Novel CSF Biomarkers CHIT1 and DDAH1 May Predict ARIA Risk in Alzheimer's Patients Receiving Anti-Amyloid Therapies
Key Insights
Researchers identified two cerebrospinal fluid biomarkers, CHIT1 (search) and DDAH1 (search), that may help predict amyloid-related imaging abnormalities (ARIA (search)) risk in Alzheimer's disease patients receiving anti-amyloid antibody treatments.
The study analyzed extreme risk phenotypes in AD patients and found that high-risk patients showed elevated CHIT1 (search) levels and decreased DDAH1 (search) levels compared to low-risk patients and controls.
ARIA (search) occurs in 10-40% of patients receiving anti-amyloid therapies like lecanemab and donanemab, with most cases being asymptomatic but rare instances potentially fatal.
Researchers have identified two cerebrospinal fluid (CSF) biomarkers that could help predict which Alzheimer's disease patients are at highest risk for developing amyloid-related imaging abnormalities (ARIA (search)), a potentially serious side effect of newly approved anti-amyloid antibody therapies. The findings, published in Alzheimer's Research & Therapy, represent the first comprehensive investigation of how ARIA risk profiles affect the CSF proteome in AD patients.
The study focused on ARIA (search), which occurs in 10-40% of patients receiving anti-amyloid therapies such as lecanemab (Leqembi; Eisai) and donanemab (Kisulna (search); Eli Lilly). While approximately 70% of ARIA cases are asymptomatic, the condition can range from mild symptoms to, in rare cases, death. ARIA presents as either microhemorrhages or superficial siderosis (ARIA-H) or vasogenic edema or sulcal effusions (ARIA-E) on magnetic resonance imaging.
Identifying High-Risk Patient Profiles
The research team analyzed CSF samples from 156 AD dementia patients and 100 cognitively unimpaired individuals from the Amsterdam Dementia Cohort. They defined extreme risk phenotypes based on established ARIA (search) risk factors: presence of microbleeds (MBL+), APOE E4 (search) carriership (APOE4+), and extremely low CSF Aβ42 (search) levels (AL).
The highest-risk group (MBL+APOE4+AL) comprised 13 patients, while the lowest-risk group (MBL-APOE4-AU) included 23 patients. Using proximity extension assay technology, researchers measured 979 proteins, with 642 meeting quality criteria for analysis.
Novel Biomarker Discovery
Two proteins emerged as potential ARIA (search) risk biomarkers after surviving multiple testing correction: CHIT1 (search) (chitinase-1 (search)) and DDAH1 (search) (dimethylarginine dimethylaminohydrolase 1 (search)). CHIT1 levels were significantly elevated in high-risk patients (β = 1.006, p = 0.014), while DDAH1 levels were significantly decreased (β = -0.305, p = 0.046) compared to low-risk patients.
The biological analysis revealed that high-risk AD patients showed lower CSF protein levels related to synaptic function and axonogenesis compared to low-risk patients. Specifically, proteins related to glutamatergic and asymmetric synapses were reduced, suggesting potential astrocytic impairment that could predispose patients to ARIA (search) events.
Validation and Clinical Implications
The findings were validated in an independent cohort of 23 patients from the Amsterdam Dementia Cohort and Sant Pau Initiative on Neurodegeneration. The validation confirmed a trend toward increased CHIT1 (search) levels (p = 0.104) and significantly decreased DDAH1 (search) levels (p = 0.010) in the highest-risk group.
Meta-analysis across both cohorts showed an overall increase in CHIT1 (search) levels with an estimate of 0.86 (95% CI [0.31-1.41]) and an overall decrease in DDAH1 (search) with an estimate of -0.34 (95% CI [-0.53 to -0.15]).
Biological Mechanisms
DDAH1 (search)'s primary function involves metabolizing asymmetric dimethylarginine (ADMA), which increases nitric oxide levels—a signaling molecule involved in vasodilation, immune response, and neurotransmission. The protein is mainly expressed by neurons and endothelial cells in the brain. Reduced DDAH1 levels may indicate blood-brain barrier dysfunction and reduced neuroprotective capacity, potentially increasing ARIA (search) susceptibility.
CHIT1 (search), expressed primarily by activated macrophages in the brain's white matter, plays a crucial role in innate immunity. Elevated CHIT1 levels may indicate an activated immune response or increased macrophage infiltration that could prime perivascular macrophages for ARIA (search) development following treatment initiation.
Clinical Monitoring Requirements
Current clinical practice requires extensive MRI monitoring for ARIA (search) detection. For lecanemab, mandatory MRIs are scheduled before the 3rd, 5th, 7th, and 14th infusions, while donanemab requires monitoring before the 3rd, 4th, and 5th infusions. Additional unscheduled MRIs may be necessary if patients develop new headaches, focal symptoms, or other concerning signs.
As Dr. Sharon Cohen, an Alzheimer's disease expert, noted at the 2025 Alzheimer's Association International Conference, "Most ARIA (search) is asymptomatic, resolves on its own, and doesn't lead to long-term impairment in cognition. However, occasionally—rarely—ARIA can be serious, severe, and even fatal."
Future Clinical Applications
The identification of CHIT1 (search) and DDAH1 (search) as potential ARIA (search) risk biomarkers could facilitate the development of predictive tools to identify high-risk patients before treatment initiation. This could enable more personalized treatment decisions and potentially more intensive monitoring protocols for patients at greatest risk.
The researchers acknowledge limitations including small sample sizes in extreme phenotype groups and the use of risk factor proxies rather than actual ARIA (search) cases due to limited real-world post-treatment data. However, the validation in an independent cohort using orthogonal assays strengthens confidence in these findings.
These biomarkers represent a significant step toward addressing the unmet clinical need for tools that can accurately predict ARIA (search) risk, potentially improving the safety profile of anti-amyloid therapies that are becoming increasingly important in Alzheimer's disease treatment.