The Physiology and Genetics Behind Alzheimer Disease

Alzheimer disease is a progressive and ultimately fatal brain disorder, in which communication between cells are halted and eventually lost. It is the most common form of dementia, and is generally (though not exclusively) diagnosed in patients over the age of 65. As communication amongst neurons is lost, symptoms such as inability to recall memories, make appropriate judgment, and proper motor function are lost and worsen over time. Affecting an estimated 2.4 million to 4.5 million Americans, with the number predicted to double within the next few years, Alzheimer Disease is the most common form of dementia in adults.

The brain is divided into three main portions: the cerebrum, the cerebellum, and the brainstem. Though a single organ, each portion is further broken down into sections with distinct control in specific skills. The area most affected by AD is the cerebrum, which is divided into five lobes: frontal, parietal, occipital, temporal, and insula. Each lobe has control over various functions such as memory, voluntary motor functions, different senses, and processing. These “actions” are conducted through signaling between neurons. These nerve cells contain properties like excitability, conductivity, and secretion. Communication amongst neurons is vital for proper functioning of the whole body.

In a healthy neuron, communication is conducted via neurotransmitters. A presynaptic neuron will release neurotransmitters resulting in the postsynaptic neuron responding to the message. Depending on the location of these nerves in the brain will result in whichever action is taking place. It is the prevention of proper signaling within the brain and cell death that leads to loss of function throughout the body, and ultimately to AD.

Two major contributors to the progression of Alzheimer Disease are the production of beta-amyloid plaques and neurofibrillary tangles. Amyloid Precursor Protein (APP) is believed to assist in neuronal growth and repair. As persistent use is continued, it is potentially broken down and recycled. Alpha-secretase cuts the extracellular portion of APP while gamma-secretase makes its cut in the membrane of the neuron, resulting in a soluble fragment of APP. The creation of beta-amyloid plaque begins when beta-secretase joins alpha-secretase and gamma-secretase in the process of breaking down APP. Beta-secretase creates an addition cut leaving behind an insoluble monomer, amyloid beta. With the characteristic of being sticky, these fragments join together resulting in beta-amyloid plaques. These clumps block signaling at the synaptic cleft, preventing neurotransmission. These plaque buildups trigger an immune response leading to swelling of the brain causing damage to nearby neurons. They also make amyloid angiopathy deposits around blood vessels causing a weakening in the vessel walls. This could lead to hemorrhaging and blood loss.

Neurofibrillary tangles are also extremely prevalent in AD patients, resulting in the degradation of microtubules within the neuron. With the buildup of beta-amyloid plaques, this initiates pathways within the neuron leading to the activation of kinase. Kinase transfers phosphate groups to the tae proteins; this alters the shape of tau protein. A change in shape means a change in function, so tau protein no longer binds the microtubules; they instead get “tangled” with each other, and the microtubules fall apart. With signaling unable to occur, affected neurons undergo apoptosis. As the number of neuronal deaths increase, large scale changes in brain take place. The brain atrophies with the gyri narrowing. As this occur, the sulci widen and the ventricles become larger.

To discuss these alterations without the details, if one was to view a segment of a brain affected by Alzheimer disease, there would be two common characters: beta-amyloid plaques and tangles. The formation of the plaque originates from portions of the neurons of the brain. On a normal functioning neuron, amyloid-precursor proteins (APP) stick out through the cell’s membrane. Enzymes swing by and “chop off” the beta-amyloid protein fragment, leaving a somewhat sticky snippet behind. As more enzymes chop off more beta-amyloid proteins from neurons, these sticky fragments begin to clump together along with other molecules resulting in beta-amyloid plaque. It is thought that these plaques block cell to cell communication between neurons; it is also thought that they activate an immune response. This would explain the swelling of the brain and the damage done to affected neurons.

Neurofibrillary tangles are another common theme to AD, but they occur within the neuron. The microtubules in the neuron are bound by tau proteins allowing for the transport of nutrients and messages to adjacent neurons. In AD, these tau proteins are chemically altered, and they no longer want to stabilize the microtubules. They begin to pair with other tau proteins and get tangled. Since the microtubules are no longer bound by the tau proteins, they fall apart and disrupts the transport of materials.

