Alzheimer's disease

Alzheimer's disease (AD), a neurodegenerative disease, is the most common cause of dementia and characterized clinically by progressive intellectual deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. The most striking early symptom is memory loss (amnesia), usually manifest as minor forgetfulness that becomes steadily denser with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language (aphasia), coordinated movement (apraxia), recognition (agnosia) and those functions (such as decision-making and planning) closely related to the frontal lobe of the brain, reflecting extension of the underlying pathological process. This consists principally of neuronal (cell) loss (or atrophy), together with deposition of amyloid plaques and neurofibrillary tangles. Genetic factors are known to be important, and polymorphisms (variations) in three different autosomal dominant genes - Presenilin 1, Presenilin 2, and Amyloid Precursor Protein - have been identified that account for a small number of cases of familial, early-onset AD. For late onset AD (LOAD), only one susceptibility gene has so far been identified - the epsilon 4 allele of the APOE gene. Age of onset itself has a heritability of around 50%.

History
The symptoms of the disease as a distinct entity were first identified by Emil Kraepelin, and the characteristic neuropathology was first observed by Alois Alzheimer, a German psychiatrist, in 1906. In this sense, the disease was co-discovered by Kraepelin and Alzheimer, who worked in Kraepelin's laboratory. Because of the overwhelming importance Kraepelin attached to finding the neuropathological basis of psychiatric disorders, Kraepelin made the generous decision that the disease would bear Alzheimer's name                                                  (J. Psychiat. Res., 1997, Vol 31, No. 6, pp. 635-643).

For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45-65 who developed symptoms of presenile dementia, which was considered to be a more or less normal outcome of the aging process. In the 1970s and early 1980s, however, the name "Alzheimer's disease" began to be used, within and outside the medical profession, equally for individuals age 65 and older with senile dementia, and was eventually adopted formally for all individuals with the common symptom pattern and disease course in the psychiatric and neurological nomenclature.

Clinical features
The usual first symptom noticed is memory loss which progresses from seemingly simple and often fluctuating forgetfulness (with which the disease should not be confused) to a more pervasive loss of recent memory, then of familiar and well-known skills or objects or persons. Aphasia, disorientation and disinhibition usually accompany the loss of memory. Alzheimer's disease may also include behavioral changes, such as outbursts of violence or excessive passivity in people who have no previous history of such behavior. In the later stages, deterioration of musculature and mobility, leading to bedfastness, inability to feed oneself, and incontinence, will be seen if death from some external cause (e.g. heart attack or pneumonia) does not intervene. Average duration of the disease is approximately 7-10 years, although cases are known where reaching the final stage occurs within 4-5 years, or up to 25 years.

Diagnosis
The diagnosis is made primarily by clinical observation and tests of memory and intellectual functioning over a series of weeks or months, with various physical tests (blood tests and neuroimaging) being performed to rule out alternative diagnoses. No medical tests are available to conclusively diagnose Alzheimer's disease pre-mortem, however.

Interviews with family members and/or caregivers can be extremely important in the early phases as well, as the sufferer him/herself may tend to minimize his symptomatology or may be being observed on a day when his/her symptoms are in temporary dormancy.

Initial suspicion of dementia may be strengthened by performing the mini mental state examination, after excluding clinical depression. Psychological testing generally focuses on memory, attention, abstract thinking, the ability to name objects, and other cognitive functions. Results of psychological tests do not easily distinguish between Alzheimer's disease and other types of dementia but can be helpful in establishing the presence of and severity of dementia. They can also be useful in distinguishing true dementia from temporary (and more treatable) cognitive impairment due to depression or psychosis, which has sometimes been termed "pseudodementia".

While expert clinicians who specialize in memory disorders can now diagnose AD with an accuracy of 85-90%, a definitive diagnosis of Alzheimer's disease must await the autopsy.

Microscopy
There are several changes found in the brain in AD (in order of appearance):
 * The deposition of an abnormal protein (amyloid beta) outside nerve cells in the form of amyloid. These are called diffuse plaques and amyloid also forms the core of more organized plaques called senile or neuritic plaques. Recently evidence has begun to accumulate implicating simpler, soluble forms of amyloid (oligomers) in the pathological process, and the presence of plaque amyloid does not correlate well with the degree of dementia. Amyloid also accumulates in the walls of small blood vessels in the brain. This is termed amyloid angiopathy (also called congophilic angiopathy). Another pathological feature of AD is the accumulation of abnormal protein filaments inside nerve cells in the brain, formed from aggregation of tau protein, which is normally present to stabilise microtubules. In AD, an abnormally phosphorylated form of tau protein accumulates as paired helical filaments. Tau accumulates in various forms:
 * As masses of filaments inside nerve cell body termed neurofibrillary tangles
 * Inside nerve cell processes in the brain termed neuropil threads
 * Inside nerve cell processes that surround amyloid plaques - termed dystrophic neurites or plaque neurites.

