TY - JOUR
T1 - Exploring Genetic Associations of Alzheimer’s Disease Loci With Mild Cognitive Impairment Neurocognitive Endophenotypes
AU - Espinosa, Ana
AU - Hernández-Olasagarre, Begoña
AU - Moreno-Grau, Sonia
AU - Kleineidam, Luca
AU - Heilmann-Heimbach, Stefanie
AU - Hernández, Isabel
AU - Wolfsgruber, Steffen
AU - Wagner, Holger
AU - Rosende-Roca, Maitée
AU - Mauleón, Ana
AU - Vargas, Liliana
AU - Lafuente, Asunción
AU - Rodríguez-Gómez, Octavio
AU - Abdelnour, Carla
AU - Gil, Silvia
AU - Marquié, Marta
AU - Santos-Santos, Miguel A.
AU - Sanabria, Ángela
AU - Ortega, Gemma
AU - Monté-Rubio, Gemma
AU - Pérez, Alba
AU - Ibarria, Marta
AU - Ruiz, Susana
AU - Kornhuber, Johannes
AU - Peters, Oliver
AU - Frölich, Lutz
AU - Hüll, Michael
AU - Wiltfang, Jens
AU - Luck, Tobias
AU - Riedel-Heller, Steffi
AU - Montrreal, Laura
AU - Cañabate, Pilar
AU - Moreno, Mariola
AU - Preckler, Silvia
AU - Aguilera, Nuria
AU - de Rojas, Itziar
AU - Orellana, Adelina
AU - Alegret, Montserrat
AU - Valero, Sergi
AU - Nöthen, Markus M.
AU - Wagner, Michael
AU - Jessen, Frank
AU - Tárraga, Lluis
AU - Boada, Mercè
AU - Ramírez, Alfredo
AU - Ruiz, Agustín
N1 - Publisher Copyright:
© Copyright © 2018 Espinosa, Hernández-Olasagarre, Moreno-Grau, Kleineidam, Heilmann-Heimbach, Hernández, Wolfsgruber, Wagner, Rosende-Roca, Mauleón, Vargas, Lafuente, Rodríguez-Gómez, Abdelnour, Gil, Marquié, Santos-Santos, Sanabria, Ortega, Monté-Rubio, Pérez, Ibarria, Ruiz, Kornhuber, Peters, Frölich, Hüll, Wiltfang, Luck, Riedel-Heller, Montrreal, Cañabate, Moreno, Preckler, Aguilera, de Rojas, Orellana, Alegret, Valero, Nöthen, Wagner, Jessen, Tárraga, Boada, Ramírez and Ruiz.
PY - 2018/10/30
Y1 - 2018/10/30
N2 - The role of genetic risk markers for Alzheimer’s disease (AD) in mediating the neurocognitive endophenotypes (NEs) of subjects with mild cognitive impairment (MCI) has rarely been studied. The aim of the present study was to investigate the relationship between well-known AD-associated single-nucleotide polymorphisms (SNPs) and individual NEs routinely evaluated during diagnosis of MCI, AD, and other dementias. The Fundació ACE (ACE) dataset, comprising information from 1245 patients with MCI, was analyzed, including the total sample, amnestic MCI (aMCI) (n = 811), and non-amnestic MCI (naMCI) (n = 434). As probable-MCI (Pr-MCI) patients with memory impairment have a higher risk of AD, which could influence the statistical power to detect genetic associations, the MCI phenotype was also stratified into four related conditions: Pr-aMCI (n = 262), Pr-naMCI (n = 76), possible (Pss)-aMCI (n = 549), and Pss-naMCI (n = 358). Validation analyses were performed using data from the German study on Aging, Cognition, and Dementia in primary care patients (AgeCoDe), and the German Dementia Competence Network (DCN). SNP associations with NEs were calculated in PLINK using multivariate linear regression analysis adjusted for age, gender, and education. In the total MCI sample, APOE-ε4 was significantly associated with the memory function NEs “delayed recall (DR)” (β = -0.76, p = 4.1 × 10-10), “learning” (β = -1.35, p = 2.91 × 10-6), and “recognition memory” (β = -0.58, p = 9.67 × 10-5); and with “DR” in the aMCI group (β = -0.36, p = 2.96 × 10-5). These results were confirmed by validation in the AgeCoDe (n = 503) and DCN (n = 583) datasets. APOE-ε4 was also significantly associated with the NE “learning” in individuals classified as having Pss-aMCI (β = -1.37, p = 5.82 × 10-5). Moreover, there was a near study-wide significant association between the HS3ST1 locus (rs6448799) and the “backward digits” working memory NE (β = 0.52, p = 7.57 × 10-5) among individuals with Pr-aMCI, while the AP2A2 locus (rs10751667) was significantly associated with the language NE “repetition” (β = -0.19, p = 5.34 × 10-6). Overall, our findings support specific associations of established AD-associated SNPs with MCI NEs.
