Lessons Learned from Approval of Aducanumab for Alzheimer's Disease

Annual Review of Medicine, Год журнала: 2024, Номер 75(1), С. 99 - 111

Опубликована: Янв. 29, 2024

When the US Food and Drug Administration used accelerated approval process to authorize use of antiamyloid drug aducanumab treat Alzheimer's disease (AD), many people hoped this signaled a new era disease-modifying treatment. But 2 years later, aducanumab's failure launch provides cautionary tale about complexities dementia need for thorough transparent review role that regulatory agencies various stakeholders play in approving AD drugs. We highlight events leading controversial discuss some key lessons learned from drug's deliver hoped-for benefits. These include inherent limitations strategies complex which amyloid is only one several pathological processes, clinical trials better reflect diversity communities affected by AD, potential pitfalls futility analyses trials, greater transparency other modifications process, field's unreadiness move highly controlled environment widespread chronic resource-intensive, drugs real-world treatment scenarios. People with desperately effective therapies. hope story will inspire changes process—changes restore public trust improve future efforts therapies clinic.

Язык: Английский

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N1-methylation of adenosine (m1A) in ND5 mRNA leads to complex I dysfunction in Alzheimer’s disease

Molecular Psychiatry, Год журнала: 2024, Номер 29(5), С. 1427 - 1439

Опубликована: Янв. 29, 2024

Abstract One mechanism of particular interest to regulate mRNA fate post-transcriptionally is modification. Especially the extent m 1 A methylation highly discussed due methodological differences. However, one single site in mitochondrial ND5 was unanimously reported by different groups. a subunit complex I respiratory chain. It considered essential for coupling oxidation and proton transport. Here we demonstrate that this might be involved pathophysiology Alzheimer’s disease (AD). pathological hallmarks neurodegenerative dysfunction, mainly induced Amyloid β (Aβ). Aβ disturbs functions IV molecular dysfunction still not fully understood. We found enhanced an AD cell model as well patients. Formation catalyzed increased TRMT10C protein levels, leading translation repression ND5. As consequence, here demonstrated first time, leads dysfunction. Our findings suggest newly identified Aβ-induced

Язык: Английский

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The advent of Alzheimer treatments will change the trajectory of human aging

Nature Aging, Год журнала: 2024, Номер 4(4), С. 453 - 463

Опубликована: Апрель 19, 2024

Язык: Английский

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Cathepsin B prevents cell death by fragmentation and destruction of pathological amyloid fibrils

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Фев. 15, 2025

Amyloid fibrils cause organ and tissue dysfunction in numerous severe diseases. Despite the prevalence severity of amyloidoses, there is still no effective safe anti-amyloid therapy. This study investigates impact cysteine protease cathepsin B (CTSB) on amyloids associated with Alzheimer's Parkinson's diseases, hemodialysis, lysozyme amyloidosis. We analyzed effect CTSB size, structure, proteotoxicity amyloid formed from alpha-synuclein, abeta peptide (1-42), insulin, using a combination spectroscopic, microscopic, electrophoretic, colorimetric methods. Our comprehensive research revealed dual fibrils. Firstly, induced fragmentation while preserving their ordered morphology, and, secondly, it "loosened" tertiary structure reduced regularity secondary structure. mechanism action was universal across different pathologies, although disruption efficacy predominant type degradation products depended amyloids' clustering. Notably, CTSB-induced irreversible significantly toxicity for immortalized primary cell lines low-clustered fibrils, such as alpha-synuclein disease. These findings enhance our understanding how endogenous may regulate content at molecular level neuropathologies. In addition, results suggest potential component drugs agents that accessibility proteolytic sites within clots reduce these clusters stability.

Язык: Английский

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

Advances in Clinical and Experimental Medicine, Год журнала: 2023, Номер 32(9), С. 943 - 947

Опубликована: Сен. 7, 2023

On July 6, 2023, the U.S. Food and Drug Administration (FDA) approved lecanemab (Leqembi) for treatment of Alzheimer's dementia (AD) patients.In 2 clinical trials, reduced amyloid in brain slowed cognitive decline.Here, I review detail trial by van Dyck et al. (2023) entitled "Lecanemab early disease", published The New England Journal Medicine on January 5, 2023.In this 18-month trial, did not slow decline women.This is especially significant because women have a twofold increased risk AD compared to men, that is, there are times more than men living with AD.Lecanemab APOE4 carriers; rather, it enhanced study participants genes.This bad news patients, 60-75% whom carry at least 1 gene.These negative results regarding lecanemab's therapeutic value make me wonder if approval was worst decision FDA up till now, after aducanumab June 7, 2021.

