurofibrillary tangles, the second characteristic lesion of AD, has also been the subject of recent research advances. Found in the same areas of diseased brains as plaques, but inside neurons, tangles are the wreckage of the cell’s internal structural support and nutrient transportation system. In healthy cells, microtubules are formed like train tracks—long, parallel rails stabilized by “railroad ties” consisting of the protein tau. In AD and in some other dementias, the altered tau can no longer hold the microtubule “tracks” together, causing the transport system to collapse. The tau itself twists into paired helical filaments, like two threads wound around each other. Disruption of the microtubule assembly can lead to cell death. Tau also has long been associated with nerve cell destruction. Although evidence correlates the formation of tangles and the loss of neurons in the part of the brain most affected by AD with increased severity of dementia, until recently there was no evidence that changes in tau protein could directly initiate neuronal degeneration. This changed radically in 1998 when teams of researchers linked several tau mutations on chromosome 17 to inherited dementias characterized by AD-like brain tangles and nerve cell destruction. Now, after years of multinational research on families affected by rare dementias, there is hard evidence that tau can play a primary role in causing at least some cases of neurodegenerative disease. These findings confirmed that mutations in tau alone can lead to dementia. These advances offer new directions for exploring treatments for these dementias, perhaps […]

Read more at www.nia.nih.gov

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