APOE e4 Allele Impacts Changes in Alzheimer’s Disease in Down Syndrome Patients

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Disclosures: Bejanin does not report any relevant financial disclosure. Please see the full study for relevant financial information from all other researchers.


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The APOE e4 allele correlated with clinical changes and related to previous biomarkers of Alzheimer’s disease in patients with Down syndrome, according to the results of a bicentric cohort study published in JAMA Neurology.

The results highlighted the processes by which APOE increases the risk of AD, highlighting the importance of this genotype for future clinical trials in patients with Down syndrome. Patients with Down syndrome represent an “ultra-high risk” group for developing AD due to trisomy of chromosome 21, which harbors the amyloid precursor protein gene, the researchers noted.

“The apolipoprotein E e4 allele (APOE; OMIM 107741) is the most established genetic risk factor for sporadic AD and has been consistently associated with previous symptoms and pathology of AD in the general population. ” Alexandre Béjanin, PhD, of the Memory Unit of Sant Pau of the Department of Neurology of the Hospital de Santa Creu i de Sant Pau and of the Biomedical Research Institute of Sant Pau, of the Universitat Autònoma de Barcelona, ​​and his colleagues have writing. “A similar feature of disease acceleration might exist in [Down syndrome] since studies in this population have reported that carriers of the e4 allele exhibit earlier onset of clinical symptoms and a greater amyloid load than non-carriers. However, little is known about the association of the APOE e4 allele with the evolution of AD biomarkers.

Bejanin and colleagues sought to determine the relationship between the APOE e4 allele and clinical and multimodal biomarkers of AD in adults with Down syndrome. The researchers conducted a bicentric cohort study in Barcelona, ​​Spain and Cambridge, UK, between June 1, 2009 and February 28, 2020. They included patients in whom APOE genotyping was performed and who had at least one clinical test or Depending on the results of the study, the measurement of the AD biomarker and the participants classified as carriers or not of the APOE e4 allele.

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

The study included 464 adults with Down syndrome, with fewer carriers of the APOE e4 allele (20.9%) than non-carriers (79.1%). The researchers found no difference between the groups in terms of age (median, 45.9 years [interquartile range, 36.4-50.2 years] against 43.7 years [IQR, 34.9-50.2 years]) or sex (51 male carriers [52.6%] against 199 non-carriers [54.2%]). They found that carriers of the APOE e4 allele compared to non-carriers showed symptoms of AD at a younger age (mean age, 50.7 years versus 52.7 years; P = .02) and exhibited earlier cognitive decline.

“The locally estimated point cloud smoothing curves further showed intergroup differences in biomarker trajectories with age, as evidenced by the non-overlapping CIs. Specifically, carriers showed lower levels of CSF [amyloid beta] 1-42 to [amyloid beta] Ratio 1-40 up to age 40, earlier increases in amyloid PET and plasma [phosphorylated tau 181], and earlier loss of cortical metabolism and hippocampal volume, ”Bejanin and colleagues wrote. “No difference was found in [neurofilament light chain] CSF biomarkers or total tau and [phosphorylated] tau 181. Voxel analyzes showed a lower metabolism in the subcortical and parieto-occipital structures and a lower median temporal volume in carriers of the APOE e4 allele.

The study was, to researchers’ knowledge, the first major multimodal biomarker analysis to examine the relationship between the APOE e4 allele and clinical and biomarker changes in AD in patients with Down syndrome, according to the report. ‘study.

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

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