Alzheimer's disease is named after Dr. Alois Alzheimer, a German doctor who first described this disease early in the 20th century.

it is the commonest cause of dementia in Western (developed) societies. probably is too for less developed countries but statistics are not as good there.

development of neurofibrillary tangles and neuritic plaques in the brain cause the symptoms of Alzheimer's and a definite diagnosis of AD is only really available on autopsy.

the disease course:
short term memory usually suffers first, followed by language skills, then judgement and emotional control later. progress is usually slow but can sometimes (rarely) be rapid. most patients with AD live for many years after being diagnosed with this disease.

a good writeup on this: Senile dementia/Alzheimer's type

read all about it: http://www.alzheimers.org/unravel.html

The hippocampus and amygdala are two major structures that help with memory, and these are also areas heavily damaged by the disease.

The parietal regions are often the most affected, leaving the frontal area less atrophied than usual.

The lateral ventricles also are enlarged.

The atrophy of unhealthy brain tissue causes blood to limited, which, of course, can be a bad thing, accelerating the disease and eventual death.

Alzheimer's is the predominant form of senile dementia in older adults. Approximately 50% of persons over age 75 suffer from this disease. The disease potentially affects all domains of cognition though different individuals will manifest different symptoms.

The early stages of Alzheimer's are characterized by a loss of memory, reduced attention span, and loss of verbal communication skills. Individuals in early stages of Alzheimer's are often capable of driving, living on their own and even holding simple jobs. In many individuals the early symptoms are mistaken for old age and the disease is not properly diagnosed till later stages.

As the disease progresses, some individuals will begin to misperceive objects, hallucinate and often hear voices. Some patients will believe they are speaking to a relative who has been dead for some time. They often misidentify close relatives and tend to regress back into early adulthood and sometimes childhood. Some individuals who have immigrated as adults from foreign countries will forget the English they have since learned and remember only their childhood language.

The final stages of Alzheimer's are often painful to endure for close family members. Patients will begin to sleep the majority of the day and forget how to do basic activities of daily life like eating or defecating. Often the requirements of caregiving exceed the capacities of immediate family members and the patient is institutionalized in a nursing home.

While many Alzheimer's patients die from other causes such as cancer, heart attack, pneumonia, and other diseases typical of old age, the neurological degeneration caused by Alzheimer's can cause an individual to die from aspiration.

Alzheimer's Disease:

Alzheimer's disease is one of the most common problems among the aged. It is devestating for the sufferer, but perhaps more so for the family and friends.

Symptoms:

Alzheimer's disease has initially innocuous symptoms which appear no different to the normal effects of ageing. However, these symptoms progress to a chronic state. In the early stages, there is memory impairment for recent events and spatial disorientation (e.g., the inability to find objects). Impaired concentration occurs too. Patients can become more aggressive and depressed. Later symptoms are much more severe. All aspects of memory fail, and aphasia (loss of language), apraxia (impairment of purposeful movement), and agnosia (inability to recognise objects) develops. Dementia insofar as judgement and abstract thought also develops. There is just a general impairment of all intellectual function and patients become incapacitated and wasting ensues.

Neuropathological Observations:

Patients appear to have shrinkage of gyri and enlargement of ventricles in the brain. The shrinkage in the frontal and temporal lobes is in the range of 20-30% when the disease has really developed. There is a similar loss of white matter. Imaging techniques have shown in living patients degeneration of tissue in the cerebral cortex (in the frontal, parietal, and temporal lobes), and the amygdala and hippocampus. This cell loss correlates with the degree of dementia and is much greater than normal ageing. There are microscopic abnormalities in neuronal tissue as well, such as plaques and neuronal tangles. There is also up to a 70% loss in the chemical CAT from the temporal and parietal lobes, and the hippocampus. CAT is important to normal brain function. PET has shown that early in the disease, sufferers have hypermetabolism in affected cortical areas. This probably leads to cell death, and may be the result of a compensatory increase for the loss of other cells.

