The advent of monoclonal antibodies targeting amyloid-beta—namely lecanemab and donanemab—has reshaped the therapeutic landscape of Alzheimer's disease (AD). Both agents modestly slow cognitive and functional decline in patients with early symptomatic AD, marking a long-awaited shift toward disease-modifying treatment. However, response is not uniform, and the decision to initiate therapy requires careful clinical, imaging, and biomarker-based triage.

This article synthesizes the most up-to-date 2025 data to guide clinicians on who should—and should not—receive anti-amyloid therapy, with practical insights for implementation in real-world practice.

Early Stage Disease Is Crucial

The single most reliable predictor of benefit is clinical stage. In both the CLARITY AD (lecanemab) and TRAILBLAZER-ALZ 2 (donanemab) trials, patients with mild cognitive impairment (MCI) or mild AD dementia derived the greatest benefit.

• CDR Global Score: 0.5-1.0
• CDR Sum of Boxes (CDR-SB): ≤6.5
• MMSE: Lecanemab (22-30), Donanemab (20-30)
• FAST: Stages ≤4

Patients with moderate or severe dementia (e.g., CDR ≥2.0 or FAST stage ≥5) had limited or no benefit and were excluded from clinical trials.

Tau Pathology: A Predictor of Efficacy

• Baseline tau burden is a powerful determinant of therapeutic response.
• Low to intermediate tau pathology, measured via CSF p-tau217 or tau PET, is strongly associated with greater slowing of cognitive decline.
• High tau burden is linked to reduced or absent benefit, particularly in late-stage patients.

In open-label extensions of lecanemab, some low-tau patients improved over 3 years, an unprecedented finding in AD treatment.

Implication: Tau staging should be integrated into the treatment decision whenever feasible.

Fluid Biomarkers: Confirming Target Engagement

Anti-amyloid therapies induce predictable biological shifts that can support therapeutic monitoring:

• ↓ p-tau181, p-tau217 and GFAP: Reflect reduced tau phosphorylation and astrocytic inflammation.
• ↑ Aβ42/40 ratio (CSF and plasma): Indicates amyloid plaque clearance.
• ↓ rate of NfL increase: Suggests slowed axonal injury and correlates with clinical benefit.

These biomarkers provide mechanistic reassurance, though they do not replace clinical evaluation or predict response independently.

Neuroimaging: Eligibility, Risk, and Safety

• Amyloid via PET
  • Required for therapy initiation.
  • Degree of baseline amyloid load does not predict clinical response, but is critical for diagnosis.
• Tau via PET
  • Optional but strongly prognostic.
  • Tau-PET not commercially available
  • High tau = lower likelihood of benefit.
• MRI
  • Safety gatekeeper. Required for ARIA risk stratification.

Exclusion criteria:

• ≥ 4 Microbleeds
  • What it means: Small spots of old bleeding in the brain seen on MRI (SWI or GRE).
  • Why it matters: Having more than four suggests higher risk for brain bleeding (ARIA-H) and possible underlying cerebral amyloid angiopathy (CAA).
• Any Cortical Superficial Siderosis (cSS)
  • What it means: Iron deposits from past bleeding seen on the surface of the brain (especially in brain grooves).
  • Why it matters: Strong warning sign for future bleeding. Found in advanced CAA.
• Macrohemorrhage >10 mm
  • What it means: Large brain bleed (over 1 cm in size) seen on MRI.
  • Why it matters: Indicates fragile blood vessels; risk of serious or fatal brain bleeding with treatment.
• Multiple Lacunar Infarcts
  • What it means: Small, deep strokes (3-15 mm) in brain areas like the thalamus, basal ganglia, or brainstem.
  • Why it matters: More than two, or one in a key area, suggests small vessel disease and complicates therapy response.

Implication: Avoid using in >2 infarcts, or at minimum use with caution if any are in critical regions.

