HMG CoA reductase inhibitors – known as statins – have been shown to lower cholesterol levels in the blood and to have a protective effect against heart disease. In the past few years, however, researchers have come to believe that statins might also play a role in preventing Alzheimer disease (AD).
They base this assumption on experimental studies, which suggest that cholesterol might play a role in the pathogenesis of Alzheimer disease – and that statins can reduce the production of beta amyloid, the peptide which is the main component of senile plaques and a pathologic factor for AD.
The role of statins in the treatment and prevention of AD is an active area of research right now, with several clinical trials either in planning stages or in progress. This Special Report will highlight the basic, epidemiological, and clinical trials exploring these links and their implications for treating AD.
For the past five years, basic researchers have studied the link between statins and the beta amyloid protein in animal and cell studies. Konrad Beyreuther, MD, of the University of Heidelberg in Germany and others believe that there is a link between neuronal cholesterol and the mechanisms behind amyloid beta transport and production in Alzheimer disease.
In studies published in 2001, Dr. Beyreuther and his colleagues demonstrated that the cholesterol-lowering drugs simvasatin and lovastatin reduced the production of beta amyloid peptides in primary cultures of hippocampal neurons and mixed cortical neurons, as well as in animal models. Experiments with guinea pigs showed that simvastin reduced beta amyloid production by 50 percent. (Proceedings of the National Academy of Sciences 2001; 98 (10): 5856–5861).
The paper suggested that that the physiological and pathogenic regulation of axonal transport by beta amyloid appears to be controlled by cholesterol, and that this implies a link between neuronal cholesterol, amyloid precursor protein transport, amyloid production, and the risk of developing AD.
HIGH CHOLESTEROL DIET
Animal studies by Larry Sparks, MD — Senior Scientist and Head of the Ralph and Muriel Roberts Laboratory for Neurodegenerative Disease Research at the Sun Health Research Institute in Sun City, AZ — have focused on the role of a high-cholesterol diet on amyloid beta accumulation.
Dr. Sparks found that the brains of cholesterol-fed rabbits had elevated circulating cholesterol and elevated beta amyloid after eight weeks of a high cholesterol diet. These animals also had other pathological changes that were associated with AD – including microgliosis, elevated caphepsin D, elevated free radicals, and vascular inflammation, he noted.
In a subsequent experiment, the rabbits were divided into two groups: one group received another two weeks of a high cholesterol diet while the other group was fed a normal diet after eight weeks of a high cholesterol diet. A 50 percent reduction in beta amyloid was found in the animals on a normal diet, “showing that elevation of beta amyloid related to high cholesterol levels was reversible,” said Dr. Sparks.
Lorenzo M. Refolo, PhD, and his colleagues have examined the role of statins in three separate studies in transgenic mouse models of AD. (The mice were genetically engineered to overproduce amyloid). They wanted to see if amyloid beta-peptide deposition could be modulated by diet-induced hyper-cholesterolemia.
The first study showed that a high-cholesterol diet accelerated amyloidosis in these animals (Neurobiol Dis 2000; 7 (4): 321–331). The diet-induced hypercholesterolemia resulted in significantly increased levels of amyloid beta peptides in the central nervous system.
The researchers concluded that high dietary cholesterol increases amyloid beta accumulation and accelerates the AD-related pathology observed in animal models.
In the second study, Dr. Refolo and his colleagues showed that treatment with a cholesterol-lowering compound (BM15.766) achieved a significant reduction of amyloid in the brains of transgenic mice (Neurobiol Dis 2001; 8 (5): 890–899).
“This was a proof of concept study. I used BM15.766 because it is known to lower cholesterol in mice, and, at the time, we did not know whether a statin would lower cholesterol in mice,” Dr. Refolo told Neurology Today.
In the third study (unpublished), atorvastatin was given to transgenic mice. “This compound reduced total cholesterol as well as the amount of amyloid in the brains of these animals,” he noted. Basic studies of statins in transgenic mice are ongoing at the Nathan Kline Institute, Dr. Refolo said.