Язык: Английский

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Stimulation of TREM2 with agonistic antibodies—an emerging therapeutic option for Alzheimer's disease

The Lancet Neurology, Год журнала: 2023, Номер 22(11), С. 1048 - 1060

Опубликована: Окт. 18, 2023

Язык: Английский

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sTREM2 is associated with amyloid‐related p‐tau increases and glucose hypermetabolism in Alzheimer's disease

EMBO Molecular Medicine, Год журнала: 2023, Номер 15(2)

Опубликована: Янв. 9, 2023

Report9 January 2023Open Access Source DataTransparent process sTREM2 is associated with amyloid-related p-tau increases and glucose hypermetabolism in Alzheimer's disease Davina Biel orcid.org/0000-0002-2597-1992 Institute for Stroke Dementia Research (ISD), University Hospital, LMU Munich, Germany Contribution: Conceptualization, Data curation, Formal analysis, ​Investigation, Writing - original draft, review & editing Search more papers by this author Marc Suárez-Calvet orcid.org/0000-0002-2993-569X Barcelonaβeta Brain Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain IMIM (Hospital del Mar Medical Institute), Servei de Neurologia, Hospital Mar, Centro Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Paul Hager of Radiology Artificial Intelligence Informatics Medicine, TU Anna Rubinski Dewenter Steward Sebastian Roemer Department Neurology, Michael Ewers German Neurodegenerative Diseases (DZNE), Christian Haass Munich Cluster Systems Neurology (SyNergy), Chair Metabolic Biochemistry, Biomedical (BMC), Faculty Matthias Brendel orcid.org/0000-0002-9247-2843 Nuclear Nicolai Franzmeier Corresponding Author [email protected] orcid.org/0000-0001-9736-2283 Psychiatry Neurochemistry, Neuroscience Physiology, The Sahlgrenska Academy, Gothenburg, the Disease Neuroimaging Initiative (ADNI) used preparation article were obtained from database (adni.loni.usc.edu). As such, investigators within ADNI contributed to design implementation and/or provided data but did not participate analysis or writing report. A complete listing can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf Information Biel1, Suárez-Calvet2,3,4,5, Hager6, Rubinski1, Dewenter1, Steward1, Roemer1,7, Ewers1,8, Haass8,9,10, Brendel8,9,11,†, *,1,9,12,† 1Institute 2Barcelonaβeta 3IMIM 4Servei 5Centro 6Institute 7Department 8German 9Munich 10Chair 11Department 12Department † These authors equally work *Corresponding author. Tel: +49 89 4400 46162; E-mail: EMBO Mol Med (2023)15:e16987https://doi.org/10.15252/emmm.202216987 PDFDownload PDF text main figures.PDF PLUSDownload text, figures, expanded view figures appendix. Peer ReviewDownload a summary editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Microglial activation occurs early (AD) previous studies reported both detrimental protective effects microglia on AD progression. Here, we CSF investigate stage-dependent drivers microglial determine downstream consequences We included 402 patients measures earliest beta-amyloid (CSF Aβ1-42) late-stage fibrillary Aβ pathology (amyloid-PET centiloid), as well sTREM2, p-tau181, FDG-PET. To stage, stratified participants into Aβ-accumulators (Aβ CSF+/PET−; n = 70) late CSF+/PET+; 201) plus 131 controls. In Aβ-accumulators, higher centiloid was cross-sectional/longitudinal p-tau181 increases. Further, mediated association between FDG-PET hypermetabolism. no cross-sectional hypometabolism. Our findings suggest that TREM2-related response follows fibrillization, manifests inflammatory may facilitate subsequent AD. Synopsis (AD), has been linked This study (Aβ) accumulation, amyloid-PET cross sectional/longitudinal levels. Higher levels accumulation hypometabolism accumulation. paper explained Problem Besides tau plays role pathogenesis (AD). Previous progression, thus, it critical at which stages could evaluate treatment target. address this, (i.e., soluble Triggering receptor expressed myeloid cells 2) biomarker Results first groups end, positive still negative classified PET Aβ-accumulators. increases, suggesting reactive fibrillization. line increased consumption activated microglia. hypometabolism, parallels neurodegeneration rather than once fully developed present. Impact sTREM2-related AD, while reports occur later stages. Introduction characterized (Aβ), tau, activation, metabolic brain changes, neurodegeneration, cognitive decline (Jack et al, 2018). According amyloid cascade hypothesis, triggers development spreading hyperphosphorylated aggregates followed decline, eventually dementia (Karran 2011; La Joie 2020; Selkoe, 2022; Strom 2022). Previously shown Aβ-related p-tau), detectable plasma (Janelidze 2021; Moscoso 2021) cerebrospinal fluid (CSF) (Mattsson-Carlgren 2020), precede aggregation. have recently fact drive aggregation spread across interconnected regions (Pichet Binette 2022) therefore, key link deposition However, underlying mechanisms are understood. microglia, brains innate immune system, play modulating these initial events (Pascoal 2021). Receptor Expressed Myeloid Cell 2 (TREM2) regulates change homeostatic state (Keren-Shaul 2017; Krasemann 2017) well-established vivo proxy (Suarez-Calvet 2016, 2019; 2019, 2020). Yet, yielded conflicting For instance, recent vitro induce hyperphosphorylation (Maphis 2015) release seeds (Brelstaff Similarly, sporadic strongly correlated (Suárez-Calvet 2019) promote aggregated measured via tau-PET (Vogels Pascoal Indeed, post-mortem investigating mediating effect tissue revealed mediation 33% relationship (Casaletto suggests therefore contribute addition, consume high mouse models (Xiang 2021), manifest hypermetabolic changes observed early-stage when ensuing yet apparent (Oh 2016; Gordon Thus, reflect compensatory mechanism, suggested previously, neuroinflammation (Ashraf 2015; Arenaza-Urquijo 2017). On contrary, symptomatic autosomal dominantly inherited attenuated (Ewers Morenas-Rodriguez possible chronic neuronal integrity cognition pathologic severe enough result clinically manifested deficits. an animal model TREM2 loss function seeding, further (Parhizkar 2019). It utmost importance clinical trials trying target modifying approach understand (i) what drives (ii) whether beneficial (iii) directionality progression depends stage. present study, (sTREM2) marker well-characterized sample controls versus its changes. Specifically, cognitively normal (CN) mild impaired (MCI) available Aβ1-42, amyloid-PET, 18F-fluorodeoxyglucose (FDG-PET). established assessing cerebral uptake FDG-PET-assessed previously CSF+/PET− (early Aβ-accumulators) CSF+/PET+ (late following allows stratifying individuals showing signs CSF+/PET−) CSF+/PET+) (Palmqvist total without evidence healthy CSF−/PET−). subset had longitudinal assessments, based calculated annual rates. specific aims assess first, second, Aβ-driven facilitates p-tau181). Third, assessed reflected metabolism, given large amounts expected where apparent, phases early- pathology, using combines assessments Aβ1-42 fibrillar abnormality assumed dysmetabolism precedes positivity reflecting mostly forms 2016). Therefore, grouped 70; CN 30; MCI 40) reduced suprathreshold 201; 41; 160), abnormal PET. An additional pool subjects either control group. Longitudinal Aβ/late Aβ/controls 21/75/35) 20/75/35) average follow-up time baseline assessment 1.99 ± 0.09 years. Descriptive statistics Table 1. Demographic Controls CSF−/PET−) Early Late P-value Cross-sectional N 70 201 Diagnostic (CN/MCI) 131/0 30/40 41/160 < 0.001 Sex (male/female) 64/67 47/23 112/89 0.045 Age years 72.67 (6.39) 71.65 (7.68) 73.60 (6.53) 0.093 Years education 16.85 (2.43)a 17.13 (2.24)a 16.00 (2.74)b,c (pg/ml) 1,553.122 (281.109)a,c 777.819 (147.169)a,b 656.42 (174.79)b,c 20.241 (7.059)a,c 15.825 (7.493)a,b 32.807 (14.780)b,c 4,099.933 (1,980.197)c 2,955.118 (1,751.746)a,b 3,984.107 (2,194.033)c Amyloid-PET (centiloid) −9.0315 (12.656)a −2.901 (13.530)a 78.228 (33.871)b,c global z-score −0.132 (0.649) −0.251 (0.532) 0.13 meta-ROI −0.214 (0.826)a −0.546 (0.723)c 0.002 35 20 75 Follow-up (mean years) 1.96 (0.13)c 2.05 (0.08)a,b (0.07)c 21 (0.08)b (0.07) 0.004 Values presented mean (SD); P-values derived ANOVAs continuous Chi-squared tests categorical measures. Mean values significantly (P 0.05, post hoc tests) different from—. Controls. b c tested accumulators) linear regression centiloid) (β 0.259, T 2.199, P 0.032; Fig 1A, top panel) 0.254, 2.268, 0.027; 1B, panel). 0.587, 5.425, 0.001). congruent results data, faster rates 0.550, 2.975, 0.010; 1C, 0.535, 3.725, 0.002; 1D, 0.938, 6.286, Using bootstrapped analyses 1,000 iterations, additionally accumulators, (average causal [ACME]: B 0.133, 95% CI 0.0039 0.27, 0.038; 1E, (ACME: 0.450, 0.1352 0.82, 0.004; 1F, Testing reverse models, i.e., mediates similar 0.132, 0.0084 0.26, 0.030) much lower 0.273, 0.0437 0.55, 0.014). turn Figure (in A–D. regressions (A) (B). (C) (D). Standardized beta-estimates (β), T-values, regressions. E–F. predictor, mediator, dependent variable (E). (F). Beta-estimates (B) each path displayed respective arrow. (ACME) direct (ADE) under triangle. information: green, orange. All controlled age, sex, education, status. online figure. 1 [emmm202216987-sup-0004-SDataFig1.zip] Download figure PowerPoint When above-described neither 0.040, 0.565, 0.573; bottom nor 0.051, 0.654; longer driven there 0.441, 7.004, 0.001) 0.439, 3.777, 0.001), coupled 0.203, 2.995, 0.003; panel), (n 75, β 0.137, 1.165, 0.248; Given detect cross-sectionally 0.017, −0.0444 0.08, 0.560; longitudinally 0.003, −0.108 0.10, 0.960; Together, fibrillization dynamics uncouple extent parallel remained consistent APOE4 genotype covariate (except

