APOE e4 allele impacts changes in Alzheimer’s disease in patients with Down syndrome

The APOE e4 allele correlated with earlier clinical and biomarker-related changes of Alzheimer’s disease among patients with Down syndrome, according to results from a dual-center cohort study published in JAMA Neurology.

The results highlighted the processes by which APOE increases the risk for AD, underscoring the importance of this genotype for forthcoming clinical trials conducted among patients with Down syndrome. Patients with Down syndrome represent a group “at ultrahigh risk” for the development of AD due to the trisomy of chromosome 21, which harbors the amyloid precursor protein gene, the researchers noted.

“The apolipoprotein E (APOE; OMIM 107741) e4 allele is the most established genetic risk factor for sporadic AD and has been consistently associated with earlier AD symptoms and pathology in the general population,” Alexandre Bejanin, PhD, of Sant Pau Memory Unit in the department of neurology, Hospital de Santa Creu i de Sant Pau, and the Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, and colleagues wrote. “A similar disease-accelerating feature might exist in [Down syndrome] given that studies in this population have reported that e4 allele carriers show an earlier onset of clinical symptoms and greater amyloid burden than noncarriers. However, little is known about the association of the APOE e4 allele with the evolution of AD biomarkers.”

Bejanin and colleagues aimed to determine the relationship between the APOE e4 allele and clinical and multimodal biomarkers of AD among adults with Down syndrome. The researchers conducted a dual-center cohort study in Barcelona, Spain, and Cambridge, in the United Kingdom, between June 1, 2009, and February 28, 2020. They included patients in whom APOE genotyping was done who had at least one clinical or AD biomarker measurement and categorized participants as being APOE e4 allele carriers or noncarriers, according to the study results.

The researchers performed neurological and neuropsychological evaluations. The patient population included a subset of participants with biomarker measurements: amyloid beta 1-42, amyloid beta 1-40, phosphorylated tau 181 and neurofilament light chain in cerebrospinal fluid; phosphorylated tau 181 and neurofilament light chain in plasma; amyloid PET; fluorine 18-labeled fluorodeoxyglucose PET; and/or MRI. Investigators compared age at symptom onset between APOE e4 allele carriers and noncarriers and used within-group local regression models to examine the relationship between biomarkers and age. They used voxel-wise analyses to evaluate topographical differences in gray matter metabolism and volume, according to the study results.

The study included 464 adults with Down syndrome, with fewer APOE e4 allele carriers (20.9%) than noncarriers (79.1%). The researchers observed no difference between the groups regarding age (median, 45.9 years [interquartile range, 36.4-50.2 years] vs. 43.7 years [IQR, 34.9-50.2 years]) or sex (51 male carriers [52.6%] vs. 199 male noncarriers [54.2%]). They found that APOE e4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean age, 50.7 years vs. 52.7 years; P = .02) and exhibited 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 [amyloid beta] 1-42 to [amyloid beta] 1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma [phosphorylated tau 181], and earlier loss of cortical metabolism and hippocampal volume,” Bejanin and colleagues wrote. “No differences were found in [neurofilament light chain] biomarkers or CSF total tau and [phosphorylated] tau 181. Voxel-wise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE e4 allele carriers.”

The study represented, to the researchers’ knowledge, the first large, multimodal biomarker analysis to examine the relationship between the APOE e4 allele and clinical and biomarker changes of AD among patients with Down syndrome, according to the study report.

“Overall, this study provided evidence that the APOE e4 allele exerts a similar association with AD pathophysiological processes in [Down syndrome] as in the general population,” Bejanin and colleagues wrote. “We believe that this work is timely in the emerging landscape of preventive trials for dementia in [Down syndrome] given that consideration of APOE genotype might be important for drugs that are designed to lower amyloid burden and/or trials that use MRI as a surrogate marker of improved outcomes.”