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Blood biomarkers for Alzheimer's disease in clinical practice and trials.

ABSTRACT: Blood-based biomarkers hold great promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD) in clinical practice. This is very timely, considering the recent development of anti-amyloid-β (Aβ) immunotherapies. Several assays for measuring phosphorylated tau (p-tau) in plasma exhibit high diagnostic accuracy in distinguishing AD from all other neurodegenerative diseases in patients with cognitive impairment. Prognostic models based on plasma p-tau levels can also predict future development of AD dementia in patients with mild cognitive complaints. The use of such high-performing plasma p-tau assays in the clinical practice of specialist memory clinics would reduce the need for more costly investigations involving cerebrospinal fluid samples or positron emission tomography. Indeed, blood-based biomarkers already facilitate identification of individuals with pre-symptomatic AD in the context of clinical trials. Longitudinal measurements of such biomarkers will also improve the detection of relevant disease-modifying effects of new drugs or lifestyle interventions.

SUBMITTER: Hansson O

PROVIDER: S-EPMC10979350 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Blood biomarkers for Alzheimer's disease in clinical practice and trials.

Hansson Oskar O Blennow Kaj K Zetterberg Henrik H Dage Jeffrey J

Nature aging 20230518 5

Blood-based biomarkers hold great promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD) in clinical practice. This is very timely, considering the recent development of anti-amyloid-β (Aβ) immunotherapies. Several assays for measuring phosphorylated tau (p-tau) in plasma exhibit high diagnostic accuracy in distinguishing AD from all other neurodegenerative diseases in patients with cognitive impairment. Prognostic models based on plasma p-tau levels can also ...[more]

PMID: 37202517

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Project description:Drug candidates directed against amyloid-β (Aβ) are mainstream in Alzheimer's disease (AD) drug development. Active and passive Aβ immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II-III clinical trials on this type of anti-Aβ drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Aβ deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Aβ drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Aβ biomarkers (CSF Aβ42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Aβ pathology. Pharmacodynamic Aβ and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-Aβ drug as disease modifying.

Project description:IntroductionPractice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome.MethodsWe investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline.ResultsOn average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run-in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design.DiscussionAssuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials.

Dataset Information

Blood biomarkers for Alzheimer's disease in clinical practice and trials.

Publications

Blood biomarkers for Alzheimer's disease in clinical practice and trials.

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