Background
Epigenetic studies have shown an accelerated epigenetic age phenotype in people with HIV (PWH). Accelerated epigenetic age has been linked to various disease outcomes including cognitive dysfunction. However, whether epigenetic age estimates predict cognitive measures in PWH remains understudied.
Methods
PWH age 50 and older were recruited at an urban academic medical. Participants provided a blood sample at the baseline visit between 2016-2019, and epigenetic age was calculated from dried blood spots using first, second, and third generation epigenetic clocks. Participants then completed a follow-up visit including cognitive testing between 2022-2023. Timed outcomes were log transformed and reverse scored, so higher scores equated to better performance. We conducted dimension reduction on the cognitive outcome measures using Principal Components Analysis (with varimax rotation) which resulted in the following Rotated Components(RCs): learning and memory, verbal fluency, visual search, processing speed, executive function/working memory, and cognitive control/inhibition. Associations between epigenetic age and RCs were examined using partial correlation analyses accounting for sex, education, and CD4:CD8 ratio.
Results
In total, 87 participants had measurement of baseline epigenetic age and completion of a follow up cognitive battery a median of 58 months [IQR: 53-63] later. The study population had a median age of 60 years (IQR:57.0,65.0), 39% female, and 42% identified as Black. First generation Horvath1 (r=0.30, p<0.01) and Horvath 2 (r= 0.31, p<0.01) residuals were associated with better processing speed. Second generation epigenetic clocks showed that greater PhenoAge (r= -0.23, p= 0.04) and GrimAge (r= 0.30, p=0.007) residuals were associated with poorer learning and memory. GrimAge residuals were also associated with better processing speed (r=0.24, p=0.026). The third generation epigenetic clock DunedinPACE was associated with poorer learning and memory (r= -0.26, p= 0.02) [Figure].
Conclusions
In this longitudinal study of a diverse cohort of older PWH, first generation clocks were associated with processing speed, second and third generation epigenetic aging clocks associated with poor learning and memory performance a median time of 5 years later. Epigenetic clocks may be a key predictive biomarker of cognitive performance spanning multiple domains in older PWH and warrant further study.
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