DOI: 10.1002/alz.083267 ISSN: 1552-5260

Biomarker changes and their relationships to clinical efficacy outcomes in Alzheimer’s disease

Katherine Dawson
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Biological and clinical evidence points to Alzheimer’s disease (AD) as an amyloid‐beta (Aβ)–driven tauopathy, with Aβ and tau remaining high‐priority targets for therapeutic development. Alterations of fluid and imaging biomarkers are key indicators of underlying Aβ and tau pathological changes in the brain during AD and are important for evaluating investigational agents and assessing clinical effects efficiently (e.g., via shorter trials with fewer participants).


Anti‐Aβ monoclonal antibodies (mAb) and anti‐extracellular tau antibodies, as well as antisense oligonucleotides (ASO) that target intracellular tau, have been evaluated across multiple clinical studies. Outcome measures were broadly consistent across trials and assessed both clinical efficacy and longitudinal effects on fluid and imaging biomarkers of disease (e.g., those detected via cerebrospinal fluid [CSF], plasma, and imaging (positron emission tomography [PET]).


The results presented here show that anti‐Aβ mAb treatment reduced amyloid and tau PET standardized uptake value ratios across multiple brain regions and also impacted CSF Aβ1‐42, CSF phosphorylated tau (p‐tau), total tau (t‐tau), and plasma p‐tau181 biomarkers of disease in a dose‐dependent manner. Relevant biomarker changes generally correlated with positive clinical effects across multiple clinical efficacy scales. Anti‐tau antibody treatment demonstrated robust extracellular tau engagement in CSF but did not show clinical efficacy or any corresponding effect on tau pathology as assessed by PET. A Phase 1b trial evaluating an ASO targeting intracellular tau demonstrated a reduction in CSF t‐tau in a dose‐dependent manner; at the end of a long‐term extension study, this ASO also reduced tau burden as assessed by PET in all brain regions examined.


Results across therapeutic targets and modalities suggest that, with disease modification, relevant changes that occur in proximal and distal fluid and imaging biomarkers are linked to clinical effects. Lessons from the anti‐tau mAb study indicate that these relationships are still maintained even where, without a clinical effect, changes in AD biomarkers are not observed. Ongoing clinical trials will continue to expand our understanding of biomarker changes in AD, the contribution of amyloid and tau to disease pathology, and the temporal dynamics of biomarker changes, and their relationships to clinical efficacy outcomes.

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