Designing a Prevention Trial for Alzheimer Disease Using Lecanemab: The AHEAD 3-45 Study

Alzheimer disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline. It is a disease driven by the accumulation of amyloid β plaques and tau neurofibrillary tangles. Previous studies show that AD pathology can develop over a continuum, with amyloid and tau changes starting 10 to 20 years prior to the onset of symptoms, highlighting the importance of early intervention. The literature defines the preclinical stage of AD as amyloid buildup in the cortex without clinical impairment, with symptoms emerging once neurodegeneration impacts memory-related brain regions.¹

Lecanemab (Leqembi; Eisai), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, is currently being assessed in the AHEAD 3-45 Study (NCT04468659) to see whether the therapy can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. This is considered the first secondary prevention trial to employ plasma-based biomarkers to improve the screening process and potentially substantially decrease the number of screening PET scans.

Launched in 2020, AHEAD 3-45 consists of 2 sister trials, known as the phase 2 A3 trial and the phase 3 A4 trial, in patients who are cognitively unimpaired (CU).¹ The design, published in Alzheimer's & Dementia, includes specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans. In A45, the primary outcome measure is the cognitive outcome measure Preclinical Alzheimer's Cognitive Composite 5 (PACC5), whereas the primary outcome measure in A3 trial is amyloid PET and the key secondary outcome measure is tau PET.

Michael S. Rafii MD, PhD

(Credit: University of California, San Diego)

“The AHEAD 3-45 Study comprises two parallel trials—A3 and A45—targeting individuals with intermediate (20–40 Centiloids) and elevated (>40 Centiloids) amyloid levels, respectively. The dosing strategies were tailored to the pathophysiological stage of each group: In the A3 Trial (Intermediate Amyloid) participants receive lecanemab 10 mg/kg every 4 weeks over 4 years, aiming to slow amyloid accumulation before it reaches the threshold associated with tauopathy and cognitive decline,” lead author of the study design publication Michael S. Rafii MD, PhD, Professor of Clinical Neurology at the Keck School of Medicine and Medical Director of the Alzheimer's Therapeutic Research at the University of California, San Diego, told NeurologyLive® in a recent interview. “In the A45 Trial (Elevated Amyloid), participants begin with biweekly dosing (10 mg/kg) for 2 years to rapidly reduce amyloid burden, followed by monthly maintenance dosing to prevent re-accumulation. This stratified approach reflects a precision medicine approach, optimizing therapeutic intensity based on disease stage. Clinically, it may enhance efficacy while minimizing unnecessary exposure and risk, especially in asymptomatic individuals”

Key secondary biomarker outcomes will be used to assess effects on the pathophysiology of AD, including amyloid and tau. Exploratory biomarkers in the trial include measures of amyloid, measures of tau, and measures of neurodegeneration. Investigators will assess safety in the trial by monitoring and recording all adverse events, monitoring of hematology, blood chemistry, and urinalysis; measurement of vital signs; electrocardiography (ECG); and the performance of physical and neurological examinations.

“The integration of the C2N plasma p-tau217 assay was a major innovation in the AHEAD trial. It allowed for efficient prescreening by which participants unlikely to have elevated amyloid were excluded early, reducing the need for costly and burdensome PET scans. It also improved trial feasibility since it allowed us to screen more participants (~15,000), accelerate enrollment and reduce costs while reducing radiation exposure from PET scans,” Rafii added.

Eligible participants for this study are patients aged between 55 and 80 years with plasma biomarkers that indicate intermediate or elevated brain amyloid at screening or known amyloid positivity from prior PET, CSF, or plasma testing. Those aged 55 to 64 years must also have a risk factor such as a first-degree relative with dementia onset before age 75, at least 1 APOE4 allele, or documented elevated amyloid before screening. Additional inclusion criteria include a Global Clinical Dementia Rating (CDR) score of 0, a Mini Mental State Examination (MMSE) score of at least 27, and a Wechsler Memory Scale-Revised Logical Memory II score of at least 6 at screening. Participants will be classified by amyloid PET results as either elevated (>40 Centiloids) for the A45 trial or intermediate (20–40 Centiloids) for the A3 trial.

Participants will be excluded from this study if they are pregnant, breastfeeding, or of childbearing potential without effective contraception. Other exclusion criteria include a history of stroke, TIA, or seizures in the past year; recent or active psychiatric disorders; contraindications to MRI; hypersensitivity to monoclonal antibodies; uncontrolled immune or bleeding disorders; abnormal thyroid or vitamin B12 levels; HIV positivity; recent or active malignancies; significant suicidal risk; substance abuse history; or use of prohibited medications. Additionally, participants with prior exposure to antiamyloid therapies, recent investigational treatments, or planned surgeries requiring general anesthesia may also be excluded.

