Utilization and future of biomarkers in biofluid as outcome measures in clinical trials for Alzheimer’s disease: a systematic review

Abstract

AbstractBackgroundIn recent years, the availability of biofluid markers in Alzheimer’s disease (AD) has increased substantially, but it is unclear to what extend these are applied to support drug development. Therefore, we provide an overview of biofluid biomarker use within trials.MethodTo identify how fluid biomarkers are used in clinical trials, we performed a search (8‐FEB‐2022) on www.clinicaltrials.gov, using the search term ‘Alzheimer’s disease’, and selected trials aimed at disease modification starting from 1‐JAN‐2017 to 1‐JAN‐2022. Biofluid markers and their purpose in each trial were described. Results are summarized by trial phase, target class, and endpoint information.ResultWe identified 186 trials of which 44% used biofluid markers. 15% of phase 1 trials, 15% of phase 2 trials, and 6% of phase 3 and 4 trials employ fluid biomarkers as primary outcome (Figure 1). Blood and CSF biomarkers were used equally frequent. CSF biomarkers for Aβ, Tau, and other biomarkers were employed in 21%, 25%, and 16% of the 186 trials, respectively. Blood biomarkers for Aβ, Tau, and other biomarkers were used in 14%, 13%, and 23% of the trials, respectively. Moving further in the drug development phases, contribution of classic AD biomarkers increased, especially in CSF. Overall, a combination of Aβ, Tau and other biomarkers was used most frequent. 25% of the trials use biofluid target engagement markers. Target engagement marker use is most prominent in amyloid and tau targeting drugs. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis, gut‐brain axis targeting drugs.ConclusionThere exists a need for new fluid biomarkers, to reflect pathology which can be used in certain target classes where there currently is a lack of fluid biomarkers. To support future use biofluid markers as surrogate outcomes, research into the specific pathological processes they reflect and their correlation with cognition is warranted. This can pave the way into implementation of surrogacy biomarkers in AD clinical trials.