General non-specific findings include:
 * Diffuse neuropathology, nerve cells, their processes, and synapses are lost from key brain regions. This results in atrophy of the affected areas and enlargement of the ventricles.
 * Loss of synaptic contacts between neurons may be related to disruption of axonal transport and to the dysregulation of cell adhesion proteins by presenilins. The presenilins have been identified as part of the processing pathways that produce the amyloid beta protein.

Neurochemistry
The neurotransmitters serotonin, acetylcholine, norepinephrine, and somatostatin are at decreased levels. Glutamate levels are usually elevated.

Disease mechanism
Three major competing hypotheses exist to explain the cause of the disease.

The oldest hypothesis is the "cholinergic hypothesis". It states that Alzheimer's begins as a deficiency in the production of acetylcholine, a vital neurotransmitter. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by inhibiting acetylcholinesterases (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical.

The other two hypotheses each have their advocates, and have often been described (lightheartedly) as the "tau-ist" and "ba-ptist" viewpoints in scientific publications by Alzheimer's disease researchers. "Tau-ists" believe that the tau protein abnormalities come first and lead to a full disease cascade. "bA-ptists" believe that beta amyloid deposits are the causative factor in the disease. For example, the presence of the APP gene on chromosome 21 is believed to explain the high incidence of early-onset AD pathology in patients with Down syndrome, who carry three copies of chromosome 21 and thus APP itself. The "ba-ptist" theory is finding new supporters due to recent discoveries of impaired vascular and cerebrospinal fluid transport of beta amyloid out of the brain tissues, resulting in a greater risk for plaque formation. A third protein, alpha synuclein, which has already been shown to be important in Parkinson's disease, has also been demonstrated to be associated with amyloid plaques in AD.

The presence of plaques and tangles, however, does not always correlate perfectly with clinical Alzheimer's; in other words, not all people who have plaques and/or tangles manifest symptoms of the disease. Loss of synapses correlates much better with the decline of cognition than the presence of plaques and tangles. Some recent research is focusing on the possibility that plaques and tangles arise as a defense against another, as yet undiscovered, process or substance that itself causes the disease. Researchers are intrigued by the idea that the plaques and tangles might not be the problem, but rather a symptom of the problem. The plaques and neurofibrillary tangles might be doing an adequate job of "containing" the disease until they simply are overwhelmed.

There is compelling evidence that genetic predisposition underlies the development of Alzheimer's disease. However, the most obviously genetic cases are also the rarest. Most cases identified are "sporadic" with no clear family history. It is probable that environmental factors have to interact with a genetic susceptibility to cause development of disease. Head injury has been consistently shown to be linked to later development of AD in epidemiological studies. In addition, small cranial diameter has been shown to correlate well with early onset of recognizable symptoms. The most commonly accepted explanation for this last feature is that larger brains simply may have more cells that can afford to be lost. Inheritance of the epsilon 4 allele of the ApoE gene is regarded as a risk factor for development of disease, but large-scale genetic association studies raise the possibility that even this does not indicate susceptibility so much as how early one is likely to develop Alzheimer's. There is speculation among genetic experts that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease (LOAD). Intriguing work is currently going on investigating the possibility that the regulatory regions of various Alzheimer's associated genes could be important in sporadic Alzheimer's, especially inflammatory activation of these genes. These hypotheses include the inflammatory 5-lipoxygenase gene.

Studies have not shown strong link with toxins, vitamins, metals or diet, although rabbits fed a high-cholesterol diet in the presence of copper ions in their water did develop amyloid brain lesions and cognitive deficiencies,. Likewise, linkage has been found between zinc or copper and reactive oxidative stress contributing to Alzheimer's pathology, and the amyloid precursor protein has been shown to alter expression in response to metal supplementation and chelation , ,. Therefore, it is hasty and premature to dismiss any and all environmental effects out of hand. There have been studies that link aluminium to the progression of Alzheimer's, but the results from these studies have not been confirmed and are not widely accepted by Alzheimer's experts.

