Important Facts, Concepts, and Data to know about CVD, Cognitive Impairment, and Corruption in AD Research
Important Facts, Concepts, and Data to know about CVD, Cognitive Impairment, and Corruption in AD Research
There is not a day that goes by that I don’t read more about the disappointing and unimaginable fraudulent research papers published years ago regarding Alzheimer’s disease. Sadly, it appears that this fraud continued in other research papers published by the same researchers that has now come to light. This fraudulent alteration of test results and imaging, was promulgated by other researchers also who led us down a path in hopes of them developing a drug that would reverse AD. This led to the medical field chasing drugs that would alter/remove beta-amyloid protein from neurons in hopes of reversing the AD progression. The lure of publication, grant funding, academic professorship, and prestige was too tempting for some researchers resulting in fraudulent studies. Sadly, after billions of dollars spent, we are realizing that we may have been chasing a ghost, as AD is so much more of a multifactorial complex disease that requires so much more than simply removing beta-amyloid plaque with monoclonal antibodies. A small part of my presentation at the Annual Symposium will be to address the most recent research as to what does work for AD prevention and why, as well as what doesn’t work and why. However, AD is just a small segment of the overall disease process that should be prevented and treated.
In tandem with this blog are papers that I think you may find of interest. I would like to take you down a path so that you can conceptualize that what we are doing in medicine is not working. It should be changed and EBM literature should not be ignored, but politics and economics drive medicine and much of our lives. Nevertheless, the above paragraph demonstrates that doctors/researchers may lie but true medical science and outcome studies do not. (As I have mentioned many times before in the courses, only trust your mother). I hope that you will enjoy the papers I have collated for you.
Incidence of CVD Becoming Worse
In the first article, the first paper demonstrated that from 2000 to 2011 the age-adjusted heart disease death rate decreased 3.7% per year. However, the decline slowed (got worse) to 0.7% per year from 2011 to 2019. Why? CVD remains our leading cause of death. So, why is the incidence of CVD becoming worse? With all the cholesterol medications at our disposal, why is mortality worse? The leading lipidologists Snyderman and Dayspring focus on the apo-B molecule as the culprit. Peter Attia and lipidologists chase this surrogate marker with statins, PCSK-9 inhibitors, bempedoic acid, and inclisiran, but the incidence of CVD still gets worse, proving that the cholesterol-centric model is not working as it should. As I mentioned in previous newsletters, these experts completely miss the inciting cause of CVD as they chase their surrogate markers with drugs. What are we missing or not doing that increases the CVD risk every year over the last 10 years? (Doing the same experiment over and over again expecting different results each time?)
In the International Journal of Epidemiology, the CVD-mortality rate increased in the last year in North America and other high-income countries. In JAMA, CHD accounts for the largest proportion of deaths, with the prevalence greater in men (7.7%) than women (4.6%). The risk appears to be driven by obesity and type 2 diabetes. In addition, cancer deaths rose globally in 2019, an increase of 26%. Researchers found that cancer was second to CVD in number of deaths. The absolute burden of cancer is growing substantially worldwide. Why?
Lastly, another study proved the incidence of obesity doubled in the last 2 decades. As a result, there is an increase in cancer. “Our findings add evidence of the urgent need to halt and reverse the global trend in weight gain.” So, the incidence of cancer is increasing along with the incidence of CVD. Could the causative factor be the same for both? How should we treat it as we have been very unsuccessful in preventing disease as demonstrated in the foregoing papers? What can we do to increase the incidence of DM, obesity, CVD, and AD? Whatever it is that we are doing, it’s working! Does everyone see the elephant in the room?
Cognitive Impairment Increase
In the second article, researchers from JAMA proved a recent increase of 36% in dementia in older adults, an increase. Cognitive impairment doubled in the last decade. In Nature Reviews researchers addressed the disappointing results of drugs to treat AD. They described AD as a 4-step process:
Step 1: deposition of beta-amyloid
Step 2: hyperphosphorylated tau aggregates in neurons
Step 3: neurodegeneration
Step 4: cognitive decline
Drugs to stop production of beta-amyloid have not been demonstrated to be efficacious in multiple studies. In fact, some patients with significant amyloid do not develop dementia which changes the thought process as to what is actually causing the neurotoxicity. The probabilistic model suggests genetic, environmental, metabolic and inflammatory causes. (There was no mention of hormones). They did introduce upcoming tests to detect beta-amyloid and tau proteins in the blood, but I don’t know how that changes the course of the disease or treatment. Lastly, an old paper (seemingly ignored) in the journal Neuron proved that the AD brain exhibits impaired energy metabolism with diminished cerebral use of glucose. Glucose deprivation and impaired energy metabolism increased levels of beta-amyloid plaque. However, what causes this change in glucose utilization and how can it be prevented/treated/reversed?
