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Dementia in Alzheimer's disease
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('''AD'''), a
Neurodegenerative Disease , is the most common cause of
Dementia and characterized clinically by progressive cognitive deterioration together with declining activities of daily living and
Neuropsychiatric symptoms or behavioral changes. The most striking early symptom is memory loss (
Amnesia ), 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 (cell) 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 (variations) 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%.
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.
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.
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 Test s 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 neurologic 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".
There are several charcateristic 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 ( Oligomer s) 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 ).
- Accumulation of abnormal protein filaments inside nerve cells in the brain, formed from aggregation of Tau Protein , which normally stabilizes Microtubule s. 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.
- 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 .
The neurotransmitters
Serotonin ,
Acetylcholine ,
Norepinephrine , and
Somatostatin are at decreased levels.
Glutamate levels are usually elevated.
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
Acetylcholinesterase s (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.
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. 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. 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 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 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16470248&query_hl=6 , insulin-degrading enzyme
endothelin-converting enzymes [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15340356&query_hl=10 , and inflammatory 5-lipoxygenase gene [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16278051&query_hl=34].
Studies have not shown convincing links with toxins,
Vitamin s, metals or diet. 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.
Alzheimer's disease is linked to the 1st, 10th, 14th, 9th, 19th, and/or 21st chromosomes, among others. While some genes predisposing to AD have been identified, most cases are sporadic. However, sporadic AD most often involves some form of genetic susceptibility.
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 people aged 65 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. 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.
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 [http://www.chessmaniac.com/2006/02/playing-chess-may-decrease-chance-of.php played chess on a regular basis developed 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 Puzzle s, 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).
Association studies have indicated that
Non-steroidal Anti-inflammatory Drug s (NSAIDs) like
Ibuprofen and
Aspirin may lower the risk of developing 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 reduce the relative risk for Alzheimer's.
It should be noted that some drugs such as
Acetaminophen ,
Naproxen , and
COX-2 Inhibitor s, 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).
One 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
IU 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 IU 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
Antioxidant s). 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 . 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-morbid role of stroke supports other research showing that quitting smoking, weight reduction, and avoidance of diabetes all reduce Alzheimer's risk. 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 Acid s are thought to most effective.
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
Statin s (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).
Cigarette s 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 .
Some work is being done to investigate the role of raised levels of
Homocysteine , and possible
Nutrition al prevention or treatment through taking of foods high in B vitamins and
Antioxidant s 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.
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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 (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:
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 independent clinicians, dispute the findings of the study, based on methodologic grounds.
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)
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 possible benefit 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.
Some studies, summarised in a shows promise for alleviating the effects of Alzheimer's; however, the paper concedes that further research is required, as consumption of ginkgo biloba can have undesirable side-effects, especially for those with blood circulation disorders and those taking certain medications. Ginkgo should not be used by anyone taking
Anti-coagulant s, pregnant women, or anyone using the
Anti-depressant drugs known as
Monoamine Oxidase Inhibitors (MAOI).
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
Caregiver s 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.
- Areosa SA, McShane R, Sherriff F. ''Memantine for dementia.'' Cochrane Database Syst Rev 2004(4);CD003154.pub2. PMID 15495043
- 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.
- KEGG Metabolic pathways in Alzheimer's.
