World Alzheimer’s Day: Unveiling the Brain’s “Eraser”
September 21, 2025, marks the 32nd World Alzheimer’s Day. Alzheimer’s disease (AD) is not a natural part of aging but a progressive neurodegenerative disorder and the leading cause of dementia. It damages neurons in the brain, gradually eroding memory and cognitive abilities, and in advanced stages, even disrupting basic physiological functions. In recent years, progress has been made in understanding disease mechanisms, improving early diagnosis, and advancing drug development. However, currently available therapies only provide symptomatic relief or modestly slow disease progression—they cannot fundamentally reverse its course. Developing more effective and targeted treatments remains an urgent priority.
The Pathological Network of AD: Core and Synergistic Mechanisms
The core pathological features of AD are driven by two interacting cascades: abnormal Aβ deposition and tau hyperphosphorylation. Amyloid precursor protein (APP) is sequentially cleaved by β-secretase (BACE1) and γ-secretase to generate Aβ peptides, which assemble into neurotoxic oligomers. These oligomers bind to neuronal membranes through receptors such as Nogo, causing calcium imbalance, mitochondrial dysfunction, and impaired synaptic transmission. Meanwhile, dysregulated kinases including GSK-3β, CDK5, and MAPKs drive tau hyperphosphorylation, leading to its detachment from microtubules and aggregation into neurofibrillary tangles. This disruption of axonal transport ultimately leads to neuronal loss and progressive cognitive decline.
Beyond these core features, AD is influenced by a range of synergistic mechanisms: cholinergic deficits (due to abnormal AChE and BChE activity leading to acetylcholine insufficiency), neuroinflammation (e.g., risk associated with the APOE4 allele and TREM2-mediated microglial dysfunction, which impairs Aβ clearance), synaptic dysfunction (such as NPTX2 downregulation and Nogo receptor-mediated inhibition of neuronal plasticity), and metabolic abnormalities (e.g., progranulin deficiency and lipid metabolism disorders). Together with Aβ and tau, these processes converge into a complex pathological network that drives disease progression.
Drug Development: From Symptomatic Relief to Disease Modification
Traditional Symptomatic Treatment: Addressing Neurotransmitter Deficits
For years, clinical management of AD has primarily relied on cholinesterase inhibitors (such as donepezil, rivastigmine, and galantamine) and NMDA receptor antagonists (memantine). These medications work by elevating acetylcholine levels or modulating glutamatergic signaling in the brain, offering partial improvement in cognitive symptoms and behavioral abnormalities. However, they cannot halt the underlying neurodegenerative process.
Targeting Aβ for Disease Modification: Promise and Challenges
Immunotherapies targeting Aβ represent a major breakthrough in recent AD treatment. Monoclonal antibodies such as lecanemab and donanemab are now approved for patients with early-stage AD, where they effectively reduce cerebral Aβ plaques and have demonstrated significant efficacy in slowing cognitive decline in clinical trials. However, limitations remain—including potential side effects such as amyloid-related imaging abnormalities (ARIA)—and benefits appear limited in moderate to advanced disease stages.
Exploring Novel Targets: Multi-Target Strategies for the Future
With deeper insights into AD pathogenesis, drug development is moving beyond the traditional Aβ-targeting approach, advancing toward multi-target and multi-pathway strategies:
Anti-tau therapies: Including aggregation inhibitors, monoclonal antibodies, and vaccines designed to prevent the formation and spread of neurofibrillary tangles.
Anti-neuroinflammation approaches: Targeting receptors such as TREM2 to modulate microglial polarization from pro-inflammatory to protective phenotypes and enhance clearance of pathological proteins.
Metabolic and neurotrophic modulation: Improving brain energy metabolism and promoting neuronal survival through mechanisms such as enhancing brain insulin signaling.
Multi-target agents: Developing small molecules that act on multiple pathways simultaneously—for instance, combining cholinesterase inhibition with modulation of GSK-3β or MAO-B—to achieve synergistic therapeutic effects.
ACROBiosystems’ Solutions: Driving Progress in AD Research
As the brand focused on neuroscience of ACROBiosystems, Aneuro offers cutting-edge solutions, including target proteins, pre-formed fibrils (PFFs), stable cell lines, and p-tau antibodies, to accelerate AD research and drug development.
Reference
Pinto-Hernandez P, Castilla-Silgado J, Coto-Vilcapoma A, et al. Modulation of microRNAs through lifestyle changes in Alzheimer’s disease[J]. Nutrients, 2023, 15(17): 3688. https://doi.org/10.3390/nu15173688
Mohapatra T K, Nayak R R, Ganeshpurkar A, et al. Navigating the treatment landscape of Alzheimer's disease: Current strategies and future directions[J]. ibrain, 2025, 11(2): 162-184. https://doi.org/10.1002/ibra.12197
Zhang J, Zhang Y, Wang J, et al. Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies[J]. Signal transduction and targeted therapy, 2024, 9(1): 211. https://doi.org/10.1038/s41392-024-01911-3
Singh B, Day C M, Abdella S, et al. Alzheimer's disease current therapies, novel drug delivery systems and future directions for better disease management[J]. Journal of Controlled Release, 2024, 367: 402-424. https://doi.org/10.1016/j.jconrel.2024.01.047
Jayaprakash N, Elumalai K. Translational Medicine in Alzheimer's Disease: The Journey of Donanemab From Discovery to Clinical Application[J]. Chronic Diseases and Translational Medicine, 2025, 11(02): 105-116. https://doi.org/10.1002/cdt3.155
Cummings J L, Zhou Y, Lee G, et al. Alzheimer's disease drug development pipeline: 2025[J]. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2025, 11(2): e70098. https://doi.org/10.1002/trc2.70098