Risk factors for cognitive decline in HIV patients

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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 patients with a suppressed viral load.

This is according to US research led by Dr Dana Gabuzda, department of cancer immunology and virology, Dana Farber Cancer Institute, Centre for Life Science.

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 patients 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 patients 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, 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.”

The proportion of HIV-positive patients 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 HIV-infected population 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 patients 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.

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. Patients and controls 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 tests scores suggesting depressive symptoms (p = 0.08).

Patients 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 patients remained significant in an analysis that excluded patients with evidence of cognitive impairment at baseline and also in an analysis restricted to patients with sustained viral suppression below 50 copies/ml.

In patients 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.”

Abstract
Background.Dyslipidemia and apolipoprotein E4 ( APOE ϵ4) allele are risk factors for age-related cognitive decline, but how these risks are modified by human immunodeficiency virus (HIV) infection is unclear.
Methods.In a longitudinal nested study from the Multicenter AIDS Cohort Study, 273 HIV type 1–infected (HIV +) men aged 50–65 years with baseline HIV RNA 12 years. HIV+ men had similar baseline total cholesterol and LDL-C, but lower HDL-C and higher triglycerides than controls (P < .001). Higher total cholesterol and LDL-C were associated with faster rates of cognitive decline (P < .01), whereas higher HDL-C attenuated decline (P = .02) in HIV+ men. In HIV+ men with elevated cholesterol, statin use was associated with a slower estimated rate of decline (P = .02). APOE ϵ4 genotype accelerated cognitive decline in HIV+ but not HIV– men (P = .01), with trajectories diverging from HIV– ε4 carriers after age 50. Total cholesterol levels did not modify the association of ϵ4 genotype with decline (P = .9). Conclusions.Elevated cholesterol and APOE ϵ4 genotype are independent risk factors for cognitive decline in ART-adherent HIV+ men aged >50 years. Treatment of dyslipidemia may be an effective strategy to reduce cognitive decline in older HIV+ individuals.

Authors
Shibani S Mukerji, Joseph J Locascio, Vikas Misra, David R Lorenz, Alex Holman, Anupriya Dutta, Sudhir Penugonda, Steven M Wolinsky, Dana Gabuzda

Aidsmap material
Clinical Infectious Diseases abstract


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