ALZHEIMERS RESEARCH PROJECT / CLINICAL PROJECT: Mechanistic and clinical studies in Alzheimer's disease and related disorders

National Institute On Aging

Investigators

Linked publications & trials

Abstract

Methods development and mechanistic studies in vitro In a recent large study involving multiple methodologies to analyze single EVs, we validated the use of L1CAM as a selection marker for enriching neuronal EVs from peripheral blood. Seeking to further develop the methodology for neuronal EV isolation, we have established a CRADA with Neurodex, Inc, and have recently published results of an alternative methodology for isolating neuronal EVs by targeting neuronal markers NLGN3 and GAP43. We also collaborate with investigators at Johns Hopkins to identify additional neuronal markers for optimum isolation of neuronal EVs. We have implemented a methodology for conducting mitochondrial function measurements with SeaHorse in frozen brain samples and have shown that cellular respiration increases with prenatal brain development. We recently published a study demonstrating the relationship of mitochondrial changes in neuronal cells in culture and mitochondrial ATP synthase in secreted EVs from culture supernatant. We also developed a method for measuring NAD+ in neuronal EVs with the goal of demonstrating target engagement and pharmacodynamic responses to nicotinamide riboside in clinical trials. Finally, we are in the process of examining differences in mitochondrial function, metabolism, growth and survival of astrocytes derived form hiPSCs with different APOE genotypes. Clinical research We completed and published results from a study of intermittent fasting (IF)implementing 5-2 IF (alternating 5 days of regular calorie intake and 2 days of dramatically fewer calories). This was a 8-week study of 5-2 IF compared to the Healthy Living USDA diet in overweight middle aged subjects with insulin resistance. We demonstrated beneficial effects on systemic and brain-specific insulin resistance, brain metabolism, cognitive performance, MRI-derived BrainAge. We recently published results in Cell Metabolism. We found that both diets were good for overall health and brain health, but 5:2 IF showed stronger effects for reversing insulin resistance, improving executive function, and optimizing brain metabolism than the healthy living diet. However, we did not find any evidence that these two diets change any AD/ADRD-related biomarkers in the short term. Finally, we produced preliminary evidence that sex and genetic factors important for AD/ADRD, such as APOE, may modify responses to the diets. Moreover, we completed a randomized controlled study of an oral ketone ester in middle aged individuals with metabolic syndrome and we are in the process of analyzing results. Using cognitive testing, as well as MRS and EV biomarkers, we will examine whether the intervention was able to increase brain ketone concentrations and switch brain metabolism toward ketone utilization, as well as improve cognitive performance. Moving into the future, we have designed a randomized, open-label, parallel-group clinical trial with two arms aimed at evaluating whether psilocybin enhances the neuroplastic and cognitive benefits of cognitive training in two populations: older adults with normal cognition and individuals with early-stage AD. Participants will be randomized to either two oral doses of 25 mg of psilocybin, administered two weeks apart, plus cognitive training for four weeks or cognitive training alone for four weeks. The primary outcome will be the change from baseline in a Neuroplasticity Composite Score. This trial will begin by the end of 2025. We have shown that EV biomarkers can demonstrate target engagement in clinical trials of metabolic interventions in AD (intranasal insulin) and PD (exenatide), as well as biologics with anti-inflammatory action (infliximab) in Bipolar Disorder. By leveraging plasma samples from two clinical trials testing GLP-1 agonists (lixisenatide, exenatide) in Parkinson's disease and measuring insulin signaling markers in neuronal EVS, we will show whether GLP-1s engaged the insulin cascade in parent neurons. In collaboration with Dr. Mohamad El Haj from the University of Lille, France, I have been involved in the design and analysis of clinical studies on cognitive and neuropsychological features of AD and Frontotemporal Dementia (FTD). Initially, 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 recently studied autobiographical memory in FTD, demonstrating that despite the decreased ability to retrieve specific memories, an increased ability to produce categoric memories can be observed in patients with FTD.