In summary, is it the beta-amyloid plaque that is causative and damaging or loss of glucose utilization, mitochondrial dysfunction, and inflammation that triggers the foregoing pathologic process? Is it the tau aggregates that lead to beta-amyloid plaque and is that leading to neuron cell death? So far, removal of plaque does not reverse the disease process or prevent cell death. What causes the impaired energy metabolism, diminished glucose utilization and glucose deprivation? One of the first papers I will present demonstrates impaired insulin and IGF-1 signaling early in the disease course. Should we not be addressing the cause of the pathology instead of removing the end pathologic product with monoclonal antibodies?
Losing Weight, Decreasing Insulin Levels, and AD
In the third set of articles, researchers demonstrate that exercise increases brain glucose metabolism, which correlates with improved brain function. (OK Mrs. Smith, I know that you are demented at age 67 and can’t find your way out of a box, but today we are going to run 5 miles). Exercise improves insulin and BMI to prevent dementia and loss of gray matter. Multiple studies prove reduced glucose metabolism as the inciting event for dementia. Does anyone see the elephant in the room yet? “Decreasing insulin levels (IR) and losing weight are modifiable factors.” Losing weight is the best option but next to impossible to achieve and maintain with 95% recidivism. However, there are multiple ways to decrease insulin levels and this needs to start early in everyone. “There is growing evidence that AD is mediated by tau pathology and not amyloid.” The researchers failed to address if it is the exercise per se that is of benefit or the weight loss that is of benefit. “The literature clearly demonstrates that CVD risk factors increase the risk of AD and dementia.” So, just what are those risk factors and how should they be treated? With statins that increase IR and DM? Lastly, researchers in the Journal of Preventive Cardiology suggest that estrogen improves all lipids and lipoproteins that lead to a decrease in CVD and dementia, but this is still controversial as researchers cannot sort out the difference between different types of hormones. (It is not controversial to me at all). Estrogen (E2) has significant effects in reducing DM, improving insulin levels, without the side effects of driving glucose into the cell to be stored as fat as with diabetes medicines. In summary, it appears that IR and decrease in glucose utilization are the main factors in initiation of AD. Estrogen (E2) offers the greatest CVD prevention in women as well as preventing the IR and DM seen after the menopausal transition. But what about premenopausal women and men? And what about the claims that AD and CVD start 30 years before clinical symptoms become manifest? We will review the many controversies and use outcome studies to prove what works best for AD prevention. We’ll review which estrogens work best, which ones don’t work, which ones reverse amyloid plaque, and improve symptoms and which ones don’t. We’ll prove the USPSTF is wrong in their recommendations and that they are actually causing harm to women because they don’t understand the literature and studies.
Corruption and Data in AD Research
In the next article, the recent allegations of fraudulent publications are reviewed from August 2022. Matthew Schrag wrote in the journal Science the detailed research around the drug simufilam, which was based on manipulated images. Schrag reviewed scores of images in scientific papers authored by neuroscientist Sylvain Lesne suggesting imaging tampering. (Ouch). The recent FDA approval of aducanumab-against expert advice which warned there wasn’t enough evidence to show it worked-has also been problematic. Is the field of Alzheimer’s research corrupt? Apparently, this has changed the thinking as to what drugs do work. Nevertheless, there are many studies demonstrating what does work, and this plethora of data should not be ignored.
The next paper addresses results from the 2022 Alzheimer’s Association International Conference where scientists discussed recent research. It is estimated that AD will reach 13 million people by 2050. (Bredesen states that AD will disappear by 2050. Hmmm). As more drugs failed to improve AD, a new drug is being developed to overcome insulin resistance seen in AD patients. (Does anyone see the elephant yet?) Brain inflammation and mitochondrial dysfunction also play a role. “The amyloid hypothesis has been taking a lot of hits lately. The drug trials keep coming through and failing.” Experts agree that there are multiple mechanisms that are responsible for AD. The paper goes on to discuss the benefits of exercise (again) but I think that concept comes 30 years too late in the course of the disease. Research now focuses on tau proteins, brain inflammation, and the role of microglia in both being ineffective as well as too hyperactive causing destruction. AD is therefore proving to be a complex disease process involving many different pathways.
