Frontiers In Aging Neuroscience
Icahn School of Medicine at Mount Sinai, United States
Washington University in St. Louis, United States
The editor and reviewers’ affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review.
Cholesterol’s Role In The Brain
The brain comprises only 2% of the body’s total weight, yet itcontains nearly 25% of the total cholesterol in the body. It has beendetermined that the limiting factor allowing the growth of synapses isthe availability of cholesterol, supplied by the astrocytes.Cholesterol plays an incredibly important role in the synapse, byshaping the two cell membranes into a snug fit so that the signal caneasily jump across the synapse . So inadequate cholesterol in thesynapse will weaken the signal at the outset, and inadequate fatcoating the myelin sheath will further weaken it and slow it downduring transport. A neuron that can’t send its messages is a uselessneuron, and it only makes sense to prune it away and scavenge itscontents.
People with the apoE-4 allele tend to have high serum cholesterol. Thequestion of whether this high cholesterol level might be an attempt onthe part of the body to adjust for a poor rate of cholesterol uptakein the brain was addressed by a team of researchers in 1998 .They studied 444 men between 70 and 89 years old at the time, for whomthere existed extensive records of cholesterol levels dating back toseveral decades ago. Most significantly, cholesterol levelsfell for the men who developed Alzheimer’s prior to theirshowing Alzheimer’s symptoms. The authors suggested that their highcholesterol might have been a protective mechanism against Alzheimer’s.
Change In Cholesterol And Risk Of Dementia
Finally, change in cholesterol between visits was examined as a predictor of subsequent dementia using Cox proportional hazards regression . Cholesterol change was analyzed by quartiles as a time-dependent variable at each examination. While the intervals between examinations varied over the follow-ups, the range for each quartile was relatively consistent. The middle 2 quartiles was the reference group. The quartiles showing the greatest decline and the greatest increase were examined in relationship to risk of dementia. Compared to the middle 2 quartiles, the quartile of greatest decrease in cholesterol was related to increased risk of dementia . While there was a similar trend for AD, results were not significant.
Table 4 Time-dependent cholesterol level change between examinations and risk of dementia and Alzheimer disease over 32 years
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The American Heart Associations Diet Is A Killer
The landmark Lyon Diet Heart Study followed approximately 600 participants who were at extreme risk for heart attacks.
They were overweight, sedentary, smoked, and had high cholesterol levels.
Half were put on a Mediterranean diet and half were put on what was called a prudent Western-type diet recommended by the American Heart Association.
The study was halted before it was completed.
People on the Mediterranean diet were 45% less likely to die over the 4-year period than those on the prudent diet even though their cholesterol levels didnt budge.
However, so many people on the American Heart Associations diet were dying that researchers felt it was unethical to continue putting study participants at risk.
Cholesterol And Lipid Management
In addition to some knowledge about the brain, you will also need toknow something about the processes that deliver fats and cholesterolto all the tissues of the body, with a special focus on thebrain. Most cell types can use either fats or glucose as a fuel source to satisfy their energyneeds. However, the brain is the one huge exception to this rule. Allcells in the brain, both the neurons and the glial cells, are unableto utilize fats for fuel. This is likely because fats are tooprecious to the brain. The myelin sheath requires a constant supplyof high quality fat to insulate and protect the enclosed axons. Sincethe brain needs its fats to survive long-term, it is paramount toprotect them from oxidation and from attack byinvasive microbes.
Fats come in all kinds of shapes and sizes. One dimension is thedegree of saturation, which concerns how many double bonds theypossess, with saturated fats possessing none, monounsaturated fatshaving only one, and polyunsaturated fats having two or more. Oxygenbreaks the double bond and leaves the fat oxidized, which isproblematic for the brain. Polyunsaturated fats are thus the mostvulnerable to oxygen exposure, because of multiple double bonds.
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Cholesterol May Be Key To New Therapies For Alzheimer’s Disease Diabetes
- University of Arizona Health Sciences
- A researcher examined the role of cholesterol in both Alzheimer’s disease and Type 2 diabetes to identify a small molecule that may help regulate cholesterol levels in the brain, making it a potential new therapeutic target for Alzheimer’s disease.
A University of Arizona Health Sciences researcher examined the role of cholesterol in both Alzheimer’s disease and Type 2 diabetes to identify a small molecule that may help regulate cholesterol levels in the brain, making it a potential new therapeutic target for Alzheimer’s disease.
There is no known cure for Alzheimer’s disease, which affects more than 5.5 million people in the United States. In the last decade, scientists have found increasing evidence linking the underlying causes of Type 2 diabetes and Alzheimer’s disease.
Type 2 diabetes occurs when insulin becomes less efficient at removing glucose from the bloodstream, resulting in high blood sugar that can cause abnormal cholesterol levels. A similar situation occurs in Alzheimer’s disease, but rather than affecting the body as a whole, the effects are localized in the brain.
The paper, “Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes,” was published in the journal ACS Pharmacology and Translational Science.
