Do Statins Increase Or Decrease Alzheimers Risk
James M. Ellison, MD, MPH
Swank Center for Memory Care and Geriatric Consultation, ChristianaCare
- Expert Advice
Learn why statins may both increase and decrease the risk of dementia symptoms.
After late-onset Alzheimers disease was diagnosed in his father, Martin* took greater care of his own health. At age 63, he wanted to do everything he could to improve his chances of avoiding AD. At his fathers appointment, he asked about something that was bothering him: My primary care doc says my cholesterol has been too high and that I should take a statin. I know thats supposed to lower my cholesterol and my primary care physician says it will reduce my dementia risk, but Ive also read that statins can interfere with memorywhat should I do? Do statins increase or decrease AD risk?
* The name and details were changed to protect privacy.
Is it possible for a medication both to increase and to decrease dementia risk? In the case of statins, this can appear to be true. Overall, the beneficial effects of statins seem to outweigh their small risk of interfering with cognitive functioning, but we cant ignore the many reports of memory impairment associated with these medications. How can this be? There is evidence both for statin-associated brain protection and for statin-associated cognitive interferenceand there is a credible explanation.
Does Brain Cholesterol Control Alzheimers
Brain cholesterol levels may be the key to understanding and treating Alzheimers disease, according to a new study.
Most people have heard of cholesterol. Your doctor may have told you that you need to lower your cholesterol, or you may know someone who takes a cholesterol-lowering medication. High cholesterol is generally a concern because it can cause heart attacks and stroke. However, new research suggests it may also play a role in a disease that affects an estimated 5.8 million Americans: Alzheimers disease.
Alzheimers disease, also called AD, is a devastating disease that damages a persons cognitive functions in everyday life. It is neurodegenerative, which means that people with AD experience increasing damage to their nervous system over time. They may lose key memories of their lives, become unable to navigate their surroundings, forget who their loved ones are, and have uncontrollable changes in their personality. Recent scientific advances have resulted in treatments that can slow some of the symptoms of AD. However, the Mayo Clinic reports that, on average, people will still not survive more than 11 years after diagnosis. AD generally strikes people after the age of 60, according to the CDC, but younger people can also develop early onset forms of the disease. There is a strong genetic link to who is affected, as well.
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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High Cholesterol Linked To Alzheimer’s Disease
So-called “bad” cholesterol in the blood has been linked to a rare form of Alzheimer’s disease in a study.
Researchers looked at the link between LDL cholesterol levels and early-onset Alzheimer’s disease: a rare type of dementia which generally hits people in their 40s and 50s. Also known as young-onset Alzheimer’s disease, past studies have shown specific genetic mutations are a likely cause of the condition which around 200,000 people in the U.S. are estimated to have.
LDL cholesterol can cause fatty deposits to build up in and narrow the arteries, which can raise the risk of conditions including heart disease, stroke and peripheral artery disease. “Good” HDL cholesterol, on the other hand, is thought to prevent heart attacks and stroke, by helping to transport LDL away from the arteries so it can be processed by the liver.
Scientists think there is a link between developing Alzheimer’s disease later in life and high cholesterol. There appears to be a connection between a genetic mutation of the APOE gene called APOE E4 and Alzheimer’s, as well as high levels of LDL. In the study published in the journal JAMA Neurology, the team wanted to see if there is a similar connection with early-onset Alzheimer’s.
Dr. Thomas Wingo, lead author of the study, commented: “The big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer’s disease risk.
Statin Side Effects: Memory Loss Depression And More
There is little doubt that cholesterol-lowering statin drugs like Mevacor, Lipitor, and Crestor are linked to serious memory loss, fuzzy thinking, and learning difficulties.
One way statins do this is by , a nutrient thats protective of both the heart and the brain.
CoQ10 deficiency is believed to be responsible for the fatigue and muscle pain commonly experienced with statin use.
- Of all the people who are hospitalized for a heart attack, only 25% have high cholesterol.
- The other 75% have normal cholesterol.
Clearly, high cholesterol is not the risk factor weve been led to believe.
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Intracellular Cholesterol Metabolism The Basics
It is important to note, that many basic rules underlying intracellular cholesterol metabolism have been uncovered so far, as discussed above. However, most of this knowledge is acquired from experiments in dividing fibroblast culture systems. Cholesterol metabolism in the central nervous system and, particularly in neurons, is under added pressure due to the postmitotic nature of these cells, their long-life span, large size and highly specialized metabolic demand which requests specific mechanisms to maintain lifelong cholesterol homeostasis in the brain.
Is There A Link Between Dementia And Cholesterol
Without this, people would not be able to produce hormones or digest food.
We can describe cholesterol as a waxy-like fatty substance that the liver produces.
It is also present in some foods. Cholesterol circulates through the blood-stream in carries known as lipoproteins made of proteins and fats.
Even though the fatty substance is beneficial, too much cholesterol in the blood can harm vascular and heart health.
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What To Do If You Think Statins Are Causing Memory Loss
If you currently take a statin and are experiencing side effects like memory loss, mental confusion, or muscle pain, make an appointment to talk to your doctor today.
Go in armed with as much information on cholesterol as possible.
