In 1901, Alois Alzheimer was working at Frankfurt Asylum when he noticed that a hospital patient, Auguste Deter, was suffering from memory problems, increased confusion, difficulty sleeping, and drastic mood changes. When she passed away, Alzheimer carried out an autopsy to test his idea that her symptoms were caused by an irregular brain structure. What he found were plaques (misfolded protein clumps) and neurofibrillary tangles that had worked together to break down the patient's brain structure.
Alzheimer's has been around for over a century, yet scientists are still clueless when it comes to its origins and finding a cure. Before we can understand why it is so difficult, we must first look into what Alzheimer's really is.
Alzheimer's is a neurodegenerative disease that can lead to dementia, mood changes, and death. Unlike many diseases, Alzheimer's is not contagious and develops in people due to errors in a common cell process. There is no spreading capacity for Alzheimer's, yet it is diagnosed every 4 seconds. How is it so common? We aren't sure. In fact, the cause of Alzheimer's is yet to be found. However, there has always been a special process which seems to start all cases of Alzheimer's: The breakdown of APP.
APP (Amyloid Precursor Protein) is a protein found in the membranes of nerve cells; its role is to help neurons repair themselves and grow. Over time, however, it will no longer serve a purpose, and its parts will need to be broken down and reused. Before this can happen, two enzymes called alpha-secretase and gamma-secretase must cut the APP into 3 small parts. These parts are soluble and can be recycled, so there is no problem there. However, if the enzyme beta-secretase appears instead of alpha-secretase, it will cut the protein irregularly and leave one part insoluble. This part becomes a monomer called amyloid-beta, and it marks the beginning of Alzheimer's disease.
Amyloid-beta monomers are chemically sticky, bonding together as cells produce more and more. These clumps of amyloid-beta are called plaques, and they get between synapses and block electrical signals between nerve cells. This process is what causes impaired memory and thinking in Alzheimer's patients. Plaques can cause inflammation, which can damage surrounding neurons. Amyloid plaques may also deposit around blood vessels in the brain, a condition called Amyloid Angiopathy, weakening the walls of the blood vessels and causing hemorrhage or blood loss.
Plaques can initiate pathways inside the neuron and activate an enzyme called Kinase. Kinase then makes its way to microtubules which provide nutrients for the cell, and it attaches a phosphate group onto a protein called Tau. This protein is responsible for maintaining the structural integrity of the microtubules, ensuring that the neuron is getting nutrients to survive. Once a phosphate group attaches to it, the protein stops supporting the microtubule and clumps together with other Tau protein to form neurofibrillary tangles. In the process, the microtubules lose their support and they fall apart. Because of this, nutrients can no longer make it to the cell, and the cell dies. The death of brain cells causes the atrophy seen in Alzheimer's patients, in which the ventricles become larger, gyri become smaller, and sulci become wider.
There are two groups of Alzheimer's: sporadic and familial. Sporadic Alzheimer's often occurs at an older age, and the exact cause isn't very well defined. It may be a combination of genetic and environmental risk factors. It accounts for 90-95% of all cases. In contrast, familial Alzheimer's often occurs at a younger age due to the dominant gene for Alzheimer's speeding progression. Mutations on the PSEN-1 gene of chromosome 14 and the PSEN-2 gene of chromosome 1 have been linked to early-onset Alzheimer's. These genes code for presenilin 1 and 2, both of which are protein subunits of gamma-secretase. Mutations in these genes can cause gamma-secretase to change its cutting location on the APP, leading to beta-amyloid creation. Another gene that possibly contributes to an increased risk of Alzheimer's disease is the e4 allele of the apolipoprotein E gene (otherwise known as APOE e4).
Another cause of Alzheimer's is Trisomy 21 (Down Syndrome). Chromosome 21 contains the gene which codes for APP, which means that a patient with Down Syndrome has 2 copies of the APP gene, potentially increasing the amount of amyloid-beta produced.
As more and more cells die from malnutrition, certain neurons and the interactions they had with other neurons can no longer be recalled, resulting in dementia. As plaques and tangles build up, they progress throughout the brain, destroying everything in their wake. Eventually, they reach the part of the brain that manages bodily function, and they kill off its neurons, killing the patient in the process.
The reason why Alzheimer's is so difficult to cure is deeply connected to the natures of plaques and tangles. It can take long after patients develop their first plaque for them to experience any symptoms, and by that time, it is already too late. This makes clinical trials very difficult since there is no way to identify someone at the initial stages of the disease. This means that we are unable to test medications and check to see whether they work or not. In addition, Alzheimer's affects different people in different ways, hence a drug that is effective on one person may not be as effective on another. Due to a lack of fundamental understanding, we are unable to cure Alzheimer's as of now. However, we may one day understand how it works, and when that day comes, we can finally put an end to this disease, once and for all.