Язык: Английский

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Senolytic therapy to modulate the progression of Alzheimer’s Disease (SToMP-AD) – Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Апрель 24, 2023

Abstract Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance senescent cells using the senolytic compounds dasatinib (D) quercetin (Q) reduced neuropathological burden improved clinically relevant outcomes mice. Herein, we conducted vanguard open-label clinical trial therapy for AD with primary aim evaluating central nervous system (CNS) penetrance, well exploratory data collection safety, feasibility, efficacy. Participants early-stage symptomatic were enrolled an open-label, 12-week pilot study intermittent orally-delivered D+Q. CNS penetrance was assessed by drug levels cerebrospinal fluid (CSF) high performance liquid chromatography tandem mass spectrometry. Safety continuously monitored adverse event reporting, vitals, laboratory work. Cognition, neuroimaging, plasma CSF biomarkers at baseline post-treatment. Five participants (mean age: 76±5 years; 40% female) completed trial. The treatment increased D Q blood all ranging from 12.7 73.5 ng/ml 3.29-26.30 Q. detected four 0.281 0.536 (t(4)=3.123, p=0.035); not detected. Treatment well-tolerated no early discontinuation six mild moderate events occurring across study. Cognitive neuroimaging endpoints did significantly differ IL-6 GFAP post-treatment (t(4)=3.913, p=008 t(4)=3.354, p=0.028, respectively) concomitant decreased several cytokines chemokines associated senescence, trend toward higher Aβ42 (t(4)=-2.338, p=0.079). Collectively indicate provide preliminary support tolerability, feasibility intervention suggest that astrocytes Aβ may be particularly responsive treatment. While results are promising, fully powered, placebo-controlled studies needed evaluate potential modification novel approach targeting cellular senescence.

Язык: Английский

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Tipping points in neurodegeneration

Neuron, Год журнала: 2023, Номер 111(19), С. 2954 - 2968

Опубликована: Июнь 28, 2023

In Alzheimer's disease (AD), Aβ deposits form slowly, several decades before further pathological events trigger neurodegeneration and dementia. However, a substantial proportion of affected individuals remains non-demented despite AD pathology, raising questions about the underlying factors that determine transition to clinical disease. Here, we emphasize critical function resilience resistance factors, which extend beyond concept cognitive reserve include glial, immune, vascular system. We review evidence use metaphor "tipping points" illustrate how gradually forming neuropathology in preclinical stage can dementia once adaptive functions system are lost self-reinforcing cascades unleashed. Thus, propose an expanded framework for pathomechanistic research focuses on tipping points non-neuronal mechanisms, may represent previously untapped therapeutic targets AD.

Язык: Английский

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Navigating the dementia landscape: Biomarkers and emerging therapies

Ageing Research Reviews, Год журнала: 2024, Номер 94, С. 102193 - 102193

Опубликована: Янв. 10, 2024

Язык: Английский

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