Lecanemab (Leqembi) is not the right drug for patients with Alzheimer’s disease

Kurkinen, Markku Tapio

doi:10.17219/acem/171379

Cited by 26 publications

(12 citation statements)

References 29 publications

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“…This choice was guided by the more severe Aβ pathology reported in female 3xTg mice in comparison to males (Hirata-Fukae et al, 2008), and by the higher risk of developing AD in women (Lautenschlager et al, 1996). However, recent data indicates a higher efficiency of AD-targeting treatments in men in comparison to women (Kurkinen, 2023), and future investigations of sleep after SCD inhibition or related interventions should include males. Secondly, even if justified from previous research (Hamilton et al, 2015, 2022), the present study has solely evaluated the impact of a 28-day treatment administered at a relatively early age (approximately 4 months).…”

Section: Discussionmentioning

confidence: 99%

Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer’s Disease

Hector,

da Costa Caiado,

Leduc

et al. 2024

Preprint

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The symptomatology of Alzheimer's disease (AD) includes cognitive deficits and sleep disturbances. Recent findings suggest the involvement of dysfunctions in lipid metabolism, such as oleic acid build-up, in the brain of AD patients and animal models. In addition, the inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. Alterations in astrocytes and their function were reported in AD patients and animal models, and astrocytes have been implicated in the regulation of sleep. However, the relationship between sleep disturbances, astrocytes and lipid metabolism remains to be explored in AD. This project thus aimed at assessing whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associated with modifications in astrocytic function. Wild-type (WT) and 3xTg-AD female mice (4-months old) received intracerebroventricular infusion of a SCD inhibitor (SCDi) or vehicle for 28 days, and a 24-hour electrocorticographic (ECoG) recording was conducted post-treatment. Post-mortem brain slices were stained for the astrocytic markers glial fibrillary acidic protein (GFAP) and 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) to perform cell counting and/or morphological evaluation in the hippocampus, lateral hypothalamus and thalamus. The results indicate that the reduced time spent awake and increased time spent in slow wave sleep (SWS) in 3xTg-AD mice was not restored by the SCDi treatment. Similar observations were made concerning the increased number of wake and SWS bouts in 3xTg-AD mice. Rhythmic and scale-free ECoG activity were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi significantly altered these phenotypes in a different manner in mutant mice in comparison to WT mice. GFAP- and ALDH1L1-positive cell densities were elevated in the hippocampus and lateral hypothalamus/thalamus of 3x-Tg-AD mice, respectively, and SCDi rescued the increase in the CA1 region in particular. Overall, these findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not substantially restored by targeting lipid metabolism using SCD inhibition, at least for the targeted age window, but that this treatment can revert hippocampal changes in astrocytes. This work will benefit the understanding of the pathophysiology related to AD and associated sleep disturbances.

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Section: Discussionmentioning

confidence: 99%

Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer’s Disease

Hector,

da Costa Caiado,

Leduc

et al. 2024

Preprint

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“…The efficacy of lecanemab was greater, and the risk of amyloid-related imaging abnormalities (ARIA) was significantly reduced, in APOE4 non-carriers compared with carriers. However, the data originally presented by van Dyck and colleagues in 2023 were recently reassessed and it was concluded that the impact of lecanemab was less than reported, and was ineffective in females ( Kurkinen, 2023 ).…”

Section: Is There Evidence Of Sex-related Differences In Response To ...mentioning

confidence: 97%

“…Women report difficulties with palatability (Ruiz et al, 2019). Benefits of lecanemab were greater in men than women (van Dyck et al, 2023) or ineffective in women (Kurkinen, 2023).…”

Section: Memantine 2002mentioning

confidence: 99%

A case for seeking sex-specific treatments in Alzheimer’s disease

Lynch

2024

Front. Aging Neurosci.

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There is no satisfactory explanation for the sex-related differences in the incidence of many diseases and this is also true of Alzheimer’s disease (AD), where females have a higher lifetime risk of developing the disease and make up about two thirds of the AD patient population. The importance of understanding the cause(s) that account for this disproportionate distribution cannot be overestimated, and is likely to be a significant factor in the search for therapeutic strategies that will combat the disease and, furthermore, potentially point to a sex-targeted approach to treatment. This review considers the literature in the context of what is known about the impact of sex on processes targeted by drugs that are in clinical trial for AD, and existing knowledge on differing responses of males and females to these drugs. Current knowledge strongly supports the view that trials should make assessing sex-related difference in responses a priority with a focus on exploring the sex-stratified treatments.

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“…Lecanemab and aducanumab are monoclonal antibodies directed against oligomeric Aβ-peptides and capable of reducing amyloid deposits in the brain in early onset AD. General results from trials exploring the effects of lecanemab showed small significance and raised concerns on its clinical relevance in clinical practice ( 22 , 23 ). By contrast, aducanumab was approved on the basis of its ability to reduce Aβ deposits in the brain despite an interim analysis in 2019 that demonstrated its futility ( 24 ).…”

Section: Resistance To Anti Aβ- Monoclonal Antibodiesmentioning

confidence: 99%

Is Alzheimer's disease an individual-centered disease? Hypotheses from the atomic levels up to mathematical models for biological systems

Giorelli,

Accavone,

De Liso

2024

Front. Neurol.

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Lecanemab (Leqembi) is not the right drug for patients with Alzheimer’s disease

Cited by 26 publications

References 29 publications

Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer’s Disease

Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer’s Disease

A case for seeking sex-specific treatments in Alzheimer’s disease

Is Alzheimer's disease an individual-centered disease? Hypotheses from the atomic levels up to mathematical models for biological systems

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