“Designing a unified protocol with both biomarker and cognitive endpoints posed several challenges. There is a temporal mismatch, that is, amyloid and tau changes precede cognitive decline by years, complicating endpoint alignment. To address this, the AHEAD trial employed unique dosing for the appropriate stage of disease with different primary outcomes. The study utilized shared screening pathways, and harmonized assessment schedules across both arms while our use of the PACC5 as a sensitive cognitive composite and tau PET as a secondary biomarker help bridge mechanistic and clinical goals,” Rafii told NeurologyLive.

In January 2023, the FDA originally approved lecanemab for the treatment of patients with early-stage AD and then months later, the agency granted the antiamyloid therapy traditional approval in July 2023.^2,3 The accelerated approval pathway was supported by data from the phase 2b proof-of-concept clinical trial, known as Study 201 (NCT01767311). The pivotal phase 3 Clarity AD trial (NCT03887455).

Clarity AD was an 18-month, double-blind, multicenter trial that featured 1795 participants with early-stage AD with evidence of amyloid on PET or by cerebrospinal fluid testing. The study met its primary end point of change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, with lecanemab-treated patients demonstrating a statistically significant 27% reduction over an 18-month treatment period. Overall, lecanemab-treated patients showed adjusted least-squares (LS) mean changes of 1.21 vs 1.66 for those on placebo (P <.001).⁴

Lecanemab also met secondary end points in Clarity AD, including change in amyloid PET centiloids (difference in LS, –50.12; P <.0001) and Alzheimer’s Disease Assessment Scale-Cognitive 14 (LS difference, –1.442; P = .00005) relative to placebo over the 18-month period. Additionally, it outperformed placebo on ADCOMS (LS difference, –0.00; P = .00002), and Alzheimer’s Disease Cooperative Study–Activities of Daily Living (LS difference, 2.016; P <.00001). Specifically, it slowed disease progression on ADsCOMS by 24% and disease progression on ADCS MCI-ADL by 37% at the same time point.

Safety has been a major concern for antiamyloid therapies and was a point of contention during aducanumab’s approval process. In Clarity AD, lecanemab continued to show a safety profile that was within expectations, with ARIA-E rates of 12.5% in treated patients. Symptomatic ARIA-E occurred at a rate of 2.8% in the lecanemab group and 0.0% in the placebo group. ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis (ARIA-H) occurred at a rate of 17.3% in lecanemab-treated patients and 9.0% for those on placebo. Symptomatic ARIA-H was found in 1.4% of the lecanemab group and 0.2% of the placebo group.

Events of ARIA-E with lecanemab were mostly mild to moderate (91%) based on central reading of imaging with the use of protocol definitions. The most common adverse events in the lecanemab group were infusion-related reactions (26.4%), followed by ARIA-H (17.3%), ARIA-E (12.6%), headache (11.1%), and falls (10.4%). ARIA-H that occurred with ARIA-E tended to occur early, within 6 months of treatment, while isolated ARIA-H occurred throughout the trial. ARIA-E and ARIA-H were numerically less common among noncarriers of apolipoprotein ε4 allele (APOE ε4) than among carriers, with higher frequency among APOE ε4 homozygotes than among APOE ε4 heterozygotes.

There were 3 patient deaths throughout the study, including 1 most recently reported in early January 2023. The case was of a 65-year-old man who was participating in the open-label extension and treated with lecanemab. The individual, homozygous for the APOE ε4 allele, was in the early stages of cognitive decline before being presented to an emergency department 30 minutes after the acute onset of aphasia and left gaze preference due to an ischemic stroke.

After using tissue plasminogen activator (t-PA) to treat the ischemic stroke, the individual experienced acute intracerebral hemorrhage, with the first symptom occurring 8 minutes after t-PA infusion. A CT scan immediately following also showed the presence of cerebral hemorrhages. MRI was performed 3 days after the CT scan and death occurred after the decision by the family to withdraw life support 4 days after the CT scan.

REFERENCES
1. Rafii MS, Sperling RA, Donohue MC, Zhou J, Roberts C, Irizarry MC, Dhadda S, Sethuraman G, Kramer LD, Swanson CJ, Li D, Krause S, Rissman RA, Walter S, Raman R, Johnson KA, Aisen PS. The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer's disease. Alzheimers Dement. 2023 Apr;19(4):1227-1233. doi: 10.1002/alz.12748. Epub 2022 Aug 15. PMID: 35971310; PMCID: PMC9929028.
2. FDA grants acclerated approval for Alzheimer's disease treatment. FDA. News release. January 6, 2023. Accessed July 24, 2025. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
3. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. FDA. News release. July 6, 2023. Accessed July 24, 2025. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
4. Swanson CJ, Zhang Y. Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer disease with lecanemab, an anti-Aß protofibril antibody. Alzheimers Res Ther. 2021;13(80). doi:10.1186/s13195-021-00813-8
5. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer disease. N Engl J Med. Published online November 29, 2022. doi:10.1056/NEJMoa2212948