Alzheimer’s disease (AD) is the neurological disease with incidences exponentially increasing throughout the world. Alzheimer’s disease is correlated to multiple genes in the genome which are amyloid-beta precursor protein (APP), presenilin 1 and 2(PSEN1 and PSEN2), and apolipoprotein E (APOE). If a parent has familial Alzheimer’s disease variations, then the children will have a 50% chance of inheriting and getting the disease with 100 % penetrance. If the victim inherits the APOE gene in its recessive e4 form then there is a 35% penetrance of expressing the gene, and will form late-onset AD. Risk factors other than genetics can also form late-onset AD. The gene product of these mutations is nonfunctioning amyloid-beta, which clumps together in the brain to form amyloid plaques and neurofibullary tangles. The increase in worldly incidences indicates it is critical to come up with novel treatments before to many victims are effected. In this research report is an in-depth overview of AD which summarizes the discovery, genetic information about the disease, and medical information on the disease. AD is turning into an epidemic and as biotechnology advances the hopes of curing this disease is becoming more and more possible.
Section 1: Discovery of Alzheimer disease
The discovery of Alzheimer disease took place over the time period of 1906-1960. The disease was first discovered by Dr. Alois Alzheimer who was a German psychiatrist and neuropathologist studying dementia patients. In 1906 Dr. Alzheimer was studying a 51 year old woman with dementia consisting of short term memory loss, language issues, erratic behavior, and rapid deterioration eventually resulting in her death and autopsy . After the autopsy Dr. Alzheimer noticed changes in the brain tissue of the women under his microscope which were the neurofibullary tangles and amyloid-beta plaques. In 1910 Dr. Alzheimer and his partner Emil Kraepelin first published the name “Alzheimer’s disease” in the eighth edition of the book “Psychiatrie”. In 1931 was the invention of the electron microscope which allowed in-depth study of affected brain tissue, first fully envisioning the root cause of the disease and its mechanisms of development. 1960 the development of the cognitive measurement scale was designed which enabled the complete diagnostic and confirmation of Alzheimer’s disease victims . When Alzheimer’s was discovered it wasn’t clear what caused the plaques and tangles. But after future studies and with contributions from the human genome project, it was seen to be correlated with genetics.
Section 2: Alzheimer’s from a genetic perspective
Section 2.1: Cause of disease and genetic background
As mentioned in the discovery section, Alzheimer disease is mainly cause by amyloid-beta plaque build ups and neurofibrillary tangles within the brain. These are deadly gene products that ultimately result in the loss of connections between neurons, and neuron death. There are two types of Alzheimer’s disease each with their own unique individual causes, early-onset and late onset Alzheimer’s. .
The research in this report shows that the root cause of Alzheimer’s disease from a genetic perspective is mutations causing amyloid-beta plaque build ups. If these genes were functioning correctly, there would be a proper soluble amyloid precursor protein ratio to the amyloid beta peptide. But this ratio is much higher for the non-soluble production in Alzheimer’s disease. Also the amyloid beta peptide if cleaved properly should be digested by Neprilysin or Insulin-Degrading enzyme in the brain. But because of the amyloid-betas irregular shape, the digestion does not occur correctly . The normal function of the APP molecule is for communications in the brain, the cleaved products also have growth-promoting properties which are involved in formation of neurons . Overall these genetic mutations decrease neuron communications and development, leading to the disease. This first forms in the hippocampus of the brain, which effects memory but then moves into other regions to deteriorate other cognitive activities.
Another root cause of the disease is the formation of neurofibullary tangles. These neurofibullary tangles are formed by destabilized microtubules found in the neurons which are used for brain transmissions. The Tau proteins holds these microtubules together, but become defective detaching from the neuron and destabilizing it. This results in neuron degeneration into the neurofibullary tangles, resulting in the loss of communication. This is because of the buildup of amyloid plaques. The immune system targets the Tau proteins as a result of the plaque buildup, causing the destabilization. .
Section 2.1.1: Early – Onset Alzheimer’s
Early-Onset Alzheimer’s occurs at an earlier age in humans, from 30 to 60 years old, but this represents less than 5 percent of Alzheimer’s victims. Early onset Alzheimer’s is rare and results from the inheritance called familial Alzheimer’s. This is the result of mutations in specific genes that are directly passed down from the parents, and is caused by the gene recessive gene mutations in APP, PSEN1, and PSEN2 . If a parent has a familial Alzheimer’s disease variations, then the children will have a 50% chance of inheriting and getting the disease . All of these mutations affect the amyloid beta precursor protein (APP) which is a prominent protein in the brain and spinal cord. APP creates the beta amyloid after cleavage, which forms the amyloid plaques.