Causes:

There may be some genetic factor at work here since some families have high incidences of Alzheimer's. However, genetics may not be a major cause because the disorder can occur sporadically. An environmental toxin may be at work, but nothing has really been identified. Studies have linked aluminium to the illness, since it accumulates in the cells of affected areas. But it cannot be said if the aluminium is causative, or a result of the illness. There may be a link to head injuries, as boxers can develop a similar dementia to Alzheimer's. There is also a "nasal infection theory". Since Alzheimer's effects the areas with links to the olfactory system, such as the amygdala, hippocampus, and sensory association areas, whereas it leaves other areas (like the primary motor and visual cortices) untouched, it has been suggested that some toxin may enter through the olfactory bulb and cause this degeneration. However, the nature of such a toxin is unknown, and the olfactory system is only effected in the later stages of the illness. Nasal infection theory has been widely rejected. Given that there are several possible causes, it could, of course, be the case that there are several ways the same disorder could be produced.

Treatment:

There is no treatment for Alzheimer's. The degeneration cannot be halted. Methods to improve the memory problems have been made, but at the neglect of the anti-social behaviour sufferers have. Hydergine causes some improvement to cognitive function by altering neurotransmitters, blood flow, and oxygen usage. The outlook is a little bleak, but the best hope is trying to find the root of the degeneration so that preventative and corrective action can be taken.

Bibliography:

"Brain, Biochemestry and Brain Disorders", P. G. Strange, Oxford University Press, 1992

Oxidation, Mitochondrial damage and Cytotoxicity in Alzheimer's Disease

In 1907, Dr Alois Alzheimer first characterised a disease of memory loss and dementia in elderly patients. It is the most common cause of senile dementia, affecting almost 40% of individuals over 85 years of age. The majority of cases are apparently spontaneous, although a small number of gene mutations are associated with increased risk and earlier onset of disease in some families. The disease involves extensive cortical atrophy, visible on brain sections as abnormally wide sulci.

An explanation of the cause of cell death has long been elusive. Numerous studies have been published that show cell death to be entirely by apoptosis, while another set have shown exclusively necrosis. This obviously suggests that either outcome can occur depending on the situation. What is almost totally certain is the involvement of the plaques of crystalline protein found extensively in Alzheimer's patient brains: amyloid. A complex picture is emerging of how this amyloid plaque is associated with cell death, with the precise mechanisms becoming increasingly clear.

A likely culprit: The Amyloid-beta peptide

The plaques found in the brains of Alzheimer's disease sufferers are composed of amyloid fibrils, a material made up of an ordered crystalline precipitate of misfolded protein. Amyloid occurs when some form of environmental stress disrupts the folding pattern of a normally soluble protein. The disrupted form, either broken into fragments or seriously contorted, is no longer soluble in solution. It converts into flat beta-sheets and forms ordered stacks which accumulate into long protofilaments. These twist together like strands in a rope to form fibrils, which aggregate into large plaques such as those seen around brain cells in Alzheimer's disease.

The protein responsible for Alzheimer's amyloid is APP, or Alzheimer's Precursor Protein, is a 770 residue protein whose precise function is unclear. APP can be degraded by proteases along two pathways, only one of which generates the 49-43 residue A-Beta peptides. Which pathway is taken appears to be related to cholesterol levels.

These A-Beta peptides, henceforth referred to as A-Beta, are capable of generating reactive oxygen species, or ROS, through a series of redox reactions with metal ions. They have been shown to do this in vitro and in the absence of cellular material of any kind. As ROS can cause serious damage to cells, this ability immediately suggests a mechanism for cytotoxicity.

It appears increasingly likely that the fully formed plaque itself is not the cause of the disease. Plaque is found in the brains of many elderly people who have retained entirely normal brain function, while some patients with severe Alzheimer's have only minimal levels. This alone cannot discount the idea that A-Beta is responsible, however, when there is extensive biochemical evidence suggesting its involvement in several different mechanisms of cell damage. While the fully formed and relatively stable amyloid fibrils may not be cytotoxic, the smaller precursor elements are probably responsible. While monomeric A-Beta is not considered neurotoxic, small diffusible oligomers have been shown to be neurotoxic in mice.

