Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. It is the most common cause of dementia. The most striking early symptom is memory loss (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language (aphasia), skilled movements (apraxia), recognition (agnosia), and those functions (such as decision-making and planning) closely related to the frontal and temporal lobes of the brain as they become disconnected from the limbic system, reflecting extension of the underlying pathological process. This consists principally of neuronal loss or atrophy, together with an inflammatory response to the deposition of amyloid plaques and neurofibrillary tangles. Genetic factors are known to be important, and autosomal dominant mutations in three different 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 apolipoprotein E gene. Age of onset itself has a heritability of around 50%.

History

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. Kraepelin, E. 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, because the symptoms and brain pathology were identical, 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 short-term memory, then of familiar and well-known skills or objects or persons. Aphasia, disorientation and disinhibition often 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 15 years.

Diagnosis

The diagnosis is made primarily on the basis of history, 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. Functional neuroimaging studies such as PET or SPECT scans can provide additional supportive evidence for the diagnosis. No medical tests other than brain biopsy are available to diagnose Alzheimer's disease conclusively pre-mortem. Thus, Alzheimer's disease is primarily a clinical diagnosis based on the presence of characteristic neurological features and the absence of alternative diagnoses. 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 microscopic examination of brain tissue, generally at autopsy.

Interviews with family members and/or caregivers are extremely important in the initial assessment, as the sufferer him/herself may tend to minimize his symptomatology or may undergo evaluation at a time when his/her symptoms are less apparent, as quotidian fluctuations ("good days and bad days") are a fairly common feature. Such interviews also provide important information on the affected individual's functional abilities, which are a key indicator of the significance of the symptoms and the stage of dementia.

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, visuospatial abilities, and other cognitive functions. Results of psychological tests may not readily distinguish Alzheimer's disease from 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".

Pathology

Microscopy

There are several characteristic neuropathological changes found in the brain in AD:

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).
- 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.
Diffuse atrophy and loss of neurons, neuronal processes and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions and enlargement of the lateral ventricles.

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. This hypothesis has been given the name "syn-ners" among AD researchers. There is also a "triple lesion" hypothesis that proposes a pathological interaction among these three candidate proteins. The extent of each protein's contribution may determine whether or not the "lesion disorder" manifests as AD, Parkinsonism, or other degenerative diseases.

Abnormal protein aggregation in the brain is a common thread in neurodegenerative disorders. Besides beta-amyloid in Alzheimer's and synuclein in Parkinson's, examples include prions in prion diseases; huntingtin in Huntington's disease; BRI in familial British dementia; and tau protein in frontotemporal dementia with Parkinson's disease, progressive suprnuclear palsy, and Pick's disease. Many reaserchers believe the the protein aggregates formed are toxic and give rise to the multiple brain changes that characterize the different neurodegenerative diseases. If one relationship between these diseases really is abnormal protein aggregation, then discovering ways to prevent aggregation, or the processes set in motion by the aggregation, may halt the disease process. The presence of plaques and tangles, however, does not always correlate well 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, as well as loss of dendrites and dendritic spines. 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 may be the result of the brains's efforts to contain the abnormal proteins produced by the disease.

Genetics of AD

There is compelling evidence that genetic predisposition underlies the development of Alzheimer's disease. 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 impaired hippocampal-dependent learning which is correlated with reduced adult neurogenesis in the dentate gyrus ^*). Mutations in the APP gene on chromosome 21 can also cause early onset disease. The presenilins have been identified as essential components of the proteolytic processing machinery that produces beta amyloid peptides through cleavage of APP.

Unfortunately, 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. 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 amyloid beta precursor protein the beta secretase enzymes ^*," target="_blank" >endothelin-converting enzymes ^*.

Genetic linkage

Alzheimer's disease is definitely linked to the 1st, 14th, and 21st chromosomes, but other linkages are controversial and not, as yet, confirmed. While some genes predisposing to AD have been identified , such as ApoE4 on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation.

Epidemiology and prevention

Alzheimer's disease is the most frequent type of dementia in the elderly and affects almost half of all patients with dementia. Correspondingly, advancing age is the primary risk factor for Alzheimer's. Among people aged 65, 2-3% show signs of the disease, while 25 - 50% of people 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. Every five years after the age of 65, the probability of having the disease doubles. The proportion of people 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. Famous Alzheimer's disease sufferers have included President Ronald Reagan, Ralph Waldo Emerson, and Rita Hayworth.

The evidence relating certain behaviors, dietary intakes, environmental exposures, and diseases to the likelihood of developing Alzhemier's varies in quality and its acceptance by the medical community. It is important to understand that interventions that reduce the risk of developing disease in the first place may not alter disease progression after symptoms become apparent. Due to their observational design, studies examining disease risk factors are often at risk from confounding variables. Several recent large, randomized controlled trials—in particular the Women's Health Initiative—have called into question preventative mesasures based on cross-sectional studies. Some proposed prevenative measures are even based on studies conducted solely in animals.

