One of the most common things you hear in relation to Alzheimer’s is “Oh all the men in my family get it, so I’m going to get it” or “It’s not in my family so I am not concerned.” The question here is how straightforward is Alzheimer’s that you can just predict it based on family history? The answer is more complex than you would think.
For a second let us only look at the APOE gene and the heritability of Alzheimer’s. The APOE gene is an apolipoprotein E protein located on chromosome 19 and is responsible for synthesizing a protein that transports cholesterol and other fat types throughout the bloodstream. This APOE gene has three types: e2, e3, and e4. Specifically, the APOE-e4 type gene is the only one that has a correlation to the development of Alzheimer’s. When you receive one copy of the -e4 gene from one parent, you are at an increased risk for developing Alzheimer’s. If you have inherited two copies of the -e4 gene, you are at an even higher risk, but not at certainty to the development of the disease. Approximately 20-30% of US individuals have one copy of the gene, whereas only 2% have two copies.
However, one thing this theory fails to consider is the penetrance of the genes, or the expression of the gene. Someone who has two copies of the -e4 gene with a low penetrance are probably at a decreased risk for developing Alzheimer’s. Many psychologists actually discourage genetic testing for this gene because most testing does not account for penetrance or other factors that would increase your risk, such as sustaining concussions or Type 2 Diabetes. Also, most commonly the inherited form of Alzheimer’s that is inherited is late-onset, so many researchers wonder what there is to stress about now if the disease won’t start showing until you are 70-80 years old.
Wait, did I just say Type 2 Diabetes increases your risk for developing Alzheimer’s? Why yes I did. One review study examined the role of insulin signaling on the development of components of Alzheimer’s, such as neuroinflammation and Ab plaques in the brain. When a receptor (TNF-a) causes inflammation in the brain it begins a cascade of insulin resistance by activating PKR which causes IRS 1 to be inhibited. When IRS 1 is inhibited, insulin is not being properly released to regulate other events, such as autophagy, synaptic plasticity, and cell cycle events. On top of TNF-a mediated inflammation, unchecked PTP1B activity initiates inflammation further and downregulates BDNF activity reducing synaptic plasticity. Deregulated mTOR signaling also is involved in retro inhibition of IRS-1 which can lead to further dysregulation of autophagy and insulin resistance. Lastly aberrant ganglioside metabolism promotes the Ab plaque aggregation and impairs insulin receptor function.
All the above information is in relation to Alzheimer’s, but all the above information is also seen to some degree in Type 2 Diabetes. Now, Type 2 Diabetes is primarily correlated to obesity and an unhealthy diet. Would eating healthy not only reduce your risk of Type 2 diabetes but also Alzheimer’s even if you have copies of the APOEe-4 gene?
Photo Sourced From: https://genesandinheritancr.wordpress.com/2011/09/20/inheriting-the-apoe-e4-gene-and-what-it-means/
potential treatment for both diseases, and luckily, scientists are working on this! Inhibiting PTP1B would result in no or less inhibition of insulin signaling, leptin receptors, and calcium channels even under endoplasmic reticulum stress. This would help to decrease the chance of developing type II in AD patients as well as decrease any neurodegenerative symptoms caused by PTP1B caused inhibition. But, it has been deemed an extremely difficult task due to the fact that the active site on PTP1B that an inhibitor would attached to is shared by over 100 other “family members” of this molecule. This makes it difficult for the inhibitor to only effect PTP1B and not any other PTPs present in other parts of the body.
In The Brain
However, like stated previously, in AD the insulin signaling is interrupted. This interruption happens because of activated, malfunctioning macrophages. Macrophages play an important role in the immune system and cell death. These macrophages secrete proinflammatory cytokines, which are chemicals that cause inflammation. One important proinflammatory cytokine in AD is called TNF-α. High concentrations of TNF-α cause significant inflammation, which interrupts the insulin signaling pathway, by preventing insulin receptors from activating IRS1 and IRS2 phosphorylation. Therefore, TNF-α causes insulin resistance, ultimately affecting learning and memory.
CBD Vs. THC?
When functioning normally, insulin in the brain binds to insulin receptors located on the neuron’s cell membrane. These receptors, once activated, phosphorylate proteins called IRS1 and IRS2, which means that phosphate molecules are put on the proteins. This in turn activates IRS1 and IRS2 which go off to cause more activation and signaling cascades resulting in insulin’s aforementioned activities in the brain, like facilitating learning and memory.
Definitely not! First of all, Infliximab is not a preventative drug meant to keep you from developing AD or T2D. 
effects of rapamycin that was found was that, when intermittently administered, rapamycin led to stem cell regeneration. Considering some of the applications for stem cells, this is an amazing discovery that could have far reaching implications on the future of medicine. And that’s potentially just the tip of the iceberg. Because of the mTOR1 inhibition through rapamycin, it has been found that there is a decreased risk of cancer, since mTOR1 signaling can lead to cell proliferation. Tumor regression has also been observed to occur. It’s also been found that mTOR1 signalling sometimes leads to misfolded proteins. Using rapamycin, inhibiting mTOR1 led to greater autophagy and suppression of protein synthesis, which is important because this means that rapamycin can have neuroprotective effects in not just Alzheimers, but also Parkinson’s Disease and Huntington’s Disease. 
Before we all start taking insulin, it’s important to remember however that one of the most consequential aspects of a drug’s effects and effectiveness is the dosage and how often its administration. With rapamycin, the appropriate ratios of both of these factors are still unknown as of yet, but research is being done to try decipher further how to access the perceived positive effects of the drug. It has been seen though that rapamycin doesn’t fully inhibit mTORC1 processes, and so a combination with another treatment would more effectively implement the positive effects of Rapamycin.
increase insulin resistance, but the mechanism for why this occurs is speculated to be known (inhibition of mTOR2). Other negative effects included increased hyperglycemia within type 2 diabetes mouse models, and the ability for tumors to start regrowing after treatment with rapamycin stopped.
