A South Korean research team has identified the potential to use immune proteins in the blood to predict the effectiveness of Alzheimer’s disease antibody treatment and the risk of side effects.
Seoul St. Mary’s Hospital announced Sept. 15 that a research team led by Professor Kang Dong-woo of the Department of Psychiatry’s Memory Disorder Clinic found that blood levels of complement proteins C1q and C3 measured before lecanemab treatment were associated with treatment effectiveness and the occurrence of side effects. Professor Byun Ki-hwan participated as the study’s first author.
The study found that higher C1q levels before treatment were associated with smaller reductions in amyloid accumulated in the brain after treatment. Patients with lower C3 levels before treatment also showed a tendency toward more frequent amyloid-related imaging abnormalities (ARIA).
Lecanemab is an antibody treatment that targets and helps remove amyloid beta accumulated in the brain. It is used in patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease who have confirmed amyloid accumulation in the brain. It does not cure dementia or restore damaged cognitive function but is intended to slow the progression of cognitive decline.
A representative side effect is ARIA. ARIA refers to abnormalities such as brain swelling or microhemorrhages that appear on MRI scans during antibody treatment. It is often asymptomatic, but some patients may experience headaches, dizziness, visual changes, confusion or seizures.
In particular, homozygous carriers of two copies of the apolipoprotein E ε4 (APOE ε4) gene are known to face a higher risk of ARIA. As a result, genetic profiles and brain MRI findings are checked before treatment, and patients also undergo regular MRI scans during treatment to monitor safety.
The research team retrospectively analyzed real-world clinical data from 62 patients with early Alzheimer’s disease who began lecanemab treatment at Seoul St. Mary’s Hospital.
Among them, the team also analyzed changes in amyloid accumulation in 34 patients who underwent both amyloid positron emission tomography (PET) scans before treatment and after 26 weeks of treatment.
Among patients who underwent follow-up PET scans, the average Centiloid value measuring amyloid burden in the brain fell from 67.8 before treatment to 38.1 after 26 weeks. The average reduction was 29.7 Centiloids, equivalent to 43.8% of the pretreatment level.
The C1q and C3 proteins examined by the research team are part of the complement system, which is involved in the body’s innate immune response. The complement system recognizes bacteria, damaged cells and abnormal proteins and helps other immune cells remove them.
C1q is a protein that initiates the complement response, while C3 plays a central role as the immune response continues. Researchers have proposed that the complement pathway may also be activated when anti-amyloid antibodies bind to amyloid beta inside and outside the brain.
The team’s analysis found that higher blood C1q levels before treatment were associated with smaller reductions in amyloid measured by PET after 26 weeks. The association remained in the same direction after accounting for age, sex, pretreatment amyloid burden and APOE ε4 carrier status.
Patients with lower C3 levels before treatment showed a tendency toward more frequent ARIA. ARIA occurred in seven of the 62 patients, or 11.3%. Five cases were mild and two were moderate.
Currently, major indicators used to assess ARIA risk include APOE ε4 genotype and findings such as microhemorrhages and superficial siderosis identified on MRI before treatment. If confirmed in follow-up studies, a relatively simple blood test could be used alongside existing genetic and imaging tests as an additional tool to further stratify risk for individual patients.
However, the study was an exploratory analysis conducted at a single medical institution. It included only 62 patients, with ARIA occurring in just seven. The findings alone are not sufficient to use C1q and C3 as predictive tests for determining whether a patient should receive treatment.
The research team said future prospective studies involving multiple medical institutions will be needed to verify the causal relationship between the two proteins and treatment response and to establish appropriate threshold values.
Professor Kang said, “By linking blood test results and brain imaging data obtained in real-world clinical practice, we found that the complement proteins C1q and C3 may be associated with amyloid reduction and ARIA, respectively, during anti-amyloid antibody treatment.” He added, “We will verify their clinical usefulness through follow-up studies involving multiple institutions.”
The findings were published in Alzheimer’s & Dementia: Translational Research & Clinical Interventions, an international academic journal published by the Alzheimer’s Association.
