Midlife Vascular Risk Factors and Late-Life Mild Cognitive Impairment

Abstract & Commentary

Source: Kivipelto M, et al. Neurology. 2001;56:1683-1689.

Age-related cognitive decline or mild cognitive impairment (MCI) has attracted medical attention because of its relationship to Alzheimer disease (AD). Petersen and associates noted an annual conversion to AD in 10-12% of MCI subjects compared to a conversion rate of only 1-2% in the normal elderly population (Petersen RC, et al. Arch Neurol. 1999;56:303-308). There also is evidence that a relationship exists between hypertension and hypercholesterolemia and late-life cognitive decline (Launer LJ, et al. JAMA. 1995;274:1846-1851; Kilander L, et al. Hypertension. 1998;31:780-786; Carmelli D, et al. Neurology. 1998;50:1580-1585).

Kivipelto and colleagues evaluated the effect of midlife elevated serum cholesterol levels and blood pressure on the subsequent development of MCI in a Finnish population. Subjects were derived from random population-based samples from surveys carried out from 1972 to 1987. After an average follow-up of 21 years, more than 1400 subjects aged 65-79 were re-examined in 1998. Subjects scoring < 24 on the MMSE (n = 280) were invited to participate in further testing that included thorough medical and neurological examinations and detailed neuropsychological evaluation. MCI was diagnosed according to criteria devised by the Mayo Clinic Alzheimer Disease Research Center (Petersen RC, et al. JAMA. 1995;273:1274-1278). By applying these criteria the prevalence of MCI in this population was 6.1% (n = 82), after excluding subjects with other health problems that may have had a direct impact on cognitive, the prevalence was 4.8% (n = 64). In these subjects, a high serum cholesterol level (> 6.5 mmol/L) at midlife was a significant risk factor for MCI (odds ratio 1.9; 95%; CI, 1.2-3.0). Subjects with MCI tended to have higher systolic blood pressure (SBP) at midlife than controls, and the distribution of SBP values was wider among MCI than control subjects. High midlife SBP approached, but did not reach, significance as a risk for MCI. Sixty-one percent of subjects with MCI had either elevated serum cholesterol or high SBP at midlife. There was no significant difference in the prevalence of cardiovascular or cerebrovascular disease between MCI and control subjects.

Kivipelto et al found a dose-response relationship between elevated cholesterol and SBP at midlife and severity of cognitive decline in late life. At midlife, subjects with MCI had cholesterol and SBP levels that were higher than those of control subjects but lower than those who developed dementia. This graded association may indicate a causal relationship between midlife hypercholesterolemia and systolic hypertension and the severity of late-life cognitive impairment.


As the proportion of the elderly increases in the population, so must the number of patients with AD. In the absence of a cure for the condition, any interventions that might delay its onset would have huge public health benefits.

Kivipelto et al have highlighted the relationship between vascular factors, especially hypercholesterolemia and cognitive impairment. These factors may simply increase the risk of dementia by inducing cerebrovascular atherosclerosis and impairing cerebral blood flow. Recently, however, the possible biologic mechanisms whereby elevated serum cholesterol could cause cognitive decline have been studied. Cholesterol modulates the metabolism of amyloid precursor protein in cell cultures, (Bodovitz S, Klein WL. J Biol Chem. 1996; 271:4436-4440) and depletion of intraneuronal cholesterol inhibits the production of ß-amyloid in vitro (Simons M, et al. Proc Natl Acad Sci USA. 1998;95: 6460-6464). Therefore, it is possible in patients with hypercholesterolemia that increased levels of CNS cholesterol could accelerate the accumulation of ß-amyloid plaques and the development of AD. If this is so, then the benefits of treatment of hypercholesterolemia with statins may be more far-reaching and important than previously appreciated. —John J. Caronna

Caronna, MD, Vice-Chairman, Department of Neurology, Cornell University Medical Center, and Professor of Clinical Neurology, New York Hospital, is Associate Editor of Neurology Alert.