However, Dr. Refolo was cautious about making the leap from mice to humans. “Just because we can cure mice of amyloid using a statin, doesn't mean we can cure people with Alzheimer disease,” Dr. Refolo continued. “Based on the epidemiological and animal data, I believe the statins are worthy of study, but it is important to select the right study population — that is, people who have very early Alzheimer disease or who are at risk. Even people with moderate Alzheimer may have brains that are too severely deteriorated to be helped by statin therapy,” he said.
Two large epidemiological studies suggested that statins reduce the incidence of AD and dementia – one published in Lancet and the other in the Archives of Neurology.
The Lancet study by Hershel Jick, MD, of Boston University, and his colleagues favored the hypothesis that statins would exert a beneficial effect on the brains of elderly persons by improving the microvasculature and its lining endothelium.
“A key primary motivating factor for conducting the study was the observation that the cerebral microvessels in AD are atrophic and tortuous, and statins improve the health of the microvasculature and blood flow by increasing endothelial nitric oxide synthase and reducing endothelin-1,” David Drachman, MD, explained.
The Lancet study, published in November 2000, reported that individuals age 50 and older who were taking a statin had a substantially lower risk of developing dementia, compared with individuals with normal lipid levels, patients with untreated hyperlipidemia, or those exposed to nonstatin lipid-lowering agents.
The study was based on a nested case-control study of 60,000 people derived from the British General Practice Research Database.
Of this population, about 25,000 were taking a statin or another lipid-lowering drug; about 25,000 had normal lipid levels; and about 10,000 had elevated lipids but were not taking drugs, said Dr. Drachman, a senior investigator in the trial, who collaborated with Dr. Jick. Dr. Drachman is Chairman of the Department of Neurology at the University of Massachusetts in Worcester.
Over six years, 284 cases of dementia were identified. The study did not distinguish between AD and other forms of dementia. The dementia cases were matched for age, sex, and number of years in the study with 1,080 controls from the same population.
The researchers found that the risk of developing dementia was not significantly different among individuals with normal cholesterol, untreated hyperlipidemia, or patients taking nonstatin lipid-lowering agents. Patients taking statins, however, had a 70 percent decrease in the relative risk of developing dementia.
EFFECT ON BETA AMYLOID
Another epidemiological study led by Benjamin Wolozin, MD, Associate Professor of Pharmacology at Loyola University Medical Center in Maywood, IL, surveyed a large database of 56,000 people treated at military hospitals to compare patients taking statins with those taking antihypertensive medications (Archives of Neurology 2000; 57 (10): 1439–1443).
A dramatic reduction in the incidence of AD was found in people taking statins compared with those taking medications for hypertension or cardiovascular disease (for example, beta blockers or furosemide), as well as compared with patients not taking any of these medications.
“Beta amyloid causes AD, and the amount of cholesterol in the cell affects the amount of beta amyloid produced in the brain and in the blood,” Dr. Wolozin said in a phone interview. Patients taking a statin had a 60 to 73 percent lower risk of probable AD compared with those taking antihypertensive drugs, he said.
“The findings of these studies point to the same converging data, that statins achieve a beneficial effect by reducing the production of beta amyloid. However, exactly how they do that is not clear.”
There are two types of statins: those that cross the blood-brain barrier and those that do not. Both types have been found to decrease beta amyloid in the brain. There could be several explanations for this somewhat puzzling phenomenon.
Dr. Wolozin suggested that statins lower beta amyloid in the blood, and that the blood acts as a sink, “soaking up beta amyloid from the brain into the serum, where it can be degraded.” It is also possible, but less likely, he said, that statins are acting on cells in the brain vasculature to decrease apolipoprotein-E (APO-E) in the brain, which in turn reduces plaque formation.
STATINS AND COGNITIVE FUNCTION
Matthew F. Muldoon, MD, however, believes the epidemiological studies by Drs. Jick and Wolozin are problematic. Dr. Muldoon, who is Associate Professor of Medicine at the Center for Clinical Pharmacology at the University of Pittsburgh in Pennsylvania, said that both are uncontrolled studies that looked at elderly people being treated with statins. But, he said, most elderly people who receive these drugs are generally healthy and take the drugs for prevention.