There are two forms of Alzheimer: familial (early-onset) and sporadic (late-onset). Both types of AD form differently on a molecular level, though they result in the degradation of proper mental function (7). Familial has the deterministic genes, meaning that it is guaranteed to develop the disease if the the mutation in the gene is inherited. Mutations in these specific genes lead to an overproduction of APP in the brain and potentially to excess beta-amyloid plaques, thus interfering with vital regulation pathways of the brain. Sporadic AD have risk genes; these genes do not directly cause the disease, but they put an individual more at risk of developing AD. Sporadic is more common, consisting of the majority of Alzheimer cases (~90-90%) (7). There are no known genetic mutations that cause late-onset; however, researchers believe that cognitive function decreases with old age without any underlying reason. Certain inherited alleles have been thought to increase one’s risk. APOE e4 has been linked to the higher chance of developing AD, but not all people who have the allele develop AD; likewise, not all people with Alzheimer inherited a copy of the allele.

Familial Alzheimer begins to appear as early as the mid-30’s up to 65. This type of AD is inherited in an autosomal dominant pattern, which is significantly less common than sporadic AD (1). Though rare, early-onset is better understood on the genetically inherited component. Three genes have been identified that lead to early-onset when a mutation occurs that normally function in certain brain “housekeeping”: PSEN-1 (chromosome 14) and PSEN-2 (chromosome 1) (1). Presenilin-1 (PSEN-1) is a subunit of gamma-secretase (4). Early-onset AD due to mutation of PSEN-1 is the most common form of early-onset, and 150 mutations have been identified (4). Mutation of PSEN-1 affects gamma-secretase’s ability to make its “cut” in APP in the accurate location (4). Presenilin-2 (PSEN-2) normally assists proteins in the transmitting of chemical signals from the membrane to the nucleus followed by the nucleus activating genes for further cell function (5). PSEN-2 also processes APP. Researchers have found about 11 mutations on PSEN-2; however, there are two specific mutations in the amino acids that make up PSEN-2 that are most commonly seen in early-onset (5). At position 141, asparagine replaces normal isoleucine, thus mutating PSEN-2 (5). The second mutation is located at position 239 where methionine replaces normal valine (5). Mutations in any of the amino acids used to make PSEN-2 disrupt APP processing which leads to the overproduction of amyloid beta peptide, thus resulting in amyloid clumps and damaging brain nerves (5).

Late-onset Alzheimer’s does not have a definite known gene to directly cause the disease; however, a combination of risk genes, lifestyle choices, and environmental influences are all factors that contribute to the development. Apolipoprotein E (APOE) gene located on chromosome 19, is the known risk gene (6,7). Various alleles aid in the age in which symptoms begin to show. APOE e2 is more rare, and it is thought to provide some “protection,” allowing AD to develop later in one’s life (6). APOE e3 is the most common, but it does not increase or decrease the risk (6). APOE e4 increases the risk as well as lowers the age of when symptoms start to show (6). The more APOE e4 alleles one inherits, the higher at risk they are.

There is not a cure for Alzheimer disease, nor are there any preventative measures that would reduce the risk of developing the disease. Through clinical studies, factors that decrease one’s risk include not having a family history, being male, obtaining more years of education, and having good cardiovascular health by having a healthy diet and exercising regularly (6). Factors that increase one’s risk are having a family history of Alzheimer’s, being female, having fewer years of education, and being in poor cardiovascular health (6). Older age also increases risk; by age 80, one’s risk for developing AD jumps to 50%. Many research projects are underway to find a cure or find preventative measures that could delay development or reverse the process. Because of the rarity, there are no major studies conducted for early-onset Alzheimer’s due to lack of funding and volunteers who may be at risk. As life expectancy continues to increase, so does the number of patients affected with AD. Organizations encourage volunteers, both healthy and at risk, to take a stand against Alzheimer’s by participating in clinical studies where hopefully someday, we will be without it.

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