amyloid-targeting immunotherapies in Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, affecting 57.4 million people worldwide (1).

Pathological hallmarks of AD include extracellular deposition of aggregated amyloid‐beta protein (Aβ) and intracellular tangles of hyperphosphorylated tau protein, along with synaptic and neuronal loss (1)

• these changes lead to network dysfunction and progressive cognitive impairment
• first lesions are believed to start accumulating 10 to 15 years before the onset of cognitive symptoms

Lecanemab and donanemab are amyloid-targeting immunotherapies that are approved in the UK:

• for mild cognitive impairment or mild dementia in Alzheimer's disease with the exclusion of homozygote carrieres of the 4-allele of the apolipoprotein E gene (APOE 4/4) (2)

A systematic review was undertaken (1):

• 17 studies that were carried out in different countries and involved 20,342 people
• average age across studies was from 70 to 74 year
• the systematic review concluded (1):
  • effect of amyloid‐beta‐targeting monoclonal antibodies (Aβ‐mAbs) in patients with mild cognitive impairment (MCI) or early dementia due to Alzheimer's disease (AD) on cognitive decline, dementia severity, and functional outcomes over an 18‐month period, is either absent or consistently small
  • differences in the main clinical outcome measures, including ADAS‐Cog (Alzheimer's Disease Assessment Scale‐Cognitive) and CDR‐SB (Clinical Dementia Rating Scale Sum of Boxes) scores, are well below the minimal clinically important difference (MCID) on these scales
  • risk of adverse events, most notably amyloid‐related imaging abnormalities (ARIA), is high
    • ARIA which includes oedema (E) and haemorrhage (H)
    • although symptomatic ARIA is uncommon, the long‐term consequences of cerebral oedema and recurrent (micro) bleedings are uncertain
      • amyloid‐beta‐targeting monoclonal antibodies
        • probably result in a small increase in the occurrence of any ARIA E (ARD (absolute risk difference) 107 more per 1000, 95% CI 77 more to 148 more; 11 studies, 13,595 participants; moderate certainty)
        • probably
          • little to no difference in symptomatic ARIA E (ARD 29 more per 1000, 95% CI 22 more to 38 more; 2 studies, 3522 participants; moderate certainty) or
          • symptomatic ARIA H (ARD 4 more per 1000, 95% CI 1 fewer to 31 more; 1 study, 1795 participants; moderate certainty)
      • “..The absence of clear reporting of symptomatic ARIA in most studies is a main limitation that precludes a thorough analysis of the true impact of ARIA…”

Reference:

1. Nonino F et al. Amyloid‐beta‐targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Cochrane Database of Systematic Reviews 2026, Issue 4. Art. No.: CD016297.
2. Rosen J, Jessen F. Patient eligibility for amyloid-targeting immunotherapies in Alzheimer's disease. J Prev Alzheimers Dis. 2025 Apr;12(4):100102.