Higher CSF Aß42/Total Tau Ratio Associated With Increased ARIA Risk in Lecanemab

Findings from a single-center retrospective study revealed that higher amyloid-ß (Aß)42/total tau index (ATI) ratios in cerebrospinal fluid (CSF) leads to an increased risk of amyloid-imaging abnormalities (ARIA) in lecanemab-treated patients with early-stage Alzheimer disease (AD). Overall, these data suggest ATI may serve as a candidate CSF biomarker for predicting ARIA risk, potentially enhancing patient selection and monitoring during therapy.¹

The trial, led by Javier Romero, MD, director of the R.H Ackerman Neurovascular Lab at Massachusetts General Hospital, featured 54 patients with AD treated with lecanemab, 27 of whom developed ARIA post-treatment. Coming into the study, the baseline characteristics were comparable between ARIA-positive and ARIA-negative patients; however, over time, investigators observed that ATI was significantly higher among patients who developed ARIA (0.8760 vs 0.6217; P = .0337). These findings were confirmed on logistic regression, as higher ATI was correlated with increased ARIA risk (OR, 8.741; 95% CI, 1.242-92.19; P = .0284), with an area under the receiver operating curve of 0.696 (P = .042).

Presented at the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, the study investigators whether CSF biomarkers could predict ARIA in patients with AD treated with lecanemab, an antiamyloid therapy approved in 2023. Lecanemab, a monoclonal antibody approved for individuals with mild cognitive impairment or mild dementia stage AD with confirmed amyloid pathology, was approved with labeling that notes required monitoring for ARIA during the first year of treatment.

In the study, findings showed no significant differences in lipid profiles, HbA1c levels, CSF Aß42, phosphorylated tau (p-tau) levels, or p-tau/Aß42 ratio based on ARIA-positivity status. ARIA-positive patients demonstrated lower total tau levels (408.6 vs 626.6 pg/mL; P = .067), but this did not reach statistical significance. The study also did not find any association between Montreal Cognitive Assessment (MoCA) scores, a measure of cognition, and ATI (P = .626).

In Clarity AD, the phase 3 trial that served as the basis for lecanemab’s approval, ARIA-edema (ARIA-E) occurred in 12.5% of treated patients, while ARIA-H, which includes cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis, occurred at a rate of 17.3%. In addition, symptomatic ARIA-E and symptomatic ARIA-H occurred in 2.8% and 1.4% of lecanemab-treated patients, respectively. The FDA-approved label reports that concomitant antithrombolytic medication (aspirin, antiplatelet, or anticoagulant) with lecanemab therapy resulted in intracerebral hemorrhage in 2.5% of individuals during clinical trials.²

When assessing ARIA risk based on apolipoprotein (APOE) genotype, results showed that homozygous ε4/ε4 carriers had higher likelihood of developing ARIA. In Clarity AD, the frequency of symptomatic ARIA-E was 9% in these individuals while the frequency of any ARIA was even greater, at 45%. In comparison, symptomatic ARIA-E and the risk of any ARIA occurred in 2% and 19%, respectively, in heterozygous patients with ε4/εx mutations. Notably, these risks were even lower among patients with no ε4 allele detected (symptomatic ARIA-E: 1%; any ARIA: 13%).³

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REFERENCES
1. Zhu S, Rohatgi, S, Ford J, et al. Elevated CSF Aß/42 total tau index predicts ARIA risk in Alzheimer’s patients treated with lecanemab. Presented at: 2025 AD/PD Annual Meeting; April 1-5; Vienna, Austria. ABSTRACT ID: 3211
2. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9-21. doi:10.1056/NEJMoa2212948
3. Kane M. Lecanemab therapy and APOE genotype. Medical Genetics Summaries. Published online August 12, 2024. Revised: November 25, 2024. https://www.ncbi.nlm.nih.gov/books/NBK605938/#