Familiarity and Perceptions of Aducanumab in Caregivers of Hawaii Alzheimer’s Disease Patients: Results of a Telephone Survey

Aim: To identify current perceptions of aducanumab among patients with Alzheimer’s disease (AD) and their caregivers. Methods: A total of 352 caregivers of AD patients seen at Hawaii’s largest multidisciplinary neuroscience center between January 01, 2019, and June 21, 2021, were surveyed by telephone to understand patient and caregiver knowledge, familiarity, and hesitancy toward aducanumab. Results: Thirty-seven percent of caregivers were familiar with aducanumab. Caregivers who were spouses of their respective patients with AD (p=0.0023) had increased odds of familiarity. Additional predictors of aducanumab familiarity included patients with higher mini-mental state examination scores (p=0.0076) and those who received mental stimulation (p=0.007). Conversely, caregivers who identified as native Hawaiian and other Pacific Islanders (NHPI) (p=0.044) or the patient’s child (p=0.010) were predictors of decreased familiarity. Only 33% of caregivers familiar with aducanumab believed it to be safe and 56% reported “side effects” as their top concern. Thirty percent of caregivers were moderately ready or very ready to use aducanumab if given the opportunity. Conclusion: Most caregivers of Hawaii AD patients were unfamiliar with aducanumab. Furthermore, those familiar were hesitant to trial the medication. Improved education and awareness of AD therapies are important, so families and caregivers of AD patients can make more informed decisions regarding AD treatment.


Introduction
Aducanumab (Aduhelm), a monoclonal antibody treatment from Biogen®, received accelerated approval by the Food and Drug Administration (FDA) on June 7, 2021, due to evidence of it removing beta-amyloid deposits in the brain, a surrogate biomarker for AD progression [1].Results showed a dose-and-timedependent reduction in beta-amyloid pathology with aducanumab in phase 3 studies of EMERGE but not ENGAGE [2].The FDA's approval of aducanumab caused reluctance and criticism with inconclusive results for demonstrating improvement in clinical endpoints [3].Due to the approval of this treatment, acknowledging the public's perception is necessary to better inform successful drug implementation strategies and address concerns expressed by patients with AD and their caregivers [4].There exists a considerable information gap with the accelerated FDA approval process, uncertainty surrounding clinical benefits, and patient information and recommendations by physicians grappling with the controversy and progress of aducanumab [5].Previous surveys measuring knowledge and attitudes toward aducanumab overrepresent non-Hispanic White individuals and conclude a lack of broad understanding or enthusiasm associated with the drug's publicity alone [6].Shortly after aducanumab's approval and during its peak publicity, caregivers of patients with AD at Hawaii's largest multidisciplinary neuroscience institution were surveyed to gauge knowledge and perception of the drug with the goal of determining patient subsets who may require further education and resources.

Materials And Methods
This quality improvement (QI) study utilized a telephone survey to understand patient and caregiver knowledge, familiarity, and hesitancy toward aducanumab.The QI survey was conducted between July 17, 2021, and July 31, 2021, with caregivers of all patients with AD who were seen at Hawaii Pacific Neuroscience (HPN).While HPN receives research funding from Biogen®, there was no financial incentive for survey participation.All participants provided verbal informed consent after disclosure of survey risks, benefits, objectives, and anonymity prior to survey administration.Patient medical records were reviewed, and all data were de-identified.

Survey design
The survey was developed following consultation with a multidisciplinary team of clinicians, including geriatricians and neurologists.All calls were in English and followed a structured script of up to 27 questions.The 10-minute survey included questions regarding AD patients' current management, overall disease progression, and caregivers' familiarity with aducanumab (Table 1).Caregivers familiar with the drug were then asked questions specific to aducanumab, including their perception of medication safety, concerns, and readiness to incorporate aducanumab into their respective patient's treatment plans (Table 2).All caregivers were also asked to identify their patient's primary medical decision-maker and provide demographic information for the patient and caregiver.

Study population and data collection
Participants included caregivers of all patients with AD who were seen at HPN between January 1, 2019, and June 22, 2021, excluding caregivers of patients with AD who were deceased at the time of the survey.Patients with AD who cared for themselves were considered their own caregivers.Sociodemographic data, including age, insurance type, race, sex, zone improvement plan (ZIP) code, and medical comorbidities, were also collected from each patient's electronic medical records.The ZIP code served as a proxy measure for the median household income and population size of each patient's municipality [7].

