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Alzheimer's Disease Biological Causes

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Alzheimer’s disease is driven by two processes: extracellular deposits of beta amyloid and intracellular accumulation of tau protein.[9] “It is characterized by accumulation of amyloid-β peptide, generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase.”[10p554] The APP gene provides instructions for making APP. This protein is found in many tissues and organs including the brain and the spinal cord. It plays a role in cell growth, formation of new synapses, differentiation of neurons, cell adhesion, calcium metabolism, and protein trafficking.[10] The length of APP varies between 695 to 770 amino acids. Protein breakdown generates Aβ, a 39- to 42-amino acid peptide. This form is the primary component of amyloid plaques found in the brains of AD.[10] APP may be processed via a non-amyloidogenic pathway that prevents Aβ formation or through a toxic, amyloidgenic pathway, resulting in Aβ plaque formation.

In the non-amyloidogenic pathway, APP is processed in peripheral cells. In this pathway, APP is cleaved by an enzyme called α-secretase followed by γ-secretase. These are integral membrane proteins where cleavage by α-secretase occurs within the Aβ domain. Cleavage by α-secretase prevents Aβ formation and releases the extracellular secreted APP α fragment.[11] Research shows that secreted APP α protects neurons, regulates stem cell production, plays a role in brain development, and promotes the formation of synapses and cell adhesion. The remaining C-terminal fragment of APP then undergoes either lysosome degradation or γ-secretase cleavage, which generates p3 and the APP intracellular domain.[11]

In the amyloidogenic pathway, APP is primarily processed in neuronal cells. Within this pathway, APP is cleaved by β-site APP cleaving enzyme 1 (BACE1), followed by γ-secretase. BACE1 initiates the production of the toxic Aβ that plays a crucial role early in the pathogenesis of AD.[11] Cleavage of APP by BACE1 releases the extracellular secreted APP β fragment which is thought to assist with axon pruning and cell death.[12] BACE1 cuts APP to produce a membrane-bound C-terminal fragment C99 that is further processed by γ-secretase to generate Aβ. The site of γ-secretase cleavage within the transmembrane domain of APP can vary and determines the type of Aβ that is produced, Aβ 39-42. Once produced, is usually secreted into the extracellular space via exocytosis.[12]

Aβ is a major component of plaques that are found in both intracellular and extracellular locations. 42 is considered to be one of the main causes of these plaques because it clumps together more quickly than other isoforms, forming clusters and fibrils.[10] In individuals with AD, elevated concentrations of Aβ plaques can lead to many cellular dysfunctions. The presence of Aβ plaques alone is not enough to diagnose AD since many people without cognitive decline have plaques.

Tau is a protein in the microtubule-associated protein family. It has several physiological functions in healthy axons including microtubule assembly and stability, vesicle transport, neuronal outgrowth and neuronal polarity. This protein consists of 352 to 441 amino acids and presents in various isoforms in the brain.[10] In AD, tau protein is hyperphosphorylated, causing disruption in microtubule transport and loss of neuronal transmission. Tau phosphorylation is the addition of phosphate to a tau protein through regulation of tau kinases. In humans, the tau gene is positioned on chromosome 17. In a normal brain, there are two to three moles of phosphate per one mole of tau, indicating that this amount of phosphorylation is necessary for tau to perform its normal biological functions. When tau becomes hyperphosphorylated, the ratio of phosphate to tau increases three to four fold compared to normal phosphorylation levels. This increased amount of phosphate alters the function of tau, making it insoluble and lacking affinity for microtubules. This leads to the degradation of the microtubules and neuronal cell death.[10]

The main risk factor for developing AD is increasing age, with those aged 65 and older at greatest risk.[10] Younger individuals may also develop the disease, however, this is often the result of genetic mutations. As mentioned, two distinct types of AD exist: familial AD and sporadic AD. The two types are distinguished by their onset periods and family history. Plaque formation and neurofibrillary tangles are present in both types of the disease.

As previously stated, fAD follows an autosomal dominant pattern of inheritance and is inherited through mutations in the genes for APP, PS1, or PS2. Each of these genes encode for proteins that are involved in the production of the Aβ peptide.

PS1 and PS2 are proteins with numerous transmembrane domains. Higher expression of the presenilins has been noted in the cerebellum and hippocampus. The genes for PS1 and PS2 have a similar structure and are located on chromosome 14 and chromosome 1, respectively. These proteins are thought to play a role in signaling pathways, cell death, and initiating the response to unfolded proteins. They are also an important part of the γ-secretase complex that is involved in APP processing.[10]

PS1 mutations are the primary cause of fAD. Currently, more than 176 PS1 mutations have been identified in 390 families. Individuals carrying a PS1 mutation typically develop more severe forms of AD and display symptoms at an earlier age than those carrying PS2 mutations. Most PS1 mutations are missense mutations in which they cause amino acid substitutions and are located in the transmembrane domains of the affected protein.[10] PS2 mutations are a much rarer cause of fAD, and currently only 14 PS2 mutations have been identified in six families.

