Association of Apolipoprotein E ε4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome

IMPORTANCE Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE epsilon 4 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 epsilon 4 allele with dinical 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 epsilon 4 allele carriers or noncarriers. MAIN OUTCOMES AND MEASURES Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: A beta 1-42, A beta 1-40, 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 epsilon 4 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 epsilon 4 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 epsilon 4 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 Cls. Specifically, carriers showed lower levels of the CSF A beta 1-42 to A beta 1-40 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 epsilon 4 allele carriers. CONCLUSIONS AND RELEVANCE In this study, the APOE epsilon 4 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.

Automated summary

The APOE ε4 allele was found to be associated with earlier clinical and biomarker changes of Alzheimer disease in individuals with Down syndrome. This study provides insights into the mechanisms by which APOE increases the risk of Alzheimer's disease in this population.