Relationship Between Genetic Variants of ACAT1 and APOE with the Susceptibility to Dementia (SADEM Study)
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Relationship Between Genetic Variants of ACAT1 and APOE with the Susceptibility to Dementia (SADEM Study) Jessica Sarahi Alavez-Rubio 1 & Nancy Martínez-Rodríguez 2 & Jorge Escobedo-de-la-Peña 3 & Osvaldo Garrido-Acosta 4 & Teresa Juárez-Cedillo 5,6 Received: 2 June 2020 / Accepted: 6 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract One of the hypotheses that have emerged to explain the origin of dementia relates the disease with altered lipid metabolism, particularly cholesterol. To maintain cholesterol homeostasis, the ACAT1 enzyme has an important function to regulate the production of Aβ. Moreover, APOE is the main cholesterol carrier in the brain, and it has been reported as a risk factor for this disease. This study evaluates the relationship between ACAT1 and APOE genetic variants with susceptibility for the development of Alzheimer’s disease and other dementias. We examined four ACAT1 polymorphisms (rs2247071, rs2862616, rs3753526, rs1044925) and two in the APOE gene (rs7412, rs429358) in a group of 204 controls and 196 cases of dementia. Our results show one protective haplotype: CGCA (OR = 0.34, 95% CI = 0.23–0.46; p < 0.001) and one risk haplotype: CGGA (OR = 1.87, 95% CI = 1.34–2.60; p < 0.001) for the development of dementia. Subjects identified as APOE-ε4 allele carriers had a higher risk of developing dementia compared with non-carriers, OR = 13.33 (95% CI = 3.14–56.31). The results support the hypothesis that the ACAT1 gene, together with the APOE gene, plays an important role in susceptibility to the development of dementia and shows genetic characteristics of the Mexican population that can be used to identify the population at risk. Keywords ACAT1 . APOE . Cholesterol . Dementia . Polymorphism
Introduction Dementia is a major cause of disability and dependency among older adults worldwide, affecting memory, cognitive abilities, and behavior, interfering with one’s ability to perform daily activities [1]. It is a multifactorial disease with modifiable lifestyle-related risk factors and non-modifiable genetic risk factors. Several hypotheses have been proposed to explain its origin and progress; one of them is related to cholesterol metabolism, which plays a fundamental role in the physiology and brain function [2].
Some studies have revealed that high cholesterol levels promote the formation of Aβ [3, 4]. Cholesterol homeostasis is regulated by a dynamic balance of its absorption, de novo synthesis, esterification, catabolism, and release [5]. The enzyme ACAT1 has an important role in cholesterol homeostasis, preventing over-accumulation of free cholesterol in the cells, forming cholesteryl esters; it has been suggested that the balance between the esters and free cholesterol is a key point in the control of amyloidogenesis. ACAT activity has been associated with amyloid level and with the formation of brain amyloid plaques [6–14].
* Teresa Juárez-Cedillo [email protected]
4
Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autó
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