Biomarkers for Alzheimer's Disease (AD) and other neurodegenerative, neurological and psychiatric diseases The Human Neuroscience Section pioneered biomarker studies using blood Extracellular Vesicles (EVs, aka exosomes) enriched for neuronal origin (isolated by immunoaffinity capture targeting neuronal surface markers, such as L1CAM), or astrocytic origin (isolated by immunoaffinity capture tarheting astrocytic surface marker GLAST). To date, we have conducted scores of case control studies measuring exosomal beta-amyloid, tau/p-tau, Ser and Tyr phosphorylated IRS-1, synaptic markers, complement, mitochondrial proteins and other signaling mediators, in AD and control subjects. We have found multiple disease-associated differences that, for some proteins, may accurately discriminate between the two groups. In addition, biomarker abnormalities may be present at the preclinical stage and may predict AD and related dementias (ADRD). We have expanded the use of exosome biomarkers in other neurological and psychiatric disorders, demonstrating their ability to identify patients with Parkinson's disease (PD), Multiple Sclerosis, Traumatic Brain Injury, Restless Legs Syndrome, Covid-19 infection / long COVID and neurological abnormalities, Bipolar Disorder, and Schizophrenia (and also animal models of AD). Moreover, we have demonstrated the ability of exosome biomarkers to assess target engagement and response to experimental therapeutics in clinical trials involving patients with AD, PD, and bipolar disorder. We recently showed that exosome biomarkers predict future cognitive decline and future AD diagnosis in large preclinical cohorts from the Baltimore Longitudinal Study on Aging, the Wisconsin Registry for Alzheimer's Prevention, and Atherosclerotic Risk in Communities. In addition, we showed that exosome biomarkers predict treatment response and show target engagement in clinical trials of metabolic interventions in AD (intranasal insulin) and PD (exenatide), as well as anti-inflammatory treatment infliximab in Bipolar Disorder. One major goal for the coming year is to conduct studies seeking to demonstrate the relationship between exosomal markers and other biomarkers for AD (PET, CSF) in large preclinical/early clinical cohorts. These studies are needed to assess longitudinal changes in exosome markers and their potential to predict AD at the preclinical stage, track disease progression and predict conversion from MCI to AD. We are in the process of analyzing samples from a large cohort of participants in the Women's Health Initiative Memory Study - Long Life Study to assess the relationship of exosome biomarkers with cognitive resilience and APOE e4 genotype. In addition we intend to further validate exosome biomarkers against cognitive performance, amyloid and tau PET deposition using longitudinal cohorts (Harvard Aging Brain Study and CHARIOT-PRO). In addition to a main focus on AD, we are conducting exosome biomarker studies in vascular cognitive impairment/vascular dementia, Parkinson's disease, Lewy Body disease, Multiple Systems Atrophy, Traumatic Brain Injury, Restless Legs Syndrome, Multiple Sclerosis, long COVID, Schizophrenia, Depression, and Bipolar Disorder. In addition, we 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, ketone bodies) and neurotransmitters (glutamate and GABA), which are relevant to AD pathogenesis. Previously, 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. Glucose concentration is positively correlated with age. Clinical studies in cognitive aging/prevention of cognitive decline We completed a study of Intermittent caloric restriction (CR)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, brain metabolism, cognitive performance, fMRI activity and biomarkers. We are currently analyzing outcomes. 5-2 CR is a candidate intervention for primary prevention of AD and cognitive aging at midlife. Moreover, we are conducting a randomized controlled study of an oral ketone ester in middle aged individuals with metabolic syndrome. Using cognitive testing, as well as MRS and exosome biomarkers, we aim to demonstrate an increase in brain ketone concentration and a switch of brain metabolism towards ketone utilization, alongside improvements in cognitive performance. We have formed a collaboration with Investigators at McGill University, Canada, who plan to start a clinical trial of intranasal insulin in the peri-operative period of heart surgery patients to prevent post-operative cognitive decline. Our main goal is to conduct exosome biomarker analysis showing target engagement and pharmacodynamic response to intranasal insulin. The project has received funding from the Alzheimer's Drug Discovery Foundation. In collaboration with Dr. Mohamad El Haj from University of Lille, France, we have been involved in the design and analysis of clinical studies on cognitive features of Alzheimer's disease. For instance, we looked at 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 have also been studying the psychological impact of COVID-19 on patients with AD, their families and healthcare providers and geriatric facility personnel.