• Severe White Matter Disease (Fazekas 3)
  • What it means: Extensive white matter damage on FLAIR MRI, either around the ventricles or deep in the brain.
  • Why it matters: Signals fragile brain tissue and poor clearance systems. Raises ARIA-E risk.
• Signs of CAA-ri (CAA-Related Inflammation)
  • What it means: Inflammation in blood vessels filled with amyloid; shows up as swelling or white matter changes on MRI.
  • Why it matters: Indicates a dangerous inflammatory state. Can worsen with treatment.
• Signs of ABRA (Amyloid Beta-Related Angiitis)
  • What it means: A rare form of brain vasculitis tied to amyloid. Diagnosed on biopsy or inferred from MRI.
  • Why it matters: Can lead to sudden and severe neurologic decline if exposed to amyloid antibodies.

Clinical and Genetic Predictors

• APOE e4
  • Homozygotes are at increased risk for ARIA-E/H, especially with donanemab.
  • APOE e4 does not negate benefit, but mandates enhanced monitoring.
  • Genotyping is recommended prior to therapy initiation.
• Sex
  • Subgroup data (e.g., Clarity AD) suggest men may experience greater benefit, although this remains exploratory.
• Age
  • No consistent differences in efficacy across age brackets.
  • Very old adults may have mixed pathology, which could diminish clinical gains.

Who Should Not Be Treated?

Clinical Exclusions

• Moderate-to-severe dementia (CDR ≥2, MMSE <20)
• Rapid progression inconsistent with AD
• Recent stroke or TIA (within 12 months)
• Use of anticoagulants (e.g., warfarin, DOACs, heparin)
• Systemic Illness
  • Active seizure disorder or seizure in past 12 months
  • Uncontrolled hypertension (MAP >93 mmHg)
  • Active bleeding/clotting disorders (platelet count <50k, INR >1.5)
  • Active malignancy or history within 5 years (unless in remission)
  • End-stage organ disease (ESRD, advanced liver disease)
  • Immunosuppression or autoimmune disease on systemic therapy

Implication: Active autoimmune disease on systemic therapy increases the risk of ARIA and other immunological complications. However, not all autoimmune diseases overlap, so use your clinical judgment.

• Other Exclusions
  • Inability to undergo MRI (e.g., metal implants, claustrophobia)
  • Pregnancy or lactation
  • Inadequate care partner support

MRI-Based Exclusions

• 4 microbleeds
• Any cSS
• Macrohemorrhage >10 mm
• Extensive white matter disease
• Signs of CAA-ri/ABRA

The "Goldilocks" Responders

Ideal candidates are in the therapeutic "sweet spot":

• Clinical diagnosis of MCI or mild AD dementia
• Amyloid-positive (PET or CSF)
• Low-to-intermediate tau burden
• No MRI signs of CAA, cSS, or extensive microbleeds
• Not on anticoagulants
• Stable systemic health
• APOE e4 status known and discussed
• Supportive care partner and informed consent obtained

Summary: 2025 Clinical Insights

Conclusion

Anti-amyloid therapies are not one-size-fits-all. As we enter the biomarker era of Alzheimer's care, the success of lecanemab and donanemab depends on precision in diagnosis, staging, and safety triage. The 2025 data support a "Goldilocks" model: early, not too early; pathologic but not too advanced; and cognitively symptomatic yet not too impaired.

Clinicians are now challenged not just to treat, but to treat wisely—identifying who stands to benefit and who might be harmed. This is the future of Alzheimer's medicine, and it has already begun.

Key References

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• Cohen, S., van Dyck, C. H., Gee, M., Doherty, T., Kanekiyo, M., Dhadda, S., Li, D., Hersch, S., Irizarry, M., & Kramer, L. D. (2023). Lecanemab Clarity AD: Quality-of-life results from a randomized, double-blind phase 3 trial in early Alzheimer's disease. Journal of Prevention of Alzheimer's Disease, 10(4), 771-777. https://doi.org/10.14283/jpad.2023.123
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• Sims, J. R., Zimmer, J. A., Evans, C. D., Lu, M., Ardayfio, P., Sparks, J. D., Wessels, A. M., Shcherbinin, S., Wang, H., Monkul Nery, E. S., Collins, E. C., Solomon, P., Salloway, S., Apostolova, L. G., Hansson, O., Ritchie, C., Brooks, D. A., Mintun, M., & Skovronsky, D. M. (2023). Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA, 330(6), 512-527. https://doi.org/10.1001/jama.2023.13239