facts for health--alzheimer's--what causes it?

Alzheimer's disease (AD) is the result of changes in and around brain cells. Why these changes occur is not fully understood. What you will read next is a description of the brain cell changes occurring in Alzheimer's disease. In an effort to provide an up-to-date understanding of the underlying brain changes, we need to describe those changes with accurate medical wording. The following information will give you a sense of the complexity of the disease and current research into its causes.

Plaques and neurofibrillary (pronounced NUR-o-FI-bri-lair-ee) tangles in the brain are hallmarks of AD. How they develop and what factors modify their rate of development, as well as other mechanisms of brain cell damage and destruction are subjects of intense study. For example, beta-amyloid (pronounced BAY-tah AM-i-loyd) may be an important clue in the development of AD as it is the major substance plaques are made of. Beta-amyloid is formed when a particular brain protein, amyloid precursor protein (APP), is broken down abnormally into shorter fragments. Three different protease enzymes (proteins that accelerate chemical reactions) called secretases (pronounced SEE-kre-tays-es) are involved in breaking down APP: alpha secretase, beta secretase and gamma secretase. Alpha secretase and gamma secretase together cut APP into shorter fragments that are easily dissolved in the brain. When beta secretase and gamma secretase together cut APP, they produce longer fragments, called beta-amyloid 40 and 42. Beta-amyloid 42 fragments are stickier than beta-amyloid 40 fragments and that causes them to build up and combine with other fragments to form Alzheimer's plaques.

Recently, a strain of mice genetically engineered to develop more APP and therefore more plaques surprised researchers. They did not develop more plaques. The explanation: very high levels of transthyretin, a protein that binds with the bad longer fragment beta-amyloid, preventing formation of plaques and other changes found in AD. Further studies of transthyretin are underway.

Mutations in the genes for amyloid precursor protein (APP) and the secretase enzymes have been linked to Alzheimer's disease. APP is controlled by a gene on chromosome 21, the same chromosome that is abnormal in individuals with Down's syndrome. Individuals with Down's syndrome often develop AD in their forties, and there may be an increased risk of AD in other family members without Down's syndrome, though this view remains controversial.

Another clue to the importance of beta-amyloid in the development of AD is the change (or mutation) of two genes of presenilin proteins (PS1 and PS2) that are found on chromosomes 14 and 1, respectively. At least 30 mutations of these proteins may cause early onset AD, again by increasing the amount of longer fragments of sticky beta-amyloid. Researchers have recently found a gene on chromosome 10 that is associated with increased risk of late-onset AD, again through increased accumulation of beta-amyloid. Beta-amyloid begins accumulating years before AD symptoms appear. Treatments aimed at preventing beta-amyloid accumulation are promising although availablility is at least several years in the future.

Neurofibrillary tangles are another hallmark feature of AD. These tangles result from alteration of a protein called tau, which helps support nerve cell structure. Understandably, loss of normal neuron structure can interfere with neuron function. In AD, these tangles are found in great numbers in the outer layer of the brain, called the cerebral cortex. Interestingly, tangles have been found in deeper brain structures, beneath the cerebral cortex, in the brains of people who have not developed dementia. It is possible, though not proven, that beta-amyloid may accelerate the creation of tangles.

Other factors that may be involved in causing AD are inflammation, oxidative stress and abnormal calcium levels in brain neurons:

Normal brain function depends heavily on acetylcholine (pronounced ah-see-til-KOH-leen), an important neurotransmitter (brain messenger). The AD process affects structures involved in memory functions and in the production of acetylcholine. In AD, less acetylcholine is produced. An enzyme, acetylcholinesterase, normally breaks down acetylcholine after use, so it can be recycled. When acetylcholine levels fall too low, memory and other brain functions are impaired. Early awareness of the structures involved and the role of acetylcholine in AD led to the development of cholinesterase inhibitors, medications that decrease the breakdown of available acetylcholine. This is the first class of drugs approved in the U.S. for treating mild to moderate AD. Recently, memantine, which affects a different neurotransmitter system, was also approved, but for moderate to severe AD. Studies are underway to assess the benefits of cholinesterase inhibitors for severe AD, and to assess the benefits of memantine for mild to moderate AD.

All of the above factors may be involved as possible causes of AD. Keep in mind that different factors may be operating in different individuals. At present, our understanding is incomplete and our ability to design specific treatments to counteract these presumed disease factors is far from certain. A great deal of research is underway and it is probable that useful treatments for AD will emerge as the underlying disease process is better understood.