Cholesterol Metabolism In The Brain Different Needs For Different Cells
As mentioned above, regulation of cholesterol metabolism is particularly important for neurons. To further fine-tune cholesterol metabolism, neurons contain another cholesterol-regulating enzyme cholesterol 24-hydroxylase , which is CNS specific and under healthy conditions only expressed by neurons . CYP46A1 converts excess cholesterol to 24S-hydroxycholesterol , which can be released by neurons and crosses the BBB through diffusion, forming a major export pathway for excess cholesterol from the brain . Due to its neuron specific origin, 24S-OHC levels in the blood also provide a direct measure of cholesterol turnover levels in the brain . Besides being an export product, as other oxysterols, 24S-OHC can promote ApoE-mediated cholesterol export by activating liver X receptor . Additional oxysterols that are produced in the brain include 27-OHC, which is generated by the enzyme CYP27A1 and can be further processed by CYP7B to form 7-hydroxy-3-oxo-4-cholestenoic acid . 7-OH-4-C can cross the BBB to be eliminated by the liver. CYP27A1 is expressed in multiple brain cell types, yet 27-OHC levels in the brain are only a fraction of the far more abundant 24S-OHC . In fact most 27-OHC is not produced in the brain but enters the brain via the BBB originating outside the CNS .
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Astrocytes Glucose Metabolism And Oxygen
Alzheimer’s is clearly correlated with a deficiency in thesupply of fat and cholesterol to the brain. IDL, when functioningproperly, is actually incredibly efficient in cholesterol and fatthroughput from the blood across cell membranes, compared to LDL. It gives up its contents much more readily than the other apo’s.And it achieves this as a direct consequence of apoE. IDL in the blood delivers fats and cholesterol to the astrocytes in the brain,and the astrocytes can thus use this external source instead of havingto produce these nutrients themselves. I suspect, in fact, that astrocytesonly produce a private supply when the external supply isinsufficient, and they do so reluctantly.
Why would it be disadvantageous for an astrocyte to synthesize itsown fats and cholesterol? In my opinion, the answer has to do withoxygen. An astrocyte needs a significant energy source to synthesizefats and cholesterol, and this energy is usually supplied by glucosefrom the blood stream. Furthermore, the end-product of glucosemetabolism is acetyl-Coenzyme A, the precursor to both fatty acids andcholesterol. Glucose can be consumed very efficiently in themitochondria, internal structures within the cell cytoplasm, viaaerobic processes that require oxygen. The glucose is brokendown to produce acetyl-Coenzyme A as an end-product, as well as ATP,the source of energy in all cells.
Solving The Mystery Of Cholesterol And Memory Loss
How does cholesterol affect memory and cognitive function? The precise answer to that question remains a mystery. Researchers speculate that HDL may improve memory in a number of ways. HDL has anti-inflammatory and antioxidant properties, which may improve brain function. HDL may also prevent the formation of beta-amyloid, associated with the plaques that form in the brain tissue of Alzheimer’s patients.
Other researchers, like William Connor, M.D., professor of medicine at Oregon Health and Science University in Portland, Oregon, believe that cholesterol affects brain functioning primarily through the link between LDL and strokes, which are caused by plaque formation in the blood vessels of the brain.
“High cholesterol levels in the blood can predispose the deposition of plaque in the blood vessels,” says Connor, a specialist in atherosclerosis . And, he adds, “stroke can result in memory loss.”
A review of studies in 2011 noted that “cholesterol seems to be intimately linked with the generation of amyloid plaques,” which develop in Alzheimer’s disease. The majority of the studies they looked at found an association between cholesterol and Alzheimer’s disease.
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Excessive Oxygen Exposure And Cognitive Decline
It has been observed that some elderly people suffer temporary andsometimes permanent cognitive decline following a lengthy operation.Researchers at the University of South Florida and VanderbiltUniversity suspected that this might be due to excessive exposure tooxygen . Typically, during an operation, people are often administeredhigh doses of oxygen, even as much as 100% oxygen. The researchersconducted an experiment on young adult mice, which had been engineeredto be predisposed towards Alzheimer’s but had not yet sufferedcognitive decline. They did however already have amyloid-betadeposits in their brains. The re-engineered mice, as well as acontrol group that did not have the Alzheimer’s susceptibility gene,were exposed to 100-percent oxygen for a period of three hours, threetimes over the course of several months, simulating repeated operations. They found that the Alzheimer’s pre-disposed mice suffered significantcognitive decline following the oxygen exposure, by contrast with thecontrol mice.
The Current State Of Knowledge On Statins And Ad
Because statins are already in widespread use, the possibility that they might be useful for AD treatment or prevention must be rigorously confirmed or denied. In the years since the connection between cholesterol and AD was uncovered , many studies have investigated the potential use of statins as AD-modulating compounds. However, the results of these studies have often been inconsistent, in large part due to major differences in study design and data analysis. While these methodological differences make it difficult to synthesize the results from various studies, we have endeavored to identify factors that could explain the observed variation in study outcomes.
Serum Cholesterol At Each Examination And Risk Of Dementia
Evaluation of the cholesteroldementia relationship using age-adjusted Cox proportional hazards models showed no associations from midlife to late life . There was also no association between cholesterol and risk of dementia when analyzing cholesterol as a time-dependent variable over the 5 examinations .
