Up to MBI

The amyloid cascade hypothesis suggests that the accumulation of amyloid beta plaques in the brain is the first step in Alzheimer's disease. This theory has been the focus of Alzheimer's research for the past three years. Alzheimer's is a major cause of dementia and is a leading cause of death in the US. Currently, the presence of certain proteins in the blood or cerebral spinal fluid, as well as PET scans, are used to diagnose early-stage Alzheimer's. The aggregation of beta-amyloid and tau proteins in the brain leads to the formation of plaques and tangles, which disrupt neuron communication and eventually lead to cell death. There are several stages of Alzheimer's disease, including preclinical stages where patients show Alzheimer's-related pathology but no symptoms, and mild cognitive impairment (MCI) stage, where subtle cognitive changes occur. Risk factors for MCI include age, gender, and APOE status. When is a dead hypothesis really dead? Jack de la Tour, New England Journal of Medicine, 2014. For the past three years, the amyloid cascade hypothesis has been the backbone of Alzheimer's research. This theory suggests that the accumulation of amyloid beta plaques in the brain is the first step in a cascade of events leading to cognitive decline and memory loss in Alzheimer's, a disease that accounts for over 80% of dementia cases. This disease is now the seventh leading cause of death in the United States and is estimated to contribute $1 billion a day in health care costs in the U.S. alone, with caregivers, often family, providing over 18 billion hours a year of unpaid home care for their loved ones. In 2013 alone, NIH funded $3.2 billion of Alzheimer's research. This disease, named in 1910, became a major subject of research in the 1960s when it was identified as a major contributor to the development of dementia. Since then, only the aforementioned amyloid cascade hypothesis has been seriously considered to be the cause of Alzheimer's since that theory was introduced in the late 1980s. Given that no other major theories have prevailed like the amyloid cascade theory, let's run through the process of Alzheimer's disease as we currently understand it through this theoretical lens. Currently, based on the amyloid cascade hypothesis, our best measure of whether or not someone has early-stage Alzheimer's is based on the presence of proteins in the blood or cerebral spinal fluid, including amyloid beta-42, amyloid beta-40, amyloid beta-56, and PTAL-217. A PET scan can also identify amyloid plaques starting to build up in the brain. Increases in the generation and aggregation of beta-amyloid and TAL in the brain is seen as the initial step of Alzheimer's disease. Though this is seen as the first step of the disease, let's talk about how beta-amyloid, the first protein that builds up, forms. Amyloid beta-protein precursor, APP for short, is a protein that can be cleaved into shorter segments by a gamma-secretase enzyme and then a beta-secretase enzyme to produce amyloid beta-peptides. At this stage, these peptides are circulating in the blood and are known as serum peptides. Although these peptides may be different lengths as denoted by the number that follows them, such as AB40, the peptide mostly implicated in forming brain plaques is AB42. These peptides very crucially are able to pass through the blood-brain barrier, passing from the blood to the cerebral spinal fluid. Here in the CSF, the 42-amino acid peptide AB42 tends to aggregate due to its hydrophobic amino acid tail and high molecular weight. As these AB42 peptides aggregate to form oligomers, which react with other AB42 oligomers to form fibrils, like so many building blocks, the fibrils then stack to form plaques and deposit themselves between nerve cells. As plaques accumulate between nerve cells in the brain, they are thought to activate signaling pathways in the neurons that phosphorylate tau proteins that normally stabilize microtubules in the axons. As these AB42 peptides aggregate to form oligomers, which react with other AB42 oligomers to form fibrils, like so many building blocks, the fibrils then stack to form plaques and deposit themselves between nerve cells. As plaques accumulate between nerve cells in the brain, they are thought to activate signaling pathways in the neurons that phosphorylate tau proteins that normally stabilize microtubules in the axons of those very same nerve cells. The phosphorylated tau proteins begin to misfold, blocking proper communication of the neurons in their synapses. As these tau tangles proliferate, blocking internal and external communication in nutrient movement, brain neurons are thought to initiate apoptosis, a programmed cell death, when they recognize that they are not functioning properly. As brain neurons die, regions of the brain shrink. Before the three stages of AD can be diagnosed, there are three stages that indicate the possibility of a dementia-related illness. The first two stages are deemed preclinical, because they are both asymptomatic, but when tested, the patient will have Alzheimer's-related pathology. Stage 1 refers to asymptomatic individuals with beta-amyloid markers that indicate that In stage 2, patients are still asymptomatic, but continue to show abnormal beta-amyloid levels, and begin to show injury markers of neurodegeneration, such as high CSF T-tau or P-tau from spinal fluid samples, or neuronal dysfunction, cortical thinning, and atrophy of the hippocampus on an MRI. The last two stages are deemed preclinical, because they are both asymptomatic, but when The length a patient may be in these two stages varies, but averages show most patients spend 6 to 10 years at this stage. 20% to 30% of those with preclinical Alzheimer's disease will advance to the third, pre-Alzheimer's stage, MCI. Higher risk for MCI includes 20% to 30% of those with preclinical AD will advance to the third, pre-Alzheimer's stage, MCI, also known as mild cognitive impairment. Higher risk for mild cognitive impairment includes being over age 65, or being over age 85, which majorly increases the risk. Women have a higher risk than men, and apopleoprotein being over age 65 increases risk, while being over age 85 majorly increases risk. Women have a higher risk than men, and apolipoprotein, apolipoprotein E, APOE, status, positive, is a higher risk. Apolipoprotein E, APOE for short, status, being positive, is a much higher risk. This third pre-Alzheimer's stage is known as mild cognitive. This third pre-Alzheimer's stage, mild cognitive impairment, this third pre-Alzheimer's stage, mild cognitive impairment, can also be seen with or without mild behavioral impairment, MBI for short. These patients will begin to show subtle cognitive changes if they have MBI, along with the abnormal beta-amyloid, tau, and injury markers of Stages 1 and 2. These individuals may exhibit. This third pre-Alzheimer's stage is known as mild cognitive.