“If they had other chronic health problems, their doctor would be paying attention to those and not putting them on a statin. A statin, then, is a marker that the patient is generally healthy – what we call ‘an indication bias,'” Dr. Muldoon said.
Dr. Muldoon led a randomized controlled prospective study, which included healthy adults with hypercholesterolemia. The study looked at 209 adults with hypercholesterolemia treated with lovastatin or placebo (American Journal of Medicine 2000; 108: 538–547). Five domains of cognitive function were assessed at baseline and again at six months. The study showed that although lovastatin did not cause psychological distress or substantially alter cognitive function, people treated with lovastatin exhibited small performance decrements in two of five cognitive domains – in tests of attention and psychomotor speed – compared with placebo.
Dr. Muldoon urged caution in jumping to conclusions about the neuroprotective effects of statins. “Much attention has been focused on statins and their presumed ability to protect against AD,” he said. “However, no randomized controlled trials to date suggest that that is true, and our study would suggest otherwise. The hypothesis may prove to be correct, but at this point, no trials show that statins improve cognitive performance or protect against AD.”
Dr. Muldoon and colleagues are conducting another trial to assess the dose-response effects of statins on cognitive function in patients with hypercholesterolemia. That trial, now nearing completion, includes about 300 patients with an average age of 52 and hypercholesterolemia randomized to low-dose simvastatin, high-dose simvastatin, or placebo.
“This study is a safety check on whether there are negative effects on the brain of lowering cholesterol. Our hypothesis is that there is a downside to lowering cholesterol in the brain,” said Dr. Muldoon.
ATORVASTATIN AND AD
Dr. Sparks is the principal investigator of a current prospective study of the cholesterol-lowering agent atorvastatin in the treatment of AD. The study —which is being funded in part by the Institute of Aging in New York City — is a three-year, single-site, placebo-controlled trial with a planned enrollment of 120 patients. Thus far, 81 patients have been enrolled. The patient population includes people over the age of 51 with a prior diagnosis of AD, excluding other disorders, such as Lewy body disease.
“A new feature of this study is that patients can remain on any of the three approved drugs for AD,” Dr. Sparks noted. “Thus, the placebo patients will receive the standard of care and will be no different from patients at home on prescribed drugs for AD.”
If individuals complete the 12-month double-blind study, they have the option of continuing in a one-year open-label trial with the active drug. During this time, patients will be monitored for safety and cognitive effects.
Dr. Sparks explained that the goal of statin therapy is to eliminate cholesterol in the blood. He chose to use atorvastatin because he believes it is the safest of the statins, since it does not cross the blood-brain barrier and does not inhibit cholesterol synthesis in neurons and other cells in the brain.
Another large, placebo-controlled study funded by the National Institutes of Health (NIH) will assess the role of anti-inflammatory agents in prevention of AD. This trial is called the ADAPT (Alzheimer Disease Anti-inflammatory Prevention Trial). The study will include 2,625 persons older than 70 years who are cognitively normal but have a first-degree relative with AD-like dementia. Placebo will be compared to two different nonsteroidal anti-inflammatory agents. Patients enrolled in ADAPT can be on a statin as well.
Dr. Sparks is the principal investigator of an ancillary study called ADAPT: Cholesterol and Statin Parameters. “This study will provide a real-time analysis of statin use,” Dr. Sparks explained. “We will know who is on a statin when the patient walks through the door, and we'll know which statin he or she is taking,” he said.
Dr. Sparks will monitor cholesterol levels and statin use in ADAPT patients over a seven-year period. He plans to analyze the effects of different statins and determine whether all statins — those that cross the blood-brain barrier and those that do not — have similar effects.
Dr. Sparks' personal bias is that only the statins that do not cross the blood-brain barrier will be preventive against AD. “All the statins will lower cholesterol in the blood, and that is good. But direct cholesterol synthesis inhibition in the brain might be deleterious,” he speculated.
