Alzheimer's Disease: Pathogenesis, Research Progress and Innovative Diagnostic-Therapeutic Strategies

1. Concept

Alzheimer's Disease (AD), the most prevalent form of dementia, is a progressive neurodegenerative disorder characterized by irreversible impairment of brain function and massive neuronal death. Unlike age-related mild memory decline, AD manifests as a series of severe clinical symptoms, including progressive memory loss, difficulty in performing daily activities, impaired judgment and comprehension, as well as profound changes in behavior and emotion. Two core pathological hallmarks define AD: extracellular deposits of β-amyloid (Aβ) peptides forming senile plaques, and intracellular neurofibrillary tangles (NFTs) resulting from hyperphosphorylation of Tau protein.

Aβ plaques disrupt interneuronal signal transmission and ultimately induce neuronal apoptosis. Under physiological conditions, Tau protein plays a crucial role in maintaining the transport of nutrients within neurons; however, in AD patients, abnormally phosphorylated Tau proteins misfold and aggregate into NFTs, obstructing axonal transport and leading to neuronal degeneration and death. As a major chronic disease posing a significant challenge to aging societies globally, AD has become a key focus of national strategies for active aging response in many countries.

2. Research Frontiers

With the accelerating global aging process, research on Alzheimer's Disease has advanced rapidly, focusing on several cutting-edge directions that hold great promise for transforming AD diagnosis and treatment:

•         Digitalized early screening systems: Integrated screening frameworks combining home-based preliminary screening, community-based re-screening, and hospital-based confirmation have been developed. Leveraging mobile applications or mini-programs, these systems enable rapid cognitive assessment (completable within 1.5 minutes), efficiently stratifying risks by filtering out 50% of low-risk individuals in the home screening phase and an additional 20% in the community re-screening phase, ultimately referring only 10%-15% of high-risk subjects for precise hospital diagnosis.

•         Novel biomarker research: Blood-based biomarkers such as Neurofilament Light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), and Phosphorylated Tau-217 (Ptau217) have emerged as promising indicators for neurodegeneration and AD pathology. These non-invasive biomarkers offer great potential for early AD detection and disease progression monitoring.

•         Nanotechnology-enabled diagnosis and therapy: Nanoparticles, with their high specific surface area and modifiable properties, serve as ideal platforms for AD biomarker detection. Optical sensing nanomaterials (e.g., gold nanoparticles, quantum dots) achieve high-sensitivity detection of trace Aβ through surface plasmon resonance or fluorescence signal amplification. Electrochemical sensing technologies utilizing nanomaterials (e.g., carbon nanotubes, graphene) enhance conductivity, facilitating the development of portable AD diagnostic devices. In therapeutic applications, surface-functionalized nanocarriers (e.g., PEGylated or targeting peptide-conjugated) cross the blood-brain barrier via receptor-mediated transcytosis or passive diffusion, enabling precise accumulation in lesioned brain regions.

•         Mechanistic exploration with advanced methodologies: High-dimensional mediating transfer learning approaches (e.g., TransHDM) have been developed to identify lipid metabolic pathways mediating the effect of the APOE ε4 gene on AD pathological progression, including glycerophospholipid metabolism, glycerolipid metabolism, sphingolipid metabolism, and ether lipid metabolism, providing new insights into AD pathogenesis.

•         Novel genetic target discovery: Recent studies have revealed that reduced expression of the Ap1s1 gene in the aging brain enhances neuronal vulnerability to Aβ and oxidative stress, highlighting its critical role in AD pathogenesis. Ap1s1 thus represents a potential therapeutic target for alleviating age-related cognitive decline and delaying AD onset.

3. Research Significance

Alzheimer's Disease poses a severe burden on patients, families, and society worldwide. As the seventh leading cause of death globally and a major contributor to disability and dependency among the elderly, AD has become a pressing public health challenge. Research on AD is of profound significance for improving human health and promoting social sustainable development.

In the clinical context, advancing early diagnosis technologies and shifting intervention windows forward are crucial for improving patient outcomes. Studies have demonstrated that precise intervention in Aβ-positive high-risk populations reduces the progression rate to AD to approximately 10% within 3-5 years, significantly lower than the global average of 1/3. Mechanistic research on AD not only deepens our understanding of neurodegenerative processes but also identifies novel therapeutic targets, laying the foundation for the development of disease-modifying therapies. Additionally, the exploration of modifiable risk factors (e.g., diabetes, hypertension, obesity) provides actionable strategies for AD prevention, potentially reducing the global disease burden. The integration of innovative technologies such as nanotechnology into AD diagnosis and treatment holds the promise of transforming AD from an irreversible, untreatable disorder into a manageable chronic disease.

4. Relevant Mechanisms, Research Methods and Product Applications

4.1 Core Pathogenic Mechanisms

The pathogenesis of Alzheimer's Disease is complex and multifactorial, with the interaction between Aβ deposition and Tau hyperphosphorylation serving as the central pathogenic cascade:

•         Aβ cascade hypothesis: Abnormal cleavage of the amyloid precursor protein (APP) produces Aβ peptides, which aggregate into oligomers and further form insoluble senile plaques. These plaques not only disrupt synaptic transmission but also trigger neuroinflammation and oxidative stress, leading to neuronal damage and death.