Table 2 Cholesterol level at each examination and risk of dementia over 32 years
Brain Cholesterol And You
Brain cholesterol affects brain cells through a set of interactions with other proteins. It is transported by a protein known as apoE to the neurons. After cholesterol is transported by apoE, it collects with other molecules called lipid rafts. Lipid rafts, with cholesterol and apoE, interact with APP, the larger protein containing A. Changes to the gene coding for apoE are commonly seen in AD, particularly one called an E4 variant. A problem in any part of this pathway could cause the brain to produce too much A, leading to plaques.
Due to brain cholesterols role in producing A, scientists at Scripps Research Institute hypothesized that increased cholesterol in the brain might be to blame for too much A forming. Cholesterol could be the step where things go awry, especially since high cholesterol has also been found in people with AD. This, along with the apoE E4 variant connection to AD, led them to suspect that interactions between these molecules might underlie the plaques seen in AD.
This study was published in the peer-reviewed journal Proceedings of the National Academy of Sciences of the United States of America .
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Blood Cholesterol In Middle Age Linked To Dementia And Alzheimers Disease More Than 10 Years Later
High levels of low-density lipoprotein cholesterol in mid-life are associated with an increased risk of developing dementia and Alzheimers over a decade later, according to a study published in Lancet Healthy Longevity.
Elevated levels of total cholesterol were also associated with an increased risk of dementia and Alzheimers disease, although this link was weaker, suggesting it is largely driven by LDL cholesterol.
The largest study to date, led by the London School of Hygiene & Tropical Medicine with the University of Tsukuba, Japan and OXON Epidemiology, London and Madrid, provides the strongest evidence so far on the relationship between blood cholesterol and dementia and Alzheimers disease.
Funded by Alzheimers UK, the researchers used anonymised data from the UK Clinical Practice Research Database on more than 1.8 million UK adults aged over 40 who had a blood cholesterol measurement between 1992 and 2009, with a follow-up period up to 23 years or until dementia diagnosis. They were able to calculate the risks of subsequent dementia and Alzheimer´s disease for blood total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides, adjusting for other factors.
In the 953,635 people in the study who had an LDL cholesterol recording, 2.3% went on to be diagnosed with dementia or Alzheimers disease. Of the more than 1.8 million people who had a first total cholesterol reading, nearly 50,000 had a subsequent diagnosis in the 23-year follow-up period, up to 2015.
Evidence For Statins Increasing Risk Of Dementia
Alarming case reports began to accumulate in the early 2000s. A description of 60 case reports, published in 2003, advised taking concerns about statin-related cognitive impairment seriously, though cognitive adverse responses were most likely uncommon.4 Simvastatin, atorvastatin, and pravastatin were the medications taken by the patients who were described. About half of these patients noticed cognitive problems within two months of starting treatment. The symptoms improved after drug discontinuation in about half of those affected, which is different from what would be expected of a person with Alzheimers disease, which is a progressive condition.
The link between cognitive symptoms and statins, furthermore, is supported by a couple of additional lines of evidence: first, some patients with this problem who noted improvement after stopping their statin medication experienced a recurrence when the medication was restarted.4 Second, a couple of small but well-designed experimental double-blind, placebo-controlled trials associated poorer performance on neuropsychological tests with the use of statins.5,6 In a description of statin effects on a couple of affected patients, the authors reminded us that a cognitive effect which looks small on neuropsychological testing can cast a much larger shadow over actual day-to-day functioning.7
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Cholesterol And Alzheimers Disease From Risk Genes To Pathological Effects
- 1Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research , Amsterdam University Medical Center, Amsterdam, Netherlands
- 2Department of Functional Genomics, Center for Neurogenomics and Cognitive Research , VU University Amsterdam, Amsterdam, Netherlands
- 3Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, Netherlands
While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the bodys cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimers disease , where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimers disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell -technology can aid to study these problems.
How Too Much Cholesterol Can Contribute To Alzheimers Disease
Written By Michael Greger M.D. FACLM on January 23, 2018
Millions suffer from Alzheimers disease, and the available and foreseeable treatments are disappointing at best. Given the absence of disease-modifying treatments, there has been growing interest in effective strategies for the prevention of the disease in the first place. Even if we were able to just delay the onset by as little as 1 year, we could potentially prevent more than 9 million cases over the next 40 years. Once cognitive functions are lost in Alzheimers disease patients, they may be lost forever. Consequently, prevention, rather than a cure for Alzheimers disease appears to be a more realistic strategy to offset the catastrophic impact of this dementia.
As I discuss in my video Cholesterol & Alzheimers Disease onsiderable evidence now indicates that Alzheimers disease is primarily a vascular disorder, based on a number of lines of evidence that point toward impaired circulation of blood to the brain. Vascular risk factors, such as high cholesterol, can be thought of as a ticking time bomb to Alzheimers disease. Whats bad for the heart may be bad for the mind.
Amyloid degradation is also less efficient in a high cholesterol environment. Cholesterol can then help seed the clumping of the amyloid. Using an electron microscope, researchers can see the clustering of amyloid fibers on and around little microcrystals of cholesterol.
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