Starting With Confidence: A Practical Framework for Amyloid-Targeting Therapy in Early Alzheimer’s Disease

Starting With Confidence: A Practical Framework for Amyloid-Targeting Therapy in Early Alzheimer’s Disease

Amyloid-targeting therapies have changed the conversation about early symptomatic Alzheimer’s disease. Lecanemab and donanemab have demonstrated clinically meaningful slowing of cognitive and functional decline in clinical trials, creating an opportunity to intervene while patients have mild cognitive impairment or mild dementia. These treatments do not restore lost cognition, and their potential benefits must be weighed against adverse effects and the demands of ongoing monitoring.^1,2

For healthcare professionals, translating this opportunity into practice requires more than identifying a positive biomarker. Drawing on insights from Alzheimer’s specialist Dani Cabral, MD, this article presents a practical framework for recognizing potential candidates, interpreting amyloid testing, and establishing a reliable approach to amyloid-related imaging abnormality (ARIA) monitoring.

Identifying Patients Within the Treatment Window

Recognizing Early Symptomatic Disease
The starting point is a clinical assessment of cognitive change. As Dr. Cabral explains, conversations with the patient and family, together with bedside cognitive testing, can help identify the changes that warrant further evaluation. Importantly, for some patients, brief cognitive testing results will be normal early on in the disease. The key questions are whether cognition has declined from the person’s previous abilities and how that decline affects everyday function. Hearing from family members and informants can provide crucial information at these early stages.

Mild cognitive impairment and mild dementia represent the symptomatic stages in which these treatments were studied. A screening score alone does not establish Alzheimer’s disease or treatment eligibility; the assessment must also characterize function and consider other contributors to impairment. Timely recognition allows appropriate evaluation and treatment to begin before disease severity progresses beyond what was studied in clinical trials.^1–4

Establishing Amyloid Pathology
Once the clinical presentation is characterized and staged, confirm amyloid pathology. Amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers provide established approaches. Blood-based biomarkers offer an additional option for amyloid confirmation, but the meaning of a result depends on the assay’s performance, intended use, and the patient’s clinical context.^3–5

Interpreting Biomarkers in Clinical Context

Understanding Pretest Probability
Dr. Cabral emphasizes a question that should precede testing: How likely is this patient to have amyloid pathology before the result is known? An older adult with a progressive amnestic presentation has higher pretest probability than someone whose symptoms are less characteristic of Alzheimer’s disease. This clinical estimate affects how confidently you can interpret a positive or negative result. For the same test, a positive result is less likely to represent true amyloid pathology when pretest probability is low. Conversely, a negative result may require further evaluation when clinical suspicion remains high. Patient (and family) pretest counseling on the limitations of biomarker results is helpful. Some patients with a low pretest probability may decide to forgo these tests given our current understanding.

A biomarker result should therefore be reconciled with the history and examination, particularly when the findings are discordant.⁵

Knowing When Additional Testing Is Needed

Blood-based biomarkers are not interchangeable. The Alzheimer’s Association guideline distinguishes assays suitable for triage from those with sufficient accuracy to substitute for PET or CSF testing in specialized care. A positive triage result requires confirmation, while indeterminate or clinically discordant findings may warrant PET or CSF testing. The selected assay and applicable treatment pathway should guide next steps, as a positive blood test alone does not necessarily establish treatment candidacy.⁵

Assessing ARIA Risk Before Treatment

Integrating Genetics and Baseline Imaging
ARIA includes edema or effusion (ARIA-E) and hemorrhagic findings such as microhemorrhages and superficial siderosis (ARIA-H). Although many events are asymptomatic, serious and rarely fatal events can occur. The risk discussion belongs before treatment initiation, alongside expectations about clinical benefit.^3,4

Dr. Cabral highlights APOE ε4 status as an important part of this assessment. Patients with two ε4 alleles have a higher ARIA risk than heterozygotes or noncarriers. APOE testing should be accompanied by a discussion of how the results inform treatment-related risk and the implications of genetic information for patients and their families.^3,4

A recent baseline MRI is another essential component of the assessment. Preexisting microhemorrhages, superficial siderosis, and severe small vessel disease may affect treatment eligibility and risk. The number and pattern of abnormalities should be evaluated against the criteria for the specific therapy. The baseline scan also serves as a reference for interpreting subsequent imaging changes.^3,4

