The Tangled Neuron

Cholesterol, Statins and Alzheimer's: Part 3 of 3

Summary: A new study shows that a decline in total cholesterol may be associated with the early stages of dementia. More research is needed to understand what this means.

When Dad was in his mid-60’s, the results of his annual physicals were straight out of an advertisement about healthy aging. His weight and blood sugar were normal, and his blood pressure and cholesterol were low.

Now it seems Dad’s low cholesterol levels weren’t such a good sign after all. Some research links high cholesterol in mid-life to increased risk of heart problems and dementia. But later in life, low cholesterol levels, not high, are linked to increased risk of dementia and even death.

A new study, published in the Archives of Neurology, shows that a decline in total cholesterol may be associated with the early stages of dementia. Researchers at King’s College London Institute of Psychiatry looked at 26 years of total cholesterol readings for over 1000 Japanese American men participating in the Honolulu-Asia Aging study. They found that “cholesterol levels in men with dementia, and, in particular, those with Alzheimer disease had declined at least 15 years before the diagnosis and remained lower than cholesterol levels in men without dementia throughout that period.”

What do the results of this study mean? I fired off a list of questions to the study’s lead author, Dr. Robert Stewart, Head of Section of Epidemiology at the Institute of Psychiatry at King’s College.

Robert Stewart, MD, MRCPsych

Q: Should Dad have been worried about his low cholesterol readings? Could the drop in cholesterol seen in the new study be a “biomarker” for Alzheimer’s or dementia?

Dr. Stewart: This is a possibility. However, the drop in cholesterol in our study occurred quite a long time before the onset of dementia and so you would have to wait a long time to know if such a ‘biomarker’ was accurate. This is a finding that needs further investigation.

Q: Did the men in the Honolulu-Asia Aging Study who developed dementia have high cholesterol levels at the beginning of study?

Dr. Stewart: The analysis was designed to measure change in cholesterol over time, so it’s not strictly possible to comment on differences in initial levels. There have been a few studies which have suggested that high cholesterol levels in middle age may predict a higher risk of developing dementia later on in life, but this is still a slightly controversial issue.

Q: Is a drop in cholesterol an underlying cause of dementia and death, or simply a sign of some disease process such as heart disease or a disease process in the brain?

Dr. Stewart: We really can't be sure what it was due to. In the paper we mention that a drop in cholesterol can be caused by an inflammatory event or possibly a nutritional deficit, but you are right in that it could be secondary to cardiovascular disease or secondary to some early brain change. We simply don't know and need to investigate this issue further.

Q: Finally, what does this study say about the potential use of statins to treat dementia?

Dr. Stewart: I don't think that our findings have any particular implication for statin trials. It is likely that the drop in cholesterol in our study was secondary to other processes and was not a direct cause of later dementia. It is also highly unlikely that it was related to cholesterol lowering treatment as these medications were not widely available at the early stages of this study when the cholesterol decline occurred.

We may never know whether Dad’s low cholesterol was a bad sign, or whether taking Mevacor affected his dementia. With the ongoing studies on the use of statins to treat Alzheimer’s, and further research into late-life drops in cholesterol, we should have a better picture of the relationship between cholesterol and dementia in the next few years.

Cholesterol, Statins and Alzheimer’s, Part 2 of 3

Summary: In a small pilot trial, Lipitor (a statin), seemed to improve scores on neuropsychological tests, especially for patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation. The results of two large trials of statins for treatment of Alzheimer’s should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias.

In my last post, I wrote how recent research has dampened hopes that the cholesterol-lowering drugs called statins can reduce the risk of dementia. But what about people who’ve already been diagnosed with dementia?

Two large trials of statins to treat Alzheimer’s are underway. Dr. Larry Sparks, Head of the Ralph & Muriel Roberts Laboratory For Neurodegenerative Research at the Sun Health Research Institute in Arizona, is a lead investigator for one of these trials. He’s enthusiastic about exploring the connection between cholesterol and Alzheimer’s.

“Think about it,” Dr. Sparks says. “APOE4 [the genetic variation linked to increased risk of Alzheimer’s] leads to elevated cholesterol. I don’t think cholesterol causes Alzheimer’s, but I believe it negatively influences it, or causes it to progress faster. There’s definitely a vascular influence.”

Earlier in his career, Dr. Sparks was a Medical Examiner in Kentucky. While performing autopsies of non-demented people with coronary artery disease, he noticed they had amyloid plaques similar to those in people who had been diagnosed with Alzheimer’s. Later, working at the Sun Health Research Institute, he found that rabbits fed high cholesterol diets developed amyloid plaques in their brains. This plaque build-up was reversed when the cholesterol was removed from the rabbits’ diet.