The importance of oxidation

The simple explanation for the majority of cell death in Alzheimer's disease is oxidative damage. Autopsies of Alzheimer's sufferers show extensive oxidative degradation of proteins and DNA present in areas of the brain affected by the disease. This evidence is backed up by studies which found the progression of neurodegeneration was impeded by the addition of high levels of antioxidants. Oxidative damage would also explain one of the first problems observed in cell cultures when A-Beta is added: rapid mitochondrial problems, usually involving the failure of proton pumping. Such mitochondrial failure is a common symptom of oxidative stress on a cell: mitochondrial enzymes are extremely sensitive to oxidative damage. Worse still, disruption to mitochondrial function can lead to the production of more ROS inside the organelle, exacerbating the damage.

Damage to mitochondrial membrane integrity could very easily kill a cell. If the outer membrane is perforated and Cytochrome c escapes into the cytoplasm, the pathway of internal activation of apoptosis via caspase activation will be triggered. Apoptosis could also possibly be triggered if serious oxidative damage to DNA occurs.

There are also more brute-force ways that attack by ROS can prove lethal to a cell. Disruption of membrane stability, structural proteins or normal enzyme activity could prove sufficiently traumatic to a cell to result in necrosis. Whichever pathway to cell death is involved in any particular case, the importance of oxidative damage is well established. One question remains: how could the A-Beta peptide cause these effects?

The production of radicals

As the importance of oxidation and the creation of ROS has been evident for some time, much thought has gone into investigating the way A-Beta could be responsible. The first and most obvious explanation involves the ability of A-Beta to react with copper and produce reactive species.

A-Beta and copper redox reactions

A-Beta's ability to insert in bilipid layers ensures the presence of reactive oligomers just outside the cell. There, in close association with the membrane, they may undergo a series of redox reactions with trace levels of copper present in the brain, generating ROS. The close proximity to the membrane means that the most likely result of ROS attack will be lipid peroxidation, damage to channels and transporters and ultimately serious disruption of ion balance. Such disruption puts the cell under significant oxidative stress, with all the associated mitochondrial failure which is an early sign of Aâ toxicity.

Despite the elegance of this model, the precise mechanisms involved were not at all well explained. It now appears that despite its logical merits, experimental evidence indicates that an alternative mechanism is being used.

The role of direct perforation and Calcium influx

Recent studies have indicated that the presence of A-Beta in the membrane alone is not directly related to increases of ROS inside the cell. Two interesting factors were observed: firstly, that ROS generation was dependent on rising intracellular calcium. Secondly, and oddly enough, that rises in ROS are not seen at all in neurons, while they are seen in astrocytes. This suggests that some unique characteristic of astrocytes is responsible for the lion's share of ROS generation.

The apparent relationship between calcium and ROS depends on the ability of A-Beta amyloid to insert into the membrane and perforate it. This provides an elegant explanation for why single monomers A-Beta are not toxic, but tetramers are: the transmembrane domains of the tetramers can combine to form a pore. This would allow an influx of extracellular calcium. Disruption of the normal homeostatic balance of the cell would result, putting it under a great deal of stress and promoting oxidation.

The relationship between this calcium influx and generation of ROS in astrocytes is explained by the discovery that these cells contain an enzyme previously only identified in immune phagocytes. NADPH oxidase is used by these cells to produce large quantities of ROS for use as a weapon against microbes. It is found associated with mitochondria, and is activated by increased intracellular calcium levels.

Alternatives to oxidative damage: An enzyme binding model

One flaw in the membrane perforation theories is that there is evidence that it does not occur at all in neurons. This, added to the fact that neurons lack NADPH oxidase and thus cannot undergo the mechanism of ROS generation outlined above, raises some interesting questions. It is well established that in Alzheimer's disease there is extensive neuronal death, and also that A-Beta fibril intermediates are neurotoxic. Are neurons dying because of lack of astrocyte support, or because of the toxic debris released by nearby mass necrosis? The neurotoxicity of A-Beta in pure cultures of neurons suggests otherwise. Is A-Beta causing an alternative mechanism of cell death in neurons?

What is A-Beta AD and how could it be involved?

