Predictors and biomarkers of Alzheimer's Disease (AD) and other neurodegenerative diseases In collaboration with Dr. Ed Goetzl from UCSF and other investigators, we developed a methodology for isolating blood exosomes and enriching them for neuronal origin by immunoprecipitation using neuronal surface marker L1CAM or enriching them for astrocytic origin by immunoprecipitation using astrocytic surface marker GLAST. To date, we have conducted several case control studies measuring exosomal beta-amyloid, tau, Ser and Tyr phosphorylated IRS-1, synaptic markers, complement and other proteins, in AD and control subjects. We found highly significant differences that, for some proteins, accurately discriminate between the two groups. In addition, exosomal differences may be present at the preclinical stage and may predict AD. I published several manuscript on the topic (in the journals Alzheimer's and Dementia, FASEB J (six times), Neurology, Annals of Neurology, Annals of Clinical and Translational Neurology, Frontiers in Neuroscience, and WIRES RNA). One major goal for the coming year is to complete and publish studies of exosomal markers in diagnosis of AD in large preclinical cohorts from the Baltimore Longitudinal Study of Aging (BLSA) and Wisconsin Registry for Alzheimer's Prevention. These cohorts are ideal for assessing longitudinal changes in these markers and their potential to predict AD at the preclinical stage, disease progression and conversion from MCI to AD. In addition to a main focus on AD, I am conducting exosome biomarker studies in Parkinson's disease, Multiple Systems Atrophy, Traumatic Brain Injury, and Multiple Sclerosis. In addition, I have employed a novel Magnetic Resonance Spectroscopy (MRS) methodology at the NIA 3T MRI facility, which allows us to obtain in vivo measures on brain metabolites (glucose, lactate) and neurotransmitters (glutamate and GABA), which are relevant to AD pathogenesis. First, I conducted a study of healthy volunteers combining MRS with resting fMRI, which provides measures of brain functional connectivity, and showed a link between neurotransmitter levels and brain connectivity. The study was published in Neuroimage. In a case-control study of patients with MCI/AD and healthy volunteers, we showed higher glucose and lactate, and lower glutamate and GABA in patients compared to controls, suggesting that these MRS markers may be used as diagnostic biomarkers for AD. The manuscript was published in the Annals of Clinical and Translational Neurology. In collaboration with Dr. Mohamad El Haj from University of Lille, France, we conducted several studies on autobiographical generation of past and future events in a cohort of AD patients compared to controls. We found that future and past events are more similar in patients compared to controls and that the ability to generate future events is closely related with the patient's episodic memory. In addition, the ability to generate future events was associated with Frontal Lobe functions. These findings suggest that remembering the past and imagining the future rely on common brain structures, which are both impaired in AD. In addition, we published a study on minimal interference in AD. Treatment studies in AD Exendin-4 (or exenatide) is an agonist of glucagon-like peptide-1 (GLP-1) receptors that has been shown to engage multiple targets in the pathogenesis of AD (reverse brain insulin resistance, decrease amyloid production and deposition, reverse synaptic changes and neurodegeneration) and, therefore, has therapeutic potential for AD. We conducted a pilot clinical trial to assess the safety and tolerability of exenatide in participants with Mild Cognitive Impairment (MCI)/early AD and have generated preliminary efficacy data. The study was terminated early by the sponsor, but a total of 57 participants were accrued, twenty-seven (27) participants received the experimental drug (exenatide or placebo), out of which 18 completed the study. Participants were randomized into exendin-4 vs. placebo groups and outcome measures were collected every six months for 18 months. The analysis of the data has been completed and deposited at clinicaltrials.gov. I continue to conduct a Phase I, double-blind, placebo-controlled, ascending, single-dose, safety, tolerability and pharmacokinetic study of Bisnorcymserine, a selective butyrylcholinesterase inhibitor, in healthy volunteers. Inhibition of butyrylcholinesterase is a novel therapeutic approach for symptomatic treatment in moderate/advanced AD. Finally, I am conducting a study of Intermittent caloric restriction (ICR)implementing 5-2 CR (alternating 5 days of regular calorie intake and 2 days of CR). This is a 8-week study of 5-2 CR in overweight middle aged subjects to assess potential beneficial effects on insulin resistance, metabolism, cognitive performance, fMRI activity and biomarkers. If this study is positive, 5-2 CR may be a candidate intervention for primary prevention of AD at midlife.