A second treatment trial conducted by the AD Cooperative Study (ADCS) group will begin enrollment soon. This is the first NIH-sponsored treatment trial of statins in AD and will probably be the first multicenter study to be conducted, said Mary Sano, PhD, Associate Professor of Neuropsychology at Columbia University College of Physicians and Surgeons. Dr. Sano, who is affiliated with the neurology department of Columbia Presbyterian Medical Center in New York City, is the principal investigator of the ADCS.
The ADCS is a one-year, placebo-controlled study with a planned enrollment of 300 patients from 20 centers in the US, Dr. Sano explained. The study population will include patients with mild to moderate AD, as exemplified by a Mini-Mental Status Exam (MMSE) score of 12 to 26, all of whom will have normal lipid levels. Subjects will be allowed to continue on their usual AD medications and then randomized to placebo or a statin.
The choice of statin has not yet been made, Dr. Sano said. However, an advisory committee comprised of AD and lipidology experts recommended that the statin be one that crosses the blood brain barrier and is centrally acting. This recommendation is based on a large body of data on centrally-acting statins demonstrating good safety with no serious central nervous system (CNS) side effects. Statins that are centrally-acting include lovastatin and simvastatin.
“The statins that do not cross the blood-brain barrier [for example, atorvastatin] have less exposure in randomized controlled trials and there are fewer data regarding their CNS effects,” Dr. Sano said.
The ADCS is not an industry-supported trial. “The nuance of this is that the trial is independent of pharmaceutical sponsorship, and results will be from a trial conducted by experts in AD,” she added.
THE PROSPER STUDY
PROSPER (Prospective Study of Pravastatin in Elderly Risk) will be the first large, prospective double-blind study to assess cognitive function and document the development of dementia in patients taking a statin – in this case, pravastatin.
PROSPER, begun in 1998 and to be completed during 2002, includes 5,804 people – aged 70 to 82 years – who have evidence of vascular disease or are at high risk of vascular disease, including, for example, cigarette smokers or people who have hypertension. Patients from three different centers - Cork in Ireland, Glasgow, and Leiden in The Netherlands – have been randomized to receive either pravastatin 40 mg per day or placebo.
The principal investigator of the PROSPER trial is James Shepherd, MD, Professor of Biochemistry at the University of Glasgow in Scotland.
Once they are enrolled in the trial, a battery of tests for cognitive function is given at baseline and annually throughout the four-year study. Additionally, a cohort of just fewer than 1,000 patients enrolled in Leiden will undergo MRI brain scans at baseline and at the end of the study.
PROSPER is not a study of the effects of statins on AD, Dr. Shepherd explained. The trial was designed to look at whether pravastatin can reduce cerebral ischemia and improve or preserve cognitive function in the elderly. “Cognitive function could be improved without improving AD,” Dr. Shepherd commented.
“This study will show whether healthy people who take statins will have fewer myocardial infarctions, strokes, and less cognitive deterioration. The study will not show specifically whether a statin has on impact on AD or on other causes of mental deterioration, such as multi-infarct dementia. In the pre-mortal state, we can't tell which patients have AD in the study, but we can identify strokes as a cause of mental deterioration in some of the patients.”
Dr. Shepherd suggested that if the results of PROSPER turn out to be positive for cognitive function, then researchers might want to identify people with early AD in their late 40s and 50s and study the effects of statins in this group. However, Dr. Shepherd said that people with symptoms of AD may have deteriorated to a point beyond which they can benefit from treatment.
WHAT THE RESEARCH MEANS
Can the field expect to see more large randomized trials looking at statins and AD in the future? Yes, according to the researchers interviewed for this article. Said Dr. Refolo: “I believe the data for cholesterol-lowering drugs are at least as promising as the data on vaccines for AD. I await the results of the randomized controlled treatment trials conducted by Dr. Sparks and the ADCS. Hopefully, the trials will include patients with early or mild AD and not just select people whose brains have already become severely deteriorated. If one statin works, then all statins may work. My bias is that what is important [in AD] is to lower cholesterol and to lower brain amyloid.”