•         Tau hyperphosphorylation hypothesis: Hyperphosphorylation reduces the ability of Tau protein to bind to microtubules, resulting in microtubule destabilization and impairment of axonal transport. Misfolded Tau proteins then aggregate into NFTs, which further exacerbate neuronal dysfunction and death. The formation of NFTs correlates closely with the severity of cognitive impairment in AD patients.

•         Genetic and environmental interactions: AD is classified into sporadic (accounting for over 95%) and familial (less than 5%) forms. Sporadic AD arises from the complex interplay of genetic factors (e.g., APOE ε4 allele), environmental factors, and lifestyle choices. Familial AD is caused by mutations in genes such as APP, PSEN1, and PSEN2, leading to early onset. Approximately half of AD cases are associated with seven modifiable risk factors: diabetes, hypertension, obesity, smoking, depression, low cognitive activity/education level, and physical inactivity.

4.2 Key Research Methods

A diverse range of research methods has been developed to advance AD research, spanning from early screening and diagnosis to mechanistic exploration and therapeutic development:

•         Early screening and diagnostic techniques: Digital cognitive assessment tools enable rapid, convenient home-based screening. Nuclear medicine techniques such as amyloid-specific PET-CT imaging can detect abnormal Aβ deposition in the brain up to 10 years before the onset of clinical symptoms, facilitating preclinical AD diagnosis. Blood-based biomarker detection (NfL, GFAP, Ptau217) offers a non-invasive, cost-effective alternative for large-scale AD screening and progression monitoring.

•         Animal model establishment: AD animal models are essential for studying pathogenesis and evaluating therapeutic strategies. Common models include those induced by Aβ peptides (e.g., Aβ1-42, Aβ1-40, Aβ25-35), D-galactose, streptozocin, and scopolamine. These models recapitulate key AD pathological features and cognitive impairments, providing valuable platforms for preclinical research.

•         Mechanistic research tools: Techniques such as high-dimensional mediating transfer learning (TransHDM) enable the identification of key molecular pathways mediating AD pathogenesis in small sample populations. Genetic manipulation techniques (e.g., CRISPR-Cas9) facilitate the study of genes such as Ap1s1 in AD development. Immunological methods (e.g., immunohistochemistry, Western blot) using specific antibodies against Tau, α-Synuclein, and other proteins are widely used to detect pathological changes in AD tissues and cells.

•         Therapeutic evaluation methods: Preclinical and clinical evaluations of AD therapeutic agents (e.g., cholinesterase inhibitors, NMDA antagonists) rely on cognitive function tests, pathological marker detection, and survival analysis. Dual-luciferase reporter assays and other molecular biology techniques are used to screen and validate potential therapeutic targets.

4.3 Product Applications

ANT BIO PTE. LTD. provides a comprehensive portfolio of high-quality reagents and kits through its specialized sub-brands (Absin, Starter, UA) to support all stages of AD research, from model establishment and mechanistic exploration to drug screening and therapeutic evaluation. The key products are categorized as follows:

4.3.1 AD Therapeutic Small Molecule Compounds

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4.3.2 AD Model Establishment Related Products

4.3.3 Neurodegenerative Disease Related Antibodies

4.3.4 AD Research Related Recombinant Proteins

5. Brand Mission

ANT BIO PTE. LTD. is dedicated to advancing life science research by providing high-quality, reliable reagents and comprehensive solutions. We recognize the profound impact of Alzheimer's Disease on global health and the urgent need for innovative research tools to accelerate AD diagnosis and treatment progress. Through our specialized sub-brands (Absin, Starter, UA), we have developed a full-spectrum product portfolio tailored to AD research needs, covering small molecule compounds, model establishment reagents, specific antibodies, and recombinant proteins.

Our team adheres to stringent quality control standards throughout the product development and production process, ensuring the consistency, purity, and reliability of each product. We are committed to providing professional technical support and customer-centric services, helping researchers overcome experimental challenges, optimize research protocols, and accelerate the pace of AD research breakthroughs. ANT BIO PTE. LTD. strives to be a trusted partner for scientists worldwide, contributing to the fight against Alzheimer's Disease and the advancement of global neurological health.

6. Related Product List

7. Disclaimer

This article is AI-compiled and interpreted based on the original work in DOI: 10.1002/advs.202413562. All intellectual property (e.g., images, data) of the original publication shall belong to the journal and the research team. For any infringement, please contact us promptly and we will take immediate action.

8. Brand Promotion Copy

ANT BIO PTE. LTD. – Empowering Scientific Breakthroughs

At ANTBIO, we are committed to advancing life science research through high-quality, reliable reagents and comprehensive solutions. Our specialized sub-brands (Absin, Starter, UA) cover a full spectrum of research needs, from general reagents and kits to antibodies and recombinant proteins. With a focus on innovation, quality, and customer-centricity, we strive to be your trusted partner in unlocking scientific mysteries and driving medical progress. Explore our product portfolio today and elevate your research to new heights.