Biomarkers in Alzheimer’s Disease (May 2025)

EP: 1.Presentation of Alzheimer’s Disease in Clinical Practice

EP: 2.Diagnosis and Treatment of Alzheimer’s Disease

EP: 3.Lecanemab for Treatment of Early Alzheimer Disease

EP: 4.ARIA With Monoclonal Antibody Treatments for Alzheimer Disease

EP: 5.Clarity-AD-OLE Study in Alzheimer’s Disease

EP: 6.Continuous Dosing of Lecanemab for Alzheimer’s Disease

EP: 7.Donanemab for Treatment of Alzheimer’s Disease

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EP: 8.Biomarkers in Alzheimer’s Disease (May 2025)

EP: 9.Emerging Agents in Alzheimer’s Disease

Summary for Physicians

Recent Advances in Alzheimer’s Disease

1. Disease-Modifying Therapies (DMTs):
   1. Lecanemab and donanemab, two monoclonal antibodies targeting amyloid-beta plaques, have been approved or are in advanced stages of approval for early Alzheimer’s disease. These therapies aim to reduce amyloid plaques, slow cognitive decline, and delay disease progression.
   2. The introduction of amyloid-modifying therapies has shifted Alzheimer’s treatment paradigms from symptomatic management to potential disease modification in early stages, providing hope for slowing disease progression.
2. Biomarker-Driven Diagnosis:
   1. Advances in neuroimaging, including amyloid PET and tau PET scans, allow for more accurate diagnosis and staging of Alzheimer’s disease, particularly in pre-symptomatic or mild cognitive impairment (MCI) stages.
   2. Blood-based biomarkers have emerged as promising tools for early detection and monitoring of disease progression, enabling non-invasive, cost-effective methods for Alzheimer’s diagnosis and management.

The Role of Blood-Based Biomarkers in Alzheimer’s Disease

Blood-based biomarkers are rapidly transforming Alzheimer’s disease management, with several key advantages and uses:

1. Early Diagnosis and Screening:
   1. Blood tests measuring amyloid-beta (Aβ) and tau proteins (including phosphorylated tau or p-tau) are increasingly validated as reliable markers for detecting amyloid plaque deposition and tau pathology.
   2. Plasma Aβ42/40 ratio is a strong predictor of amyloid plaque burden and can help confirm a diagnosis of Alzheimer’s disease earlier than clinical assessments alone.
   3. Plasma p-tau has shown strong correlation with tau PET imaging, providing a non-invasive alternative to imaging, and can help in staging disease progression.
2. Predicting Disease Progression:
   1. Blood biomarkers can help monitor disease progression by tracking changes in Aβ and tau levels over time.
   2. Elevated levels of p-tau or changes in the Aβ42/40 ratio are associated with the conversion from MCI to Alzheimer’s dementia, making these biomarkers useful for predicting cognitive decline.
   3. Neurofilament light chain (NfL) is another emerging biomarker that tracks neurodegeneration and has shown promise for monitoring disease progression and treatment response.
3. Treatment Monitoring and Personalization:
   1. Blood-based biomarkers can assist in monitoring treatment efficacy, particularly for amyloid-targeting therapies like lecanemab and donanemab. By tracking amyloid clearance or tau propagation in blood, clinicians can assess how well patients are responding to therapy.
   2. Blood tests may also guide the personalization of treatment plans, helping to identify which patients are likely to benefit from disease-modifying therapies based on their biomarker profiles.
4. Reduced Barriers to Access:
   1. Blood-based tests are more accessible, less expensive, and less invasive compared to traditional imaging modalities like PET scans or lumbar punctures, which can improve screening in primary care settings and widen access to Alzheimer’s diagnosis and management, especially in underserved regions.

Clinical Implications and Future Directions

• Implementation in Practice:
  • While blood biomarkers are not yet universally used in clinical practice, their growing availability and accuracy make them a critical tool for early detection, monitoring, and treatment decisions.
  • The FDA has recently approved several blood-based biomarkers for use in Alzheimer’s diagnosis (e.g., Eli Lilly’s blood test for amyloid plaques), bringing them into routine clinical practice.
• Limitations and Considerations:
  • Although promising, blood-based biomarkers still require further validation and standardization for use across diverse populations and clinical settings.
  • Blood biomarker testing should be considered in conjunction with clinical evaluation and neuroimaging, particularly when diagnosing earlier stages of Alzheimer’s disease or when confirming disease progression.
• Future Outlook:
  • Ongoing research into additional biomarkers, such as tau seeding or synaptic markers, may further improve the sensitivity and specificity of blood-based tests.
  • There is potential for combining blood-based biomarkers with other digital health tools, like cognitive testing or wearables, to provide a comprehensive approach to Alzheimer’s care.

Key Takeaways:

• Blood-based biomarkers are increasingly playing a central role in Alzheimer’s disease management, providing an accessible, reliable, and non-invasive way to diagnose, predict progression, and monitor treatment.
• Advances in biomarker technology align with the growing shift towards disease-modifying therapies, potentially altering the trajectory of Alzheimer’s disease.
• While promising, further standardization and validation are needed before blood tests become routine practice for diagnosis and ongoing management.