Abstract
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. To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS. 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. 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. 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. 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.
Highlights
In this study, the apolipoprotein E (APOE) ε4 allele was associated with earlier clinical and biomarker changes of Alzheimer disease (AD) in Down syndrome (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
Recent estimates indicate a lifetime dementia risk of more than 90% and identify Alzheimer dementia as the leading cause of death in this population.[1]. This elevated risk has led to the conceptualization of DS as a genetically determined form of AD that is similar to autosomal dominant forms
This idea is further supported by a recent study that showed that the pattern of AD biomarker changes follows a similar temporal profile in DS as in autosomal dominant forms, with a long preclinical phase and pathophysiological processes that are qualitatively comparable to sporadic AD.[2]
Summary
This cohort study was approved by the Clinical Research Ethics Committee at Hospital Sant Pau and the University of Cambridge Research Ethics Committee and by the Administration of Radioactive Substances Advisory Committee. In Spain, all study participants or their legally authorized representatives gave written informed consent before study enrollment. For participants in England and Wales who lacked the capacity to consent, the procedures in the Mental Capacity Act of 2005 were followed. In Barcelona, Spain, adults with DS were recruited from a population-based health plan that was developed for the screening of AD from which the Down Alzheimer Barcelona Neuroimaging Initiative cohort was formed.[2,18] In Cambridge, UK, participants were selected from a convenience sample that was recruited from services for people with intellectual disabilities in England and Scotland.[14]
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