The effect of the tumour necrosis factor-alpha-inhibitor etanercept on microglial activation patients with mild cognitive impairment—a PET study

Alexander Gerhard, Richard Sharples, Tsepo Goerttler, Kathryn Mcdonald, Eszter Visi, Rainer Hinz, Federico Turkheimer, Isabel Lewzey, Karl Herholz, Andreas H. Jacobs, Clive Holmes

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Aim: Microglial activation is increasingly recognised as a factor in the progression of Alzheimer’s disease (AD) and may be modified by systemic inflammatory signals including serum tumour necrosis factor (TNF)-α. The aim was to investigate whether blockade of peripheral TNF-α with peripheral inhibitors such as etanercept reduces microglial activation in prodromal AD.
Methods: A one-year, multi-centre, phase 2, double-blind randomised placebo-controlled trial (RPCT) was performed, to assess the effect of weekly 50 mg s.c. etanercept in amyloid positive mild cognitive impaired participants on the change in microglial activation as measured by [11C](R)-PK11195 positron emission tomography (PET). Secondary objectives were to ascertain the change in cortical amyloid load on PET and the change in the Montreal Cognitive Assessment (MoCA).
Results: Forty-four subjects consented to the study. Twenty-eight subjects failed screening including six subjects who were amyloid negative on visual read of the AmyvidTM PET scans. Thirteen of sixteen subjects with mild cognitive impairment (MCI) due to AD completed the baseline [11C](R)-PK11195 PET scan and were randomised to either placebo or etanercept. Three patients who consented were not able to complete screening due to early termination of the study following delays in study commencement. [11C](R)-PK11195 binding potential (BP) at baseline showed an almost global increase in MCI patients as compared to age-matched controls. Compliance to medication was high over the twelve-month trial period with etanercept being well tolerated. The study did not achieve statistical power to show a significant effect of etanercept over 52 weeks in the limited number of patients with MCI on microglial activation as measured by [11C](R)-PK11195 PET. Overall uptake of florbetapir in the follow up (FU) scans remained stable. The study was not powered to show statistical differences in psychometric ratings between groups.
Conclusions: This study did not show evidence that treatment with etanercept over one year would modulate microglial activation in amyloid positive MCI patients.
Original languageEnglish
Pages (from-to)52-66
JournalExploration of Neuroscience
Early online date26 Mar 2023
Publication statusE-pub ahead of print - 26 Mar 2023


  • Alzheimer’s disease
  • mild cognitive impairment
  • positron emission tomography
  • inflammation
  • randomised placebo-controlled trial


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