Amyloid Pathology and Therapeutic Approaches in Alzheimer's Disease

Alzheimer’s disease is marked by the accumulation of amyloid-β (Aβ) peptides, derived from amyloid precursor protein (APP) by sequential cleavages by β- and γ-secretases. Misfolded Aβ monomers assemble into soluble oligomers that disrupt synaptic function, impair long-term potentiation and trigger neuroinflammatory responses. With further aggregation, insoluble fibrils and extracellular plaques form, promoting tau hyperphosphorylation, neurofibrillary tangle formation and widespread neuronal loss. Therapeutic strategies aim to modulate secretase activity, enhance Aβ clearance via immunotherapy, inhibit oligomerisation with small molecules or promote aggregate disassembly. Monoclonal antibodies targeting diverse Aβ species have demonstrated the potential to slow cognitive decline in early-stage patients, though challenges remain in blood-brain barrier penetration, target selectivity and vascular side effects. Emerging small-molecule disaggregants and biologics that engage microglial phagocytosis or reinforce proteostatic mechanisms hold promise for disease-modifying interventions, emphasising the need for precision dosing and early intervention to intercept pathology before irreversible synaptic damage.

Research from Nature Portfolio

Recent studies in transgenic models have highlighted the complexity of amyloid quantification in preclinical drug evaluation. In one investigation, phospho-tau aggregates were shown to bind conventional β-sheet dyes alongside Aβ fibrils, indicating that dye-based measurements may overestimate plaque burden and mask therapeutic efficacy. Another seminal study demonstrated that a small molecule, when administered orally after the development of severe pathology, binds Aβ aggregates and converts them into monomers, leading to reduced glial inflammation and rescue of hippocampus-dependent behavioural deficits. These findings underscore the dual necessity of accurate aggregate detection and the therapeutic potential of direct disaggregation approaches in modifying established amyloid pathology.

Amyloid Pathology and Therapeutic Approaches in Alzheimer's Disease publication trend

The graph below shows the total number of articles in amyloid pathology and therapeutic approaches in alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Amyloid-β (Aβ): Peptide fragment derived from APP that forms aggregates in Alzheimer’s disease.

Oligomer: Soluble assembly of a few peptide monomers that can be neurotoxic.

Fibril: Insoluble, β-sheet-rich polymer formed by extensive peptide aggregation.

Plaque: Extracellular deposit of amyloid-β fibrils observed in brain tissue.

Secretase: Enzyme (β or γ) that cleaves APP to generate or process Aβ peptides.

Tau: Microtubule-associated protein that forms intracellular neurofibrillary tangles upon hyperphosphorylation.

References

1. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Molecular Medicine (2016).
2. Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis. Molecules (2020).
3. Thioflavin-positive tau aggregates complicating quantification of amyloid plaques in the brain of 5XFAD transgenic mouse model. Scientific Reports (2021).
4. EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques. Nature Communications (2015).
5. APP Osaka Mutation in Familial Alzheimer’s Disease—Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance. International Journal of Molecular Sciences (2020).