Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease With Non-invasive Techniques

Study Overview
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Brief Summary
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Default mode network (DMN) dysfunction is a well-established feature of Alzheimer's Disease (AD) and is already present in preclinical stages and in subjects at risk for AD, thus offering a potential target for early intervention. Non-invasive stimulation techniques are candidate approaches to modulate network dysfunction, however interventions specifically targeting subjects at risk for AD are lacking. This project will test a non-invasive intervention to modulate the DMN in cognitively healthy older adults carrying the main genetic risk factor for AD, the APOE e4 allele. The proposal will non-invasively stimulate the DMN in at risk subjects and will assess the neuronal-cognitive effect of this approach with multimodal neuroimaging and neurophysiological techniques.

Detailed Description
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Sixty-four participants will be enrolled (n=32 APOE e4 carriers, 32 non-carriers as reference group) and will undergo rTMS stimulation, TMS with concurrent electroencephalography (TMS-EEG), multimodal imaging (resting-state and task functional MRI, and diffusion tensor imaging) and cognitive assessment at baseline, after the intervention (week 1) and after 2 months. Participants will be randomized to 2 groups: active DMN stimulation (real-rTMS) or placebo (sham-rTMS). Each subject will undergo a rs-fMRI scan before the intervention to derive individualized DMN stimulation targets. rTMS will be applied over the left inferior parietal lobule node of the DMN.

Official Title
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Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease With Non-invasive Techniques

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Device: real-rTMS
* Device: sham-rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 60 years and older MMSE score > 24 Exclusion Criteria: Pathological scores in at least two standardized cognitive tests Participation in other interventional studies Known carriers of an autosomal dominant genetic mutation associated to AD Neurological, psychiatric or medical conditions not compatible with the study Exclusion Criteria for MRI and rTMS: metal implants, pace-makers, prosthetic heart valves claustrophobia history of epilepsy pregnancy

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: real-rTMS<br>4 daily 25-minutes high-frequency rTMS sessions over one week | Device: real-rTMS<br>* Each subject will undergo 4 rTMS sessions using a 70-mm figure-eight coil (20Hz for 25 minutes). Target localization will be performed with a stereotaxic neuronavigation system.<br>|
| Sham Comparator: sham-rTMS<br>4 daily 25-minutes sham-rTMS sessions over one week | Device: sham-rTMS<br>* The sham condition will match the real-rTMS protocol, but a sham coil will be used.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in DMN connectivity on rs-fMRI following real-rTMS compared to sham-rTMS in APOE4 carriers | Default mode network (DMN) mean functional connectivity is assessed on resting state functional MRI. Higher values denote greater functional connectivity. A positive change at post rTMS compared to baseline represents an increase in resting-state functional connectivity. | Baseline, post rTMS (1 week) | 
| Change in DMN connectivity on TMS-EEG following real-rTMS compared to sham-rTMS in APOE4 carriers | Single pulse TMS will be applied with concurrent EEG to derive online measures of cortical excitability and connectivity. The response in the natural frequency of the target area will index cortical excitability. Effective connectivity will be measured through amplitude and latency of TEPs. | Baseline, post rTMS (1 week) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in task-fMRI associative memory performance following real-rTMS compared to sham-rTMS in APOE4 carriers | Memory is assessed on task fMRI using a face-name associative paradigm | Baseline, post rTMS (1 week) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, Default mode network, APOE, rTMS, connectivity