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Front Aging Neurosci. 2018 Oct 30;10:340. doi: 10.3389/fnagi.2018.00340. eCollection 2018.

Exploring Genetic Associations of Alzheimer's Disease Loci With Mild Cognitive Impairment Neurocognitive Endophenotypes.

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Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain.
Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany.
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
Department of Psychiatry and Psychotherapy, University Clinic Erlangen, Erlangen, Germany.
Department of Psychiatry, Charité University Medicine, Berlin, Germany.
Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Center for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany.
Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
Department of Economic and Social Sciences & Institute of Social Medicine, Rehabilitation Sciences and Healthcare Research (ISRV), University of Applied Sciences Nordhausen, Nordhausen, Germany.
Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.


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.


Alzheimer’s disease; genome-wide association studies; mild cognitive impairment; neurocognitive endophenotypes; single-nucleotide polymorphism

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