Neuroprotective Pharmacotherapy for Alzheimer's Disease

Alzheimer’s disease (AD) is characterised by progressive cognitive decline, synaptic dysfunction and neuronal loss driven by amyloid-β (Aβ) accumulation, tau pathology, neuroinflammation and oxidative stress. Current pharmacotherapy aims primarily to alleviate symptoms, with acetylcholinesterase inhibitors (such as donepezil, rivastigmine and galantamine) enhancing cholinergic transmission and the NMDA-receptor antagonist memantine modulating excitotoxicity. However, these agents do not halt disease progression. Emerging neuroprotective strategies seek to target upstream pathogenic processes, including inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) to reduce Aβ production, activation of α-secretase to promote non-amyloidogenic APP processing, and modulation of intracellular protein trafficking to enhance clearance of toxic peptides. Attention has also turned to mitigating neuroinflammatory cascades through suppression of microglial overactivation, reducing oxidative damage and restoring mitochondrial bioenergetics in vulnerable neuronal populations. Novel drug-delivery platforms, such as intranasal or liposomal systems, are under development to overcome the blood–brain barrier and achieve therapeutic concentrations in key regions. Combination therapies that integrate cholinergic enhancement, amyloid and tau modulation, anti-inflammatory actions and mitochondrial support represent a promising multifaceted approach. Advances in biomarker-guided patient stratification and adaptive trial designs are essential to translate these mechanistic insights into clinically effective neuroprotective treatments.

Research from Nature Portfolio

A recent study has unveiled an off-target mechanism of donepezil whereby the drug up-regulates sorting nexin 33 (SNX33) in primary cortical neurons. Enhanced SNX33 expression promotes cell-surface localisation of amyloid precursor protein (APP), shifting its processing towards the protective α-secretase pathway. This intervention leads to a concentration- and time-dependent decrease in Aβ levels independent of acetylcholinesterase inhibition. By revealing how modulation of endosomal sorting proteins can influence APP cleavage, this work opens new avenues for developing compounds that harness intracellular trafficking pathways to confer neuroprotection in AD.

Neuroprotective Pharmacotherapy for Alzheimer's Disease publication trend

The graph below shows the total number of articles in neuroprotective pharmacotherapy for alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Amyloid-β (Aβ): Peptide fragments that aggregate into extracellular plaques and drive synaptic dysfunction in AD.

α-Secretase: Enzyme that cleaves amyloid precursor protein (APP) within the Aβ domain, yielding non-toxic soluble fragments.

BACE1: β-site amyloid precursor protein cleaving enzyme responsible for initiating pathogenic Aβ formation.

Blood–brain barrier (BBB): Selective endothelial interface that regulates transport of molecules between the bloodstream and the central nervous system.

Nose-to-brain delivery: Administration route utilising the olfactory and trigeminal pathways to deliver therapeutics directly to the brain.

SNX33 (Sorting nexin 33): Intracellular sorting protein that regulates endosomal trafficking of transmembrane receptors including APP.

References

1. Extract of Aster koraiensis Nakai Leaf Ameliorates Memory Dysfunction via Anti-inflammatory Action. International Journal of Molecular Sciences (2023).
2. Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro. The AAPS Journal (2024).
3. Donepezil modulates amyloid precursor protein endocytosis and reduction by up-regulation of SNX33 expression in primary cortical neurons. Scientific Reports (2019).