Amyloid-Reducing Treatments Target Downstream Biomarkers in Alzheimer Disease

Amyloid-reducing treatments are important in targeting the neuroinflammatory and neurodegenerative processes in patients with dominantly inherited Alzheimer disease (DIAD), according to study findings published in JAMA Neurology. 

Antiamyloid treatments were developed to target fibrillar or soluble monomeric amyloid peptides, but it is unclear what downstream effects these treatments have on AD-related pathology. Researchers conducted a study to evaluate longitudinal biomarker changes linked to synaptic dysfunction, neurodegeneration, and neuroinflammation among patients with DIAD who were prescribed antiamyloid treatments. 

The Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001; ClinicalTrials.gov Identifier: NCT04623242) study was a phase 3 placebo-controlled, double-blind, randomized clinical trial assessing 2 antiamyloid monoclonal immunoglobulin G1 antibodies (gantenerumab and solanezumab). The study was conducted at 25 locations in 7 countries from December 2012 through November 2019.

Participants were individuals with a confirmed DIAD gene variant. The Clinical Dementia Rating (CDR [Knight ADRC]) dementia staging instrument was used to classify baseline clinical status. Participants were randomly assigned 3:1 to the drug or placebo, and the dose was increased to the maximum of 1200 mg for gantenerumab and 1600 mg for solanezumab towards the middle of the trial. 

The researchers collected cerebrospinal fluid (CSF) samples at years 1, 2, and 4. Participants underwent amyloid imaging, magnetic resonance imaging (MRI), and positron emission tomography (PET) scan at the time of CSF collection.

Of the 236 participants screened for inclusion, 142 (average age, 44; women, 51%) were included in the study. A total of 52 (37%) patients were taking gantenerumab, 50 (35%) were taking solanezumab, and 40 (28%) were taking placebo. 

At year 4, patients taking gantenerumab showed significantly decreased CSF neurogranin levels compared with the placebo group (mean β, -242.43 pg/mL; SD, 48.04 ng/mL; P <.001), while patients taking solanezumab showed no significant changes in CSF neurogranin.

The plasma CSF glial fibrillary acidic protein (GFAP) levels at year 1 (mean β, -0.02 ng/mL; SD, 0.01 ng/mL; P =.02), year 2 (mean β, -0.03 ng/mL; SD, 0.01 ng/mL; P =.002), and year 4 (mean β, -0.06 ng/mL; SD, 0.02 ng/mL; P <.001) were stabilized with gantenerumab but not impacted by solanezumab compared to placebo.  

The CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels were increased among patients taking gantenerumab compared to placebo at year 2 (mean β, 1.12 ng/mL; SD, 0.43 ng/mL; P =.01) and year 4 (mean β, 1.06 ng/mL; SD, 0.52 ng/mL; P =.04). 

While there were no significant differences in CSF neurofilament light protein (NfL) levels among patients taking gantenerumab, patients taking solanezumab vs placebo showed a significant increase at year 4 (mean β, 0.14; SD 0.06; P =.02). 

The correlation analysis revealed that both treatments had similar positive correlations for the CSF biomarkers, while solanezumab tended to show higher correlation coefficients. 

Study limitations included the original study not providing sufficient power to detect differences in subgroups, some participants not receiving the maximum dose, and a potential limitation in generalizability. 

“Antiamyloid agents removing fibrillar amyloid plaques demonstrated effects on glial and postsynaptic fluid biomarkers downstream of initial amyloid deposition, whereas binding soluble amyloid-β was associated with increased measures of neurodegeneration,” the researchers concluded.