Donanemab in Early Alzheimer’s Disease

Mintun, Mark A.; Lo, Albert; Evans, Clifford; Wessels, Alette M.; Ardayfio, Paul; Andersen, Scott W.; Shcherbinin, Sergey; Sparks, JonDavid; Sims, John R.; Bryś, Mirosław; Apostolova, Liana G.; Salloway, Stephen; Skovronsky, Daniel

doi:10.1056/nejmoa2100708

Cited by 922 publications

(968 citation statements)

References 37 publications

Supporting

Mentioning

933

Contrasting

Unclassified

Order By: Relevance

“…These observations have been replicated in vivo using PET ligands that detect neocortical AD-like tau pathology with high accuracy, 7 because increased tau PET retention was associated with worse concurrent cognitive performance 10,14-16 as well as reductions in gray matter volume, glucose metabolism, and synaptic density. 9,42,43 Recent studies have indicated that elevated baseline tau PET levels were associated with accelerated cognitive decline over time, [21][22][23][24][25][26][27] but most of these studies had relatively modest sample sizes, included retrospective cognitive time points, lacked a replication cohort focused on only 1 stage of the AD clinical continuum, and/or did not perform head-to-head comparisons against MRI and amyloid PET markers. We included a large study population with prospective longitudinal assessment of MMSE across the clinical AD spectrum and demonstrate that tau PET is a powerful predictor of cognitive change over time and outperformed MRI and amyloid PET markers.…”

Section: Discussionmentioning

confidence: 99%

Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease

et al. 2021

View full text Add to dashboard Cite

IMPORTANCE Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear.OBJECTIVE To examine the prognostic accuracy of baseline fluorine 18 ( 18 F)-flortaucipir and [ 18 F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. DESIGN, SETTING, AND PARTICIPANTS This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). EXPOSURES [ 18 F]Flortaucipir PET in the discovery cohort (n = 1135) or [ 18 F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. MAIN OUTCOMES AND MEASURES Baseline [ 18 F]flortaucipir/[ 18 F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. RESULTS Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [ 18 F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R 2 , 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R 2 , 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R 2 , 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [ 18 F]RO948 PET cohort. MRI mediated the association between [ 18 F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, −17.5% to 39.0%]; P = .71). Age (t = −2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [ 18 F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau...

show abstract

Section: Discussionmentioning

confidence: 99%

Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In addition, all major gene modifications, which have been identified so far in association with an increased AD risk, are related to Aβ generation, aggregation and clearance, and microglia responses [ 4 ]. Furthermore, the anti-Aβ antibodies aducanumab [ 32 ] and donanemab [ 33 ] have shown potential to delay cognitive decline by reducing brain Aβ load, when treatment of patients with antibody takes place very early in the disease. These and other anti-Aβ antibodies, such as gantenerumab, BAN2401, are currently under clinical investigation [ 3 , 32 , 33 ].…”

Section: Alzheimer’s Disease—toxic Amyloid-β Proteins and Triggered Neuropathogenic Phenomenamentioning

confidence: 99%

Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

Großmann

2021

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is caused by neurodegenerative, but also vascular and hemostatic changes in the brain. The oral thrombin inhibitor dabigatran, which has been used for over a decade in preventing thromboembolism and has a well-known pharmacokinetic, safety and antidote profile, can be an option to treat vascular dysfunction in early AD, a condition known as cerebral amyloid angiopathy (CAA). Recent results have revealed that amyloid-β proteins (Aβ), thrombin and fibrin play a crucial role in triggering vascular and parenchymal brain abnormalities in CAA. Dabigatran blocks soluble thrombin, thrombin-mediated formation of fibrin and Aβ-containing fibrin clots. These clots are deposited in brain parenchyma and blood vessels in areas of CAA. Fibrin-Aβ deposition causes microvascular constriction, occlusion and hemorrhage, leading to vascular and blood–brain barrier dysfunction. As a result, blood flow, perfusion and oxygen and nutrient supply are chronically reduced, mainly in hippocampal and neocortical brain areas. Dabigatran has the potential to preserve perfusion and oxygen delivery to the brain, and to prevent parenchymal Aβ-, thrombin- and fibrin-triggered inflammatory and neurodegenerative processes, leading to synapse and neuron death, and cognitive decline. Beneficial effects of dabigatran on CAA and AD have recently been shown in preclinical studies and in retrospective observer studies on patients. Therefore, clinical studies are warranted, in order to possibly expand dabigatran approval for repositioning for AD treatment.

show abstract

“…One of the major focuses of drug discovery efforts in the AD area has been the development of drug candidates to regulate abnormal Aβ aggregation. Several synthetic drugs have been evaluated in clinical trials, including LY2886721 [ 113 ], AN1792 [ 114 ] and verubecestat [ 115 ], along with monoclonal antibody drugs such as donanemab, which targets Aβ 3–42 [ 116 ] and aducanumab (BIIB037), which targets a conformational epitope found on Aβ [ 117 ]. However, none of them have been successful in the treatment of AD.…”

Section: Neuroprotective Mechanisms Of Natural Products For Admentioning

confidence: 99%

Neuroprotective Natural Products for Alzheimer’s Disease

Chen

Drew

Berney

et al. 2021

Cells

137

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the number one neurovegetative disease, but its treatment options are relatively few and ineffective. In efforts to discover new strategies for AD therapy, natural products have aroused interest in the research community and in the pharmaceutical industry for their neuroprotective activity, targeting different pathological mechanisms associated with AD. A wide variety of natural products from different origins have been evaluated preclinically and clinically for their neuroprotective mechanisms in preventing and attenuating the multifactorial pathologies of AD. This review mainly focuses on the possible neuroprotective mechanisms from natural products that may be beneficial in AD treatment and the natural product mixtures or extracts from different sources that have demonstrated neuroprotective activity in preclinical and/or clinical studies. It is believed that natural product mixtures or extracts containing multiple bioactive compounds that can work additively or synergistically to exhibit multiple neuroprotective mechanisms might be an effective approach in AD drug discovery.

show abstract

Donanemab in Early Alzheimer’s Disease

Cited by 922 publications

References 37 publications

Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease

Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease

Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

Neuroprotective Natural Products for Alzheimer’s Disease

Contact Info

Product

Resources

About