Alzheimer’s disease is a neurologic disorder that causes brain atrophy and death. It is the leading cause of dementia, which is characterized by a gradual decline in thinking, behavioral, and social skills, rendering patients unable to function autonomously. Statistics show that approximately 5.8 million Americans over the age of 65 years suffer from the disease. The main sign of Alzheimer’s is memory impairment, which makes people forget recent occurrences and conversations. The disease does not have a cure, but its symptoms can be slowed using drugs. The pathology of a disease addresses three main components: cause (etiology), mechanisms of development (pathogenesis), structural alterations of cells (morphologic changes), and the consequences of changes (clinical manifestations). This paper will discuss the aforementioned components as they relate to Alzheimer’s disease.
Etiology
Alzheimer’s disease is largely caused by the irregular accumulation of two proteins within and around brain cells, namely beta-amyloid and tau. Microscopic studies have shown that the brain cells of people with the disease have uncharacteristic deposits of a protein known as amyloid. The amalgamation of these proteins forms clusters that affect neuronal functioning and alter cell-to-cell communication (Tiwari et al., 2019). The accumulation of these clusters leads to the formation of amyloid plaques. Another protein known as tau is also responsible for the formation of neurofibrillary tangles (NFTs) of these deposits in the brain cells that disrupt the transport system. The exact cause of this deposition is unknown. However, scientists have established that it begins long before the onset of symptoms. These deposits affect brain cells by decreasing the amounts of neurotransmitters that transmit signals between brain cells, forming the main channel of communication.
The two types of Alzheimer’s, early-onset and late-onset, have a genetic component that has been cited as a causative factor. A specific gene that is responsible for late-onset Alzheimer’s has not yet been identified. However, researchers have found out that an individual whose chromosome 19 possesses a genetic variant of the apolipoprotein E (APOE) gene, has a higher risk of developing the disease (Tiwari et al., 2019). This gene plays a key role in the manufacture of a protein that facilitates the transportation of cholesterol and other fats in the body. Early-onset Alzheimer’s has been associated with an inherited mutation in one of the following genes: amyloid precursor protein (APP) on chromosome 21, presenilin 1 (PSEN1 ) on chromosome 14, and presenilin 2 (PSEN2 ) on chromosome 1 (Tiwari et al., 2019). Factors such as poor sleep patterns, excessive alcohol consumption, air pollution, obesity, lack of exercise, high blood pressure, and smoking increase the risk of developing Alzheimer’s disease.
Pathogenesis
The pathogenesis of Alzheimer’s can be clearly understood through the study of two abnormal proteins: beta amyloid and tau. The development of Alzheimer’s takes place through two main processes, namely extracellular deposition of beta amyloid and intracellular accumulation of tau protein (Perl, 2010). When beta-amyloid deposits accumulate in and around brain cells and neurofibrillary tangles form, there are widespread losses of synapses and neurons (Perl, 2010). This leads to total atrophy of the cells containing the protein deposits, beginning at the mesial temporal lobe. The beta-amyloid plaques begin forming in the basal, temporal, amygdala, neocortex, hippocampus, diencephalon, and the basal ganglia regions of the brain (Tiwari et al., 2019). In very severe cases, they are deposited throughout the cerebellar cortex and the lower brain stem. Deposits of tau protein appear first in the entorhinal cortex, followed by the hippocampus, and later in association cortex (Perl, 2010). The interaction between tau protein and the kinases secreted due to the accumulation of beta amyloid, the process of hyperphosphorylation is initiated (DeTure & Dickson, 2019). The disassociation of tubule units leads to their conversion into large tau filaments that coalesce into NFTs that cause apoptosis and an abnormal loss of communication between neurons (Perl, 2010). The destruction of the hippocampus leads to memory loss. The accumulation of senile plaques (SPs) and NFTs in the brain lead to loss of neurons and synapses, dilation of the lateral ventricles, and brain degeneration.
