Journal Article

APOE ε4 Does not increase rate of amyloid accumulation or tau phosphorylation in adults with Down Syndrome

Schmitt, Frederick A, Burns, Jeffrey M., Harp, Jordan P., Ptomey, Lauren, Rafii, Michael S., Handen, Benjamin L, Lott, Ira T., Abdelmoity, Omar, Krinsky‐McHale, Sharon J., Ibanez, Laura, Christian, Bradley T, Lee, Joseph H., Hartley, Sigan L, Rosas, H. Diana, Hom, Christy L., Mapstone, Mark, Head, Elizabeth, Zaman, Shahid, Ances, Beau, Wisch, Julie K., Lai, Florence

2025

Overview

Background Down syndrome (DS) represents a genetic form of Alzheimer's disease (AD) with an earlier expected symptom onset compared to late onset AD (LOAD). It is thought that the extra copy of the Amyloid Precursor Protein (APP) gene, located on chromosome 21 contributes to the earlier onset due to increased amyloid deposition in the brain. Hyperphosphorylation of tau protein is also thought to be elevated in the beginning stages of AD pathology within DS. Although APOEε4 has been associated with greater AD risk in LOAD, prior cross‐sectional investigations into the effects of APOEε4 in DS have suggested that there is no additional impact of APOEε4 on the accumulation of amyloid. We aimed to extend this work by examining the associations between longitudinal plasma pTau217 and amyloid PET as a function of APOEε4 status. Method Participants with DS were recruited from the Alzheimer's Biomarker Consortium‐Down Syndrome (ABC‐DS) study. Both p‐tau217 (N = 564 results from 223 individuals including 122 that had 3 results each, Lilly MSD) and Amyloid PET ([11C]‐PiB or [18F]‐AV45) (N = 366 scans with 253 unique participants including 113 that had 2 scans each) were acquired. We analyzed the influence ɛ4 allele carrier status had on changes in pTau217 and amyloid across age using linear mixed‐effects modeling, including the age, APOEε4 carrier status and their interaction as covariates. Age was also included as a covariate. Result Individuals that are carriers of the APOEε4 allele present with similar baseline amyloid and pTau217 values (p = .591 & p = .455 respectively). The rate of amyloid and pTau217 accumulation increased across age similarly for both groups (p = .772 & p = .657 respectively). Although not statistically significant, visual inspection suggests that, with a larger number of participants, individuals between the ages of 45 and 50 who are ɛ4 allele carriers may exhibit elevated pTau217 levels compared to non‐carriers. Conclusion We did not observe increased amyloidosis or tau phosphorylation in APOEε4 carriers with DS. Future studies targeting individuals aged 45‐50 are suggested to investigate the potential APOEε4 effect on tau phosphorylation observed in this narrow chronological window, which is close to the average expected age of symptom onset of 52.5 years for DS.

• Publisher: John Wiley & Sons, Inc
• Subject: Accumulation / Adults / Age differences / Age groups / Age of onset / Alleles / Alzheimer's disease / Biological markers / Brain / Carriers / Chromosomes / Down syndrome / Genetics / Pathology / Phosphorylation / Symptoms