On the Therapeutic Use of Monoclonal Antibodies Against Amyloid Plaques in Older Adults with Down Syndrome: A Narrative Review and Perspective

Abstract

Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21 (trisomy 21 or T21) and is associated with an increased risk of early-onset Alzheimer's disease (AD), also known as DS-associated AD (DSAD). Individuals with DS typically develop amyloid neuropathology in their late-thirties to early-forties and the mean age of onset of clinical dementia is approximately 55 years. Recent advances in AD clinical research have focused on monoclonal antibodies (mAbs) targeting amyloid-β (Aβ) plaques as a potential therapeutic approach. Therefore, there has been guarded enthusiasm about using anti-amyloid mAbs in the prevention/treatment of DSAD. This narrative review and perspective explores the current understanding of amyloid pathology in AD and DSAD, the rationale for using anti-amyloid mAbs in the treatment of DSAD, and the challenges and opportunities for research toward the application of this therapeutic strategy to older adults with DS.

Keywords: Alzheimer’s disease; Down syndrome; amyloid hypothesis; anti-amyloid monoclonal antibodies; bioethics; intellectual disability; trisomy 21.

Figure 1

This figure reproduces the primary results of two different trials of AD therapies. (a) Adjusted changes in baseline CDR-SB scores in the CLARITY AD trial of the anti-Aβ amyloid mAb lecanemab for the treatment (in orange) and placebo (blue) arms of the study; (b) Adjusted changes in baseline ADCS-ADL severity scores in a phase 3 trial of the NMDAR antagonist memantine for the treatment moderate-to-severe AD [64], with the memantine arm appearing as orange and the placebo arm as blue symbols. In all four panels, symbols represent means ± 95% CI.

Figure 2

T1-weighted anatomical 3-Tesla MRI images taken from two females with DS, both in the sixth decade of life (generously shared by Dr. Katherine Koenig). One of these individuals (MRIs depicted in panels (a,c)) did not show signs and symptoms of cognitive decline, whereas the other individual (b,d) had a formal diagnosis of DSAD at the time of the brain scan. (a) Axial section showing expected degrees of neocortical atrophy and lateral ventricular dilation for an older adult with DS; (b) Axial section taken at approximately the same anatomical plan as panel a, showing extensive neocortical atrophy and ventriculomegaly indicative of DSAD; (c,d) Sagittal views from the same individuals taken in the same MRI sessions shown in panels a and b, respectively.