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Alzheimer’s Disease
Alzheimer’s Disease
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Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common form of acquired cognitive behavioral impairment and dementia. The disease has a long progressive natural course that interferes with social and occupational functioning. To date, there are no cured cases. Hippocampal/cerebral plaques are most prominently known to impair memory encryption, thinking, and decision-making processes. It is still unclear if the plaques themselves cause the disease or are the result of an underlying pathology. The disease is named after Dr. Alois Alzheimer, a German psychiatrist who first observed short-term memory loss and anomalous behavioral changes in a 51-year-old female patient, Mrs. Auguste D., at a Frankfurt asylum in 1901. After her death in 1906, Dr. Alzheimer performed microscopic examination of brain sections that led to identification of the disease specific amyloid plaques and neurofibrillary tangles. The diagnosis of Alzheimer’s disease is mostly clinical, with only a limited number being diagnosed on brain biopsy. However, there have been reports that the specific pathological changes can exist without the concomitant clinical manifestations of the disease.
Types
Early onset (<5%): Symptoms appear before age 60 and are less common than late onset. It progresses and worsens quickly. Early onset disease can be hereditary; mutations in the genes for amyloid precursor protein, presenelin-1, and presenelin-2 have been identified.
Late onset: The most common type. Symptoms occur after 60. Although hereditary associations have been identified, the role of genes is less clear. Converging environmental and genetic risk factors appear to contribute in the development of the disease. Advancing age, family history, ApoE (apolipoprotein E) genotype, obesity, insulin resistance, vascular factors, Down syndrome, and traumatic brain injury are the most common etiologies. Newer epidemiologic studies have associated aluminum and previous depression with AD development.
Stages
Preclinical stage. In the preclinical stage, the patient may appear normal on physical and mental status examination, but specific areas of the brain (e.g., entorhinal cortex, hippocampus) begin to be affected more than 10 years before symptomatic impairment.
Mild cognitive impairment. Definitive diagnosis is possible at this stage with memory loss, confusion, and difficulties in language and executive functions. Agnosia (loss of the ability to recognize objects, persons, sounds, shapes) and apraxia (inability to execute learned purposeful movements) are prominent. AD does not affect all memory capacities equally; episodic memory (older memories), semantic memory (learned fact), and implicit memory (the memory of the body on how to do things) are relatively less affected than newer facts or memories. Many patients experience vocabulary and fluency difficulties but continue to perform tasks independently.
Moderate. Progressive deterioration leading toward complete dependence marks the moderate stage of AD. Speech difficulties, urinary incontinence, incoordination in complex motor activities, inability to read or write, and worsening memory problems including loss of previously intact long-term memory become more evident. Behavioral changes are also observed with patient displaying increased irritability, labiality of emotions, and aggression especially toward caregivers. Approximately 30% show illusionary misidentifications and delusional disorder.
Advanced. In advanced-stage AD, the patient becomes completely dependent upon caregivers. Language is limited to small phrases or single words, eventually leading to complete loss of speech. Aggressiveness can still be present, although apathy and fatigue are much more common. Patients cannot perform the most simple of tasks without assistance, leading to eventual immobility. Death in most instances is caused by systemic infections like pneumonia or secondary to pressure sores.
Pathophysiology
Macroscopically, AD is characterized by gross atrophy of the temporal and parietal lobe, and parts of the frontal cortex and cingulate gyrus.
Three major hypotheses exist to explain the cause of the disease, although other possible explanations also exist.
Cholinergic Hypothesis
The oldest major hypothesis is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. Some available drug therapies in Alzheimer’s are directed toward increasing acetylcholine levels, however, these medications only improve disease symptoms and do not affect the original disease process.
Amyloid Hypothesis
Alzheimer’s disease has been identified as a protein-misfolding proteopathy. In 1991, the amyloid hypothesis was proposed, based on the discovery that senile plaques were composed of 39 to 43 amino acid peptides called beta amyloid or A-beta (Aβ) peptides, which were proteolytic fragments of a larger precursor protein, the APP (amyloid precursor protein). The enzymes involved in proteolysis were found to be gamma secretase and BACE-1. Beta amyloid deposits outside neurons to form dense senile plaques, thought by scientists to be the fundamental cause of disease.
The location of the gene for APP on chromosome 21 and the strong association of AD with Down syndrome (trisomy 21) as well as the presence of mutations in the gene for presenelin (proteins involved in processing of APP) in patients with AD support the amyloid hypothesis. It is further noted that ApoE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise, indicating Aβ deposition precedes clinical AD. Mature amyloid plaques are suspected to be neurotoxic, and it is also proposed that normal mitochondrial function is disrupted in brain neurons by selective Aβ build-up, leading to decreased glucose utilization in neurons, formation of reactive oxygen species, calcium influx, and apoptosis even before formation of fibrils and plaques by unknown mechanisms. The primary mechanisms remain unclear.
Tau Hypothesis
The other most prominent microscopic finding in AD is neurofibrillary tangles composed of hyperphosphorylated tau protein. The tau protein is a soluble microtubule-associated protein that stabilizes the cytoskeleton by phosphorylation. When the protein becomes hyperphosphorylated, it becomes insoluble and filamentous.
According to the tau hypothesis, the hyperphosphorylated tau forms threads that tangle inside neurons to form masses or neurofibrillary tangles. This leads to disintegration of the neuronal cytoskeleton and transport system.
Although both the amyloid plaques and the neurofibrillary tangles are also identified on microscopy in other neurodegenerative diseases, they are found in larger numbers in Alzheimer’s disease.
Alternative Hypotheses
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