While standard-of-care treatments for enhancing brain function have been available for years (e.g., donepezil, rivastigmine, galantamine, memantine), none have been shown to slow disease progression. Hence, the introduction of novel disease-modifying treatments (DMTs) herald a new phase in AD research and development, detailed below.

Current Treatment Landscape

Monoclonal antibodies for the treatment of AD have a similar mechanism of action to and target the underlying cause of the condition: β-amyloid (Aβ) plaque formation. However, given that disease development spans approximately 20 years and involves multiple mechanisms, available treatments do not prevent disease progression and are currently used only in patients with an early-stage AD (i.e., mild cognitive impairment due to AD and mild AD dementia). Table 1 provides an overview of the currently available DMTs for the treatment of AD.

Table 1. FDA-Approved DMTs for the Treatment of Early-Stage AD

ARIA: Amyloid-Related Imaging Abnormalities
*Combined ARIA-Edema and ARIA-Hemorrhage, including asymptomatic radiographic events.

Notably, the first agent approved by the US Food and Drug Administration (FDA) in June 2021, aducanumab (brand name Aduhelm®), was discontinued by the manufacturer (Biogen) in 2024. Biogen publicly shared the decision was driven by the company’s shifting priorities, not by aducanumab’s efficacy or safety.

Clinical data for both lecanemab and donanemab have demonstrated they are highly efficacious at slowing the disease progression (by an average of six months in clinical trials), but there are several factors limiting widespread adoption:

• Variability in treatment duration (potentially indefinite for lecanemab vs. variable for donanemab), coupled with limited long-term follow-up outcomes data, may preclude not only HCPs from prescribing these treatments but also payers from covering them.
• The risk of ARIAs with subsequent requirements for regular magnetic resonance imaging poses not only a clinical but also a financial burden, which may limit the use and adoption of currently approved AD treatments.
• Previous history of bleeding disorders and concomitant use of anticoagulants limit the use of AD DMTs in these patient populations.
• Infusion-related reactions and overall infusion burden (including limited access to infusion centers) further limit treatment adoption.
• A high net price coupled with stringent payer coverage criteria may pose limitations for some patients.
• Individuals with at least one copy of the APOE4 gene (a demonstrated risk factor for developing AD) are at a higher risk of developing ARIA when being treated with one of the approved DMTs. For this reason, donanemab was not approved in Europe. In the US, the use of both DMTs in patients with APOE4, particularly those who are carriers of two gene copies, is limited or not allowed due to payer coverage restrictions.

These factors present unmet needs that require further research, evidence generation and updated commercialization strategies that consider alternative treatment options.

Clinical Development Pipeline

The clinical pipeline for AD is very robust, with more than 100 drugs being evaluated in over 180 clinical trials, spanning Phases I through III (Figure 1). A variety of treatment options are being evaluated, including disease-modifying small molecules and biologics, as well as cognitive enhancers and symptomatic treatments for neuropsychiatric symptoms.

Pipeline agents vary greatly not only in their mechanisms of action (targeting amyloid, tau, neurotransmitter receptors, inflammation, immunity, and many other targets), but also in the targeted patient populations. Potential treatment populations range from preclinical AD to severe dementia, indicating heightened R&D interest in this space and a subsequent downstream need for differentiation amidst a crowded drug class during the commercialization phase.

Figure 1 demonstrates a continued interest in investigating both small molecules and biologics, but a sharp decrease in the number of Phase III vs Phase II pipeline assets indicates that proof of efficacy and safety remains challenging. The complexity of AD pathophysiology, with numerous potential treatment targets (amyloid plaques, tau tangles, oxidative stress, mitochondrial dysfunction, inflammation, etc.), coupled with challenges in the blood-brain barrier and delivery mechanisms, are among the setbacks manufacturers face in their AD research efforts. The most common reasons for discontinuation of clinical trials for small molecules are adverse events or inability to impact cognitive functions. While biologics show promise in treating AD, especially when coupled with novel delivery mechanisms, they may not address all underlying causes of the disease in every patient, which may limit their applicability to the broader patient population. Thus, additional consideration should include not only evaluating mono-therapies that may be used at different AD stages, but also combinations either with other drugs or non-pharmacological interventions that address multiple disease mechanisms and exhibit synergistic effects.

Figure 1: Alzheimer’s Disease Clinical Development Pipeline, as of 2025

DMT: Disease-Modifying Therapy
Sources: 1. Cummings et al. (2025). Alzheimer’s disease drug development pipeline: 2025. Alzheimer’s & dementia (New York, N. Y.), 11(2), e70098. https://doi.org/10.1002/trc2.70098. 2. Clinicaltrials.gov.
Note: Multiple agents are being investigated across different phases, resulting in double-counting.

Value Differentiation

As the product pipeline continues to grow, the need for market entrants to differentiate their offerings beyond clinical efficacy and safety becomes increasingly acute. A strong value proposition supported by a robust clinical evidence package, including long-term follow-up data, is likely to become a requirement for payer coverage. Additionally, the inclusion of biomarkers as either patient inclusion criteria or as informing primary outcome measures will require manufacturers not only to educate payers but also to develop distinct stand-alone vs. companion diagnostic strategic approaches to remain competitive in the market.  It will also be essential for manufacturers to have a trusted roadmap for assessing the efficacy and commercial readiness of new biomarker-based tests for patient selection and frictionless access to therapies.

Next Steps

With expertise in market access, life-cycle management, and strategic evidence generation, and biomarker commercialization, Avalere Health is equipped to support AD therapeutic and biomarker manufacturers with evidence generation, product differentiation, value proposition, and other strategies that strengthen their market positioning. For more information on how Avalere Health can assist you, connect with us.

This Insight is the first in a series exploring the US and global AD treatment and diagnostic landscape, payer coverage, and societal perspectives surrounding this condition. Look out for our next insight about diagnostic approaches, developments, and dynamics in AD, coming in March.