Elevated lipids associated with cognitive decline in middle-aged HIV-positive men doing well on ART

Statin use slows rate of cognitive decline
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Elevated cholesterol and a gene associated with Alzheimer’s risk in the general population are both risk factors for cognitive decline in middle-aged HIV-positive people with a suppressed viral load, according to US research published in the online edition of Clinical Infectious Diseases.

The longitudinal observational study involved 273 HIV-positive individuals and 516 matched HIV-negative controls. Higher cholesterol and LDL cholesterol were associated with faster cognitive decline in people with HIV and the presence of the APOE ε4 genotype accelerated cognitive decline in HIV-positive but not HIV-negative men. Statin use lessened the effect of elevated cholesterol on cognitive decline in people with HIV.

“These findings suggest that control of dyslipidemia may reduce the risk of midlife cognitive decline in aging PLWH [people living with HIV] on ART [antiretroviral therapy], and the APOE ε4 genotype likely influences cognitive trajectories via mechanisms distinct from its effect on lipid metabolism,” comment the researchers. “For every 10mg/dl increase in cholesterol or LDL between the ages 50-65, the rate of cognitive decline among HIV+ men increased.”



A waxy substance, mostly made by the body and used to produce steroid hormones. High levels can be associated with atherosclerosis. There are two main types of cholesterol: low-density lipoprotein (LDL) or ‘bad’ cholesterol (which may put people at risk for heart disease and other serious conditions), and high-density lipoprotein (HDL) or ‘good’ cholesterol (which helps get rid of LDL).


A blood fat (lipid). High levels are associated with atherosclerosis and are a risk factor for heart disease.



Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.


Abnormal levels of lipids (fats), including cholesterol and triglycerides, in the blood.


In a case-control study, a process to make the cases and the controls comparable with respect to extraneous factors. For example, each case is matched individually with a control subject on variables such as age, sex and HIV status. 

The proportion of HIV-positive people aged over 50 years is growing and the diseases of older age are now a leading cause of illness among HIV-positive individuals. A large proportion of the older population living with HIV have elevated cholesterol and triglycerides, known risk factors for cognitive decline in the general population.

The APOE ε4 genotype is the most important genetic risk factor for Alzheimer’s disease and is also a risk factor for age-related cognitive decline in the general population. However, its role in cognitive decline and interaction with lipids in HIV-positive people has been little studied.

Investigators from the MACS study designed a study to assess the longitudinal effects of dylipidemia and the APOE ε4 genotype on cognitive decline in middle-aged HIV-positive men who have sex with men adherent to ART with a viral load below 400 copies/ml. The study excluded people who were regular users of heroin, cocaine or crack cocaine.

A total of 273 people with HIV were matched with 516 HIV-negative controls also being followed in the cohort. Lipid profiles – total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides – were measured and participants were tested for the APOE ε4 genotype. All study participants underwent a battery of tests at baseline and during follow-up to assess cognitive function.

Median age at study entry was 51 years and the mean duration of follow-up was a little over six years. The majority of participants (81%) were white. Education levels were similar between the HIV-positive and HIV-negative participants, but individuals with HIV were somewhat more likely to have test scores suggesting depressive symptoms (p = 0.08).

Participants with HIV had a median CD4 count at baseline of 514 cells/mm3 and 70% had a viral load below 50 copies/ml.

Baseline cholesterol and LDL cholesterol were similar between both study groups, however, men with HIV had higher triglycerides and lower HDL cholesterol than HIV-negative men (p < 0.001). Half the HIV-positive group had been taking statins for at least a year.

HIV-positive men had a faster rate of cognitive decline compared to the HIV-negative controls (p = 0.003). The impact of cholesterol levels on cognitive decline appeared to emerge at the age of 50 years.

Higher LDL cholesterol and triglycerides were associated with a steeper slope in cognitive decline (p < 0.001), however higher HDL cholesterol lessened the rate of decline in men with HIV (p = 0.02).

Higher cholesterol was associated with a more pronounced decline in attention and working memory (p < 0.001) and also verbal memory (p = 0.05).

The association between cholesterol level and cognitive decline in HIV-positive participants remained significant in an analysis that excluded individuals with evidence of cognitive impairment at baseline and also in an analysis restricted to people with sustained viral suppression below 50 copies/ml.

In people with HIV, the cognitive decline associated with elevated cholesterol was attenuated by statin use (p = 0.0019).

Baseline analysis showed that HIV-positive carriers of the APOE ε4 genotype had significantly higher triglyceride levels (p < 0.001). Once again, the effect emerged at around the age of 50 years.

The rate of cognitive decline was accelerated among HIV-positive carriers of ε4 (p = 0.001). On average, cognitive decline began to accelerate around a decade earlier in this group compared to HIV-negative carriers of the gene.

Further analysis suggested that lipids and the ε4 genotype had independent effects on cognitive decline, so that having high cholesterol levels did not further exacerbate the effect of the ε4 genotype.

“Our findings suggest that clinical management of dyslipidemia with statins in ART-adherent HIV+ individuals may reduce the risk of midlife cognitive decline, and a window of opportunity likely occurs between ages 50-65,” conclude the investigators. “Given impressive efforts that have improved survival among HIV+ individuals, this study underscores the importance of lipid profiles and APOE ε4 allele to midlife cognitive health in aging HIV+ adults and suggests that clinical management of dyslipidemia may be an effective adjunctive strategy to reduce cognitive decline in ART-treated HIV+ individuals.”


Mukerji SS et al. Lipid profiles and APOE4 allele impact midlife cognitive decline in HIV-infected men on antiretroviral therapy. Clin Infect Dis, online edition, 2016.