Now, in a small pilot trial, Dr. Sparks and his colleagues have shown that a statin called Lipitor may actually improve scores on neuropsychological tests for some people with Alzheimer’s. In an article published last year, they wrote that Lipitor seemed to help the most in patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation.

So reducing cholesterol to treat Alzheimer’s seems logical, right? Nothing is that simple with Alzheimer’s and dementia.

First, some scientists think statins might work by reducing inflammation in the brain, rather than by reducing cholesterol. Second, brain cells produce cholesterol because they need it to function. While bringing down cholesterol levels in the blood might prove helpful for Alzheimer’s, decreasing cholesterol in the brain may harm neurons. Three statins, Mevacor (Lovastatin), Zocor (Simvastatin) and Baycol (Cerivastatin – now off the market in the US) appear to work in the brain as well as in the blood. Two trials at the University of Pittsburgh testing the effects of Mevacor and Zocor on cognitive functioning in people with high cholesterol showed the drugs may have caused a small decrease in performance on some neuropsychological tests. While the effect of these statins on the brain is unknown, Dr. Sparks thinks a safer approach is to influence the brain indirectly by using statins that reduce cholesterol in the blood rather than in the brain.

Finally, a new study shows a late-life drop in cholesterol may actually be associated with an increased risk of Alzheimer’s. I’ll talk about that in my next post.

The results of the two large trials of statins for treatment of Alzheimer’s [CLASP (testing simvastatin or Zocor) and LEADe (testing atorvastatin or Lipitor)] should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias. Dr. Sparks puts it this way: “if you’re sufficiently resilient that you don’t succumb to cardiovascular disease, then you’re looking down the barrel of dementia.”

Cholesterol, Statins and Alzheimer's: Part 1 of 3

Summary: Cholesterol is the Anna Nicole Smith of the Alzheimer’s world – it’s always in the news, and its relationships are hard to understand. High cholesterol in mid-life may be a risk factor for developing dementia. Studies on whether cholesterol-lowering drugs called statins can reduce that risk have had mixed results, with more recent research finding no effect. As with the men claiming to be the father of Ms. Smith’s baby, further tests will determine the role cholesterol-lowering drugs will play.

Going through my father’s medical records, I found a 2004 notation from his first neurologist: The recent total cholesterol (on Mevacor) was only 139 (LDL 81). Therefore, the Mevacor will be decreased to 10 mg. daily beginning today.

Mevacor is a statin, prescribed to lower cholesterol levels. But as far as I know, Dad’s cholesterol was always low – why was he taking Mevacor?

In the last few years, headlines on the use of statins to prevent dementia have swung from wild optimism to flat-out skepticism, and it seems Dad was dragged along for the ride.

In early 2000, when Dad started calling himself “stupid,” Loyola University researchers announced their analysis of hospital records showed patients taking statin drugs had a lower prevalence of probable Alzheimer’s. A paper by Boston University scientists that same year showed that British patients taking statins seemed to have a reduced risk of developing dementia. Dad probably saw the headlines: “Cholesterol drug may prevent Alzheimer’s” and “Statins Take On the Brain: Cholesterol-lowering drugs may also treat or prevent Alzheimer's disease.”

By 2001, he was combing through newsletters from Mayo Clinic and Harvard Medical School looking for ways to improve his memory. That year, Finnish researchers at the University of Kuopio published an article in BMJ that seemed to confirm the Alzheimer’s/cholesterol link. In their study of 1449 Finns followed over 21 years, high cholesterol levels at midlife were a risk factor for Alzheimer’s disease later in life. Shortly after that, studies in several labs showed a relationship between cholesterol and beta amyloid plaques and suggested that, at least in a test tube, high cholesterol leads to increased beta amyloid production. Surely the newsletters Dad subscribed to carried stories about these studies.

In 2003 or 2004, his family doctor must have prescribed Mevacor, but none of us know why. Maybe both Dad and his doctor had read about these studies, and agreed to give a statin a try.

By early 2005, Dad wasn’t reading much at all. But when I called to say hi one day, he was exasperated by a headline he’d seen in the local paper. “Did you see that?” he asked. “Now they say those drugs don’t help your brain.” The story was about a study by Johns Hopkins University researchers. After following approximately 5000 people over a period of five years, they found “no association between statin use and subsequent onset of dementia or AD”. Later that year, University of Washington scientists said that their analysis of statin use and dementia prevalence among 2798 participants in the Cardiovascular Health Study showed the use of statins was not associated with decreased risk of dementia. They wrote that the results of their investigation and similar studies depended on how they looked at the data, and that more research is needed.

After these negative results were published, the excitement about using statins to prevent Alzheimer’s had died down. Dad had stopped taking Mevacor anyway, and had definitely developed dementia.

Although statins may not prevent Alzheimer’s, studies are underway to see if they can be used to treat the disease after onset. I’ll write more about that in my next post.