Effect of Neflamapimod on Brain Inflammation in Alzheimer's Disease Patients

The present project is an intervention proof of concept study to test the efficacy of neflamapimod in a population of AD patients at an early stage.

To track the impact of this drug in patients, the investigators will use an innovative radiotracer, [18F]DPA-714, as a promising ligand of microglial activation targeting the translocator protein (TSPO), specific of microglial activation. The use of [18F]DPA-714 will allow to monitor the evolution of neuroinflammation in patients as a function of treatment. The main objective will be to compare the level of inflammation using the [18F]DPA-714 in neflamapimod and placebo groups after 12 weeks of treatment. Blood and cerebrospinal fluid (CSF) samples and magnetic resonance imaging (MRI) will also be collected to assess inflammation markers and brain structure respectively in these patients.

Inclusion criteria

• A group of 40 AD patients at an early stage (prodromal) will be recruited. Patient's recruitment will follow the most recent research criteria for AD in its "typical form" (Dubois, Feldman et al. 2014):

• Age 50 - 90 (inclusive)
• Willing and able to provide informed consent
• Objective memory impairment corroborated by level of performance on a standardized memory test (Free and Cued Selective Reminding test, (Grober, Hall et al. 2008)) < -1.5 DS according to established norms and
• Documented cerebral amyloidopathy using CSF analysis or PET amyloid imaging and
• Early stage of the disease (Mini Mental State Examination > 20) (Folstein, Robins et al. 1983).

Exclusion criteria

• • Evidence of neurodegenerative disease other than AD

• Inability for any reason to undergo MRI scans (e.g. pacemaker). Patients who require sedation for screening procedures such as MRI may receive a short-acting sedative.
• Psychiatric disorder that would compromise ability to comply with study requirements
• History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years
• Significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder or metabolic/endocrine disorders or other disease that would preclude treatment with p38 MAP kinase inhibitor and/or assessment of drug safety and efficacy
• Recent (<60 days) changes to AD medications prescribed for cognitive reasons or with the potential to impact cognition
• Psychotropic drugs taken within 1 month. Anticoagulant drugs taken within 1 week.
• Participation in a study of an investigational drug less than 6 months or 5 half-lives of the investigational drug, whichever is longer, before enrollment in the study
• Male subjects with female partner of child-bearing potential who are unwilling or unable to adhere to contraception requirements
• Female subjects who have not reached menopause or have not had a hysterectomy or bilateral oophorectomy/salpingoophorectomy
• Positive urine or serum pregnancy test or plans desires to become pregnant during the course of the trial
• History of alcohol and/or illicit drug abuse within 6 months.
• Infection with hepatitis A, B or C or HIV.
• Any factor deemed by the investigator to be likely to interfere with study conduction