Multidomain preventive intervention trials and plasma biomarkers
Authors: Marco Bucci, Agneta Nordberg
Journal: The Lancet Healthy Longevity (2024)

Multi-domain prevention trials for Alzheimer's disease are needed but their design is not straightforward. These trials require an enrolled population at risk of decline in cognition during a limited time period. Apart from assessing the effect of a combinatory intervention compared with placebo in reducing the expected cognitive decline, one could investigate as a sub-goal whether a biomarker (or preferably a set of biomarkers) could be sufficiently sensitive to measure or predict the effects of the intervention. In the Lancet Healthy Longevity, in Nicola Coley and colleagues’ study1Coley N Zetterberg H Cantet C et al.Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial.Lancet Healthy Longev. 2024; 5: e120-e130Google Scholar from the Multidomain Alzheimer Preventive Trial (MAPT)2Andrieu S Guyonnet S Coley N et al.Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial.Lancet Neurol. 2017; 16: 377-389Summary Full Text Full Text PDF PubMed Scopus (523) Google Scholar, a large population of community dwellers (with a mean age of 75 years old) with subjective memory complaints (of which 40% had a Clinical Dementia Rating of 0·5) were enrolled as participants in a multidomain lifestyle intervention (which included cognitive training, physical activity, and advice on nutrition). The lifestyle intervention was administered alone or in conjunction with omega-3 polyunsaturated fatty acid (PUFA) supplements. Plasma p-tau181 was measured (in a subset of 527 individuals) retrospectively from previously stored samples at baseline and after 36 months from trial enrolment. In the seminal paper of MAPT from Andrieu and colleagues2Andrieu S Guyonnet S Coley N et al.Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial.Lancet Neurol. 2017; 16: 377-389Summary Full Text Full Text PDF PubMed Scopus (523) Google Scholar the change from baseline to 36 months in a composite Z score (combining four cognitive tests) was not different between intervention groups compared with placebo. From Coley and colleagues,1Coley N Zetterberg H Cantet C et al.Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial.Lancet Healthy Longev. 2024; 5: e120-e130Google Scholar in a subset of the original MAPT cohort, we learn that different plasma p-tau181 concentrations at baseline did not result in significant cognitive decline between intervention groups, even though participants with elevated plasma p-tau181 at baseline (and increased brain amyloid load in 56/138 PET amyloid scans) showed greater cognitive decline. Furthermore, the interventions did not significantly affect the time-course of plasma p-tau181 from baseline to 36 months. The non-significant findings in the original MAPT study find support in a shorter trial (12 months) in which cognitive outcomes were not improved in a somewhat similar but smaller cohort (40% with mild cognitive impairment) supplemented with PUFAs and cocoa flavonols.3Vauzour D Scholey A White DJ et al.A combined DHA-rich fish oil and cocoa flavanols intervention does not improve cognition or brain structure in older adults with memory complaints: results from the CANN randomized, controlled parallel-design study.Am J Clin Nutr. 2023; 118: 369-381Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Some have already criticised the MAPT trial regarding the inadequate intensity of the intervention in terms of dose of PUFA dose4Yassine HN Schneider LS Lessons from the Multidomain Alzheimer Preventive Trial.Lancet Neurol. 2017; 16: 585-586Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar and frequency of visits.5Kivipelto M Mangialasche F Ngandu T Can lifestyle changes prevent cognitive impairment?.Lancet Neurol. 2017; 16: 338-339Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar MAPT's authors responded regarding the intensity that higher doses would have constituted a risk for safety; regarding the visits we can speculate that higher visit frequency could have hindered the compliance. Nonetheless, the intervention was not effective and likewise did not produce a reduction in plasma p-tau181 in Coley and colleagues’ study.1Coley N Zetterberg H Cantet C et al.Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial.Lancet Healthy Longev. 2024; 5: e120-e130Google Scholar Two questions arise, should we expect plasma p-tau181 to be modifiable by a multidomain prevention intervention in the future? Or should we simply focus on plasma p-tau and its other isoforms (ie, p-tau217) as an enriching strategy at baseline to identify participants at risk of decline? The mounting evidence of plasma p-tau181 used in trials for anti-amyloid therapy6Wu W Ji Y Wang Z et al.The FDA-approved anti-amyloid-β monoclonal antibodies for the treatment of Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials.Eur J Med Res. 2023; 28: 544Crossref Scopus (0) Google Scholar suggests, first that p-tau181 can be reduced within 1·5–3 years in participants with mild cognitive impairment due to Alzheimer's disease or prodromal Alzheimer's disease and, second that there is a connection between amyloid reduction and tau pathology that makes changes in p-tau181 detectable. Plasma p-tau181, as well as other p-tau isoforms significantly correlate with measured amyloid PET in the brain.7Bucci M Bluma M Savitcheva I et al.Profiling of plasma biomarkers in the context of memory assessment in a tertiary memory clinic.Transl Psychiatry. 2023; 13: 268Crossref Scopus (1) Google Scholar The unchanged plasma p-tau181 in the study by Coley and colleagues probably reflects that the intervention did not change the amyloid load in the brains of the patients. In another MAPT trial paper,8Delrieu J Payoux P Carrié I et al.Multidomain intervention and/or omega-3 in nondemented elderly subjects according to amyloid status.Alzheimers Dement. 2019; 15: 1392-1401Crossref PubMed Scopus (25) Google Scholar data from plasma amyloid beta (Aβ) produced better results in response to intervention than Coley and colleagues’ study, hinting probably that plasma Aβ is more fluid and sensitive than plasma p-tau181 at least in this population and in response to such an intervention. An additional study to support the use of plasma p-tau181 in clinical trials comes from Ferreira and colleagues,9Ferreira PCL Ferrari-Souza JP Tissot C et al.Potential utility of plasma p-tau and neurofilament light chain as surrogate biomarkers for preventive clinical trials.Neurology. 2023; 101: 38-45Crossref Scopus (1) Google Scholar which ultimately suggests enriching the population enrolled when levels of both plasma Aβ and p-tau181 are beyond a specific threshold. We suggest that if the therapy is likely to have slow-steady action with cumulative effects, long term-trials of 4 years or more on a relatively healthy but at-risk population should be part of the design. Regarding the enrolment, some questioned that the voluntary nature of the enrolment of the MAPT trial could constitute a bias for selecting participants who were goal-oriented and willing to comply.5Kivipelto M Mangialasche F Ngandu T Can lifestyle changes prevent cognitive impairment?.Lancet Neurol. 2017; 16: 338-339Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar An alternative could be to combine advertisement of the study alongside a memory clinic, like that described for MIND-ADmini,10Sindi S Thunborg C Rosenberg A et al.Multimodal preventive trial for Alzheimer's disease: MIND-ADmini pilot trial study design and progress.J Prev Alzheimers Dis. 2022; 9: 30-39Google Scholar which might enrich the study with objective memory complaints. Furthermore, one could take into consideration both amyloid (imaging, cerebrospinal fluid, or plasma, in order of preference) and tau (imaging, cerebrospinal fluid, or plasma) to enrol participants with amyloid pathology at the birth of progression. Combination of two or more biomarkers is a strategy already adopted by several trials for enrichment and for the prediction of amyloid positivity in clinical studies. AN reports consulting fees from AB Lundbeck and AVVA pharmaceuticals, consulting fees and honoraria for a lecture from Hoffman La Roche, and is the deputy chairman of Wennergren Foundations, Sweden. MB has nothing to declare. Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trialOur results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required. Full-Text PDF Open Access