I. The Current State: A Drug-Centered Paradigm

The modern treatment of Alzheimer's disease has been significantly influenced by anti-amyloid monoclonal antibodies, particularly lecanemab and donanemab. These therapies have made history by demonstrating that targeted interventions can notably reduce amyloid burden and modestly slow down clinical decline in the early stages of the disease.

However, a pivotal question remains:

When is treatment complete?

As of early 2026, there is no unified answer in the literature. Current recommendations are drug-specific rather than disease-specific, resulting in varied treatment approaches.

• Donanemab (Kisunla): This adheres to a finite-course, treat-to-clearance model, allowing therapy to be halted once amyloid PET shows reduction to predefined thresholds (e.g., <11 Centiloids or sustained <25 Centiloids). These thresholds originate from the TRAILBLAZER trials and represent the most concrete biomarker-based stopping criteria available.
• Lecanemab (Leqembi): This has transitioned to a maintenance-based model, where therapy extends beyond the initial 18-month induction phase with ongoing dosing, based on the understanding that Alzheimer's disease remains biologically active even after amyloid reduction.

For both therapies, the most consistent reasons for stopping are safety-driven—including ARIA, macrohemorrhage, or inability to safely monitor.

These approaches align with their respective trials but highlight a fundamental issue:

We are defining treatment endpoints based on the drug—not the disease.

II. The Core Limitation: Amyloid-Centric Thinking

Currently, treatment success is predominantly defined by global amyloid burden, usually measured in Centiloids. This standardization also introduces critical blind spots.

1. Global Amyloid Measures Mask Regional Disease

Amyloid PET simplifies a spatially complex process into a single number. However, Alzheimer's pathology is not uniformly distributed.

A patient may achieve:

• Global Centiloid <25

while still presenting:

• regionally elevated SUVR in key cortical areas such as:
  • posterior cingulate
  • precuneus
  • lateral temporal cortex
  • inferior parietal regions

These areas represent:

• the default mode network,
• the core architecture of cognitive integration, and
• the primary pathways of tau propagation

Thus:

A "globally negative" scan may still indicate biologically active disease if regional hotspots persist.

2. Amyloid Reduction Does Not Equal Disease Quiescence

Clinical trials consistently show that:

• amyloid burden decreases rapidly,
• yet tau pathology continues to evolve, albeit more slowly.

Similarly:

• plasma p-tau181 and p-tau217 decline,
• but often do not normalize.

This leads to a critical insight:

Amyloid removal attenuates the disease process—but does not necessarily extinguish it.

From a systems perspective:

• the upstream trigger (A) may be reduced,
• while the downstream propagation engine (T) remains active.

3. The ATN Framework Defines Disease—But Not Treatment Endpoints

The NIA-AA ATN framework defines Alzheimer's disease biologically through:

• A (amyloid deposition)
• T (tau pathology)
• N (neurodegeneration)

This model is foundational for:

• diagnosis
• staging
• research classification

However, it has not been fully translated into therapeutic decision-making, particularly regarding:

• when to continue therapy
• when to transition
• when to stop

This creates a central contradiction:

We define Alzheimer's disease using ATN—but we treat it using A alone.

III. Reframing the Goal: From Plaque Removal to System Stabilization

To close this gap, treatment should be reframed from a single-biomarker endpoint to a system-level endpoint.

Therapy should not be considered complete when amyloid is reduced, but when the ATN system is biologically stabilized.

IV. Proposed ATN-Guided Clinical Framework

A - Amyloid: Beyond Global Centiloids

Current paradigm:

• Global Centiloid <25 — treatment complete (donanemab model)

Proposed refinement:

• Global Centiloid <25 AND
• No residual regional SUVR elevation in key ROIs

This ensures:

• elimination of focal amyloid reservoirs
• suppression of network-level disease activity
• alignment with true disease biology

T - Tau: Marker of Ongoing Disease Activity

Current paradigm:

• Tau biomarkers tracked but not used for stopping decisions

Proposed refinement:

• Serial monitoring of:
  • plasma p-tau181
  • plasma p-tau217

Target:

• normalization or stable low plateau

Rationale:

• p-tau reflects active phosphorylation and propagation dynamics
• persistent elevation signals ongoing disease activity

Thus:

Tau becomes the real-time indicator of whether the disease has truly quieted.

N - Neurodegeneration: Stability as the Endpoint

Current paradigm:

• clinical progression observed but not integrated into stop rules

Proposed refinement:

• define success as:
  • clinical stability (cognition, function)
  • structural stability (MRI)

Acknowledging:

• neurodegeneration may not reverse
• but can be stabilized if upstream drivers are controlled

V. Integrated Treatment Endpoint

Under this model:

Treatment completion = ATN stabilization

Defined as:

• A: global amyloid reduction + regional normalization
• T: p-tau181 / p-tau217 normalized or plateaued
• N: no meaningful clinical or structural progression

This represents a multi-dimensional biologic endpoint, rather than a single imaging threshold.

VI. Why This Model Matters

1. Aligns With Disease Biology

Moves from:

• plaque removal to:
• system-level disease control

2. Prevents Premature Discontinuation

Avoids stopping therapy when:

• regional amyloid persists
• tau signaling remains active

3. Explains Clinical Heterogeneity

Provides a framework for why:

• some patients stabilize
• others progress despite "amyloid clearance"

4. Enables Precision Medicine

Transitions from:

• fixed-duration therapy

to:

• biomarker-guided treatment duration

VII. Relationship to Current Evidence

This model is not a rejection of existing data—it is an extension of it.

Current evidence supports:

• amyloid PET-based stopping (donanemab)
• maintenance therapy (lecanemab)
• tau and plasma biomarkers as response indicators

However:

• no current guideline integrates these into a unified stopping rule
• no standard requires tau normalization or regional PET normalization

Thus:

This framework represents an evidence-aligned evolution toward biologic completeness.

VIII. Practical Implications for Our Clinic

Our clinic adopts a disease-centered approach:

• Amyloid reduction is necessary—but not sufficient
• Treatment decisions incorporate:
  • regional PET analysis
  • plasma p-tau dynamics
  • clinical and structural trajectory

We therefore define treatment success as:

Global amyloid suppression + regional normalization + tau stabilization + clinical stability

This is intentionally more stringent than current trial-based endpoints—but more consistent with the underlying biology of Alzheimer's disease.

IX. Final Position

Anti-amyloid therapy should not be defined solely by the removal of plaques, but by the stabilization of the biologic system that defines the disease.

In this model:

• Amyloid clearance is necessary
• Tau suppression is critical
• Neurodegenerative stability is the true endpoint

One-Line Summary

We are not treating centiloids—we are treating the full biologic system of Alzheimer's disease.

References

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• Alzheimer's Association. (2025). Lecanemab appropriate use recommendations (executive summary). Alzheimer's Association Professional Resources.
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• Food and Drug Administration. (2025). Leqembi (lecanemab-irmb) prescribing information. U.S. Department of Health and Human Services.
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