PHILADELPHIA—“We have moderate evidence linking high serum cholesterol at midlife to an increased risk of Alzheimer’s disease later in life, but the role of high cholesterol at late life is still unclear. We have some evidence that dietary fat intake plays a role, and some evidence that statins may reduce the risk or be beneficial in the treatment of Alzheimer’s disease. We have strong biological evidence and experimental studies supporting the association. We need more research in all these areas to find out whether and how cholesterol is associated with dementia,” Miia Kivipelto, MD, PhD, said at the Ninth International Conference on Alzheimer’s Disease and Related Disorders. “High cholesterol is a common but modifiable risk factor, and we have many means available to prevent and treat it—both nonpharmacologic and pharmacologic.”

A LINE OF EVIDENCE

Dr. Kivipelto asserted that the association between low cholesterol and Alzheimer’s disease is not surprising, since the brain is the most cholesterol-rich organ in the body, and cholesterol plays roles in many brain functions. “In experimental studies, disturbances in brain-lipid homeostasis have been associated with all the major neuropathologic aspects of Alzheimer’s disease, including ß-amyloid formation and accumulation, hyperphosphorylation of tau protein, impaired synaptic plasticity, and neuronal degeneration,” she said.

Genetic evidence also links lipids to Alzheimer’s disease. For example, Dr. Kivipelto said, the apolipoprotein E (APOE) ε4 allele that is the most important genetic risk factor for Alzheimer’s disease also plays a central role in lipid metabolism. Further, polymorphism in gene coding for cholesterol 24-hydroxylase, which mediates removal of cholesterol from the brain, has been associated with an increased risk of Alzheimer’s disease in some recent studies.

Evidence that has attracted more attention links high serum cholesterol levels to Alzheimer’s disease. “We have some studies showing that high serum cholesterol at midlife increases the risk of Alzheimer’s disease 20 to 25 years later. Other recent studies indicated that midlife elevated serum cholesterol is associated with amyloid plaques and neurofibrillary tangles at autopsy,” Dr. Kivipelto said.

The role of high cholesterol levels in late life is less clear. One recent study found no association between either high serum lipid levels at age 76 or life-long lipid exposure and Alzheimer’s disease, Dr. Kivipelto said. Another study found an inverse association between lipid levels in persons ages 70 to 79 and development of Alzheimer’s disease up to 20 years later. Results from studies with shorter follow-up times (two to seven years) have yielded inconsistent results, she noted.

One factor in these discrepancies may be the decline in serum cholesterol levels that occurs during aging, Dr. Kivipelto speculated. Alzheimer’s disease changes in the brain may start to develop 20 to 30 years before the manifestation of dementia; long-term follow-up studies may be required to assess the role of high serum cholesterol levels as a risk factor for Alzheimer’s disease, she said.

FINNISH FINDINGS

Dr. Kivipelto, a Postdoctoral Fellow at the Aging Research Center, Karolinska Institutet, and at the Karolinska University Hospital, Huddinge, Sweden, and colleagues have been working on a long-term, longitudinal, population-based study in eastern Finland (Cardiovascular Risk Factors, Aging, and Dementia study [CAIDE]) with subjects who were first evaluated in 1972, 1977, 1982, or 1987—when they were approximately age 50—and followed for an average of 21 years. A random sample of 2,000 persons were invited for reexamination in 1998, and nearly 1,500 persons participated.

“We found altogether 117 dementia cases from this population. As expected, we found that APOE ε4 was a significant risk factor for Alzheimer’s disease. Adjustment for a large number of potentially confounding factors including midlife cholesterol did not change the association, which had an odds ratio of 2.1.” Midlife cholesterol higher than 6.5 mmol/L was a significant risk factor for Alzheimer’s disease, and adjustment for APOE ε and other confounders did not change the association; the odds ratio was still 2.8. High systolic blood pressure was also a significant risk factor for Alzheimer’s disease, she noted.

“Based on these results, we concluded that APOE ε4, elevated midlife cholesterol, and high midlife systolic blood pressure are all independent risk factors for Alzheimer’s disease, and that the combination of these risk factors increased the risk in an additive manner. The risk of Alzheimer’s disease related to the treatable factors of elevated cholesterol and blood pressure appeared to be greater than the risk related to APOE ε4 in this population,” Dr. Kivipelto said.

The researchers also found that serum cholesterol values declined during the follow-up from midlife to late life among all the participants but declined more rapidly among those who later developed Alzheimer’s disease.

DIET AND DEMENTIA

The next question was whether dietary fat intake was associated with Alzheimer’s disease. “It could be hypothesized that saturated fat intake increases the risk and unsaturated fat intake decreases the risk of Alzheimer’s disease,” Dr. Kivipelto said. “There are some studies showing this kind of association but others showing the opposite or no association. The limitation in all these studies was the short follow-up time, which makes these studies quite prone to bias. Because of subclinical dementia, poor dietary habits could be a consequence, not a cause, of this cognitive decline,” Dr. Kivipelto said.

A recent analysis of dietary data from the CAIDE study showed an association between fat intake and serum cholesterol levels such that persons using more saturated fats had higher serum cholesterol and those using more polyunsaturated fats had lower serum cholesterol. “We also found that saturated fat intake increased the risk of dementia and of Alzheimer’s disease with an odds ratio of nearly two, and polyunsaturated fat intake decreased the risk of dementia and Alzheimer’s disease with an odds ratio of 0.4,” Dr. Kivipelto said.

Based on this, she suggested that high serum cholesterol levels at midlife play an important role in the development of Alzheimer’s disease and that new risk factors for Alzheimer’s disease should include high fat intake, high body mass index, and physical inactivity at midlife. “These factors tend to be interrelated and often associated with dyslipidemia and may at least partly mediate the effects on dementia through high serum cholesterol,” she said.

A possible mechanism by which high cholesterol leads to Alzheimer’s disease might involve high serum cholesterol–mediated vascular changes that impair cognition and trigger neuronal degeneration. It was thought that serum lipid levels and brain lipid levels were independent pools, but Dr. Kivipelto said that recent experimental data suggest some signaling or exchange systems between these pools. One example of this was a recent study pointing to a correlation between low serum HDL cholesterol and hippocampal atrophy, which suggests that high serum HDL may be protective against hippocampal atrophy.

REDUCING THE RISK

The final question Dr. Kivipelto addressed was whether lipid-lowering agents reduce the risk of Alzheimer’s disease. She said that the available studies all have some methodologic limitations. “The Heart Protection Study is the only randomized study with statins that has dementia as an outcome, and follow-up time is quite short. I was surprised that the occurrence of dementia was very low. There were only 60 new cases of dementia, which is 0.3%, and I would have expected at least 10 times more. That makes this study quite underpowered to detect any differences in dementia as an outcome.”

Two pilot studies have suggested that statins could be useful in the treatment of Alzheimer’s disease; confirmatory trials are ongoing, Dr. Kivipelto noted. “Based on our own data, I would suggest that primary prevention and early treatment are important for the prevention of Alzheimer’s disease,” she concluded.

NR

—Janis Kelly

Suggested Reading
Kivipelto M, Helkala EL, Laakso MP, et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer’s disease. Ann Intern Med. 2002;137:149-155.
Kivipelto M, Laakso MP, Tuomilehto J, et al. Hypertension and hypercholesterolaemia as risk factors for Alzheimer’s disease: potential for pharmacological intervention. CNS Drugs. 2002;16:435-444.
Wolf H, Hensel A, Arendt T, et al. Serum lipids and hippocampal volume: the link to Alzheimer’s disease. Ann Neurol. 2004;56:745-749.

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