The phenotype of Down syndrome is variable, but common to all individuals with the syndrome is some degree of intellectual disability.1 Alzheimer's disease pathology is seen both at autopsy and by ...amyloid PET in all adults with Down syndrome by the age of 40 years, putting this population at especially high risk of developing early-onset Alzheimer's disease. Preclinical testing of drugs for improving cognition in people with Down syndrome is usually done in the Ts65Dn transgenic mouse model.2 In this model, increased GABAA-mediated synaptic inhibition has been postulated as one mechanism contributing to the learning and memory deficits.3 On the basis of this hypothesis, trials of an α5-GABAA-negative allosteric modulator (basmisanil; NCT02024789) were conducted in people with Down syndrome, but no effect was seen. On the basis of the rationale for its use in people with Alzheimer's disease, memantine was tested in the Ts65Dn model and was shown to enhance learning and memory.6 A pilot trial of memantine in 40 young adults (aged 18–32 years) with Down syndrome showed a significant effect on one secondary measure of memory.7 However, in 173 adults with Down syndrome (aged >40 years), no effect was seen.8 In The Lancet Neurology, Alberto Costa and colleagues9 report the results of a two-centre, randomised, double-blind, placebo-controlled, phase 2 trial to study the effects of 16 weeks of memantine treatment on cognitive function in 160 adolescents and young adults (aged 15–32 years) with Down syndrome.
This Viewpoint explains the genetic association between Alzheimer disease and Down syndrome and the negative impact of excluding people with Down syndrome from clinical trials on treatment for ...Alzheimer disease.
Trial of Solanezumab in Preclinical Alzheimer’s Disease Sperling, Reisa A.; Donohue, Michael C.; Raman, Rema ...
New England journal of medicine/The New England journal of medicine,
09/2023, Letnik:
389, Številka:
12
Journal Article
Recenzirano
Odprti dostop
In cognitively normal persons with brain amyloid deposition, solanezumab (an antibody targeting monomeric amyloid) did not slow cognitive decline as compared to placebo over a period of 4.5 years.
Individuals with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD) pathology and this has provided significant insights into our understanding of the genetic basis of AD. ...The present review summarizes recent clinical, neuropathologic, imaging, and fluid biomarker studies of AD in DS (DSAD), highlighting the striking similarities, as well as some notable differences, between DSAD and the more common late-onset form of AD (LOAD) in the general population, as well as the much rarer, autosomal-dominant form of AD (ADAD). There has been significant progress in our understanding of the natural history of AD biomarkers in DS and their relationship to clinically meaningful changes. Additional work is needed to clearly define the continuum of AD that has been described in the general population, such as the preclinical, prodromal, and dementia stages of AD. Multiple therapeutic approaches, including those targeting not only β-amyloid but also tau and the amyloid precursor protein itself, require consideration. Recent developments in the field are presented within the context of such efforts to conduct clinical trials to treat and potentially prevent AD in DS.
Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this ...population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because symptoms are overshadowed by the intellectual disability associated with Down syndrome. In people with Down syndrome, fluid and imaging biomarkers have shown good diagnostic performances and a strikingly similar temporality of changes with respect to sporadic and autosomal dominant Alzheimer's disease. Most importantly, there are no treatments to prevent Alzheimer's disease, even though adults with Down syndrome could be an optimal population in whom to conduct Alzheimer's disease prevention trials. Unprecedented research activity in Down syndrome is rapidly changing this bleak scenario that will translate into disease-modifying therapies that could benefit other populations.
Alzheimer's disease (AD) pathology and early‐onset dementia develop almost universally in Down syndrome (DS). AD is defined neuropathologically by the presence of extracellular plaques of aggregated ...amyloid β protein and intracellular neurofibrillary tangles (NFTs) of aggregated hyperphosphorylated tau protein. The development of radiolabeled positron emission tomography (PET) ligands for amyloid plaques and tau tangles enables the longitudinal assessment of the spatial pattern of their accumulation in relation to symptomatology. Recent work indicates that amyloid pathology develops 15–20 years before neurodegeneration and symptom onset in the sporadic and autosomal dominant forms of AD, while tau pathology correlates more closely with symptomatic stages evidenced by cognitive decline and dementia. Recent work on AD biomarkers in DS illustrates similarities between DS and sporadic AD. It may soon be possible to apply recently developed staging classifications to DS to obtain a more nuanced understanding of the development AD in DS and to provide more accurate diagnosis and prognosis in the clinic.
Introduction
The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread ...cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3‐45 Study (BAN2401‐G000‐303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3‐45 Study is conducted as a Public‐Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc.
Methods
The AHEAD 3‐45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET‐imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial‐Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC‐PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J‐TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results.
Result
The focus of this article is on the innovative design of the study.
Discussion
The AHEAD 3‐45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma‐based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.
