Nils Lindblom - Institutionen för experimentell medicinsk vetenskap

Title: Anti-amyloid immunotherapies for Alzheimer's disease

Main supervisor: Gunnar Gouras

Reviewers: Katrin Mani, Lars Tjernberg, Yiyi Yang

Abstract

Background

Alzheimer’s disease is the leading cause of dementia and an increasing public health concern globally as our lifespan increases. The first disease modifying treatments for the disease, antibodies targeting Aβ, demonstrated successful clinical trials 3 years ago and are now in clinical use around the world. Remarkably, the mechanism(s) for the beneficial effect of immunotherapy against amyloid-beta remain unclear.

Research questions

• Are soluble protofibrils a better correlate to the drop in CSF Aβ42/40 ratio and increase in the neurodegeneration markers nfl, t-tau in AD than plaques?
• What are the precise anatomical and cellular localization of Aβ antibodies in the brain after Aβ immunotherapy?
• How does lecanemab affect the different cell types of the brain?
• How are CSF and plasma biomarkers changed over time with Aβ antibody treatment?

Preliminary results

In the first paper we demonstrated that the correlation between amyloid plaques and CSF markers of pathology/neurodegeneration are mediated by Aβ protofibrils and that the CSF Aβ42/40 ratio, corresponding to protofibrils, provides different information compared to Aβ PET, corresponding to Aβ plaques. In the second paper we show that Aβ antibodies widely distribute in the brain and localize to several cell types, including AD vulnerable neurons, astrocytes, microglia and perivascular macrophages.

In the third paper/manuscript that is ongoing we show that lecanemab reduces brain amyloid pathology and tau phosphorylation. Importantly, lecanemab affects all the major cell types in the brain; neurons, microglia, oligodendrocytes, OPCs and astrocytes. In neurons, lecanemab reduces cholesterol synthesis and Bace1 protein level while increasing synaptic translation. 

In the final paper/manuscript we demonstrate that Aβ antibodies can be taken up by neurons, where they help clear intraneuronal amyloid aggregates. 

Significance

Aβ immunotherapy is the first and only disease modifying treatment for AD. An increased understanding of the biological effect of these treatments can help aid the development of new and improved immunotherapies for the AD. 

Published studies 

1. https://www.nature.com/articles/s43587-025-00810-8

2. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71121