Clinical signs of Alzheimer's disease are characterized by progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatric symptoms or behavioral changes. It is the most common type of dementia. Plaques which contain misfolded proteins called beta amyloid form in the brain many years before the clinical signs of Alzheimer's are observed. Together, these plaques and neurofibrillary tangles form the pathological hallmarks of the disease. These features can only be discovered at autopsy and help to confirm the clinical diagnosis. Medications can help reduce the symptoms of the disease, but they cannot change the course of the underlying pathology.
The ultimate cause of Alzheimer's is unknown. Genetic factors are suspected, and dominant mutations in three different genes have been identified that account for the small number of cases of familial, early-onset AD. For the more common form of late onset AD (LOAD), ApoE is the only repeatedly confirmed susceptibility gene.
History
Auguste D.In 1901, Dr. Alois Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease, in a 50 year-old patient Auguste D and followed her to her death in 1906, when he first reported the case publicly.
For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of presenile dementia. Senile dementia, as a set of symptoms, was considered to be a relatively normal outcome of the ageing process, and thought to be due to age-related brain arterial "hardening."
In the 1970s and early-1980s, because the symptoms and brain pathology were identical for any age, the name "Alzheimer's disease" became used equally for afflicted individuals of all ages; however, the term senile dementia of the Alzheimer type (SDAT) was often used to describe the condition in those over 65. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with the characteristic common symptom pattern, disease course, and neuropathology. The term Alzheimer disease (without the apostrophe and s) is also sometimes used in literature for learning.
Clinical features
The first readily identified symptoms of Alzheimer's disease are usually short-term memory loss and visual-spatial confusion. These initial symptoms progress from seemingly simple and often fluctuating forgetfulness and difficulty orienting oneself in space such as in a traffic lane while driving, to a more pervasive loss of short-term memory and difficulty navigating through familiar areas such as one's neighborhood, then to loss of other familiar and well-known skills as well as recognition of objects and persons.
Since family members are often the first to notice changes that might indicate the onset of Alzheimer's they should learn the early warning signs and serve as informants during initial evaluation of patients clinically. Aphasia, disorientation and disinhibition often accompany the loss of memory. Alzheimer's disease (AD) 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 of the disease, 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. Once identified, the average lifespan of patients living with Alzheimer's disease is approximately 7-10 years, although cases are known where reaching the final stage occurs within 4-5 years or at the other extreme they may survive up to 21 years.
Stages and symptoms
Mild — In the early stage of the disease, patients have a tendency to become less energetic or spontaneous, though changes in their behavior often go unnoticed even by the patients' immediate family. This stage of the disease has also been termed Minor Cognitive Impairment (MCI), when the patient does not meet the criteria for a diagnosis of dementia.
Moderate — As the disease progresses to the middle stage, patients might still be able to perform tasks independently (such as using the bathroom), but may need assistance with more complicated activities (such as paying bills).
Severe — As the disease progresses from the middle to the late stage, patients will not be able to perform even simple tasks independently and will require constant supervision. They become incontinent of bladder and then incontinent of bowel. They will eventually lose the ability to walk and eat without assistance. Language becomes severely disorganized, and then is lost altogether. They may eventually lose the ability to swallow food and fluid, and this can ultimately lead to death.
Diagnosis
Alzheimer's disease (AD) is primarily a clinically diagnosed condition based on the presence of characteristic neurological and neuropsychological features and the absence of alternative diagnoses. Determination of neurological characteristics is made utilizing patient history and clinical observation, while neuropsychological evaluation includes memory testing and assessment of intellectual functioning over a series of weeks or months. Supplemental physical testing, including blood tests and neuroimaging, is utilized to rule out other diagnoses. Psychological testing, to include screening for depression and a mini mental state examination, can be helpful in establishing the presence and severity of dementia. Although certain clues from history may suggest a diagnosis of vascular dementias instead of, or in addition to, AD (for example, see the Hachinski scale [9]), the ability of certain neuroimaging modalities such as SPECT to differentiate vascular type from Alzheimer disease types of dementias, appears to be superior to clinical exam (PMID 15545324).
Interviews with family members and/or caregivers are also utilized in the initial assessment of the disease, as a patient with Alzheimer's may tend to minimize his or her symptoms, or may undergo evaluation at a time when his or her symptoms are less apparent, as quotidian fluctuations ("good days and bad days") are a common feature of the disease. Observations noting that a patient's good memory function decreases over time plays a critical role in the diagnosis of Alzheimer's.
No medical tests are available to diagnose Alzheimer's disease conclusively pre-mortem. Expert clinicians who specialize in memory disorders can now diagnose AD with an accuracy of 85 - 90%. However, a definitive diagnosis of Alzheimer's disease must await microscopic examination of brain tissue which generally occurs at autopsy.
Pathology
Main article: Biochemistry of Alzheimer's disease
Biochemical characteristics
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded amyloid beta protein and tau protein in the brains of AD patients. Amyloid beta, also written Aβ, is a short peptide that is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation. Although amyloid beta monomers are soluble and harmless, they undergo a dramatic conformational change at sufficiently high concentration to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils that deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques.
Neuropathology
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains. At an anatomical level, AD is characterized by gross diffuse atrophy of the brain 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, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[13] Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated.
Disease mechanism
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the "cholinergic hypothesis" and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. The medications that treat acetylcholine deficiency have served to only treat symptoms of the disease and have neither halted nor reversed it. The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholingeric effects have been proposed to initiate large-scale aggregation leading to generalized neuroinflammation.
Research after 2000 includes hypotheses centered on the effects of the misfolded and aggregated proteins, amyloid beta and tau. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other believes that beta amyloid deposits are the causative factor in the disease. The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss; however, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.
The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on chromosome 21, and patients with trisomy 21 - better known as Down syndrome - who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age. The traditional formulation of the amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing apoptosis. A more recent and widely supported hypothesis suggests that the cytotoxic species is an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species. Relevantly, much early development work on lead compounds has focused on the inhibition of fibrillization, but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.
It should be noted further that ApoE4, the major genetic risk factor for AD, leads to excess amyloid build up in the brain before AD symptoms arise. Thus, beta-amyloid deposition precedes clinical AD. Another strong support for the amyloid hypothesis, which looks at the beta-amyloid as the common initiating factor for the Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop first diffuse and then fibrillar beta-amyloid plaques, associated with neuronal and microglial damage.
Genetics
Rare cases of Alzheimer's 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 Alzheimer's disease (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.
Most cases identified are "sporadic" with no clear family history. Environmental factors sometimes claimed to increase risk of Alzheimer's including prior head injury, paticularly repeated trauma, previous incidents of migraine headaches, exposure to defoliants, low activity levels during adulthood. owever, with the exception of previous concussion, none of these environmental risk factors are widely accepted.
Inheritance of the ε4 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). Researchers are 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-β precursor protein (APP), e beta secretase enzymes nsulin-degrading enzyme endothelin-converting enzymes nd inflammatory 5-lipoxygenase gene.
Genetic linkage
Alzheimer's disease is definitely linked to the 1st, 14th, and 21st chromosomes, but other linkages are controversial and not 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.
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