Selecting Alzheimer’s Patients for Anti-Amyloid Therapy

Recently approved disease-modifying treatments for Alzheimer’s disease have created a sudden demand, but these and other drugs in the pipeline are not for all patients with clinical Alzheimer’s symptoms, experts said.

“Alzheimer’s disease has been recognized on clinical grounds for many decades, but the availability of targeted treatments has increased the importance of clinical biomarkers to establish the diagnosis with certainty,” said Lyell Jones Jr., MD, of the Mayo Clinic in Rochester, Minnesota, who co-authored the American Academy of Neurology (AAN) Quality Committee’s guidance about the drugs.

The new anti-amyloid monoclonal antibodies “are specifically targeted for patients with Alzheimer’s disease, not other causes of dementia such as dementia with Lewy bodies, frontotemporal dementia, or vascular cognitive impairment,” Jones emphasized.

The AAN Quality Committee developed its report about Alzheimer’s anti-amyloid drugs given “the urgent need to inform clinicians about these novel therapies,” he added.

To date, two monoclonal antibodies targeting amyloid in early Alzheimer’s disease have been approved by the FDA: lecanemab (Leqembi), which received full approval in 2023; and aducanumab (Aduhelm), which received accelerated approval in 2021 and is now being discontinued by the drugmaker. The FDA is expected to decide on full approval for a third agent in the class, donanemab, early in 2024.

“Patients and families should be aware that these treatments involve careful patient selection, require a commitment to monitoring over time, and may be incompatible with other common therapies in this patient population such as anticoagulation,” Jones pointed out.

The anti-amyloid treatments approved so far share the requirement that treatment candidates are patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease — the same population used in clinical trials — not people with presymptomatic Alzheimer’s or moderate/severe dementia. Both mild cognitive impairment and mild dementia can be characterized by objective evidence of cognitive impairment.

Evidence of amyloid is also required. In the phase III trials, amyloid PET scans or cerebrospinal fluid (CSF) tests fulfilled this requirement, though acceptable blood tests may be available in the future. “Imaging or other biomarkers assessing tau protein deposition may help identify patients most likely to benefit from the therapies,” Jones noted.

Pretreatment evaluations can help identify candidates with acceptable risk for adverse events. “The primary risks of anti-amyloid monoclonal antibody therapies that clinicians should be familiar with are ARIA [amyloid-related imaging abnormalities],” Jones said.

“These come in two categories, ARIA associated with cerebral edema [ARIA-E], and ARIA associated with hemorrhage [ARIA-H],” he continued. “These are usually asymptomatic but occasionally lead to clinically meaningful complications, and therefore require careful patient screening, selection, and monitoring clinically and with imaging.”

Lecanemab prescribing information carries a boxed warning about ARIA. In the phase III CLARITY-AD trial, 12.6% of participants treated with lecanemab had ARIA-E. Most ARIA-E events were asymptomatic, occurred in the first 3 months of the treatment period, and resolved within 4 months after they were detected. The incidence of isolated ARIA-H was 8.9%, which occurred throughout the trial.

“MRI is useful for risk stratification by screening for microhemorrhages, which increase the risk of complications of the anti-amyloid monoclonal therapies, and also for excluding other potential causes of cognitive impairment,” Jones noted. In addition to a screening MRI, candidates will need additional MRIs for treatment monitoring and for any urgent studies if adverse events occur.

Other important factors to consider include patients’ APOE genotype and medical history. “Patients with APOE4, particularly those who have two copies of the gene, are at high risk for ARIA,” noted Jeffrey Cummings, MD, ScD, of the University of Las Vegas, who led the independent Alzheimer’s Disease and Related Disorders Therapeutics Work Group that produced appropriate use recommendations for lecanemab.

“Our appropriate use recommendations suggest testing all patients being considered for monoclonal antibody therapy for their APOE genotype, so that an informed risk discussion can occur between the clinician and the potential recipient of therapy,” Cummings said.

Medical history includes reviewing all other medications, including anticoagulants, that patients are using. The lecanemab label cautions against using blood thinners while on the medication.

“There may be a slight increase in ARIA in patients on lecanemab and anticoagulants, and our appropriate use recommendations currently suggest not using lecanemab in patients who require anticoagulants. This may be revised as new data accumulate,” Cummings said.

“As far as we can tell, aspirin poses no additional risk of ARIA, and this would not be a factor in selecting patients for treatment with monoclonal antibodies,” he added.

While much patient selection guidance comes from data in phase III anti-amyloid trials, the AAN committee noted that a flexible interpretation may be appropriate for some treatment candidates. Some patients outside the age groups or Mini-Mental Status Examination (MMSE) scores used in the lecanemab phase III trial might be considered reasonable candidates for therapy, including younger patients with sporadic Alzheimer’s disease, the committee said.

The key is judicious patient selection, observed AAN Quality Committee member Vijay Ramanan, MD, PhD, also of the Mayo Clinic in Minnesota. “This places a premium on clinicians having a strong working understanding of treatment indications, goals, side effects and lifestyle impacts, and alternatives, and utilizing that foundation to engage in shared decision-making with patients and caregivers to chart the best path forward,” he said.

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