Network-Level Mechanisms for Preclinical Alzheimer?s Disease Development

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PROJECT SUMMARY Currently, no FDA-approved therapy exists for cognitively normal (CN) older subjects who have abnormal functional connectivity and are at increased risk for progression to dementia. To take the full advantage of early disease intervention, we propose a pilot project to test our hypothesis that, during the preclinical Alzheimer's disease developmental phase in cognitively normal (CN) older subjects with the apolipoprotein ε4 allele (APOE 4), decreased abnormal hyperfunctional connectivity can be correlated with improved episodic memory using a perturbation, such as a low dose of levetiracetam (LEV). Specifically, we will 1) determine network-level changes in hippocampal functional connectivity due to a 26- week, low-dose LEV perturbation (125 mg, twice daily) in 50 CN older subjects (ranging in age from 55 to 75 years) with the APOE 4 allele, and 2) correlate the network changes with changes in episodic memory before and after 26 weeks of placebo or low-dose LEV perturbation. We will employ the harmonized Human Connectome Project protocol for imaging acquisition and the FIX method to determine the network activity changes. The following outcome measurements will be used to test our proposed hypothesis. Primary outcome measures: Network changes in the bilateral sensory motor cortex regions of the HFC after LEV perturbation (time frame: 26 weeks). Secondary outcome measures: Episodic memory performance as assessed in the baseline and post-perturbation procedures and in the neuropsychological test battery (time frame: 26 weeks). Analogous to the use of baby aspirin to prevent the risk of cerebrovascular stroke, we hope a daily low dose of LEV will effectively prevent or slow memory decline.