Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome
Authors: Alexandre Bejanin, Maria Florencia Iulita, Eduard Vilaplana, Maria Carmona-Iragui, Bessy Benejam, Laura Videla, Isabel Barroeta, Susana Fernandez, Miren Altuna, Jordi Pegueroles, Victor Montal, Silvia Valldeneu, Sandra Giménez, Sofía González-Ortiz, Laia Muñoz, Concepción Padilla, Mateus Rozalem Aranha, Teresa Estellés, Ignacio Illán-Gala, Olivia Belbin, Valle Camacho, Liam Reese Wilson, Tiina Annus, Ricardo S. Osorio, Sebastián Videla, Sylvain Lehmann, Anthony J. Holland, Henrik Zetterberg, Kaj Blennow, Daniel Alcolea, Jordi Clarimon, Shahid H. Zaman, Rafael Blesa, Alberto Lleó, Juan Fortea
Journal: JAMA Neurology (2021)

<h3>Importance</h3> Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the<i>APOE</i>ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce. <h3>Objective</h3> To investigate the association of the<i>APOE</i>ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS. <h3>Design, Setting, and Participants</h3> 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<i>APOE</i>and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either<i>APOE</i>ɛ4 allele carriers or noncarriers. <h3>Main Outcomes and Measures</h3> 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<i>APOE</i>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. <h3>Results</h3> Of the 464 adults with DS included in the study, 97 (20.9%) were<i>APOE</i>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;<i>P</i> = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]).<i>APOE</i>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;<i>P</i> = .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<i>APOE</i>ɛ4 allele carriers. <h3>Conclusions and Relevance</h3> In this study, the<i>APOE</i>ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which<i>APOE</i>increases the risk of AD, emphasizing the importance of<i>APOE</i>genotype for future clinical trials in DS.