Amyloid-Targeted Therapy (ATT) in Early Alzheimer’s Disease: Donanemab and the Shift Towards Disease Modification

Alzheimer’s disease (AD) is emerging as one of the most pressing healthcare challenges of the modern era, with its global burden rising rapidly. Current estimates indicate that more than 100 million individuals worldwide are living with symptomatic AD, including those in the prodromal stage of mild cognitive impairment (MCI)^(3,4). This increasing burden necessitates the critical need for efficient treatment approaches that can change the course of the disease rather than only treat its symptoms.

Recent advances in disease biology and biomarker development have paved the way for amyloid-targeted therapies (ATTs), with donanemab (Lormalzi®) representing a promising addition to the evolving treatment landscape.

The Alzheimer’s Disease Continuum: Why Early Intervention Matters?

Alzheimer's disease (AD) develops along a spectrum that starts with preclinical alterations, proceeds through MCI, and ends with overt dementia. About 69 million people worldwide are in the prodromal phase and 32 million have been diagnosed with AD dementia, implying that a sizable proportion of patients are still in the early stages of symptoms⁽⁴⁾.

There is a crucial treatment window during these initial phases. Intervention during this stage may decrease the progression of the disease and postpone functional loss, according to growing evidence^(3,6). This strategy, however, depends on prompt diagnosis and appropriate patient identification.

Pathophysiological Basis for Emerging Targeted Therapy

The hallmark pathological features of AD include extracellular amyloid-beta (Aβ) plaque deposition and intracellular tau aggregation, both of which contribute to neuronal dysfunction and cognitive decline^(7,10,11). Advances in biomarker science have enabled clinicians to detect these pathological processes in vivo using modalities such as Positron Emission Tomography (PET) imaging and Cerebro-Spinal Fluid (CSF) analysis^(11-13). These tools have not only improved diagnostic accuracy but also facilitated the development of therapies targeting core disease mechanisms. Amyloid-targeted therapies (ATTs) aim to reduce Aβ plaque burden, thereby addressing a central driver of disease progression.

Donanemab in Alzheimer's disease: Mechanism and Clinical Potential

A humanized monoclonal antibody called donanemab (Lormalzi®) is intended to target a modified, N-terminal truncated version of amyloid-beta(Aβ) that is only found in amyloid plaques^(8,9,14). Donanemab addresses a major pathogenic feature of AD by binding to these plaques and facilitating their removal via microglial-mediated phagocytosis^(1,8,9,14). This mechanism empowers donanemab as a potent amyloid-targeted therapy with the potential to modify disease progression, particularly when administered during the early symptomatic phase.

Clinical Evidence with Donanemab: TRAILBLAZER-ALZ 2 Study

The TRAILBLAZER-ALZ 2 trial established donanemab's efficacy by assessing its influence on cognitive and functional deterioration using the integrated Alzheimer's Disease Rating Scale (iADRS)⁽⁹⁾. At 76 weeks, donanemab demonstrated:

• Patients with low/medium tau load experienced 35.1% slower cognitive and functional deterioration (p<0.0001).

• Furthermore, donanemab therapy reduced the probability of disease development by 37%, according to the Clinical Dementia Rating-Global Score (CDR-GS)⁽⁹⁾.

These findings underscore donanemab's ability to reduce disease development while also delaying clinical worsening in patients with early symptomatic AD.

Patient Selection Considerations for Donanemab

The success of amyloid-targeted therapy (ATT), such as donanemab, is closely linked to appropriate patient selection. Candidates for donanemab should meet the following criteria:

• Presence of early symptomatic AD (MCI or mild dementia)

• Confirmed amyloid pathology

• Motivation to maintain functional independence^(8,9,15)

Confirmation of amyloid pathology is a prerequisite for treatment initiation and can be achieved through PET imaging or CSF biomarker assessment. Blood-based assays are currently under investigation and may expand access to diagnosis in the future.^(12,13) This biomarker-driven approach reflects a broader shift toward precision medicine in AD.

Applying Donanemab Effectively- Early Diagnosis as the Gateway to Treatment

With the introduction of disease-modifying medications, diagnosis has become increasingly important in Alzheimer's disease management. Timely and precise patient identification is critical to ensuring that therapy begins early at the for optimal benefit^(3,12,13,16). Delays in diagnosis not only limit therapeutic options but also lower the likelihood of preserving cognitive and functional abilities. As a result, clinicians may like to consider a proactive approach to screening patients with early cognitive symptoms.

Final Takeaways

•  The development of amyloid-targeted treatments (ATTs) like donanemab represents a huge step forward in Alzheimer's disease treatment.
•  By directly targeting core pathogenic mechanisms, treatments like donanemab have the potential to reduce disease progression and delay functional deterioration in Alzheimer's disease.
•  However, the successful application of these therapies is strongly dependent on prompt and precise diagnosis, which is aided by biomarker confirmation.
•  As the therapeutic landscape evolves, incorporating early detection tactics and precision medicine approaches will be critical for maximizing patient benefit and addressing the growing worldwide burden of Alzheimer's disease.

Abbreviations

AD-Alzheimer’s Disease; Aβ- Amyloid-Beta; PET- Positron Emission Tomography; CSF-Cerebro-Spinal Fluid; ATT-Amyloid Targeted Therapy

References

1. Leisher S, et al. CNS Drugs. 2023;37(8):671-677.

2. Cummings J. Drugs. 2023;83(7):569-576.

3. Hampel H, et al. Alzheimers Dement. 2022;18(10):1993-2002.

4. Gustavsson A, et al. Alzheimers Dement. 2023;19(2):658-670.

5. Dumas A, et al. Aging Brain. 2023;4:100093.

6. GBD 2019 Dementia Forecasting Collaborators. Lancet Public Health. 2022;7(2):e105-e125.

7. Jack CR Jr, et al. Alzheimers Dement. 2018;14(4):535-562.

8. Lormalzi (Donanemab) Abridged Pack Insert; 2025.

9. Sims JR, et al. JAMA. 2023;330(6):512-527.

10. Rashad A, et al. Healthcare (Basel). 2022;11(1):32.

11. Iaccarino L, et al. J Prev Alzheimers Dis. 2023;10(3):426-442.

12. Jack CR Jr, et al. Alzheimers Dement. 2024;20(8):5143-5169.

13. Hampel H, et al. Nat Aging. 2022;2(8):692-703.

14. Demattos RB, et al. Neuron. 2012;76(5):908-920.

15. Porsteinsson AP, et al. J Prev Alzheimers Dis. 2021;8(3):371-386.

16. Wahlberg K, et al. J Intern Med. 2024;295(3):281-291.

17. Mintun MA, et al. N Engl J Med. 2021;384(18):1691-1704.

CMAT- 22292 | 13th April 2026

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