Higher HDL-C Levels May Curb Alzheimer's Disease Risk

Megan Brooks

December 16, 2010

December 16, 2010 — High levels of high-density lipoprotein cholesterol (HDL-C) may help protect older adults from late-onset Alzheimer's disease (AD), researchers report in the December issue of Archives of Neurology.

Dyslipidemia and late-onset AD are common in older adults in Western populations, Christiane Reitz, MD, PhD, and colleagues from Columbia University's Taub Institute for Research on Alzheimer's Disease and the Aging Brain in New York City, note in their report. Yet, despite numerous studies, it remains unclear whether dyslipidemia increases the risk for AD.

The new study examined the association of lipid profiles and AD in 1130 Medicare recipients 65 years and older with no history of dementia or cognitive impairment at baseline, 1999 through 2001.

During 4469 person-years of follow-up, clinicians diagnosed 89 cases of probable AD and 12 cases of possible AD. The mean age at onset of probable and possible dementia was 82.9 years and 83.1 years, respectively. Compared with subjects who did not develop dementia, those who did were more often Hispanic and had a higher prevalence of diabetes at baseline.

Higher levels of HDL-C (defined as >55 mg/dL) were associated with a decreased risk for both probable and possible AD after multivariate adjustment for confounding factors. There was a definite threshold effect, the researchers say, with a clear reduction in AD risk for people in the highest HDL-C level quartile (>56 mg/dL).

Table. Quartiles of Plasma HDL-C Levels and Risk for Incident Alzheimer Disease

HDL-C Quartile Hazard Ratio (95% CI) P Value
1 (≤38.00 mg/dL) 1 (Reference) 1 (Reference)
2 (38.01 – 46.00 mg/dL) 0.8 (0.4 – 1.5) .43
3 (46.01 – 56.00 mg/dL) 1.1 (0.6 – 1.9) .9
4 (>56.00 mg/dL) 0.4 (0.2 – 0.9) .03
P value for trend   .1

Hazard ratios adjusted for age, sex, education, ethnic group, APOE e4 genotype, and vascular risk factors (diabetes, hypertension, heart disease, body mass index, and lipid-lowering treatment). CI = confidence interval; HDL-C = high-density lipoprotein cholesterol

Higher levels of total cholesterol, non–HDL-C, and low-density lipoprotein cholesterol were also associated with decreased risk for AD in analyses adjusting for age, sex, education, ethnic group, and APOE e4 genotype. However, these associations became nonsignificant after adjusting for vascular risk factors or lipid-lowering treatment.

Results of additional analyses relating lipid levels to vascular dementia also suggested that a higher HDL-C level was associated with a lower risk for vascular dementia. The hazard ratio for the highest HDL-C quartile was 0.4 (95% confidence interval, 0.1 – 2.3). The researchers emphasize, however, that these analyses were limited by the small number of cases of vascular dementia (n = 16).

Contrasting Findings

The findings of the current study linking higher HDL-C to a lower risk for incident dementia contrast with a prior study by the same researchers. This earlier study involved 1168 participants recruited from the same community in 1992 – 1994 and showed no association between HDL-C and AD (Reitz et al. Arch Neurol. 2004;61:705-714).

The investigators think "period effects" are likely the reason for the difference between the 1992 – 1994 cohort and the 1999 – 2001 cohort. In 1994, they explain, the landmark Scandinavian Simvastatin Survival Study (4S) was published, which sparked widespread use of β-hydroxy-β-methylglutaryl-CoA reductase inhibitors (statins).

Compared with the 1992 – 1994 cohort, the 1999 – 2001 cohort had a higher proportion of subjects receiving lipid-lowering treatment (23.4% vs 14.5%), higher mean HDL-C levels (48.3 vs 47.2 mg/dL), and fewer individuals who smoked (9.4% vs 10.6%) and had heart disease (18.8% vs 34.1%).

The differences in characteristics between the 2 cohorts, they note, are in line with the secular trends in better cardiovascular health and use of lipid-lowering statins in the most recent cohort. "We believe that this is why the inverse relation of HDL-C level with AD risk was not statistically significant in the 1992 – 1994 cohort and is significant in the 1999 – 2001 cohort," they write.

Strengths of the current study include its prospective design and use of sensitive measures of cognitive change in several specific domains, including memory. A limitation is obtaining only 1 measurement of lipid levels.

Because this was an urban, multiethnic, elderly cohort with a high prevalence of risk factors for mortality and dementia, the results may not be generalizable to cohorts with younger individuals or to cohorts with participants with a lower morbidity burden, they note.

The study was supported by grants from the National Institute on Aging, the Charles S. Robertson Memorial Gift for Research in Alzheimer's Disease, and the Blanchette Hooker Rockefeller Foundation. The authors have disclosed no relevant financial relationships.

Arch Neurol. 2010;67:1491-1497. Abstract


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