Statistical analysis
Bivariate analyses utilized nonparametric testing.Categorical variables were assessed with Pearson's chisquared test or Fisher's exact test of independence for sample sizes less than five with Haldane-Anscombe correction, as necessary [8][9][10][11][12].These were reported as odds ratios (OR) with 95% confidence intervals (95% CI).Each OR represented the odds of being familiar with aducanumab.Continuous variables were assessed by the independent Wilcoxon rank sum test.Multivariable logistic regression models with Firth's correction were utilized to identify factors that independently predicted familiarity with aducanumab [13].All tests were two-tailed with an alpha level of <0.05 being considered statistically significant.Analyses were conducted through R statistical software (R Foundation for Statistical Computing, Vienna, Austria) [14].

Survey respondents
Of the 352 patients identified with AD, 13 patients were deceased, and 339 were alive at the time of the survey.Eighty-six (25.4%) survey responses out of 339 eligible caregivers were collected.Fifty-four (62.8%) caregivers were unfamiliar with aducanumab, while 32 (37.2%) caregivers were familiar with the drug.Familiarization with aducanumab was found to be greater for caregivers who were spouses of their respective patients with AD (OR:

Discussion
To the best of our knowledge, this study is among the first to survey caregivers of patients with AD on their familiarity and perceptions of aducanumab.Only 37.2% of caregivers who completed our survey were familiar with aducanumab, similar to a 2022 online survey, in which 25% of their respondents (adults nationwide aged 35 years and older) reported initial familiarity [15].In contrast to prior surveys, this is one of the first studies to directly contact caregiver units of patients with AD, rather than the general population, so it is the first to characterize familiarity based on the caregiver's relationship with the patient.Importantly, as evidenced by literature regarding the retention of AD patients in clinical trials, the caregiver plays a crucial role in the patient's continued participation in treatment trials [16].
Our results demonstrated a decreased likelihood of aducanumab familiarity among NHPI caregivers and caregivers who were children of the AD patient.Compared to previous surveys regarding aducanumab in which the NHPI population comprised less than 3.4% of respondents [6,15], our survey included a robust number of NHPI respondents that encompassed 26.6% of all respondents.NHPI are severely underrepresented in medical studies and clinical trials, previously having their data aggregated with Asian Americans and thus misreporting their race-associated outcomes [17].Previous studies have found perceived financial stress to be associated with cost-related treatment nonadherence behavior trends in NHPI populations [18].Other studies note cultural safety, an intention to learn about diverse cultures, consideration of historical contexts of different ethnic groups, and emphasizing cautious communication with NHPI patients when introducing treatment regimens [19].Insight into direct opinions concerning treatments will further illuminate both concerns and barriers to considering aducanumab.
The majority of caregivers who were familiar with aducanumab reported "safety regarding side effects" as the most concerning factor regarding the drug, whereas a smaller subset reported medication cost as their top concern.DiStefano et al. noted a general willingness (60%) to enroll a family member in a randomized placebo-controlled trial for aducanumab and a general unwillingness to pay certain premium increases [15].These discrepancies may point to different survey populations, with our study's caregivers being more directly involved in treatment finances than the age-stratified general public populations in online surveys.
Absolute generalization remains limited due to a small sample size compared to other survey studies on aducanumab.While such surveys were automated and incentivized, few investigated aducanumab hesitancy and knowledge through survey administration, none were conducted through phone interviews, and none directly contacted family units of AD patients.Since this study was conducted in Hawai'i, wherein the ethnocultural and racial population makeup is strikingly different to the rest of America, these results might be extrapolated to parts of the country with more ethnocultural and racial homogeneity [20].Additionally, aducanumab is more widely used and available, with many patients enrolled in the Biogen Phase IV ENVISION trial.Sentiments may be changing, and our group aims to collect follow-up data for comparison.
In addition, future studies may compare hesitancy and knowledge of developing medications with the current standard of care.

Conclusions
Overall, our study suggests that patients and caregivers living with AD in Hawai'i have concerns about aducanumab's efficacy, safety, and costs.Most caregivers are not willing to have their respective patients with AD participate in a therapeutic trial for aducanumab.Our findings suggest a greater need for caregiver education and involvement, especially among underrepresented racial groups (NHPI) that are less familiar with aducanumab and AD treatments.Future studies should highlight underrepresented and underserved populations specifically, as current studies of primarily Caucasian populations report aducanumab concerns inconsistent with our study's findings.Since aducanumab familiarity may not be directly associated with an accurate level of knowledge, additional medication education is necessary by clinicians and informed healthcare professionals to deliver accurate, up-to-date information to guide treatment decision-making and understanding.