Lecanemab and donanemab slow Alzheimer's decline, but is the benefit worth the cost?

Lecanemab and donanemab slow Alzheimer's decline, but is the benefit worth the cost?

New research shows that lecanemab and donanemab can slow cognitive decline and prolong patients' independence in daily activities. Are these high-cost, high-risk treatments really meaningful for Alzheimer's patients and their families?

A current oneAlzheimer's and dementiaThe study examines the effects of treatment on the length of time patients with Alzheimer's disease (AD) remain independent in basic activities of daily living (BADLs) and instrumental activities of daily living (IADLS).

Current treatments for AD

AD is a neurodegenerative disorder characterized by the cerebral accumulation of amyloid and tau pathology, leading to synaptic and neuronal injury, leading to progressive dementia. Several therapies have been developed, including anti-amyloid monoclonal antibodies, to reduce cerebral amyloid burden, which may delay AD progression.

In July 2023, the United States Food and Drug Administration (FDA) approved lecanemab as a disease-modifying therapy (DMT) to combat early symptomatic AD. Soon after, in July 2024, donanemab was also approved. However, in some cases, both treatments have been associated with minimal clinical relevance in slowing the progression of dementia.

Both lecanemab and donanemab are costly treatments that may increase the risk of neuroimaging amyloid-related abnormalities (ARIAs). As a result, some physicians are reluctant to initiate these therapies because any treatment must demonstrate clinical significance to outweigh the potential risks and costs.

Ad severity rating

Clinical Dementia Assessment (CDR)is a global scale to determine dementia status and severity by measuring the extent of cognitive loss in various domains. These domains include memory, judgment, orientation and problem solving, and functional skills in community affairs, home, and personal care.

Each CDR domain is scored from zero to three, reflecting healthy and severely impaired cognition. The sum of the scores of each CDR domain or “box” produces the CDR-Sum of Boxes (CDR-SB), a continuous measure with scores ranging from zero to 18.

Although there is no clear consensus on a “clinically meaningful” benefit for AD dementia, cognition and functional performance must be assessed to understand the benefits of AD treatment. Clinical benefits explained in terms of statistical significance do not always help caregivers or family members understand treatment outcomes. As a result, other metrics such as IADLs and BADLs can be used to quantify functional independence in AD patients.

About the study

The current longitudinal study was conducted at the Knight Alzheimer Disease Research Center (Knightadrc) at Washington University. Both cognitively unimpaired and cognitively impaired subjects who underwent amyloid positron emission tomography (PET) and lumbar puncture (LP) were included in the analysis. All study participants also provided cerebrospinal fluid (CSF) samples for amyloid beta (Aβ) and tau protein assessment.

All participants underwent clinical and cognitive assessments to obtain the CDR score. A clinical diagnosis of Ad dementia was determined based on standard criteria and a global CDR score.

Study results

This study included 282 participants, 67% of whom had very mild AD dementia and 33% with mild AD dementia, rated with a CDR of one. Approximately 56% of the study cohort were male, 88% were non-Hispanic white, and 10% were black or African American.

Most CDR 0.5 participants were independent, while only 40% of CDR 1 participants were independent. At baseline, almost all participants in BADLS were independent.

Four IADL components were considered as functions of the CDR-SB score, allowing the estimation of the level of independence. These components included paying bills, driving, remembering medications/appointments, and preparing meals.

Based on this approach, approximately 50% of study participants were addicted. Some participants were able to prepare meals independently and remember appointments/medications at a higher CDR-SB score, but were unable to pay bills and drive efficiently.

A strong relationship between CDR and ADLs was observed. Approximately 93% of participants with CDR-SB less than 4.5 were independent in IADLs, while 87% of participants with CDR-SB greater than 4.5 had no independence in IADLs.

Furthermore, 97% of participants with CDR-SB less than 11.5 were independent in BADLs. In comparison, 85% of participants with CDR-SB above 11.5 demonstrated no independence in BADLs.

The average annual CDR-SB increase was 1.30. However, when this metric was modeled as a function of baseline CDR, CDR-SB increased by 1.05 each year for individuals with CDR at baseline and one at baseline. Overall, a linear increase in CDR-SB was observed over time.

The expected time to lose independence in IADLs was approximately 29 months. Interestingly, the additional years of independence of IADLs and BADLs correlated with lecanemab or donanemab treatments, reflecting a slower rate of decline in CDR-SB.

Assuming a consistent decrease in CDR-SB score after treatment, an additional 10 and eight months of independence in IADLs were associated with lecanemab and donanemab treatments. For donanemab treatment, an additional 13 months of independence was observed in IADLs for the low/intermediate Tau -PET group, while four months of independence was measured in IADLs for the high Tau -PET.

Conclusions

The current study provides new insights into the relationship between CDR-SB scores and functional independence. These findings also highlight the clinical importance of AD treatments and whether patients and their families can make more informed treatment decisions.

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