Morphologic Changes
Brain cells undergo certain morphological changes due to the effects of beta amyloid and tau protein deposits. A key structural change that takes place is the loss of synaptic components of brain cells that is associated with impaired cognitive function. The perikaryal cytoplasm of certain neurons is altered significantly by the accumulation of NFTs (Perl, 2010). Microscopic study of affected brain regions reveals the presence of Hirano bodies, inflammation, granulovascular degeneration, and deposits of amyloid plaques and neurofibrillary tangles. NFTs are comprised of amassed tau protein and neurofilaments, and they coalesce within and around neuronal cell bodies (Perl, 2010). In addition, neuropil threads and neuritic plaques are also observed on cells. The progressive accumulation of beta-amyloid leads to the degeneration of brain cells, and eventually, death.
The perikaryal cytoplasm of pyramidal neurons contains NFTs that are structurally called paired helical filaments. Their distribution is more localized in the layer II neurons of the entorhinal cortex, the amygdala, and the hippocampus (Perl, 2010). Vascular amyloid deposits are also found in the walls of small arteries and arterioles within the cerebral cortex. Another structural change is granulovascular degeneration that is characterized by the presence of intraneuronal clusters of small vacuoles (Perl, 2010). Each vacuole contains a dense granule, and they are distributed within the perikaryal cytoplasm of neurons located in the hippocampus. Other morphological changes include the presence of eosinophilic rod-like inclusions known as Hirano bodies and synaptic loss (Tiwari et al., 2019). These structural changes are responsible for the clinical manifestations of Alzheimer’s disease in patients.
Clinical Manifestations
The initial stages of the development of Alzheimer’s are clinically manifested by progressive memory impairment. In particular, individuals begin to experience the loss of episodic memory function, and they cannot recall recent interactions or conversations (Bature et al. 2017). Free recall does not improve, even through the use of the cueing technique for memory retrieval. The deterioration of non-memory functions can also be observed during the onset stage. For instance, individuals experience difficulty with vision, word-finding, and reasoning. These symptoms might aid physicians in the diagnosis of mild cognitive impairment. This stage is followed by the gradual degeneration of other cognitive functions that are necessary for independent operations (Bature et al. 2017). This decline is a defining characteristic of the dementia phase of Alzheimer’s in which patients become functionally dependent on others. This phase is the cornerstone of the disease’s diagnostic criteria that involves the assessment of the impairment of memory, thinking skills, and functional abilities (Bature et al. 2017). The cognitive and behavioral symptoms of Alzheimer’s are caused by the loss of synapses, as well as cholinergic and noradrenergic functions in the brain (Lanctot, 2017). The disease progresses to total cognitive impairment that is characterized by abnormal neurologic and psychiatric symptoms. Other symptoms include mood and personality changes, loss of spontaneity, bad decisions due to poor judgement, difficulties competing normal daily tasks, and increased anxiety or aggression.
The clinical manifestation of Alzheimer’s depends on the stage of the disease’s progression. In moderate cases, symptoms include shortened attention span, challenges with language, reading and writing, hallucination and paranoia, problems handling change, restlessness, anxiety, and difficulty organizing thoughts (Bature et al. 2017). Symptoms of severe Alzheimer’s include inability to communicate, seizures, skin infections, groaning and grunting, loss of bowel control, weight loss, and increased sleeping. Complete dependence is characteristic of the late stage of Alzheimer’s, and it results from severe neurological degeneration (Lanctot, 2017). Changes in personality and behavior include mood swings, wandering, apathy, depression, withdrawal, loss of inhibitions, distrust in others, and delusions (Bature et al. 2017). These symptoms are critical during the diagnosis process.
Conclusion
Alzheimer’s disease is a neurodegenerative disease that is caused by interactions between genetic, environmental, and lifestyle factors. It is largely caused by the abnormal accumulation of amyloid and tau proteins within and around brain cells. The extracellular deposition of beta amyloid and intracellular accumulation of tau protein alter the morphology of the cells and their functions. When beta-amyloid deposits accumulate in and around brain cells and neurofibrillary tangles form, there are widespread losses of synapses and neurons. The microscopic analysis of affected brain regions reveals the presence of Hirano bodies, inflammation, granulovascular degeneration, and deposits of amyloid plaques and neurofibrillary tangles on brain cells. Granulovascular degeneration that is characterized by the presence of intraneuronal clusters of small vacuoles. The clinical manifestations of Alzheimer’s disease include memory loss, shortened attention span and difficulty with language, writing, and reading, inability to learn new things, depression, mood swings, hallucination, paranoia, and problems with concentration.
References
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