In a paper from GeroScience, researchers proved that microvascular disease/dysfunction is a leading cause of dementia in AD patients. I will present a paper demonstrating that statins did not improve microvascular disease (only macrovascular disease) but estrogen does. Increased microvascular diseases led to an increase in astrocytes becoming more reactive, inflammatory, and damaging as was seen on sophisticated MRI scans. “The microvascular dysfunction may be present before the damage to the brain tissue and cognitive dysfunction is apparent and at a very young age.” Elevated blood sugar and lipids cause this microvascular disease which can also lead to microscopic strokes (vascular dementia). So, why do we keep chasing beta-amyloid plaque, which is the end result of the AD process? It is the endothelial intravascular plaque build-up that results in microvascular damage that can be prevented by hormone replacement, which also treats the IR. Once the damage is done and the beta-amyloid plaque is evident, the house has burned down, and the neuron is necrotic. Trying to remove the beta-amyloid plaque is futile, especially after 30 years of the foregoing disease processes that have burned down the house. We’re trying to attack the end result (beta-amyloid plaque) which has nothing to do with the initiation and progression of the disease process. We are missing the big picture, partially due to the misleading and fraudulent publications suggesting that the cause is beta-amyloid plaque whereas the beta-amyloid plaque is the end result of the disease process.
In the next paper from Medical News Today 2022, researchers demonstrated that diabetes increases CVD, kidney disease, vision loss, and now cognitive decline and brain aging. Accelerated brain aging is now seen in younger people. Researchers found cognitive decline in a meta-analysis in patients with DM. There is a linear decrease in gray matter and brain atrophy. “They observed the most severe neurocognitive effects in participants who had the longest duration of type 2 diabetes.” That is my point of contention that I will address in the literature review in the Academic Summit. Statins cause significant increase in DM and IR leading to the above AD. Not that statins aren’t beneficial in reducing CVD events, but the collateral damage is completely ignored. The collateral damage can be completely prevented and reversed but it is not. The contemporary thinking is just to add diabetes medicine, but that does not stop the AD or neurocognitive decline.
Unfortunately, researchers saw no difference in neurocognitive effects between those taking metformin and those not taking it. “It is interesting that metformin does not improve neurocognitive symptoms in type 2 diabetes.” I wouldn’t expect it to because it does not reduce visceral fat, triglycerides, NAFLD, or raise HDL. But I know what to do. Furthermore, “type 2 DM decreases the availability of glucose in the brain which leads to faster cognitive decline. This damage occurs before type 2 DM is formally diagnosed.” (Which is again my point of contention with statins that is completely ignored.) The significant harm of IR before type 2 DM is formally diagnosed is where the damage occurs. “Yes, but the benefits outweigh the risks.” Well, no they don’t. We missed the big picture, causing type 2 DM and AD does not outweigh any benefit. The collateral damage is severe and should not be ignored, particularly when it can easily be treated and prevented.
In the last paper from the journal Brain, researchers address the concept that inflammation drives AD. And where does that inflammation originate from? “AD is a disease for which there is no cure or treatment to slow down the disease process.” I completely disagree with that statement, and it shows that the authors are unaware of the research proving that statement incorrect. However, they did address research demonstrating that microglia regulate immune responses and inflammation. An excess of microglia, or hyperfunction, increases inflammation. Researchers are searching for the “drug” that eliminates excessive numbers of microglia. The best treatment for removing microglia and improving the brain glymphatic system that occurs during deep sleep is melatonin. But it’s a big dose. Researchers in Journal of Clinical Oncology went on to discuss that men treated with androgen deprivation therapy for prostate cancer were 88% more likely to develop AD. In fact, all studies with ADT demonstrated an increase in AD and CVD. But was it the androgen deprivation or the estrogen deprivation? “Yes, but the benefits outweigh the risks.” Well, again, no they don’t. Are patients told of the increased mortality from CVD or AD? Probably not. We should be advocates for our patients, as we know the literature better than their specialists. As outcome studies prove that the benefits do not outweigh the risks. So, how should that prostate cancer patient be treated to prevent CVD and AD mortality?
Hope that was fun and enlightening. Hope to see you in New Mexico at the Academic Summit next week.