If youd like a deep scientific understanding of cholesterols role in the body, I highly recommend Dr. Peter Attias 9-part blog series The Straight Dope on Cholesterol.
Youll almost certainly know more about cholesterol than your doctor when youre done.
Tell your doctor that you want to have the small particle LDL test done.
As a matter of course, most doctors dont run this test.
Even doctors who understand the value of this test dont recommend it because its normally not covered by insurance.
You can ask for it anyway and offer to pay out of pocket.
The Wall Street Journal has called the VAP test one worth paying for out of pocket.
And finally, remember that preventing heart disease, not simply having good numbers, is the real goal.
You can proactively prevent heart disease by adopting a heart-healthy lifestyle.
Drs. Bowden and Sinatra offer these simple lifestyle recommendations to address the true underlying causes of heart disease:
- Eat a diet of unprocessed foods
- Reduce sugar, grains, and vegetable oils high in omega-6 fats like canola oil
- Eat heart-healthy fats like nuts, olive oil, coconut oil, and avocado
- Manage stress
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.
Potential Mechanisms For Cholesterols Apparent Adverse Effect On The Development Of Ad
There are several possible mechanisms that could explain the studies reviewed in the previous section that seem to connect high cholesterol levels with the development of AD neuropathology. Cholesterol may increase the activity of the – or -secretase enzymes that generate A from APP, decrease the flux of APP through the non-amyloidogenic -secretase pathway, or affect various non-amyloid factors such as local inflammation or tau metabolism.
Partial repression of the non-amyloidogenic -secretase pathway is one route postulated from animal studies by which high cholesterol levels could increase AD risk. Application of exogenous cholesterol to human embryonic kidney cells overexpressing human APP decreased the -cleavage product of APP, APPs, as did feeding mice a diet high in fat and cholesterol. Conversely, treatment of HEK cells, human neuroglioma cells, or APP-overexpressing astroglioma cells with the cholesterol-extracting agent methyl–cyclodextrin increased the secretion of APPs. Another study found that progesterone, which decreases transport of cholesterol from the plasma membrane to the cytosol, did not alter the cholesterol-mediated inhibition of APPs secretion. This result suggests that cholesterol may act on APP primarily at the cell surface.
Serum Cholesterol In 1968 And Risk Of Dementia Among Those Who Survived To The 2000 Examination
Some epidemiologic studies examining midlife cholesterol have information on dementia diagnosis only for those who survived to the follow-up examination, often decades after the midlife cholesterol measurement. In order to replicate these analyses and better determine the effects of survival on the results, the analysis was restricted to the 648 women who survived and participated in the 2000 examination . In univariate analyses, high cholesterol was associated with dementia such that the highest quartile, compared to the lowest, was associated with a fourfold increase in risk of all-cause dementia and almost a sixfold increase in risk of AD . However, the results were attenuated after age stratification and, while there was a trend for high cholesterol to increase risk, results were not significant at the p< 0.05 level.
Table 3 Cox proportional hazards models relating cholesterol level in 1968 to incident dementia and Alzheimer disease among women surviving to and participating in the 2000 examination
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Study Reveals Link Between High Cholesterol And Alzheimers Disease
The American Academy of Neurology, an association of more than 24,000 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimers disease, stroke, migraine, multiple sclerosis, brain injury, Parkinsons disease and epilepsy.For more information about the American Academy of Neurology, visit .
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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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 that forms in the brain tissue of Alzheimer’s patients.
A review of studies in 2011 noted that “cholesterol seems to be intimately linked with the generation of amyloid, ” which develops in Alzheimer’s disease. The majority of the studies they looked at found an association between cholesterol and Alzheimer’s disease.
William Connor, M.D., professor of medicine at Oregon Health and Science University in Portland, Oregon, says that cholesterol affects brain functioning primarily through the link between LDL and strokes, which are caused by atherosclerotic 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.”
And a more recent study, published in 2021 found that participants with high triglyceride levels and low HDL levels showed decreased integrity of the hippocampus, which is an area of the brain that is involved in memoryand this area often shows signs of amyloid buildup and atrophy in people who have dementia.
Understanding Cholesterol In The Brain
Researchers are also interested in cholesterol in the brain, as this substance and the way that it is processed are very important for the health of brain cells, and may be affected in dementia. For example, one of the common genes that increase the risk of late-onset Alzheimer’s disease APOE4 plays a role in the processing and use of cholesterol and other fats. Understanding any differences may lead to clues about changes in the brain that cause dementia, and things that we could tackle with treatments.
Changes with cholesterol processing in the brain may not be related to the levels of cholesterol in the blood. More research is needed to better understand this relationship and what it can tell us.
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Making Changes To Lower Risk
Computer specialist James Pitman, 44, has gotten the message and is making lifestyle changes to bring his high cholesterol down in hopes of reducing his risk for heart disease, diabetes, and dementia later in life.
The Oakland, Calif., resident, who has a family history of diabetes and Alzheimer’s disease, has lowered his total cholesterol from 280 to 260 by eating better and revamping his exercise routine. He tells WebMD that he hopes to lower his numbers more by making additional changes.
“I didn’t exactly win the genetic lottery, so I will probably have to go on drugs eventually to lower my cholesterol,” he says. “But I am going to do all I can with diet and exercise.”
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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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 .