When there is a mutation in the APP gene there is no separation of the two fragments once cleaved from the surface receptors of the cells. This makes the insoluble beta-amyloid not digestible and increased in production . There are over 50 different mutations in the APP gene that can result in the early-onset Alzheimer’s. The most prominent mutation in early onset Alzheimer’s APP gene is a point mutation at protein position 717 (Val717I1e), where the mutation replace the amino acid valine with the amino acid isoleucine. These amyloid beta fragments constantly form toxin amyloid beta plaques. .
The other 2 gene mutations resulting in early onset Alzheimer’s disease is the mutation on presenilin 1 gene on chromosome 14 and presenilin 2 gene on chromosome 1. The presenilin 1 gene (PSEN1) is a subunit in the complex of gamma secretase, which cleaves the APP into smaller polypeptides. When PSEN1 has a mutation, it is unable to cleave the amyloid surface proteins correctly, resulting in the sticky amyloid beta molecules that cause plaques. There are more than 150 PSEN1 mutations that can lead to early-onset Alzheimer’s. The PSEN1 gene mutation is the most common contributor to early onset Alzheimer’s disease resulting in 70% of causes. Most of the PSEN1 mutations are from a point mutation. An example of one of the mutations is missense point mutation PSEN1 H163R, resulting in the codon change from CAT to CGT. This substitution changes a histidine to an arginine. .
PSEN2 protein sends chemical signals from the cell membrane into the nucleus and is involved in making genes active. When a mutation in the gene occurs, it too causes the buildup of the amyloid beta plaques but by epistasis. Research finds a correlation between PSEN2 mutations with the improper expression notch receptor gene NOTCH-1 which is a subunit of the cleaving protein gamma secretase ultimately effecting its activity . This effects gamma secretase to not cleave the surface APP molecule effectively, causing a buildup of non-soluble APP molecules causing the plaques.
There is 11 known mutations with PSEN2 that have a correlation to familial Alzheimer’s. But mutations present in this gene account for 5% of early onset cases. The most common mutation for PSEN2 is an inversion mutation where the first mutation in the sequence replaces asparagine with isoleucine at the 141 position (Asn141Ile or N141I) and the other replaces methionine with valine at the 239 position (Met239Val or M239V) .
Section 2.1.2: Late – Onset Alzheimer’s
The majority of the Alzheimer’s population has the late-onset form of the disease, where the signs appear after 60 years of age. From a genetic perspective late onset Alzheimer’s is still not completely understood, but they have found one gene correlation and many epigenetic correlations. The genetic risk factor of having the apolipoprotein E (APOE) gene mutation was found to increase a person risk. . There are three different types of this mutation, APOE ɛ2, ɛ3 and ɛ4. The APOE ε2 has shown to be a source of protection against the disease, and when it starts to malfunction the disease starts to occur . The recessive APOE ε4 gene has a relation to Alzheimer’s as well, but for those who have this mutation it shows a 35% penetrance, shown from Dr. Peter D’Amato’s research . This means that about one in three people that have this gene mutation will develop the disease due to epigenetic causes. APOE ε3 is the dominant form of the allele and is most common, it is presented in healthy individuals that will not develop the disease .
Section 2.2 – Locations of genetic mutations
There is genetic proof that early onset Alzheimer’s is related to the APP, PSEN1, and PSEN2 and late Alzheimer’s is correlated with the APOE mutation. Knowing the genetic locations of these genes will help us in identifying the genetic disorder. The APP gene codes for the surface receptor and transmembrane precursor protein APP. Its position resides on the 21st chromosome, its hnRNA location is from the 25,880,550 nucleotide to the 26,171,128 nucleotide and is 290,579 base pairs long . A visual of the app gene location can be seen in figure 2.2.1 –APP gene location. PSEN1 location is on the 14th chromosome, from the 73,136,435 nucleotide to the 73, 223, 691 nucleotide and is 87, 257 bases long . A visual of the app gene location can be seen in figure 2.2.2 –PSEN1 gene location. The PSEN2 location is is on the 1st chromosome, between the 226, 870, 572 nucleotide to the 226,896,103 nucleotide and its length is 25,532 bases long . A visual of the app gene location can be seen in figure 2.2.3 –PSEN2 gene location. Lastly, the APEO gene which has the e4 version recessive allele is located on the 19th chromosome, rom the 44, 905, 749 to 44,909,395 and its size is 3 647 bases long. A visual of the app gene location can be seen in figure 2.2.4 –APEO gene location. .
