The majority of putative disease-modifying treatments in development for Alzheimer’s disease are directed against the amyloid-β (Aβ) peptide. Among the anti-Aβ therapeutic approaches, the most ...extensively developed is immunotherapy—specifically, passive immunization through administration of exogenous monoclonal antibodies (mAbs). Although testing of mAbs has been fraught with failure and confusing results, the experience gained from these trials has provided important clues for better treatments. This review summarizes the experience to date with anti-Aβ mAbs to enter clinical trials for Alzheimer’s disease and examines the evidence for clinical efficacy and the major problems with safety—i.e., amyloid-related imaging abnormalities. As mAbs differ considerably with regard to their epitopes and the conformations of Aβ that they recognize (monomers, oligomers, protofibrils, fibrils), the consequences of targeting different species are also considered. An often-cited explanation for the failure of anti-Aβ mAb trials is that they are set too late in the disease process. New trials are indeed evaluating treatments at prodromal and preclinical stages. We should expect to see additional studies of presymptomatic Alzheimer’s disease to join the ongoing prevention trials, for which mAbs continue to serve as the mainstay.
In a randomized trial, patients with brain amyloid deposition but no dementia who received a β-site amyloid precursor protein–cleaving enzyme 1 inhibitor had no benefit with respect to clinical ...outcomes and worsening on some measures of cognition and daily function.
Lecanemab in Early Alzheimer’s Disease van Dyck, Christopher H.; Swanson, Chad J.; Aisen, Paul ...
The New England journal of medicine,
01/2023, Letnik:
388, Številka:
1
Journal Article
Recenzirano
Odprti dostop
In a phase 3 trial, participants with early Alzheimer’s disease who received the monoclonal antibody lecanemab had less decline on measures of cognition and function at 18 months than those who ...received placebo.
The authors reply:
Reish and colleagues have brought forward a case of acute intracerebral hemorrhage that occurred after treatment with tissue plasminogen activator (t-PA) in a patient who had been ...participating in the open-label extension of the Clarity AD trial (Jan. 5 issue).
1
The case did not appear in the original report of the randomized trial of lecanemab because the open-label extension phase, including adverse events that occurred during that phase, was not the topic of the article.
2
These events had not been accumulated and fully adjudicated at the time of publication. A summary of adverse events up to April . . .
Clinical guidelines currently recommend against amyloid imaging for cognitively unimpaired persons. The goal of Alzheimer's disease (AD) prevention, together with advances in understanding the ...pathophysiology of AD, however, has led to trials testing drugs in cognitively unimpaired persons who show evidence of AD biomarkers. Assuming the eventual success of such trials, millions of patients will be affected. There is a need to understand the effects of biomarker disclosure on those individuals.
The Study of Knowledge and Reactions to Amyloid Testing (SOKRATES) involved 2 semi-structured telephone interviews with individuals who received amyloid PET scan results as part of screening for research participation. Post-disclosure interviews were conducted at 4 to 12 weeks and again 1 year later. Data were collected from November 5, 2014 to November 30, 2016. Interviews were transcribed and coded in NVivo 12.0.
80 adults aged 65 and older: 50 who received "elevated" and 30 who received "not-elevated" amyloid PET scan results.
Interviews examined four domains: (1) comprehension of the amyloid PET scan result; (2) implications of the result for sense of self, memory, and future; (3) sharing of results with others; and (4) AD risk-reduction behaviors.
Participants who received an elevated amyloid PET scan result viewed the result as more serious and sensitive than other medical test results given its unique implications for identity, self-determination, and stigma. In contrast, participants who received a not-elevated amyloid PET scan result described feeling relief and reinterpreted perceived memory impairments as normal aging. Participants with elevated amyloid reported contemplating and making more changes to health behaviors and future plans than their peers with not-elevated amyloid.
Clinical practice in the diagnosis and treatment of persons with preclinical AD, a stage of the disease defined by the presence of biomarkers in the absence of cognitive impairment, will need to address matters of identity, stigma, and life-planning.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Introduction
Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of ...synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density.
Methods
We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using 11CUCB‐J PET and a cerebellar reference region for calculation of the distribution volume ratio.
Results
We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume.
Conclusion
We were able to measure widespread synaptic loss due to AD using 11CUCB‐J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies.
An animal model of late-onset Alzheimer's disease is needed to research what causes degeneration in the absence of dominant genetic insults and why the association cortex is particularly vulnerable ...to degeneration.
We studied the progression of tau and amyloid cortical pathology in the aging rhesus macaque using immunoelectron microscopy and biochemical assays.
Aging macaques exhibited the same qualitative pattern and sequence of tau and amyloid cortical pathology as humans, reaching Braak stage III/IV. Pathology began in the young-adult entorhinal cortex with protein kinase A-phosphorylation of tau, progressing to fibrillation with paired helical filaments and mature tangles in oldest animals. Tau pathology in the dorsolateral prefrontal cortex paralleled but lagged behind the entorhinal cortex, not afflicting the primary visual cortex.
The aging rhesus macaque provides the long-sought animal model for exploring the etiology of late-onset Alzheimer's disease and for testing preventive strategies.
•Aging rhesus macaques exhibit tau and amyloid pathology.•Tau phosphorylation precedes in the entorhinal cortex and spreads to the association cortex.•Phosphorylated tau fibrillates into classic paired helical filaments in tangles.•Concurrent phosphorylation of ryanodine receptors suggests calcium involvement.•The aging rhesus macaque could model late-onset Alzheimer's disease.
Lecanemab in Early Alzheimer's Disease. Reply van Dyck, Christopher H; Sabbagh, Marwan; Cohen, Sharon
The New England journal of medicine,
2023-Apr-27, 20230427, Letnik:
388, Številka:
17
Journal Article
In this randomized trial involving patients with mild cognitive impairment, vitamin E did not reduce the rate of progression to Alzheimer's disease. Although an initial benefit of donepezil was ...observed during the first year, over the course of the three-year study the rate of progression to Alzheimer's disease was similar in patients treated with donepezil and those treated with placebo. The side effects of donepezil included diarrhea, nausea, muscle cramps, and insomnia.
In patients with mild cognitive impairment, vitamin E did not reduce the rate of progression to Alzheimer's disease. Over the course of the three-year study the rate of progression to Alzheimer's disease was similar in patients treated with donepezil and those treated with placebo.
Mild cognitive impairment represents a transitional state between the cognitive changes of normal aging and the earliest clinical features of Alzheimer's disease.
1
Amnestic mild cognitive impairment refers to the subtype that has a primary memory component, either alone (single domain) or in conjunction with other cognitive-domain impairments (multiple domain), but of insufficient severity to constitute dementia.
2
–
6
Previous research has shown that the rate of progression to clinically diagnosable Alzheimer's disease is 10 to 15 percent per year among persons who meet the criteria for the amnestic form of mild cognitive impairment, in contrast to a rate of 1 to . . .
PDF
