This study aims to analyse, in vivo, the interplay between microglial activation and tau pathology in Alzheimer's disease (AD) using [18F]-DPA-714 and [18F]-Ro948 tracers by Position Emission Tomography (PET), and their consequences on synaptic density using [11C]-UCB-J, a recent PET radioligand.

By coupling advanced neuroimaging techniques in AD patients, while comparing them to controls, we will be able to study, for the first time in humans, the interaction between neuroinflammation, tau pathology, synaptic density, and their impact on AD progression. Joint analyses of peripheral immune biomarkers, carried out as a secondary objective, will further aim at defining peripheral correlates of this interplay.

Overall, we aim to refine AD subgroup classification in order to improve and to refine the design of new therapeutic trials.

The present study aims to reevaluate the interplay between microglial activation, tau pathology, and synaptic density. It is an interventional, comparative, controlled, non-randomized study in which AD patients will be matched to controls. In order to better our current understanding of pathophysiological processes of neuroinflammation in AD, we will analyze regional microglial activation, cortical tau deposition, and synaptic dysfunction by employing multiple PET radioligands and MRI. The hybrid images will be acquired at baseline and at two years.

This study design opens the door to a multimodal study; first transversal (by determining whether the level and the extent of DPA-714 binding are associated with synaptic loss and tau deposition) then longitudinal (after a two-year follow-up based on PET/MRI, cognitive and clinical assessment and peripheral immune biomarkers). By using PET imaging at baseline and at two years, we will investigate the neuroinflammation dynamics in sporadic AD and its consequences on neurodegenerative biomarkers as well as its clinical repercussions.

Conservative diagnosis criteria based on clinical and CSF biomarkers have been established to avoid risks of misdiagnosis for the patients. The controls will undergo, at inclusion, an additional PiB-PET imaging to avoid bias and to identify amyloid positive controls.

A complete clinical and cognitive evaluation will accompany the image acquisition at baseline. The subjects will be followed up clinically at one year. At two years, another set of PET/MRIs will be performed as well as a cognitive evaluation. The image acquisitions will be planned within 6 months of each clinical visit at baseline and at two years.

Inclusion Criteria:

General Inclusion Criteria:

• Adult (older than 18 years)
• Women old enough to procreate under effective contraception
• Signed consent
• Absence of general or systemic disorders that may interfere with cognition.

Inclusion criteria for EOAD and LOAD patients:

• Progressive amnestic syndrome, associated or not with other cognitive impairments,
• CDR = 0.5 or 1
• Absence of general or systemic disorders that may interfere with cognition or PET imaging analysis,
• Absence of brain lesions as determined by MRI carried out within the framework of usual care.
• Presence of CSF biomarkers profile suggestive of AD

Inclusion criteria for controls:

• absence of subjective problems with memory and normal scores on the MMSE (MMSE > 27) with no more than one word missing.
• older than 50 years old.
• Scores on the Free and Cued Selective Reminding Test (FCSRT) of >25 for free recall and >44 for total recall.
• absence of general or systemic disorders that may interfere with cognition at follow-up.

Controls will be matched to AD patients for age and education level.

Exclusion Criteria:

• Subject with a psychiatric evolutionary and/or poorly checked pathology (left to the judgement of the investigator).
• Subject with a grave, severe or unstable pathology (left to the judgement of the investigator) the nature of which can interfere with the variables of evaluation.
• Current auto-immune disease
• Subject presenting contraindications to the 3T MRI
• Known or supposed histories (≤5 years) of severe alcoholism or misuse of drugs
• Vascular, inflammatory or expansive, visible lesion in the MRI which can interfere on the criteria of diagnosis.
• No health insurance
• Pregnant, breast-feeding woman or planning a pregnancy in two years of follow-up.
• Diagnosis or history of other possible etiology of dementia, including but not limited to other neurodegenerative disorders.
• Person placed under the protection of justice
• Patient under guardianship or curatorship

This is a non-randomized, open label study including three groups; early onset AD, late onset AD, healthy controls.