Amyloid-β and APOE genotype predict memory decline in cognitively unimpaired older individuals independently of Alzheimer’s disease polygenic risk score

BMC Neurology

Research

Lianne M. Reus¹  Betty M. Tijms¹  Elles Konijnenberg¹  Philip Scheltens¹  Jori Tomassen²  Pieter Jelle Visser³  Anouk den Braber⁴  Sven J. van der Lee⁵  Dorret I. Boomsma⁶  Eco J.C. de Geus⁶  Maqsood Yaqub⁷  Lyduine E. Collij⁷  Bart N.M. van Berckel⁷  Karl Herholz⁸  Stephen F. Carter⁹ 

[1] Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands;Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands;Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands;Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands;Alzheimer Center Amsterdam, Neurology, Amsterdam UMC location VUmc, PO Box 7057, 1007 MB, Amsterdam, The Netherlands;Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands;Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands;Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands;Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden;Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands;Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands;Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands;Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands;Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands;Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands;Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands;Department of Radiology & Nuclear Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands;Amsterdam Neuroscience, Brain Imaging, Amsterdam, The Netherlands;Wolfson Molecular Imaging Centre, Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK;Wolfson Molecular Imaging Centre, Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK;Department of Psychiatry, University of Cambridge, Cambridge, UK;

关键词: Preclinical Alzheimer’s disease;    APOE;    Polygenic risk score;    Amyloid-β;    Cognitive decline;    Neuropsychology;    Longitudinal design;   

DOI  :  10.1186/s12883-022-02925-6

 received in 2022-06-08, accepted in 2022-10-19,  发布年份 2022

来源: Springer

【 摘 要 】

Background:What combination of risk factors for Alzheimer’s disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-β pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals.Methods:We included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-β status was assessed by visual read of [18F]flutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-β status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-β status, and their interaction on changes in cognitive functioning over time.Results:Fifty-two participants (19%) had abnormal amyloid-β, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-β status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-β status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-β×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE β(SE)=-0.05(0.02); AD-PRS β(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-β status and AD-PRS predicted a steeper decline in memory functioning (amyloid-β β(SE)=-0.07(0.04); AD-PRS β(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-β status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-β abnormal individuals only (β(SE)=-0.13(0.06); β(SE)=-0.22(0.07), respectively).Conclusion:Our results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-β only. Furthermore, independent of amyloid-β status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.

【 授权许可】

CC BY   
© The Author(s) 2022

【 图 表 】

12982_2022_119_Article_IEq56.gif

12982_2022_119_Article_IEq22.gif

12888_2022_4137_Article_IEq1.gif

Fig. 4

Fig. 3

12864_2022_9026_Article_IEq187.gif