Amyloid precursor protein is a 695 amino acid protein that is cleaved by the γ-secretase enzyme. APP is located on chromosome 21, making individuals with trisomy 21 (Down syndrome) at higher risk for developing AD. More than 32 APP mutations have been discovered in 78 families, however the APP gene represents only a small fraction of AD.[7]

LOAD often does not show a family history and is most likely caused by risk alleles across various genes involved in Aβ production, aggregation, and degradation. The Apolipoprotein E (APOE) gene on chromosome 19 (specifically APOE-ε4) has been demonstrated to represent a major genetic risk factor for LOAD.[1] “APOE is a lipid-binding protein and is expressed in humans as three common isoforms coded for by three alleles, APOE-ε2, -ε3, and -ε4.”[1p61] One APOE-ε4 allele increases one’s risk by two to three times while two alleles increases risk by a minimum of five times. It is important to note that not everyone who has one or two APOE-ε4 genes develops Alzheimer's disease. The disease occurs in many people who have no APOE-ε4 gene, suggesting that the APOE-ε4 gene affects risk but is not a cause.

Epigenetics is the phenotype expression or silence of a gene without necessarily having the genotype.[13] One way for phenotypes to be expressed or silenced is through methylation, which is a biochemical bond of a methyl group between three hydrogen atoms and one carbon atom. When there is over-methylation, it will turn the gene off whereas decreased methylation will turn the gene on. Some epigenetic marks remain for a lifetime while others are temporary, influenced by modifiable factors, such as weight, diet, or stress.[13]

Epigenetics may explain the neurological changes that occur in AD.[13] In a study of monozygotic twins at the L.J. Roberts Center for Alzheimer’s Research in Arizona, researchers found that one twin developed AD while the other twin did not. Their postmortem autopsy revealed that the Alzheimer brain had tremendous decrease of methylation of brain cells whereas the non-Alzheimer brain did not. Researchers continue to investigate whether decreased methylation caused dementia or vice versa. In another experiment, in which they conducted test tube brain experiments, they were able to confirm that epigenetics does cause the typical hallmark changes of plaques and tangles seen in AD. Future studies are needed to determine how to identify Alzheimer-related epigenetics early to help prevent or delay this disease.[13]

Alzheimer’s disease is a clinical diagnosis. Definitive diagnosis can only be made through autopsy. Imaging studies such as computed tomography, magnetic resonance imaging, single-photon emission computed tomography, and laboratory tests help to exclude other possible causes for dementia.[14] AD progresses on a spectrum of three stages: preclinical stage of no symptoms, middle stage of mild cognitive impairment (MCI), and final stage of Alzheimer’s dementia.[15] “Interviews to assess memory, behavior, mood, and functional status are best conducted with the patient alone, so that family members or companions cannot prompt the patient.”[15p2] According to the National Institutes of Health,[15] objective and subjective clinical findings found within each stage are defined as:

  • Getting lost
  • Trouble handling money and paying bills
  • Taking longer to complete normal daily tasks
  • Poor judgment
  • Mood and personality changes
  • Increased memory loss and confusion
  • Problems recognizing family and friends
  • Inability to learn new things
  • Difficulty carrying out tasks that involve multiple steps (such as getting dressed)
  • Hallucinations, delusions, and paranoia
  • Impulsive behavior
  • Inability to communicate
  • Weight loss
  • Seizures
  • Difficulty swallowing
  • Groaning, moaning, or grunting
  • Increased sleeping
  • Bowel and bladder incontinence

Currently there are no standardized assessment tools for cognitive impairment.[16] The Alzheimer’s Association found that the mini-mental state exam is not feasible since there are copyright issues, requiring permission every time it is used. It did find that the memory impairment screen, general practitioner assessment of cognition, and the Mini-Cog were the best tools to use. According to Cordell et al,[16] they found that these assessment tools were:

  • Easy to administer
  • Took less than five minutes
  • Any medical staff could administer it
  • Easy to understand language
  • Validated for primary care or in a community setting
  • No copyright issues

After completing a thorough physical assessment of the patient, it is important to rule out other diseases or conditions that may contribute to those symptoms. In AD, there are multiple differential diagnoses, such as:

  • Traumatic or repetitive brain injury[17]
  • Drug or alcohol abuse[17]
  • Polypharmacy[17]
  • Thyroid disorders[18]
  • Vitamin B12 deficiency[18]
  • Depression[17]
  • Cerebrovascular disease[17]
  • Other types of dementia i.e. lewy body, vascular, frontotemporal, etc[17,19]
  • Huntington’s disease[17]
  • Parkinson’s disease[17]

Although this is a minute list of differentials, it is not exhaustive. Since early clinical presentations of AD are vague, primary care practitioners are typically hesitant to give the diagnosis of AD.[18] In the past, practitioners utilized “watchful waiting” when confronted with these vague symptoms. However, early diagnosis and treatment are important in symptom management. Thus, practitioners should refer patients to a neurologist or a geriatrician when they are uncertain.[18]


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