Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from ...aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. Our analysis supports the conduct of a third, phase III trial with high‐dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Some trials fail because the experimental treatment proves to be no different than a control or standard intervention. Others fail because of unacceptable side effects. In this issue of the
Journal
, ...an article by Egan et al.
1
and a letter to the editor by Henley et al.
2
describe a third reason for failure — a treatment worsens the target symptoms. The therapeutic intervention of lowering brain amyloid-beta (Aβ) peptide levels to treat patients with Alzheimer’s disease is based on a conceptual model in which accumulation of Aβ is causally related to cognitive decline. The model is rooted in the inseparability . . .
The skills of an expert clinician are needed at this second decision point to weigh multiple sources of information, assign a provisional clinical syndrome, and propose a provisional causal ...hypothesis. The physician must decide whether more information is needed to establish with higher certainty what the underlying cause is or, alternatively, if the clinically evident features are sufficiently elucidated to guide the treatment and management approach. DSK serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study; was an investigator in Alzheimer clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California, and is currently an investigator in a trial in frontotemporal degeneration with Alector; has served as a consultant for Roche, AriBio, Linus Health, Biovie, and Alzeca Biosciences, but receives no personal compensation; and receives funding from the National Institutes of Health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mild cognitive impairment (MCI) is an intermediate stage in the trajectory from normal cognition to dementia. Despite controversies about the classification of MCI, recent published criteria for MCI ...allow better comparison of the prevalence, incidence, and outcomes of MCI. Subjects with MCI have a high rate of progression to dementia over a relatively short period. In this review, we present an overview of the classification of MCI, estimates of the incidence and prevalence of MCI, risk factors for MCI, and the outcomes following an MCI diagnosis.
Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, ...variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain's modular organization and assign each region to a "meta-modular" group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer's dementia and 56 cognitively normal elderly subjects matched 1:2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer's disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer's dementia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mild cognitive impairment and mild dementia are common problems in the elderly. Primary care physicians are the first point of contact for most patients with these disorders and should be familiar ...with their diagnosis, prognosis, and management. Both mild cognitive impairment and mild dementia are characterized by objective evidence of cognitive impairment. The main distinctions between mild cognitive impairment and mild dementia are that in the latter, more than one cognitive domain is invariably involved and substantial interference with daily life is evident. The diagnosis of mild cognitive impairment and mild dementia is based mainly on the history and cognitive examination. The prognosis for mild cognitive impairment and mild dementia is an important motivation for diagnosis because in both, there is a heightened risk for further cognitive decline. The etiology of mild cognitive impairment and mild dementia can often be established through the clinical examination, although imaging and other laboratory tests may also contribute. Although Alzheimer disease is the most common cause of both, cerebrovascular disease and Lewy body disease make important contributions. Pharmacological treatments are of modest value in mild dementia due to Alzheimer disease, and there are no approved pharmacological treatments for mild cognitive impairment of any etiology. Nonetheless, new-onset cognitive impairment is a worrisome symptom to patients and families that demands answers and advice. If a patient is having difficulties managing medications, finances, or transportation independently, diagnosis and intervention are necessary to ensure the health and safety of the patient.
The amyloid cascade model of the pathogenesis of Alzheimer disease (AD) is wellsupported in observational studies. Its therapeutic corollary asserts that removal of amyloid-β peptide ("amyloid") ...would provide clinical benefits. After two decades of pursuing the strategy of amyloid removal without success, clinical trials of the anti-amyloid monoclonal antibody (AAMA) donanemab and a phase 3 clinical trial of lecanemab have reported clinical benefits linked to amyloid removal. Lecanemab (trade name, Leqembi
) is the only one with published phase 3 trial results.When administered intravenously every two weeks to patients with elevated brain amyloid and mild cognitive impairment or mild dementia, lecanemab delayed cognitive and functional worsening by about five months in an 18-month double-blind, placebo-controlled trial. The trial was well-conducted, and the results favoring lecanemab were internally consistent. The demonstration that lecanemab treatment delayed clinical progression in persons with mild symptoms due to AD is a major conceptual achievement, but a better appreciation of the magnitude and durability of benefits for individual patients will require extended observations from clinical practice settings. Amyloid related imaging abnormalities (ARIA) that were largely asymptomatic occurred in about 20%, slightly over half of which were attributable to treatment and the rest to underlying AD-related amyloid angiopathy. Persons who were homozygous for the
e4 allele had greater ARIA risks. Hemorrhagic complications with longer term lecanemab use need to be better understood. Administration of lecanemab will place unprecedented pressures on dementia care personnel and infrastructure, both of which need to grow exponentially to meet the challenge.
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