Familial and Sporadic Alzheimer's and the Effectiveness of Treatments

Alzheimer's Disease

Alzheimer's Disease is a neurodegenerative disorder characterized by brain atrophy and the death of brain cells. Dr. Alois Alzheimer first studied this condition in 1906 when he observed a female patient experiencing memory issues, difficulty in speaking and thinking, and judgment problems. After her passing, he examined her brain under a microscope and discovered abnormal growths, which he later identified as "plaques" and "tangles." These pathological features, now known as senile plaques and neurofibrillary tangles, are common in all individuals afflicted with Alzheimer's disease.

Senile plaques consist of extracellular protein deposits primarily found in the grey matter of Alzheimer patients' brains and also in individuals undergoing normal aging (Gonzalez, H. M., 2019). Neurofibrillary tangles, on the other hand, are intracellular formations of hyperphosphorylated tau protein and are among the early pathological hallmarks in Alzheimer's patients (Bu, G. et al., 2017). These senile plaques and neurofibrillary tangles collaborate to progressively impair cognitive function, memory, and behavior.

The presence of senile plaques in the brains of Alzheimer's patients leads to the destruction of brain cells and disruptions in cell-to-cell communication.

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The misfolding of tau protein impairs the transportation of nutrients and essential materials, contributing to the degeneration of brain cells.

Types of Alzheimer's Disease

Alzheimer's disease can be classified into two main types: sporadic Alzheimer's and Familial Alzheimer's. Sporadic Alzheimer's is initiated by episodes of reduced blood supply to various organs or body parts (ischemia), resulting in dysregulation of brain ischemia and the activation of genes related to amyloid precursor protein and amyloid processing enzymes.

These genetic events damage brain functionality and lead to the characteristic symptoms associated with the disease. Familial Alzheimer's, on the other hand, is closely linked to genetics, specifically involving chromosomes 1, 14, 19, and 21, with potential involvement of chromosome 10. It represents a rare autosomal dominant gene mutation, accounting for only 13% of all Alzheimer cases (Bu, G. T., 2017). Chromosome 19 also influences sporadic Alzheimer's. The two most common genetic alterations associated with Alzheimer's disease are the production of APOE 4 by chromosome 19 and changes in the markers related to Presenilin, including Amyloid Protein Precursor (APP), Presenilin-1 (PSEN-1), and Presenilin-2 (PSEN-2), which can result in early-onset familial Alzheimer's due to mutations (Lanoiselee, H. M.; Nicolas, G.; et al.).

If a parent has familial Alzheimer's disease or early-onset Alzheimer's disease, there is a 50% chance of their children inheriting the gene. However, if the child does not exhibit symptoms by a certain age, the likelihood of passing on the gene to their own children decreases to 25%. If the gene is passed on, their children have the same 50% chance of inheriting it. The disease progression is similar between familial and sporadic Alzheimer's cases, with the key distinction being that familial Alzheimer's develops before the age of 65, whereas sporadic Alzheimer's typically manifests after the age of 65, with the risk doubling every five years beyond that age (Rosenzweig, A., 2020). When diagnosing both types of the disease, medical professionals search for the presence of plaques, tangles, and brain deterioration to rule out other conditions such as tumors, hemorrhages, and hydrocephalus.

Mutations in Amyloid Protein Precursor (APP), Presenilin-1 (PSEN-1), and Presenilin-2 (PSEN-2)

Mutations in the genes encoding Amyloid Protein Precursor (APP), Presenilin-1 (PSEN-1), and Presenilin-2 (PSEN-2) are common causes of early-onset Alzheimer's disease. PSEN-1 has approximately 221 recorded mutations associated with Alzheimer's, PSEN-2 has 19 pathogenic mutations, and amyloid protein precursor has 32 pathogenic mutations linked to the disease. Amyloid protein precursor plays a crucial role in the conversion of amyloid-β protein, which leads to the formation of amyloid-β (Aβ) peptide. The accumulation of Aβ peptide in the brain's functional tissue triggers a series of events culminating in the development of Alzheimer's disease. Cerebral amyloid angiopathy, a common condition in Alzheimer's patients, results from the formation of Aβ peptide in the cerebral meningeal vessels, leading to strokes caused by hemorrhaging and lacerations in the white matter.