Rare cases are caused by dominant genes that run in families. These cases often have an early age of onset. Mutations in presenilin-1 or presenilin-2 genes have been documented in some families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial AD (FAD). Evidence from rodent studies suggests that the FAD mutation of PS1 results in impared hippocampal-dependent learning which is correlated with reduced adult neurogenesis in the dentate gyrus (Wang et al, 2004). Mutations in the APP gene on chromosome 21 can also cause early onset disease.

Genetic linkage
Alzheimer's disease is linked to the 1st, 14th, 9th, 19th, and/or 21st chromosomes. While some genes predisposing to AD have been identified, most cases are sporadic. However, sporadic AD most often involves some form of genetic susceptibility.

Epidemiology
Alzheimer's disease is the most frequent type of dementia in the elderly and affects almost half of all patients with dementia.

2-3% of persons aged 65 show signs of the disease, while 25 - 50% of persons aged 85 have symptoms of Alzheimer's and an even greater number have some of the pathological hallmarks of the disease without the characteristic symptoms. The proportion of persons with Alzheimer's begins to decrease after age 85 because of the increased mortality due to the disease, and relatively few people over the age of 100 have the disease.

Prevention
Efforts to find effective treatments for Alzheimer's after-the-fact have so far been disappointing. Age is the primary risk factor for Alzheimer's. The baby boom is approaching its golden years. Indeed, much of the concern about the solvency of governmental social safety nets is founded on estimates of the costs of caring for baby boomers, assuming that they develop Alzheimer's in the same proportions as earlier generations.

One study ("Leisure Activities and the Risk of Dementia in the Elderly," New England Journal of Medicine ) found that people who played chesson a regular basis went on to get Alzheimer's at a substantially lower rate than the general population. The chess relationship was stronger than any other factor, including dancing and solving crossword puzzles, both of which were also shown to be inversely proportional to getting Alzheimer's disease.

In a number of retrospective studies, regular physical exercise has appeared to be inversely related to the development of Alzheimer’s. The Alzheimer's risk of those exercising regularly was half that of the least active. This research is consistent with the observation that virtually all measures designed to promote cardiac fitness and reduce stroke risk also seem to reduce Alzheimer's risk. However in one study, dance appeared to be the only exercise effective in reducing risk. One explanation is that dancing requires the use of complex mental skills such as performing correct steps while at the same time keeping track of the music. The presence of cardiovascular risk factors -- diabetes, hypertension, high cholesterol and smoking -- in middle age (ages 40 to 44) was found very strongly associated with late-life dementia (Neurology 2005;64:277-281. PMID 15668425).

Some studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and aspirin may delay the onset, and lower the ultimate risk, of Alzheimer’s disease. According to population studies, low but consistent daily NSAID used over a period of years such as ibuprofen (Advil, Motrin) seems to slow the progress of Alzheimer's. It seems that NSAIDs may affect the onset of the disease but is of little use for treating it once it has progressed to early or full-blown Alzheimer's.

It should be noted that some drugs such as acetaminophen, naproxen, and COX-2 inhibitors, such as celebrex and vioxx, were found to have no demonstrated benefit (and some evidence of cardiac harm). This ineffectiveness and the increase in adverse cardiac events associated with these agents was reported in various studies in 2004, and highlights the key role of ibuprofen in the original studies showing moderated risk associated with NSAID use (PMID 15720180).

A study (Archives of Neurology 2004; 61:82-88. PMID 14732624) has reported that the combination of vitamins E and C might, over time, sharply reduce the risk of Alzheimer's disease. Marked reduction (up to 80% risk reduction) was achieved after a period of more than five years, but only if dosage was 400 i.u. per day of vitamin E plus 500 mg or more per day of vitamin C. Lesser amounts, such as those found in multivitamin pills, appeared markedly less effective. Large doses of vitamin E without vitamin C had only a mild effect, while large doses of vitamin C without vitamin E had no benefit. However in one small study, 2000 i.u. per day of vitamin E did appear to delay the progression of early Alzheimer’s by several months. Other evidence suggests that vitamin E becomes a damaging pro-oxidant if given in isolation (without other antioxidants). Vitamin E can be recharged after absorbing a free radical by another antioxidant such as vitamin C or Alpha-lipoic acid. Some studies suggest that a ratio of at least 1000 mg of vitamin C to 400 i.u. of vitamin E is ideal. Recent studies suggest that the most common forms of E sold in supplements, the dl-alpha or d-alpha tocopherol form, are of little value, and that the gamma form of vitamin E, or a mixture of all the tocopherols and tocotrienols that collectively make up vitamin E from food, provide the most benefit. Vitamin E is markedly less effective unless taken with oil.

