Alzheimer's Disease Pathogenesis and Therapeutic Strategies

Alzheimer’s disease is a progressive neurodegenerative disorder marked by cognitive decline and functional impairment, representing the leading cause of dementia worldwide and imposing a substantial socioeconomic burden. Pathogenic hallmarks include extracellular accumulation of amyloid-β peptides forming plaques, intraneuronal aggregation of hyperphosphorylated tau into neurofibrillary tangles, chronic neuroinflammation, synaptic dysfunction and neuronal loss. Genetic risk factors such as apolipoprotein E ε4 and mutations in APP or presenilins influence amyloid processing and clearance, while age-related metabolic changes, oxidative stress, impaired autophagy and vascular dysfunction contribute to disease onset and progression. Therapeutic approaches have evolved from purely symptomatic treatments—cholinesterase inhibitors and NMDA receptor antagonists—to strategies aimed at modifying underlying pathology. Monoclonal antibodies targeting soluble amyloid-β oligomers and plaque clearance have shown modest clinical benefits, and recent regulatory approvals have catalysed interest in disease-modifying therapies. Investigational agents include selective inhibitors of β- and γ-secretases, tau aggregation blockers, immunotherapies against tau and amyloid, small molecules that enhance proteostasis or modulate synaptic plasticity, gene-based technologies such as antisense oligonucleotides and proteolysis-targeting chimeras. Despite advances in biomarker-guided patient selection and trial design, challenges remain in achieving meaningful cognitive improvement, minimising adverse effects and treating individuals at preclinical stages.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Alzheimer's Disease Pathogenesis and Therapeutic Strategies publication trend

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

Technical terms

Amyloid-β (Aβ): Peptide fragment derived from amyloid precursor protein that aggregates into oligomers and plaques in the brain.

Neurofibrillary tangles: Intracellular aggregates of hyperphosphorylated tau protein associated with neuronal dysfunction.

Cholinesterase inhibitors: Drugs that increase synaptic acetylcholine levels to alleviate cognitive symptoms.

Proteolysis-targeting chimera (PROTAC): Bifunctional molecule designed to induce degradation of target proteins via the ubiquitin-proteasome system.

Biomarker-driven trial design: Clinical studies that stratify participants based on fluid or imaging markers of disease pathology.

References

1. Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies. Signal Transduction and Targeted Therapy (2024).
2. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2019. Frontiers in Aging Neuroscience (2022).
3. Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimer's Research & Therapy (2020).
4. Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer’s disease. Translational Psychiatry (2021).