Figure 2.2.1 –APP gene location 
figure 2.2.2 –PSEN1 gene location 
2.2.4 –APEO gene location 
2.2.3 –PSEN2 gene location. 
Section 2.3 – Heredity
We know that genes are involved with getting Alzheimer’s disease. If someone inherits a copy of the APOE gene with the recessive allele ɛ4 you will have about a 35% chance of getting Alzheimer’s. This heightens the risk of getting late-onset Alzheimer’s but does not confirm it. This is a gene that does not directly cause Alzheimer’s diseases but it and epigenetic interactions accounts for about 95% of all Alzheimer’s cases . Then Alzheimer’s can be inherited directly with familial Alzheimer’s disease. This is where a parent has a mutation in the APP, PSEN1, or PSEN2 genes these genes have complete penetrance if inherited. With the APP mutation it was found that the mutation only showed the disease if in the homozygous state, and did not affect the heterozygous carriers. Like the APP gene mutation, PSEN1 and PSEN2 genes are also inherited in as autosomal dominant to form Alzheimer’s. .
Section 3: Medical information about Alzheimer’s disease
Section 3.1: incidences
In 2015 one in 10 people over 65 years of age have Alzheimer’s and 50% of people over the age of 85 had it. In 2015 it was estimated that about 5.3 million Americans had Alzheimer’s disease, 5.1 million of which were over 65 years old and 200,000 that were under the age of 65. 3.2 million of these victims are women and the rest (1.9 million) are men, and this number is exponentially increasing. It is estimated that by 2025, the number of victims will increase by 40% to 7.1 million. In 2050 the number will be almost 3 times the amount at about 13.8 million victims. .
Alzheimer’s is becoming more and more prominent around the world, the victims that die from Alzheimer’s is largest in the west. The United States had the second highest mortality rate by Alzheimer’s with 455,800 deaths, and Canada with third highest with 355,000 deaths in 2014 according to worldlifeexpectancy.com, but the highest mortality rate in 2014 was Finland with 537,000 deaths . According to the Alzheimer’s association, projections for related deaths in 2015 is estimated at 700,000 people. They also predict that the amount of people living with dementia in the world will grow from 46.8 million victims in 2015 to 131.5 million victims in 2050. This is a striking statistic which shows the importances of a genetic understanding of Alzhiemers to somehow find an innovative solution to cure this disease.
Section 3.2: symptoms and prognosis
The first symptoms of Alzheimer’s start with memory loss because of the origin of the disease at the hippocampus of the brain. This means when you see a routine in forgetfulness, and not just a couple occurrences per week it could be the first signs of Alzheimer’s formation. This is the first stage of Alzheimer’s, occur in the first 2-4 years of the disease. It involved constant memory loss of events that recently happened, the victim might revealingly ask questions, have problems with language, and have coordination issues. The second stage is the moderate level, this has persistent memory loss, including loss of faces of friends and family, forgetting personal history, advanced confusion of time and place. This victim can get lost easily, change moods and behaviors quickly, and have constant stress. The person in stage two also suffers from physical issues including mobility. The final stage is stage three which is the severe Alzheimer’s stage. This results in an almost total loss in communication, memory and processing information. They have extreme mood swings and cannot control their behavior. Death eventually results from the loss of ability to eat, drink, and even take a breath. The progression is the result from the beta- amyloid plaque formations moving from the hippocampus region, to the rest of the temporal lobe, to the cerebrum and frontal lobe, to the parietal lob and lastly to the occipital lobe. .
The likely course of for someone with Alzheimer’s disease can ether occur at 40 years old if the victim has early-onset Alzheimer’s or begins at 60 for the more common late-onset Alzheimer’s. The progressing into stage one lasts 2-4 years, stage two lasts 2-10 years, and stage 3 lasts 1- 3 years on average. The likely cause of death is losing the ability to breath, and the duration of the disease is 8-10 years. .
Section 3.3: Treatments
In the current moment, although there is no cure for Alzheimer’s disease advanced treatment and cure giving is the best possible solution to this epidemic. There are five FDA approved drugs currently used for the treatment of Alzheimer’s (these medicines are mostly used in America and Canada). They are called Aricept, razadyne, Namenda, Exelon, namzaric. These drugs contain one or a combination of the drugs donepezil, galantamine, memantine, and rivastigmine. These drugs all help promote and restore communications of neurons. .