Improved nutritional status of the B vitamin folic acid was found to reduce Alzheimer's incidence in a study of an order of nuns, many of whom volunteered to have their mental status assessed and donated their brains for study after death. The "Nun's study" also revealed nuns who, in life, showed little or no dementia, but upon autopsy were found to have extensive Alzheimer’s plaques. The unimpaired nuns’ brains were free of evidence of stroke, including micro-strokes. Nuns whose brains revealed both plaques and stroke damage, however, were severely impaired in functioning while alive. Thus avoidance of risk factors for stroke may be a key element in preventing final progression to being disabled by Alzheimer's dementia. The discovery of the co-founding role of stroke supports other research showing that quitting smoking, weight reduction, and avoidance of diabetes all reduce Alzheimer's risk. Diabetes greatly increases Alzheimer's risk, and one factor at work may be that the enzyme charged with removing excess insulin from the blood, the Insulin Degrading Enzyme (IDE), also has the responsibility for removing Beta-amyloid plaques from the brain. Perhaps the excess insulin involved in the pre-diabetic metabolic syndrome, as well as insulin used to treat existing diabetes, may demand more IDE than the body is able to produce, leaving none to remove accumulating beta amyloid plaques from the brain.

Some evidence suggests that Alzheimer's risk may also be reduced by inclusion of certain kinds of fish in the weekly diet. Those that contain Omega-3 fatty acids are thought to most effective.

The natural chemical curcumin, found at 5% concentration in the spice turmeric, reduces Alzheimer's incidence in a mouse model and actually dissolves human senile plaques (beta amyloid) in the test tube (PMID 15590663). These factors suggest that inclusion of a bit of turmeric or curry spice in the diet may provide preventive value. Near 100% curcumin extract capsules are also available. Curcumin is a powerful antioxidant and a powerful anti-inflammatory. In India, where turmeric is commonly consumed in curry spices, Alzheimer's disease afflicts only approximately 1% of the elderly, whereas in the U.S. a much larger percentage are afflicted.

There may be a connection between the cholesterol level inside the brain cells and the deposition of the toxic amyloid plaques which make the brain cells die. In addition to lowering cholesterol, the so-called statins (drugs such as lovastatin, simvastatin, etc.) may have a beneficial role in reducing inflammation. However, retrospective studies into possible protective effects of statin drugs as a means of preventing or delaying Alzheimer’s have been inconclusive; no protective effect was found in one large prospective observational study (Arch Neurol. 2005;62:1047-1051. PMID 16009757).

Prospective studies and well-analyzed retrospective studies show that smoking increases the risk of developing Alzheimer's (Biomed Pharmacother. 2004 Mar;58(2):95-9. PMID 14992790). The increased risk may be substantial (J Neurol Neurosurg Psychiatry 2000;68:622-626 (May). PMID 10766894). Cigarettes contain many substances in addition to nicotine, and the increased risks incurred by smokers are not to be confused with the controversial possible slowing of the progression of established Alzheimer's disease by administration of pure medical nicotine.

Nutrition and Alzheimer's
Some work is being done to investigate the role of raised levels of homocysteine, and possible nutritional prevention or treatment through taking of foods high in B vitamins and antioxidants to control the levels of homocysteine.

See: Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002 Feb 14;346(7):476-83.

A deficiency of DHA, an omega-3 fatty acid, has also been implicated in Alzheimer's.

Insulin resistance has also been associated with Alzheimer's. Remarkably, genetic epidemiology has revealed that the ApoE4 allele is found at the highest rates in populations that are current or recently were hunter-gatherers, and at the lowest rates in populations that have long been adapted to agriculture. Some have suggested that the ApoE4 gene only contributes to Alzheimer's when it is found in conjunction with a high-carbohydrate diet. 

Treatment
There is no cure, although there are drugs which temporarily reduce neurotransmitter degradation and alleviate some of the symptoms of the disease.

Acetylcholinesterase inhibitors
Acetylcholinesterase (AChE) inhibition was thought to be important because there is selective loss of forebrain cholinergic neurons as a result of Alzheimer's. AChE-inhibitors reduce the rate at which acetylcholine (ACh) is broken down and hence increase the concentration of ACh in the brain (combatting the loss of ACh caused by the death of the cholinergin neurons). Acetylcholinesterase-inhibitors seemed to modestly moderate symptoms but do not prevent disease progression including cell death.

