The Natural History of AD and New Treatments

The progression of AD typically follows a well-established pattern, using six stages starting from a cognitively normal stage, moving through subjective cognitive decline (SCD), mild cognitive impairment (MCI), and advancing to mild, moderate, and severe stages of dementia¹. Of concern is the proposal to label A(+) asymptomatic persons as having “Alzheimer’s disease”, particularly if there is no established therapy at that stage other than modification of risk factors.

Preventive measures targeting modifiable risk factors remain crucial. However, for those with confirmed amyloid pathology, early intervention with anti-amyloid therapies may help slow the progression of cognitive decline^2,3.

Anti-Amyloid Monoclonal Antibodies: Mechanism of Action^4,5

Anti-amyloid monoclonal antibodies (MABs) are designed to target and remove amyloid plaques composed of aggregated amyloid-beta (Aβ) peptides, a hallmark of AD pathology. The mechanism involves:

• Interaction with Amyloid Plaques: The antibodies bind to amyloid plaques, as detected by amyloid PET imaging. 
• Activation of Microglia: The bound antibodies activate microglia, the brain's resident immune cells, which then engulf and degrade the aggregated amyloid.
• Reduction of Plaque Burden: The successful removal of amyloid plaques is reflected in negative amyloid PET results after treatment.

This approach is based on the hypothesis that reducing the amyloid burden in the brain can slow or halt the progression of AD.

Clinical Evidence and Efficacy^2-5

The efficacy of anti-amyloid therapies has been evaluated in several clinical trials, as highlighted in the ASAD presentations. Two monoclonal antibodies, Lecanemab and Donanemab, were discussed in detail:

• Lecanemab⁶:
  • Target: Reduces protofibrillar and fibrillar forms of amyloid. 
  • Infusion Schedule: Administered biweekly.
  • Primary Outcome: Showed a 27% slowing in the Clinical Dementia RatingSum of Boxes (CDR-SB), with a significant reduction in amyloid and p-tau biomarkers.
  • Adverse Effects: 12.6% incidence of ARIA-E (Amyloid-Related Imaging Abnormalities-Edema) and 26.4% infusion reactions.
  • Stopping: When the patient exits the window for appropriate therapy 
   
• Donanemab⁷:
  • Target: Specifically targets pyroglutamate amyloid (found only in plaques).
  • Infusion Schedule: Administered monthly.
  • Primary Outcome: Demonstrated a 35% slowing in the integrated Alzheimer's Disease Rating Scale (iADRS), particularly effective in patients with low to medium tau levels.
  • Adverse Effects: 24% incidence of ARIA-E and 8.7% infusion reactions.
  • Stopping: When plaque is below detectable levels

Both therapies have shown the ability to slow disease progression, with differences in patient response based on amyloid and tau pathology levels.

Considerations for Clinical Implementation^2-5

The implementation of immunotherapies like Lecanemab and Donanemab requires careful consideration of several factors:

• Expertise and Infrastructure: Clinicians need expertise in early AD diagnosis, MRI, and PET interpretation. Facilities should have the resources to manage potential serious side effects, such as ARIA.
• Patient Selection: Genetic testing for APOE genotype and understanding individual patient biomarkers (amyloid and tau levels) are critical for selecting appropriate candidates for these therapies. 
• Communication and Support: Effective communication channels with patients and caregivers are essential for managing expectations and ensuring adherence to treatment protocols.

Advancements in Treatment Modalities

The ease of administering anti-amyloid therapies has improved, with ongoing research exploring oral alternatives to monoclonal antibody infusions. For example, Valiltramiprosate (ABT-801), currently in Phase III trials, is an oral drug being compared to a placebo in patients with mild AD⁸. This approach aims to simplify treatment regimens, making therapy more accessible and manageable for patients.

Moreover, the use of blood biomarkers for monitoring treatment response is an area of active investigation. This could provide a less invasive and more practical method for assessing the efficacy of ongoing therapy.

Challenges and Considerations in Therapy Discontinuation^9,10

One of the critical challenges in the clinical application of anti-amyloid MABs is determining when to stop treatment. Several factors may warrant discontinuation:

• The amyloid plaque burden becomes undetectable on PET imaging.
• The occurrence of severe Amyloid-Related Imaging Abnormalities (ARIA), especially if symptomatic or recurrent.
• Progression to a more advanced stage of AD, where continued therapy may no longer be beneficial. 
• Patient or caregiver consensus based on the perceived burden of treatment.

Is Anti-Amyloid Monotherapy Sufficient?

There is growing recognition that while anti-amyloid therapies are a significant step forward, they may not be sufficient as monotherapy^2,3. The complexity of AD pathology, which includes tau tangles, synucleinopathy, inflammation, and vascular factors, suggests that a more comprehensive treatment strategy targeting multiple pathways might be necessary. Understanding the complete biological profile (ATN+SIV) of patients could guide more personalized and effective therapeutic approaches11.

Duration of Therapy

Another critical question is the optimal duration of therapy. The removal of plaques visible on PET does not necessarily correlate with the absence of oligomer production, which could continue to drive disease progression. As a result, maintenance therapy with drugs targeting oligomer production and aggregation might be required¹¹. This approach raises the possibility of combining therapies, such as initial treatment with Donanemab for 12 months, followed by maintenance with Valiltramiprosate.

Anti-Amyloid Treatment in Non-Typical AD Populations

The application of anti-amyloid therapies extends beyond typical AD cases. Populations such as those with early-onset AD, atypical AD (e.g., posterior cortical atrophy), and autosomal dominant AD might benefit from these treatments, provided specific criteria are met¹². However, more data are needed to confirm the safety and efficacy of these therapies in other groups, such as those with Down syndrome or cerebral amyloid angiopathy (CAA).

Management of Symptomatic Patients Ineligible for MABs

Not all patients with amyloid pathology are suitable candidates for monoclonal antibody therapy due to various medical, social, or geographical factors. For these individuals, alternative treatments, both pharmacological and non-pharmacological, must be offered to manage symptoms and maintain quality of life^9,10.

Addressing Amyloid-Negative Symptomatic Patients

For patients presenting with an AD phenotype but lacking amyloid pathology (amyloid-negative), the current diagnostic criteria suggest they do not have AD¹³. These cases require careful reevaluation, including possible repetition of CSF and/or PET imaging after a year. Such patients may eventually be diagnosed with a different neurodegenerative disorder, such as progressive supranuclear palsy (PSP), as their disease course becomes clearer.

Conclusion

Immunotherapies, particularly anti-amyloid monoclonal antibodies, represent a significant advancement in the treatment of Alzheimer's disease. These therapies offer the potential to modify disease progression, especially in the early stages. However, their application requires careful patient selection, monitoring, and consideration of when to discontinue treatment. The complexity of AD pathology also suggests that combination therapies targeting multiple pathways may be necessary for optimal outcomes. As research continues, these therapies will likely become an integral part of dementia management, with ongoing efforts to improve accessibility, reduce treatment burden, and tailor therapies to individual patient profiles.