Study on Early-Onset Alzheimer's

In France, a study on early-onset Alzheimer's was conducted involving 129 patients, all of whom had at least two family members diagnosed with the disease before the age of 65. For those with no family history, the diagnosis occurred before the age of 55. Blood samples were collected from each patient to identify mutations in the amyloid protein precursor, PSEN-1, or PSEN-2 genes. The study revealed 53 mutations in families with no prior history of the disease, along with 44 PSEN-1 mutations, 2 PSEN-2 mutations, 5 amyloid protein precursor duplications, and 20 amyloid protein precursor mutations (Lanoiselee, H. M.; Nicolas, G. et al., 2017).

Apolipoprotein E (APOE) and Late-Onset Alzheimer's

Apolipoprotein E (APOE) is a protein involved in lipid metabolism in mammals, binding to specific receptors in the liver. The APOE 4 gene, located on chromosome 19, is associated with late-onset Alzheimer's disease (sporadic). However, only 50% of Alzheimer cases carry the APOE 4 allele, and no other major risk factors or associations have been identified. Those carrying the APOE 4 gene are approximately six times more likely to develop the disease. There is also evidence suggesting that the gene may be located on chromosome 10, which poses a risk even without the APOE 4 allele (Bu, G., 2017).

Apolipoprotein E plays a role in lipid transport, membrane homeostasis, and brain injury repair. The APOE 3 allele facilitates the transport of sortilin, enabling these functions. However, in the presence of the APOE 4 allele, sortilin binds to the allele, preventing its transport to the neuron's center and causing it to become stuck. This disruption halts the process of endocytosis. The grey matter in the brain relies on the fatty acids provided by the APOE gene, and when this supply is compromised, cells become inflamed, break down, and ultimately lead to Alzheimer's disease (Asaro, A., 2020).

Stages of Alzheimer's Disease

Alzheimer's disease progresses through seven distinct stages:

Treatment and Management

Regrettably, there is currently no cure for Alzheimer's disease, although it remains a subject of extensive research. Various medications are available to alleviate symptoms and slow down disease progression. These include cholinesterase inhibitors, memantine, structure correctors, and electroconvulsive treatments. Additionally, cognitive therapies, vitamin and mineral supplements, as well as reminiscence therapy, which involves discussing past years and recollecting memories, particularly those that evoke positive emotions, are used to improve the quality of life for Alzheimer's patients.

Cholinesterase Inhibitors

Cholinesterase Inhibitors are used to block the typical breakdown of acetylcholine, the central neurotransmitter in the body, released by nerve cells and transmitted to various cells such as muscle cells, neurons, and gland cells. Acetylcholine plays a critical role in both the peripheral and central nervous systems. Cholinesterase inhibitors, by blocking the cholinesterase enzyme responsible for acetylcholine breakdown, increase the concentration of acetylcholine in the synaptic cleft. This elevated acetylcholine attaches to nicotinic receptors, which are linked to ion channels in the cell membrane, and muscarinic receptors, the most common end-receptors stimulated by acetylcholine production. These inhibitors are typically prescribed in stages 3 or 4 of Alzheimer's to slow down the deterioration of communication between cells, although they cannot prevent or reverse the disease's progression.

The most commonly prescribed cholinesterase inhibitors, based on patient and physician preferences, include galantamine, donepezil, rivastigmine patch, and tacrine. However, tacrine's use has diminished due to its adverse effects on the liver (Du, K. X.; Tan, M. S.; et al., 2018). Donepezil is the only one approved for use in all stages of Alzheimer's. Galantamine is commonly prescribed in the early stages after detection, and it has shown significant improvements in memory, cognition, and thinking skills in the majority of patients, benefitting around 14 out of 100 patients significantly (Informed Health, 2009). Donepezil also demonstrates positive responses, with one-fifth of patients experiencing greater benefits, while approximately one-third show no change after taking the medication (Briggs, R.; et al., 2016).

Memantine

Memantine is typically prescribed when the disease has progressed to around stage 3, depending on the patient's severity. Memantine helps stabilize glutamate levels in the brain. Glutamate is another neurotransmitter found abundantly in vertebrate nervous systems, playing a crucial role in speech, memory, and learning. In Alzheimer's patients, damaged nerves tend to produce excessive glutamate, which leads to overstimulation and excitotoxicity. Excitotoxicity occurs when neurotransmitters, such as glutamate, reach pathologically damaging levels, resulting in the overstimulation and death of nerve cells. Memantine restores the balance of glutamate levels, slowing the progression of symptoms by reducing nerve cell overstimulation.

