Low Liver Enzymes and Risk of Dementia: The Atherosclerosis Risk in Communities (ARIC) Study

Article type: Research Article

Authors: Lu, Yifei^a | Pike, James R.^b | Selvin, Elizabeth^c | Mosley, Thomas^d | Palta, Priya^{e; f} | Sharrett, A. Richey^g | Thomas, Alvin^a | Loehr, Laura^h | Sidney Barritt, A.ⁱ | Hoogeveen, Ron C.^j | Heiss, Gerardo^{a; *}

Affiliations: [a] Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA | [b] Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA | [c] Department of Epidemiology and the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA | [d] The MIND Center, University of Mississippi Medical Center, Jackson, MS, USA | [e] Division of General Medicine, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA | [f] Department of Epidemiology, Joseph P. Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA | [g] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA | [h] Division of General Medicine and Clinical Epidemiology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA | [i] Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA | [j] Department of Medicine, Baylor College of Medicine, Houston, TX, USA

Correspondence: [*] Correspondence to: Gerardo Heiss, MD PhD, 123 W. Franklin Street, Suite 450, Chapel Hill, NC 27516-8030, USA. Tel.: +1 919 962 3253; E-mail: gerardo_heiss@unc.edu.

Abstract: Background:Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective:To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods:Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results:During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values <10th percentile were associated with a higher risk of dementia (hazard ratio [HR] 1.34, 95% CI 1.08–1.65). The corresponding HR was 1.22 (0.99–1.51) for AST. Conclusion:Plasma aminotransferases <10th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia, advocating for attention to the putative role of hepatic function in the pathogenesis of dementia.

Keywords: ALT, Alzheimer’s disease, AST, dementia, liver hypometabolism

DOI: 10.3233/JAD-201241

Journal: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1775-1784, 2021