IMPORTANCE: Insulin modulates aspects of brain function relevant to Alzheimer disease and can be delivered to the brain using intranasal devices. To date, the use of intranasal insulin to treat ...persons with mild cognitive impairment and Alzheimer’s disease dementia remains to be examined in a multi-site trial. OBJECTIVE: To examine the feasibility, safety, and efficacy of intranasal insulin for the treatment of persons with mild cognitive impairment and Alzheimer disease dementia in a phase 2/3 multisite clinical trial. DESIGN, SETTING, AND PARTICIPANTS: A randomized (1:1) double-blind clinical trial was conducted between 2014 and 2018. Participants received 40 IU of insulin or placebo for 12 months during the blinded phase, which was followed by a 6-month open-label extension phase. The clinical trial was conducted at 27 sites of the Alzheimer’s Therapeutic Research Institute. A total of 432 adults were screened, and 144 adults were excluded. Inclusion criteria included adults aged 55 to 85 years with a diagnosis of amnestic mild cognitive impairment or Alzheimer disease (based on National Institute on Aging–Alzheimer Association criteria), a score of 20 or higher on the Mini-Mental State Examination, a clinical dementia rating of 0.5 or 1.0, and a delayed logical memory score within a specified range. A total of 289 participants were randomized. Among the first 49 participants, the first device (device 1) used to administer intranasal insulin treatment had inconsistent reliability. A new device (device 2) was used for the remaining 240 participants, who were designated the primary intention-to-treat population. Data were analyzed from August 2018 to March 2019. INTERVENTIONS: Participants received 40 IU of insulin (Humulin-RU-100; Lilly) or placebo (diluent) daily for 12 months (blinded phase) followed by a 6-month open-label extension phase. Insulin was administered with 2 intranasal delivery devices. MAIN OUTCOMES AND MEASURES: The primary outcome (mean score change on the Alzheimer Disease Assessment Scale–cognitive subscale 12) was evaluated at 3-month intervals. Secondary clinical outcomes were assessed at 6-month intervals. Cerebrospinal fluid collection and magnetic resonance imaging scans occurred at baseline and 12 months. RESULTS: A total of 289 participants (155 men 54.6%; mean SD age, 70.9 7.1 years) were randomized. Of those, 260 participants completed the blinded phase, and 240 participants completed the open-label extension phase. For the first 49 participants, the first device used to administer treatment had inconsistent reliability. A second device was used for the remaining 240 participants (123 men 51.3%; mean SD age, 70.8 7.1 years), who were designated the primary intention-to-treat population. No differences were observed between treatment arms for the primary outcome (mean score change on ADAS-cog-12 from baseline to month 12) in the device 2 ITT cohort (0.0258 points; 95% CI, −1.771 to 1.822 points; P = .98) or for the other clinical or cerebrospinal fluid outcomes in the primary (second device) intention-to-treat analysis. No clinically important adverse events were associated with treatment. CONCLUSIONS AND RELEVANCE: In this study, no cognitive or functional benefits were observed with intranasal insulin treatment over a 12-month period among the primary intention-to-treat cohort. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01767909
About 6 million people worldwide have Down syndrome, and these individuals represent the largest population genetically predisposed to developing early-onset Alzheimer's disease.1 Although progress ...has been made in diagnosing Alzheimer's disease dementia in people with Down syndrome,2,3 making a definitive diagnosis remains a major challenge owing to substantial variability in baseline cognitive ability. Neurofilament light protein (NfL) has emerged as a possible biomarker of neuronal injury in both sporadic Alzheimer's disease8 and adults with Down syndrome.9 In The Lancet Neurology, Juan Fortea and colleagues10 report the diagnostic performance of plasma and CSF amyloid-β (Aβ), tau, and NfL in adults with Down syndrome. Other key questions that need further examination include whether NfL contributes directly to the pathogenesis of Alzheimer's disease in people with Down syndrome; the extent to which NfL correlates with biomarkers established in sporadic Alzheimer's disease (ie, amyloid PET and tau PET imaging); and how well NfL performs as a diagnostic measure in a multicentre setting.
Alzheimer's disease is a devastating neurological disorder that affects more than 37 million people worldwide. The economic burden of Alzheimer's disease is massive; in the United States alone, the ...estimated direct and indirect annual cost of patient care is at least $100 billion. Current FDA-approved drugs for Alzheimer's disease do not prevent or reverse the disease, and provide only modest symptomatic benefits. Driven by the clear unmet medical need and a growing understanding of the molecular pathophysiology of Alzheimer's disease, the number of agents in development has increased dramatically in recent years. Truly *'disease-modifying' therapies that target the underlying mechanisms of Alzheimer's disease have now reached late stages of human clinical trials. Primary targets include beta-amyloid, whose presence and accumulation in the brain is thought to contribute to the development of Alzheimer's disease, and tau protein which, when hyperphosphorylated, results in the self-assembly of tangles of paired helical filaments also believed to be involved in the pathogenesis of Alzheimer's disease. In this review, we briefly discuss the current status of Alzheimer's disease therapies under study, as well the scientific context in which they have been developed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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