Amyloid and Tau Cerebrospinal Fluid Biomarker Normalization in a Patient with Alzheimer’s Disease treated with Lecanemab: A Case Report

Technical Summary: Amyloid and Tau Cerebrospinal Fluid Biomarker Normalization in a Patient with Alzheimer's Disease Treated with Lecanemab

Problem Statement
While anti-amyloid monoclonal antibodies (mAbs) like lecanemab are established to reduce cerebral amyloid burden and modestly slow tau accumulation, the concurrent normalization of cerebrospinal fluid (CSF) biomarkers for both amyloid and tau in a single patient has not been previously documented. Current literature indicates that anti-amyloid therapies produce substantial reductions in amyloid PET burden and downstream reductions in tau biomarkers, but the specific phenomenon of CSF biomarker values returning to within normal reference ranges remains unreported.

Methodology
This is a single-patient case report involving a 69-year-old woman with APOEε3/ε4 genotype diagnosed with Alzheimer's disease (AD) based on clinical, neurocognitive, and CSF evaluations.

• Intervention: The patient received intravenous lecanemab, titrated from 5 mg/kg to a full dose of 10 mg/kg over six months to mitigate amyloid-related imaging abnormalities (ARIA), and maintained at 10 mg/kg for 20 months.
• Concomitant Therapies: The patient was concurrently treated with donepezil, memantine, and off-label repetitive transcranial magnetic stimulation (rTMS).
• Data Collection:
  • CSF Analysis: Baseline CSF was analyzed for Aβ42, total tau (t-tau), and phosphorylated tau181 (p-tau181). A repeat analysis was performed at month 20 of full-dose treatment.
  • Neuroimaging: ¹⁸F-florbetapir amyloid and ¹⁸F-flortaucipir tau PET scans were conducted between months 12 and 14 of full-dose treatment. No pretreatment PET imaging was available.
  • Cognitive Assessment: Annual structured neurocognitive testing (WAIS-III, WMS-III, Buschke SRT) was performed by a psychologist blinded to the treatment status.

Key Results

• CSF Biomarker Normalization: Following 20 months of lecanemab therapy, the patient's CSF biomarkers demonstrated marked shifts:
  • Aβ42: Increased from 526.0 pg/mL to 1053.0 pg/mL (+100.2%).
  • t-tau: Decreased from 578.2 pg/mL to 278.0 pg/mL (−51.9%).
  • p-tau181: Decreased from 90.8 pg/mL to 23.1 pg/mL (−74.6%), falling within the laboratory reference range (<24 pg/mL).
  • Ratios: The t-tau/Aβ42 ratio decreased by 76.4% (1.1 to 0.26), and the p-tau181/Aβ42 ratio decreased by 87.1% (0.17 to 0.022). Both ratios post-treatment fell within laboratory reference ranges (≤0.28 and ≤0.023, respectively).
• PET Findings: The post-treatment amyloid PET was visually interpreted as negative with no significant cortical uptake, though the quantitative Centiloid value was 55.88. This discrepancy was radiologically attributed to artifactual high white-matter tracer uptake. The tau PET showed tracer binding restricted to the medial temporal lobes, insufficient to meet AD neuropathologic criteria, and was interpreted as negative.
• Cognitive Outcomes: Serial testing indicated relative stability in general cognitive performance, though persistent deficits in memory and auditory list learning remained. The patient maintained independence in activities of daily living.

Significance and Claims
The authors claim this is the first reported case, to their knowledge, of the normalization of both amyloid and tau CSF biomarkers following anti-amyloid monoclonal antibody therapy. Specifically, the report highlights that post-treatment p-tau181 and the tau/Aβ42 ratios returned to within laboratory reference ranges.

The paper posits that these findings support a mechanistic link between the soluble Aβ protofibrils targeted by lecanemab and downstream neuronal injury and tau pathology. The authors note that while the magnitude of the tau response is notable, it is biologically plausible given the strong association between lecanemab-associated Aβ protofibrils and tau biomarkers.

Limitations and Caveats
The authors explicitly state several limitations:

• Causality: As a single-patient case report, causality cannot be definitively established.
• Concomitant Treatments: The patient received donepezil, memantine, and rTMS; therefore, these agents cannot be fully excluded as contributors to the observed biomarker or clinical changes, although the authors deem the likelihood of them being the primary drivers low.
• Imaging Baseline: The absence of pretreatment PET imaging limits the ability to correlate biomarker changes with baseline amyloid/tau burden.
• Generalizability: The findings are specific to one individual and require further validation.

The authors conclude that while causality is unproven, the case demonstrates that substantial changes in both amyloid- and tau-related CSF biomarkers, including normalization, can occur during lecanemab therapy.