Memantine has shown therapeutic effects in moderate to severe stages of the disease, significantly slowing nerve degeneration during these stages. In a study conducted by Reisberg, B.; Doody, R.; Stoffler, A.; and Schmitt, F. for the Memantine Study Group (Reisberg, B. et al., 2003), 95% of participants were in stage 6 of the disease, with reduced ability or inability to perform daily tasks. Those who received memantine exhibited notable improvements in their abilities, including completing specific tasks, enhanced memory, and improved cognitive skills compared to those who received a placebo.

Structure Correctors

Structure Correctors are still in the developmental stages, with the aim of reshaping the APOE 4 allele to resemble either E2 or E3. This transformation is intended to reduce blockages in the brain, allowing fatty acids to continue reaching the grey matter area. Structure correctors work by identifying the E4 allele and modifying it to function like the E3 allele without the detrimental effects. They convert the E4 allele into a mutant form known as APOE4-R61T (Chen, H. K.; Liu, Z. et al., 2011). This mutant form exhibited differences in mtCOX1 (cytochrome c oxidase subunit 1) compared to the normal APOE 4 allele, which was believed to be a biological consequence of the original APOE 4 allele. After the transformation into mutant APOE4-R61T, it displayed normal levels that matched the APOE 3 allele in terms of mitochondrial motility and neurite growth ability. This suggests that the mutant APOE 4 would no longer cause blockages in the brain and would function similarly to APOE 3, thereby reducing the progression of Alzheimer's symptoms.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is still a widely used treatment for behavioral and psychotic disorders such as depression and has been explored as a potential treatment for Behavioral and Psychotic Symptoms of Dementia (BPSD). ECT involves delivering controlled electrical currents to the patient's brain to induce a seizure. When used for patients with Alzheimer's disease, it is primarily employed to address issues such as apathy (a lack of emotion, concern, or feeling) and depression. ECT has demonstrated improvements in apathy and behavioral symptoms commonly observed in Alzheimer's patients. A study conducted in 1980 on the use of electroconvulsive treatments in Alzheimer's patients revealed that 30% experienced enhanced cognitive function, memory, and reduced depression (Kerner, N.; Prudic, J., 2014).

ECT has also been associated with significant increases in cerebral blood flow, especially in regions like the thalamus (Kevin, S. L. et al., 2019), which is involved in voluntary body movements, often impaired in patients with Alzheimer's, particularly in advanced stages. However, ethical considerations come into play in such cases, as many patients at this stage may not remember or understand what they are agreeing to, given their state of constant confusion or unawareness. Decisions regarding ECT should take into account the patient's best interests and the consent process, especially if a spouse or primary caregiver is providing consent on their behalf.

Effectiveness of Alzheimer's Medications

Summary and Conclusion

In conclusion, Alzheimer's disease is a complex neurodegenerative disorder characterized by the accumulation of senile plaques and neurofibrillary tangles in the brain. It can be categorized into two main types: sporadic Alzheimer's, which typically develops after the age of 65, and familial Alzheimer's, which is linked to genetic mutations and tends to develop before the age of 65. Genetic factors, particularly the APOE 4 allele, play a significant role in the risk and progression of the disease.

The disease progresses through seven distinct stages, with each stage presenting varying degrees of cognitive decline and functional impairment. There is currently no cure for Alzheimer's disease, but various treatment approaches aim to alleviate symptoms and slow down disease progression.

Future Directions

Future research in the field of Alzheimer's disease is focused on developing more effective treatments and interventions. This includes the ongoing development of structure correctors to modify the APOE 4 allele and reduce blockages in the brain. Additionally, the exploration of alternative therapies, such as electroconvulsive treatment, for addressing behavioral and psychotic symptoms is an area of interest.

Understanding the genetic and molecular mechanisms underlying Alzheimer's disease is crucial for the development of targeted therapies. As our knowledge of the disease continues to expand, there is hope for more effective treatments and, ultimately, a cure for this devastating condition.

References

1. 1. Gonzalez, H. M. (2019). Senile Plaques and Alzheimer's Disease. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 11, 301-305.
   2. Bu, G. et al. (2017). Genetic and Molecular Mechanisms Underlying Alzheimer's Disease. Nature Reviews Neuroscience, 18(12), 661-676.
   3. Lanoiselee, H. M.; Nicolas, G. et al. (Year). Title of the Paper. Journal Name, Volume(Issue), Page Numbers.