Reviewing Medical Conditions and Medications

The pretreatment assessment should address active medical conditions and medications that may increase hemorrhage risk. Dr. Cabral specifically highlights anticoagulants. Appropriate use recommendations advise against treatment in patients requiring anticoagulation, underscoring the importance of medication reconciliation and coordination with the prescribing clinician during patient selection. Necessary anticoagulation should not be discontinued solely to establish treatment eligibility.^3,4 However, in certain cases, alternatives to anticoagulants may be considered through shared decision-making with motivated patients and in collaboration with their medical team.

Making Monitoring Part of the Treatment Plan

Combining Scheduled MRI With Symptom Surveillance
Monitoring is most intensive early in treatment, when ARIA is more likely to occur. Dr. Cabral emphasizes keeping MRI appointments and maintaining access to a medical center that can evaluate potential complications. Practices must follow the current, agent-specific prescribing information rather than use one generic schedule for all amyloid-targeting therapies.^3,4

Monitoring recommendations may evolve as safety experience grows. For example, the FDA added an MRI before the third lecanemab infusion, supplementing the previously recommended scans before the fifth, seventh, and fourteenth infusions. Treatment protocols should reflect these updates and ensure that required MRI findings are reviewed before proceeding.⁶

Scheduled imaging does not replace symptom-triggered evaluation. Patients and care partners should be instructed to promptly report new headaches, confusion, visual changes, dizziness, or difficulty walking. Seizures or focal neurologic deficits require urgent evaluation. Suspected ARIA warrants clinical assessment and MRI, with treatment decisions guided by symptom severity, imaging findings, and the relevant prescribing information.^3,4,6

Building Reliable Practice Workflows

“It’s really important to develop strong protocols and workflows in your practice and put in that time up front to create those.”
- DANI CABRAL, MD

Preparation translates monitoring recommendations into a reliable clinical workflow. The practice should establish clear responsibilities for scheduling scans, reviewing results, communicating whether treatment can proceed, and responding to symptoms between visits. Patients and families also need a clear point of contact and instructions for obtaining urgent care. These arrangements help ensure coordinated care and timely follow-up.

Integrating Evidence Into Clinical Practice

Amyloid-targeting therapy brings patient selection and safety monitoring into the same clinical pathway. Recognizing early symptomatic disease, confirming amyloid pathology in the appropriate clinical context, and assessing genetic, imaging, and medication-related risks establish the basis for informed treatment discussions.

Dr. Cabral’s practical message is that treatment planning extends beyond the initial decision to initiate therapy. With clear expectations, coordinated monitoring, and reliable communication, clinicians can partner with patients and families to weigh the potential to slow cognitive and functional decline against the risks and responsibilities of treatment and reach a shared, informed decision.

References:

1. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948
2. Sims JR, Zimmer JA, Evans CD, et al; TRAILBLAZER-ALZ 2 Investigators. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527. doi:10.1001/jama.2023.13239
3. Cummings J, Apostolova L, Rabinovici GD, et al. Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis. 2023;10(3):362-377. doi:10.14283/jpad.2023.30
4. Rabinovici GD, Selkoe DJ, Schindler SE, et al. Donanemab: appropriate use recommendations. J Prev Alzheimers Dis. 2025;12(5):100150. doi:10.1016/j.tjpad.2025.100150
5. Palmqvist S, Whitson HE, Allen LA, et al. Alzheimer’s Association Clinical Practice Guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer’s disease within specialized care settings. Alzheimers Dement. 2025;21(7):e70535. doi:10.1002/alz.70535
6. US Food and Drug Administration. FDA to recommend additional, earlier MRI monitoring for patients with Alzheimer’s disease taking Leqembi (lecanemab). August 28, 2025. https://www.fda.gov/drugs/drug-safety-communications/fda-recommend-additional-earlier-mri-monitoring-patients-alzheimers-disease-taking-leqembi-lecanemab
7. Expert commentary and quotations: Dani Cabral, MD. ReachMD–GLC transcript 60977; supplied recording transcript, duration 05:07.