Donepezil, galatamine, and rivastigmine are all cholinesterase inhibitors. The cholinesterase inhibitors are used to slow down the process that breaks down neurotransmitters . Cholinesterase inhibitors work by inhibiting the cholinesterase enzymes which increase the acetylcholine concentration at the synapses of neurons. This promotes more neuron communications and increases the parasympathetic state .
Memantine is a NMDA receptor inhibitor are used to regulate the neurotransmitter glutamate involved in memory, learning and other cognitive activities. Memantine binds to the NMDA receptor which stops calcium from entering the cell. The abundance of calcium in neurons leads to damaged cells, by blocking this receptor it decrease the damage of the cell. This improves cell signaling, memory and learning. .
Section 3.4: Future prospects
There are many potential prospects for pharmaceutical treatments of Alzheimer’s disease that is being research, and could potentially be developed in the not too distant future. Alzheimer’s disease growing exponentially as seen in section 3.1 – incidences, therefore it has also gotten incredible funding for research for future medical treatments. From a genetic perspective the beta-amyloid protein is the primary contributor to Alzheimer’s disease, therefore suppressing the beta-amyloid plaque builds ups my stop, reverse and cure victims. “Researchers are developing medications aimed at virtually every point in amyloid processing” . Some medications are targeting the beta-secretase enzyme so there is suppressed cleavage of the APP protein, which will slow the formation of beta-amyloid (BA). Also there is molecules that are attaching to the beta-amyloid to stop the clumping of multiple BA, and using antibodies to blear BA clumps .
One drug in research to suppress the BA is called Solanezumab. It is a monoclonal antibody that binds to BA molecules and carries them out of the brain. A different drug is MK-8931 which is a beta-secretase inhibitor disabling it from cleaving the APP. This is an irreversible inhibitor and has shown significantly lowered beta-amyloid levels with mild-to-moderate Alzheimer’s disease (AD). These drugs are both in phase 3 trails and are not yet available to the public. .
The other division of drugs is targeting the neurofibullary tangle suppression. Enabling the neurofibullary tangle formation will lead to improved neuron connections and communicating, which would significantly stop the symptoms of Alzheimer’s disease. A drug that is targeting tua proteins is AADvac1. AADvac1 is a vaccine that enables the immune system to target irregular tau proteins in the microtubules. Research shows that this drug was “well tolerated” in phase one clinical trials. .
Another abnormality in AD compared to healthy brain function is inflammation which is cause by an overactive immune response. The microglia (immune cells in the brain) attack the beta-amyloid, but also the tau proteins, and healthy brain cells which causes damage and deteriorates neurons into neurofibullary tangles. One drug suppressing the immune activity is called CSP – 1103. It was show in a 90 week trail to prevent beta-amyloid plaque build up, neuron degeneration, and ultimately improved cognation significantly. . All of these drugs may be a solution to AD, and with luck and support it may decrease the amount of victims in the future.
Section 4: Interesting facts
One of the most interesting and relevant facts to genetics is that this disease affects more women than men, it is actually almost double the amount of victims . This might indicate that Alzheimer’s is a sex influenced disease. It is not totally understood why this disease is more prominent in women but one paper reported a positive correlation between older women and increase beta-amyloid production. This is because the loss of estrogen increase mitochondria toxins, which increase amyloid plaque build ups, the processing of this pathway is still not totally understood. .
Another genetic related interesting fact is the effects of lifestyle choices that effect the epigenetics of Alzheimer’s development. There is a positive correlation between eating a diet that promote methylation, high in antioxidants (like vitamin E), and high in omega 3 to reducing the probability of developing dementia. This might be because of the effects of these foods on the epigenome, the ability to methylate different gene regions to promote the expression of healthy proteins is correlated with these foods. Also physical activity and constant learning are shown to reduce Alzheimer’s development, probably because of the stimulation in neuron communication and more oxygen flowing to the brain. .
Alzheimer’s disease (AD) is growing exponentially throughout the world and it is critical to come up with novel forms of treatment and possibly a cure. Understanding the genetics of AD is prerequisite for its treatment. From the research it was seen that inheriting both mutant forms of the APP, PSEN1 or PSEN2 gene will result in the formation of early-onset AD. Also if the APEO e4 gene is inherited then it is 35% likely of expressing late-onset AD. Environmental contributions also play a role in the epigenetics of this disease, eating correctly, physical activity and mind stimulation will help in the disease prevention. It was seen that there is only 5 FDA approved drugs for this treatment but there is the development of many novel treatments mainly targeting the amyloid plaque build ups. Understanding the genetics of this disease will lead to novel therapeutic treatment and screening to reduce incidences of this harmful disease worldwide.
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