AB - The role of genetic risk markers for Alzheimer’s disease (AD) in mediating the neurocognitive endophenotypes (NEs) of subjects with mild cognitive impairment (MCI) has rarely been studied. The aim of the present study was to investigate the relationship between well-known AD-associated single-nucleotide polymorphisms (SNPs) and individual NEs routinely evaluated during diagnosis of MCI, AD, and other dementias. The Fundació ACE (ACE) dataset, comprising information from 1245 patients with MCI, was analyzed, including the total sample, amnestic MCI (aMCI) (n = 811), and non-amnestic MCI (naMCI) (n = 434). As probable-MCI (Pr-MCI) patients with memory impairment have a higher risk of AD, which could influence the statistical power to detect genetic associations, the MCI phenotype was also stratified into four related conditions: Pr-aMCI (n = 262), Pr-naMCI (n = 76), possible (Pss)-aMCI (n = 549), and Pss-naMCI (n = 358). Validation analyses were performed using data from the German study on Aging, Cognition, and Dementia in primary care patients (AgeCoDe), and the German Dementia Competence Network (DCN). SNP associations with NEs were calculated in PLINK using multivariate linear regression analysis adjusted for age, gender, and education. In the total MCI sample, APOE-ε4 was significantly associated with the memory function NEs “delayed recall (DR)” (β = -0.76, p = 4.1 × 10-10), “learning” (β = -1.35, p = 2.91 × 10-6), and “recognition memory” (β = -0.58, p = 9.67 × 10-5); and with “DR” in the aMCI group (β = -0.36, p = 2.96 × 10-5). These results were confirmed by validation in the AgeCoDe (n = 503) and DCN (n = 583) datasets. APOE-ε4 was also significantly associated with the NE “learning” in individuals classified as having Pss-aMCI (β = -1.37, p = 5.82 × 10-5). Moreover, there was a near study-wide significant association between the HS3ST1 locus (rs6448799) and the “backward digits” working memory NE (β = 0.52, p = 7.57 × 10-5) among individuals with Pr-aMCI, while the AP2A2 locus (rs10751667) was significantly associated with the language NE “repetition” (β = -0.19, p = 5.34 × 10-6). Overall, our findings support specific associations of established AD-associated SNPs with MCI NEs.
KW - Alzheimer’s disease
KW - genome-wide association studies
KW - mild cognitive impairment
KW - neurocognitive endophenotypes
KW - single-nucleotide polymorphism
UR - https://www.scopus.com/pages/publications/85073340962
UR - https://www.scopus.com/pages/publications/85073340962#tab=citedBy
U2 - 10.3389/fnagi.2018.00340
DO - 10.3389/fnagi.2018.00340
M3 - Article
AN - SCOPUS:85073340962
SN - 1663-4365
VL - 10
JO - Frontiers in Aging Neuroscience
JF - Frontiers in Aging Neuroscience
M1 - 340
ER -