Apolipoprotein E Genotype Modifies the Association Between Cardiac Output and Cognition in Older Adults

Abstract

BackgroundSubtle reductions in cardiac output relate to lower cerebral blood flow, especially in regions where Alzheimer's disease pathology first develops. Apolipoprotein E (APOE)‐ε4 is a genetic susceptibility risk factor for Alzheimer's disease that also moderates vascular damage. This study investigated whether APOE‐ε4 carrier status modifies the cross‐sectional association between cardiac output and cognition.Methods and ResultsVanderbilt Memory & Aging Project participants free of clinical stroke and dementia (n=306, 73±7 years, 42% female) underwent echocardiography to determine cardiac output (L/min), comprehensive neuropsychological assessment, and venous blood draw to determine APOE genotype and ε4 carrier status. Linear regressions related cardiac output to neuropsychological test performance, adjusting for age, sex, education, race/ethnicity, body surface area, cognitive diagnosis, Framingham Stroke Risk Profile, and APOE‐ε4 status. Main effect models were null (P>0.19). With identical covariates, models were repeated testing a cardiac output×APOE‐ε4 status interaction and again stratified by ε4 carrier status. Cardiac output×APOE‐ε4 status related to naming (β=0.91, P=0.0009), category fluency (β=1.2, P=0.01), information processing speed (β=−5.4, P=0.001), visuospatial skill (β=0.85, P=0.003), and executive function performances (β=0.22, P=0.002). Stratified models suggested that lower cardiac output was associated with worse neuropsychological performances among APOE‐ε4 carriers.Conclusions APOE‐ε4 carrier status appears to modify the cross‐sectional association between cardiac output and neuropsychological performance such that lower cardiac output relates to poorer performances among carriers of the ε4 allele. These findings add to increasing evidence that APOE‐ε4 carrier status has important implications for associations between vascular and brain health in aging adults.

Lower Cardiac Output Relates to Longitudinal Cognitive Decline in Aging Adults

“…Our observations are among the first to extend prior cross-sectional findings that lower resting cardiac output relates to worse cognitive performance in community-dwelling older adults ( Jefferson et al, 2010 ; Sabayan et al, 2015 ; Bown et al, 2019 ) by providing evidence that subtle reductions in cardiac output also relate to faster cognitive decline in domains of language, information processing, visuospatial skill, and episodic memory. Subtle reductions in cardiac output correspond to reduced CBF delivery as recently reported by our group ( Jefferson et al, 2017 ).…”

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“…Cognitive diagnosis did not modify the association between baseline cardiac output and longitudinal neuropsychological performances. These longitudinal null results align with previous cross-sectional null results (Bown et al, 2019) and suggest that reduced cardiac output has a comparable effect on longitudinal cognitive trajectory regardless of cognitive status. The pathology underlying clinical symptoms in MCI may differ from the processes underlying the association between cardiac output and cognitive decline (Ye et al, 2015).…”

“…Cognitive diagnosis did not modify these associations, but a modest 3-way interaction amongst cardiac output, follow-up time, and APOE-ε4 was found, such that lower cardiac output at study entry was associated with worse longitudinal trajectory for information processing speed and episodic memory performances in APOE-ε4 carriers. Our observations are among the first to extend prior crosssectional findings that lower resting cardiac output relates to worse cognitive performance in community-dwelling older adults (Jefferson et al, 2010;Sabayan et al, 2015;Bown et al, 2019) by providing evidence that subtle reductions in cardiac output also relate to faster cognitive decline in domains of language, information processing, visuospatial skill, and episodic memory. Subtle reductions in cardiac output correspond to reduced CBF delivery as recently reported by our group (Jefferson et al, 2017).…”

“…The mostly null interactions with APOE-ε4 carrier status in a longitudinal study of older adults could highlight a phenomenon where APOE-ε4 exerts its effects earlier in the aging process and becomes less relevant later in life (Blacker et al, 1997). This age-effect phenomenon is corroborated by recent cross-sectional results of an interaction between cardiac output and APOE-ε4 status on cognition for which effects were much more robust (Bown et al, 2019). Additional research is warranted to better understand the intersection of AD genetic risk and vascular health on risk for cognitive decline.…”

“…Altered cardiac hemodynamics have been associated with cerebral blood flow (CBF) disturbances (Jefferson et al, 2017), smaller brain volumes (Sabayan et al, 2015), and poorer cognitive performances (Sabayan et al, 2015;Kresge et al, 2018), particularly among APOE-ε4 carriers (Bown et al, 2019). Prior studies, however, have been cross-sectional (Sabayan et al, 2015;Jefferson et al, 2017;Kresge et al, 2018;Bown et al, 2019) with limited investigation into the connection between subclinical cardiac dysfunction and longitudinal consequences, especially cognitive trajectories among aging adults. Given cross-sectional evidence, associations between cardiac function and longitudinal cognition may exist.…”