🧠 Concise Report on the Pathogenesis and Research Gaps in Alzheimer’s Disease

1. Overview of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss, cognitive decline, and behavioral changes. It is the most common cause of dementia globally, especially in people over 65.

2. Pathogenesis

Key Molecular Events:

• Beta-amyloid plaques: Abnormal cleavage of amyloid precursor protein (APP) by β- and γ-secretases produces Aβ42 peptides that aggregate and disrupt synaptic communication.
• Tau tangles: Hyperphosphorylated tau proteins form intracellular neurofibrillary tangles, impairing axonal transport and leading to neuron death.
• Neuroinflammation: Microglia and astrocytes respond to plaques and tangles with chronic inflammation, which accelerates neuronal loss.
• Synaptic and neuronal loss: These processes result in atrophy of memory-related brain regions like the hippocampus.

3. Protein Targets in Alzheimer’s

• Beta-amyloid (Aβ42): Targeted by monoclonal antibodies (e.g., Aducanumab, Lecanemab) and secretase inhibitors to reduce or prevent plaque buildup.
• Tau protein: Therapies aim to block hyperphosphorylation or promote tau clearance.
• Molecular chaperones: Experimental agents help correct or stabilize protein folding.

4. Key Research Gaps

Area	Gap
Protein misfolding	Incomplete understanding of Aβ and tau misfolding mechanisms (Hardy & Selkoe, 2002).
Drug development	High clinical trial failure rates; limited cognitive benefits in existing drugs (Knopman et al., 2021).
Patient inclusion	Elderly (75+) are underrepresented in clinical trials (The Guardian, 2025).
Biomarkers	Early diagnostic biomarkers are limited, despite emerging blood tests (ScienceDaily, 2019).
Alternative pathways	Lipid and endosomal dysfunction are underexplored despite genetic links (Long & Holtzman, 2019).

5. Conclusion

Although understanding of Alzheimer’s disease has grown significantly, effective treatments remain limited. A deeper focus on molecular mechanisms, earlier diagnosis, and more inclusive trials is crucial to closing the gap between research and clinical impact.

📚 References

1. Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 297(5580), 353–356. Link
2. Knopman, D. S., et al. (2021). FDA Approval of Aducanumab — Clinical Trials and Evidence. JAMA, 325(17), 1717–1718. Link
3. The Guardian (2025). Elderly people being excluded from medical research. Link
4. ScienceDaily (2019). Blood test can detect Alzheimer’s proteins 14 years early. Link
5. Long, J. M., & Holtzman, D. M. (2019). Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Nat. Rev. Drug Discov., 18, 396–412. Link