Tolerability and safety with aducanumab in Alzheimer's disease in a community‐based setting on a slower titration schedule

Aducanumab is a monoclonal amyloid beta-directed antibody that was contingently approved by the US FDA for treating Alzheimer's disease (AD) in a controversial decision.1 The FDA initially approved the drug without specifying severity level or biomarker confirmation and subsequently limited approval to those with MMSE above 23 and AD biomarker confirmation.1-3 In pivotal clinical trials, amyloid related imaging abnormalities (ARIA) of brain edema, microhemorrhages, and superficial siderosis were seen in 30% of the group receiving 3 mg/kg dose (all ApoEε4 carriers), 21% in the 6 mg/kg group (fewer ApoEε4 carriers) and 41% in the 10 mg/kg group, noted most often in the first 8 months of treatment.4 There are as yet, no available reports on using aducanumab in a clinical setting. We retrospectively reviewed side effect and tolerability data on 20 patients treated with aducanumab in a community-based setting. This report concerns 19 persons with a diagnosis of AD and one with amnestic mild cognitive impairment treated with aducanumab in a community-based practice. There were 13 women and 7 men (Table 1) with an average age of 70 years (range 32–83). The average educational attainment was 16 years (range 13–20 years). Nineteen were Caucasian, one was Asian. Diagnoses were all confirmed with biomarker testing (positive amyloid scans = 11; positive cerebrospinal fluid analysis = 9). The average mini-mental state examination (MMSE) score was 22 (range 9–29). Seventeen were ApoEε4 carriers (two were APOE4/4; one with PSEN1 mutation). Institutional review board approval was obtained from the Feinstein Northwell. Postulating that rapid plaque dissolution may exacerbate the ARIA, a slower titration schedule was adopted in these patients than was used in the pivotal trials. ApoEε4 carriers were titrated up by 1 mg/kg every 4 months and non-carriers every 3 months. At the time of writing, 16 have completed at least 8 infusions and have had at least one MRI and 10 patients have completed at least 12 infusions and have had two MRIs. All but one was ApoEε4 carriers. The current average dose is 3 mg/kg (range 1–6 mg/kg). Among the 20 patients treated, none have developed clinically apparent ARIA, confirmed in the 16 with available post-treatment MRIs. Two patients, both homozygous carriers, complained of transient headaches. One patient developed a subdural from a fall, and her infusion was stopped for a month, then restarted at 1 mg/kg. Another missed an infusion and was restarted at 1 mg/kg. A third patient opted to stop treatment after 7 months after seeking another opinion. Amyloid plaques predate the onset of symptoms by as much as 25 years.5 ARIA is a major clinical concern for physicians and patients considering anti-amyloid therapies for AD, notwithstanding debate about clinical efficacy. Careful screening and a slower titration schedule may be useful in reducing the incidence of ARIA in the clinical use of drugs of this class. There are no conflicts of interest. The author was responsible for the conception of study, data analysis, and writeup of the study. The author would like to acknowledge Casey Linnane for her help with data collection. There are no sponsors or funding for the study. The author received no funding for this work.