Predictors and biomarkers of Alzheimer's Disease (AD) 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 markers NCAM and L1 CAM. To date, we have conducted four case control studies measuring exosomal Ab, tau, Ser and Tyr phosphorylated IRS-1 peptides, REST, LRP6, Cathepsin-D, LAMP1, Uniquitin, HSP70 and HSF1 in AD and control subjects. We found highly significant differences that, for some peptides, accurately discriminate between the two groups. In addition, exosomal differences may be present at the preclinical stage and may predict AD. I presented these findings at talks at several international meetings, including the annual meetings of the Alzheimer's Association International Conference (AAIC), the American Association for the Advancement of Science (AAAS), Neuroscience 2014 (SfN), American Academy of Neurology (AAN), American Neurological Association (ANA), International Society of Extracellular Vesicles (ISEV). In addition, I published four manuscript on the topic (in the journals Alzheimer's and Dementia, FASEB, Neurology, and Annals of Clinical and Translational Neurology). One major goal for the coming year is to validate exosomal markers as diagnostic and prognostic biomarkers of AD in large cohorts from the Baltimore Longitudinal Study of Aging (BLSA), the Alzheimer's Disease Neuroimaging Initiative (ADNI), The Harvard Aging Brain Study, and the WRAP (Wisconsin). The BLSA, Harvard Aging Brain Study, and WRAP are ideal to assess longitudinal changes in these markers and their potential to predict AD at the preclinical stage, whereas ADNI is ideal for assessing changes with disease progression and conversion from MCI to AD. I implemented a data reduction technique called Independent Component Analysis to structural MRI images of subjects with AD and MCI from ADNI and studied how patterns of structural covariance predict clinical diagnosis and MCI conversion. This approach allowed us to classify subjects according to their future diagnosis with a high degree of accuracy (arguably, the highest ever achieved); the study was published in the journal Psychiatry Research Neuroimaging. In addition, I studied how peripheral insulin resistance is associated with regional brain glucose metabolism on FDG-PET in ADNI participants. We found that insulin resistance is associated with decreased glucose metabolism in patients with AD in a number of brain areas affected by AD. In addition, insulin resistance is associated with a maladaptive increase in metabolism at the hippocampus during the MCI stage, therefore, promoting AD pathogenesis; the study was published in the journal Diabetes. In collaboration with the NIA 3T MRI Facility manager, Dr. David Reiter, 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 pubmished 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 is currently under preparation. In addition, we are exploring associations of MRS measures with cognitive performance, functional connectivity within the default mode network; and CSF biomarkers. I also studied the association between cognitive performance and clinical status in AD and CSF inflammatory markers and found that higher levels of one particular pro-inflammatory cytokine, IL-12, predicts better cognition and less brain atrophy; this manuscript is currently under review. In collaboration with Dr. Mohamad El Haj from University of Lille, France, we conducted two 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. We published two studies describing these finings in the journals Neuropsychology, and Hippocampus. In addition, we published a systematic review on Episodic Memory in aging and AD, in the journal Aging Research Reviews. Treatment studies in AD I conduct a proof of concept Phase II, double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exendin-4 (exenatide) treatment in participants with Mild Cognitive Impairment (MCI)/early AD. Inclusion criteria include clinical diagnosis of MCI/early AD, and cerebrospinal fluid Ab(1-42) < 192 pg/dl. To this date, 47 participants have been enrolled and started on treatment with study drug (exenatide or placebo). Participants receive study drug for 18 months and outcome measures are being collected every six months. Fourteen participants completed the study, six participants withdrew from the study, and five continue participation. My goal for the new year is to reach the enrollment target of forty participants. I also 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, this year we acquired final IRB approval for 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, ICR may be a candidate intervention for primary prevention of AD at midlife.