Yeast-2 hybrid studies of whole-brain homogenates have yielded only one protein which binds to A-Beta peptide, which has subsequently been named A-Beta AD: Amyloid Beta binding Alcohol Dehydrogenase. It has been identified as a mitochondrial enzyme, and knockout models have shown it to be vital for survival in Drosophila. Most interesting is its binding characteristics: once bound to the amyloid fragments, the structure of A-Beta AD was shown to be highly abnormal. The enzyme binding site had clearly been completely disrupted.

Could it be that the presence of amyloid fragments causes mitochondrial toxicity by binding with and deforming a critical enzyme?

An apparently gaping flaw in this argument is the fact that A-Beta is inherently hydrophobic, as reflected by its drive to form amyloid fibrils to protect itself from the surrounding aqueous environment. Why would it leave the relative safety of the membrane and enter the cytoplasm? How and why it does so remains unclear, but there is very convincing evidence that it can be found throughout neurons, particularly in the mitochondria. Recent studies by confocal microscopy show plenty of A-Beta can be found in the mitochondria, along with A-Beta AD. This was supported by immunogold electron microscopy images.

Conclusions

The ability of the A-Beta peptide to cause cell loss in the brain is clearly more complex than was understood a few years ago. Specific mechanisms are now becoming known, providing more possible targets for therapy and prevention. Perhaps most importantly, it is now evident that the fully formed plaque is not toxic and attacking it will not be of clinical use. The reactivity of individual A-Beta peptides is another culprit which has been largely exonerated as the result of recent discoveries. It is the pore-forming, enzyme-binding behaviour of oligomers that needs to be the focus of future research.

An excellent review of this area is by Laura Canevari et al, in Neurochemical Research, Volume 29, pages 637-650: 2004. The study on ABAD colocalisation was by Joyce Lustbader et al, in Science, volume 304, pages 448-452, 2004. This has been a Node your Homework production.

What to do when Alzheimer's strikes

These first days of shock and grief are nearly unbearable. You are grieving the loss of your plans and dreams for the future. You can't avoid this grief; you must accept it. What you can do, however, is avoid unnecessary painful thoughts.

1. Stay away from the internet for those first few days.

   I am definitely one to rush to the internet to find out more about a difficulty. Termites? Here's who to call! Hangnails? Here's what to do! Usually I find that having more information solves or at least helps a situation. This is not so with Alzheimer's.

   1. Do not look up information about Alzheimer's.

      You already have a good idea of what Alzheimer's is and does. If anything, the facts are probably worse than you imagine. Why put yourself through that now? Do you really need to know the details of what will happen 5 years from now? How will that help? There will be plenty of time later on to learn about the disease and research treatment options. But the treatments currently available will be of little comfort to you today; there is no cure.

   2. Do not look up Alzheimer's support groups.

      The people corresponding here are in a different place than you. They have worked through the initial grief and the early years and are matter-of-factly trying to find support and answers for their day-to-day problems. But their descriptions of the problems will be frightening to someone who is not there yet.

   Why is this? Why should you not inform yourself as soon as possible about what will happen? The first reason is practical:

   1. It won't seem so bad at the time.

      You probably won't believe me, but one way or another, you will be able to handle the day-to-day problems that arise. Not that it will be fun, but it will not be as terrible as it all seems at the beginning. I remember grieving those first few days that someday my own mother would not know me, and I also remember that when it did happen, it was no big deal. I don't think I was even sad about it; it just didn't matter all that much.

      The second reason is more philosophical:

   2. You can't handle it.

      A great man once said, "Sufficient unto the day is the evil thereof." There is enough to grieve today, the death of your dreams for a long future with your loved one, without grieving over events years ahead. You are not required to suffer every sorrow of the next 10 years today; only bear today's sorrow today.

   Which brings me to the second thing I wished I had known:

2. You will smile again.

   You will have happy days. The three best days of my life all happened after the diagnosis, which was by far the worst day of my life. One of those days was less than two months after diagnosis. Am I a shallow person, that I seemingly shrugged off this pain so quickly? The opposite, I hope. This disease will change your life, and not entirely for the worse.

One last tip: have someone you love read you a funny book before you go to bed. Bill Bryson's "I'm a Stranger Here Myself" got me to sleep that night. I will be forever grateful to him, and to the person with the courage to read it to me.