Examples include:
 * tacrine - no longer clinically used
 * donepezil (marketed as Aricept)
 * galantamine (marketed as Razadyne, formerly Reminyl)
 * rivastigmine (marketed as Exelon)

Recently, a controversy has erupted about cholinesterase inhibitors because a study by Courtney (2004) in the respected medical journal The Lancet has suggested they are ineffective. The pharmaceutical companies, but also many unbiased clinicians, dispute the findings of the study, based on methodologic grounds.

NMDA antagonists
Recent evidence of the involvement of glutamatergic neuronal excitotoxicity in the aetiology of Alzheimer's disease led to the development and introduction of memantine. Memantine is a novel NMDA receptor antagonist, and has been shown to be moderately clinically efficacious. (Areosa et al., 2004)

Vaccine
There are ongoing tests of an Alzheimer's disease vaccine. This was based on the idea that if you could train the immune system to recognize and attack beta-amyloid plaque, the immune system might reverse deposition of amyloid and thus stop the disease. Initial results in animals were promising. However, when the first vaccines were used in humans, brain inflammation occurred in a small fraction of participants, and the trials were stopped. Participants in the halted trials continued to be followed, and some showed lingering benefits in the form of slower progression of the disease. Recent studies in mice continue to show promise that an approach may be found to avoid the inflammation issue. It is hoped that research will provide a better formulation and that in the future it can be of use in families with history of Alzheimer's disease.

Pure Medical Nicotine
One study indicated that intake of pure medical nicotine might help delay progression of Alzheimer's disease in carriers, but not non-carriers, of the ApoE4 gene. The issue of whether medical nicotine intake may delay Alzheimer's progression among some sub-populations of patients remains a focus of debate. But no one is advocating smoking, as distinct from prescription nicotine, for the treatment or prevention of Alzheimer's. In prospective studies and well-analyzed retrospective studies, smoking is shown to increase the risk of developing Alzheimer's.  Biomed Pharmacother. 2004 Mar;58(2):95-9.

Genetic and population effects
Various gene alleles have been associated with Alzheimer's disease, most notably the apolipoprotein E (ApoE) gene. ApoE normally functions to regulate cholesterol metabolism. In addition, it has recently been discovered that Chinese and North American populations differ significantly in development of full-fledged Alzheimer's from early warning symptoms. Whether the reason for this is genetic, dietary, or social has yet to be investigated.

The ApoE4 form of ApoE, which is associated with Alzheimer's, is found at the highest rates among long-time hunter-gatherers, and at the lowest rates among populations who have been accustomed to agriculture the longest. This has led some researchers to suggest that ApoE4, which exerts some of the same effects on metabolism as a diet excessively high in carbohydrates, contributes to Alzheimer's only in conjunction with an evolutionary discordant high-carbohydrate diet. 

Social issues
Alzheimer's is considered to be a major public health challenge since the median age of the industrialized world's population is increasing gradually. For this reason, money spent informing the public of available effective prevention methods may yield disproportionate benefits. The role of family caregivers has also become more prominent, as care in the familiar surroundings of home may delay onset of some symptoms and delay or eliminate the need for more professional and costly levels of care.

Famous Alzheimer's sufferers

 * Eddie Albert
 * Andrija Artukovic
 * William J. Bell
 * Billie Bird
 * Enid Blyton
 * June Bronhill
 * Charles Bronson
 * Carroll A. Campbell, Jr.
 * Imogene Coca
 * Aaron Copland
 * Raymond Davis, Jr.
 * Alfred Deakin
 * Willem de Kooning
 * James Doohan
 * Ralph Waldo Emerson
 * Geraldine Fitzgerald
 * Arlene Francis
 * Barry Goldwater
 * Rita Hayworth
 * John Hermon
 * Charlton Heston
 * Zipora Hirschfeld
 * Juliana of the Netherlands
 * Evelyn Keyes
 * Beatrice Lillie
 * Jack Lord
 * Burgess Meredith
 * Mary Hayley Bell, Lady Mills
 * Dame Iris Murdoch
 * Edmond O'Brien
 * George Oppen
 * Rosa Parks
 * Molly Picon
 * Otto Preminger
 * William Proxmire
 * Ferenc Puskas
 * Mae Questel
 * Maurice Ravel
 * Ronald Reagan
 * Sugar Ray Robinson
 * Margaret Rutherford
 * Norma Shearer
 * Robert Sargent Shriver
 * Charles Steen
 * Pauline Phillips
 * Cyrus Vance
 * E. B. White
 * Kevin White
 * Harold Wilson, Baron Wilson of Rielvaux
 * Paul von Hindenburg