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. 2021 Aug 1;78(8):937-947.
doi: 10.1001/jamaneurol.2021.1893.

Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome

Alexandre Bejanin  1   2 , Maria Florencia Iulita  1   2 , Eduard Vilaplana  1   2 , Maria Carmona-Iragui  1   2   3 , Bessy Benejam  3 , Laura Videla  1   2   3 , Isabel Barroeta  1   2 , Susana Fernandez  1 , Miren Altuna  1   2 , Jordi Pegueroles  1   2 , Victor Montal  1   2 , Silvia Valldeneu  1   2 , Sandra Giménez  4 , Sofía González-Ortiz  5 , Laia Muñoz  1   2 , Concepción Padilla  1   2 , Mateus Rozalem Aranha  1   2 , Teresa Estellés  1   2 , Ignacio Illán-Gala  1   2 , Olivia Belbin  1   2 , Valle Camacho  6 , Liam Reese Wilson  7 , Tiina Annus  7 , Ricardo S Osorio  8 , Sebastián Videla  9 , Sylvain Lehmann  10 , Anthony J Holland  7 , Henrik Zetterberg  11   12   13   14 , Kaj Blennow  11   12 , Daniel Alcolea  1   2 , Jordi Clarimon  1   2 , Shahid H Zaman  7   15 , Rafael Blesa  1   2 , Alberto Lleó  1   2 , Juan Fortea  1   2   3
Affiliations

Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome

Alexandre Bejanin et al. JAMA Neurol. .

Abstract

Importance: Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce.

Objective: To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS.

Design, setting, and participants: This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ɛ4 allele carriers or noncarriers.

Main outcomes and measures: Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18-labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ɛ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume.

Results: Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ɛ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ɛ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ɛ4 allele carriers.

Conclusions and relevance: In this study, the APOE ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Carmona-Iragui reported receiving grant GBHI_ALZ-18-543740 from the Alzheimer's Association and Global Brain Health Institute Project and grant Project No. 1913 Cycle 2019B from the Jérôme Lejeune Foundation outside the submitted work. Dr Belbin reported receiving personal fees from ADx NeuroSciences outside the submitted work. Dr Annus reported being a current employee at Johnson & Johnson. Dr Lehmann reported receiving personal fees for service on the scientific advisory boards of Roche Diagnostics and Fujirebio. Dr Holland reported receiving grants from the Medical Research Council UK and Alzheimer's Research UK during the conduct of the study as well as nonfinancial support from the Down Syndrome Association UK outside the submitted work. Dr Zetterberg reported receiving personal fees for service on the scientific advisory boards of Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx; receiving personal fees for giving lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen; and being the cofounder of Brain Biomarker Solutions in Gothenburg AB (part of the GU Ventures Incubator Program) outside the submitted work. Dr Blennow reported serving as a consultant at advisory boards or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Eli Lilly and Company, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers as well as being the cofounder of Brain Biomarker Solutions in Gothenburg AB (part of the GU Ventures Incubator Program) outside the submitted work. Dr Alcolea reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica SL, and Esteve Pharmaceuticals SA outside the submitted work as well as holding a patent for WO2019175379 A1 markers of synaptopathy in neurodegenerative disease (licensed to ADx). Dr Zaman reported receiving nonfinancial support from the National Institute for Health Research (NIHR) Cambridge Dementia Biomedical Research Unit and personal fees for a short-term advisory role from Lundbeck outside the submitted work. Dr Fortea reported receiving personal fees for service on the advisory boards or adjudication committees of AC Immune, Novartis, Lundbeck, Roche Diagnostics, and Merck outside the submitted work; receiving conference fees from Esteve, Novo Nordisk, Roche Diagnostics, Fujirebio, and Biogen; and holding a patent for markers of synaptopathy in neurodegenerative disease (licensed EP18382175.0). No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association of Apolipoprotein E (APOE) ɛ4 Allele With Clinical Diagnosis and Cognitive Performance in Adults With Down Syndrome (DS)
The horizontal lines in panel C represent the mean values, and the error bars represent the nonparametric bootstrapped 95% CIs. Bands in panels D to F represent the 95% CIs. AD indicates Alzheimer disease; CAMCOG-DS, Cambridge Cognitive Examination for Older Adults with Down Syndrome; and mCRT, modified Cued Recall Test.
Figure 2.
Figure 2.. Association of Apolipoprotein E (APOE) ɛ4 Allele With Age-Related Changes in Alzheimer Disease (AD) Biomarkers
Shading represents 95% CIs, and the dashed lines represent the age-related changes in euploid individuals for visual reference. Aβ1-40 indicates amyloid-β peptide 1-40; Aβ1-42, amyloid-β peptide 1-42; CSF, cerebrospinal fluid; 18F-FDG, fluorine 18–labeled fluorodeoxyglucose; NfL, neurofilament light chain; PET, positron emission tomography; pTau181, phosphorylated tau 181; SUVR, standardized uptake value ratio; and TIV, total intracranial volume.
Figure 3.
Figure 3.. Association of Apolipoprotein E (APOE) ɛ4 Allele With Gray Matter Metabolism and Volume
The boxplots illustrate the voxelwise results and represent the metabolism (A) and volume (B) adjusted for the covariates within the significant clusters. For each boxplot, the box represents the interquartile range, the band represents the median value, and the dots represent individual values. Results are presented in neurological convention and were generated using the Surf Ice tool (https://www.nitrc.org/projects/surfice/). eFigures 5 and 6 in the Supplement show a slice-by-slice display of the results.
See this image and copyright information in PMC

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