Risk reducers

Intellectual stimulation (e.g., playing chess or doing the crossword) Verghese, Joe, Lipton, Richard B., Katz, Mindy J., Hall, Charles B., Derby, Carol A., Kuslansky, Gail, Ambrose, Anne F., Sliwinski, Martin, Buschke, Herman. Leisure Activities and the Risk of Dementia in the Elderly. N Engl J Med 2003 348: 2508-2516 ^*
Regular physical exercise Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane P, Kukull W. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006 Jan 17;144(2):73-81 PMID 16418406
Regular social interaction
A generally healthy diet low in saturated fat supplemented in particular with:
- B vitamins
- Omega-3 fatty acids, especially DHA Lim WS, Gammack JK, Van Niekerk JK, Dangour AD. Omega 3 fatty acid for the prevention of dementia. The Cochrane Database of Systematic Reviews 2006, Issue 1. PMID 16437528Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS. Fish consumption and cognitive decline with age in a large community study. Arch Neurol. 2005 Dec;62(12):1849-53 PMID 16216930
- High doses of the antioxidant Vitamin E (in combination with vitamin C) seem to reduce Alzheimer's risk in cross sectional studies but not in a randomized trial and so are not currently a recommended preventive measure because of observed increases in overall mortality Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ; Alzheimer's Disease Cooperative Study Group. "Vitamin E and donepezil for the treatment of mild cognitive impairment." N Engl J Med 352:2379-2388. PMID 15829527Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D, Tschanz JT, Norton MC, Welsh-Bohmer KA, Breitner JC; Cache County Study Group. "Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study." Arch Neurol. 2004 61:82-88. PMID 14732624
Cholesterol-lowering drugs (statins) reduce Alzheimer's risk in observational studies but so far not in randomized controlled trials
Hormone replacement therapy is no longer thought to prevent dementia based on data from the Women's Health Initiative
Regular use of non-steroidal anti-inflammatory drugs like ibuprofen and aspirin reduces the chance of dementia but the risks appear to outweigh the drugs' benefit as a method of primary prevention

Risk factors

Advancing age
ApoE epsilon 4 genotype
Head injury
Poor cardiovascular health (including smoking, diabetes, hypertension, high cholesterol)
Exposure to heavy metals, particularly aluminum, is a proposed but not widely-accepted risk factor ^*

Treatment

There is currently no cure for Alzheimer's disease, although there are drugs which offer symptomatic benefit, specifically with respect to short-term memory impairment.

Acetylcholinesterase inhibitors

Acetylcholinesterase (AChE) inhibition was thought to be important because there is a reduction in activity of the cholinergic neurons. 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 in the respected medical journal The Lancet has suggested they are ineffective.Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P; AD2000 Collaborative Group. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-15. PMID 15220031 The pharmaceutical companies, but also many independent 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 SA, McShane R, Sherriff F. Memantine for dementia. Cochrane Database Syst Rev 2004(4). PMID 15495043

Potential treatments

Vaccines for Alzheimer's, unlike typical vaccines, would be used to treat diagnosed patients rather than for disease prevention. Ongoing efforts are based on the idea that, by training the immune system to recognize and attack beta-amyloid, the immune system might reverse deposition of amyloid and thus stop the disease. Initial results using this approach in animals were promising. However, when the first vaccines were used in humans, a small fraction of participants developed encephalitis and the trials were stopped. Participants in the halted trials continued to be followed, and some showed possible benefit in the form of slower progression of the disease. http://www.alz.org/Resources/TopicIndex/AN1792.asp Work is continuing on less toxic Aβ vaccines, such as a DNA-based therapy that recently showed promise in mice.
Vitamin E is an antioxidant that may slow disease progression when taken in large doses. A clear demonstration of the efficacy of vitamin E awaits further study Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. "A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study." N Engl J Med. 1997 336:1216-1222. PMID 9110909
Proposed alternative treatments for Alzheimer's include a range of herbal compounds and dietary supplements. In general, research on the efficacy of these substances is either non-existant or far too weak to support therapeutic claims of improved memory or slowed disease progression.http://www.alz.org/AboutAD/Treatment/Alternative.asp Only ginkgo biloba is currently being tested in a large randomized clinical study. Birks J, Grimley Evans J. "Ginkgo Biloba for cognitive impairment and dementia." Cochrane Database Syst Rev 2002(4). PMID 12519586 Morever, although they are often advertised as "natural" and available without a prescription, these substances can have serious side effects and interactions with other medications.

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. 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. 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.

External links

Alzheimer's Association - The major Alzheimer's support and advocacy group in the United States provides excellent information on topics ranging from basics of diagnosis and caregiving to the disease's legal implications and ways to talk to children about the disease
Alzheimer's Research Forum - A website intended to provide information to and foster collaboration among scientists and physicians conducting research on Alzheimer's. Features debates between and article annotations by many top Alzheimer's researchers
National Institute on Aging - Substantial website by a division of the U.S. National Institutes of Health with links to information about ongoing clinical studies
OMIM - Running, highly technical synopsis of research on Alzheimer's disease maintained by the NIH
Journal of Alzheimer's Disease - Subscription required for full text
eMedicine - Well-organized article on Alzheimer's

References

Alzheimer's disease | Neurology | Unsolved problems in neuroscience

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