Lecanemab and Vascular-Amyloid Deposition in Brains of People With Down Syndrome

Abstract

Importance: Anti-β-amyloid immunotherapy using lecanemab is becoming increasingly available to patients with Alzheimer disease (AD). Individuals with Down syndrome (DS) develop AD neuropathology by age 40 years, representing a significant cohort of genetically determined AD.

Objective: To investigate the binding properties of lecanemab in the brains of people with DS, in anticipation of their inclusion in clinical trials or access to antiamyloid immunotherapies.

Design, setting, participants: The study included cases of postmortem brain tissue analysis from 15 individuals with DS aged 43 to 68 years that were acquired from Alzheimer Disease research centers at the University of California, Irvine and the University of Kentucky from 2008 to 2021. Data were analyzed from August 2023 through May 2024.

Exposure: The binding properties of lecanemab were assessed in brain tissue.

Main outcome: The primary outcome was the extent of lecanemab binding to amyloid plaques and brain blood vessels.

Results: Tissue from 15 people (8 were female [53%]) with DS ranging in age from 43 to 68 (mean, 56.6) years were included in the study. Lecanemab-labeled amyloid plaques appeared in all 15 DS cases studied, indicating potential target engagement. However, extensive binding of lecanemab to brain blood vessels in DS was observed, raising significant safety concerns. These findings underscore the necessity for clinical trials of lecanemab in people with DS to evaluate both safety and efficacy, particularly in individuals older than 43 years.

Conclusions and relevance: These findings suggest significant binding of lecanemab to cerebral amyloid angiopathy in DS. Lecanemab should be rigorously tested in clinical trials for AD in the DS population to determine its safety and efficacy, especially in those older than 43 years.

Figure 1.. Lecanemab Labels Extensive Amyloid Deposits in Brains of People With Down Syndrome (DS)

A, Schematic of immunohistochemical protocol for using human antibody on human brain tissue. B, Low magnification of DS brain tissue labeled with lecanemab along with negative control antibody red numbers highlight different structures labeled with lecanemab but not negative control antibody (1, amyloid plaques; 2, parenchymal CAA; 3, meningeal CAA; scale bar = 500 μm. C, High magnification of different amyloid deposits recognized by lecanemab; red numbers indicated different type of deposits (1, coarse-grained; 2, cotton wool; 3, classic cored structures; 4, blood vessel amyloid angiopathy in the cortex; 5, capillary amyloid angiopathy in the cortex; 6, diffuse parenchymal Aβ deposits near blood vessels; 7, frontal cortex); scale bar = 50 μm. ABC-DAB indicates Avidin-biotin complex method using 3, 3'-diaminobenzidine; IgG, immunoglobulin G.

Figure 2.. Lecanemab Labels Extensive Vascular Amyloid Deposits in Brains of People With Down Syndrome (DS) Among Different Brain Regions

Low magnification of representative DS brain tissues triple labeled with anti-Aβ 40, anti- Aβ 42, and lecanemab; scale bar = 200 μm (A). High magnification of representative DS brain tissues triple labeled with anti-Aβ 40, anti- Aβ 42, and lecanemab; scale bar = 500 μm (B through D). ApoE indicates apolipoprotein E; DSAD, Down Syndrome pateints with Alzheimer Disease; F, female; M, male; NA, not applicable.

Figure 3.. Lecanemab Preferably Labels Aβ 40–Positive Amyloid Deposits in Brains of People With Down Syndrome (DS)

Low magnification of representative DS brain tissue triple labeled with anti-Aβ 40, anti-Aβ 42, and lecanemab, scale bar = 200 μm (A). High magnification of representative DS brain tissue triple labeled with anti-Aβ 40, anti-Aβ 42, and lecanemab; scale bar = 50 μm.