Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting over 5 million Americans, with this number expected to balloon to nearly 14 million by 2050. Annual health care costs associated with AD exceed 200 billion dollars which has led to the formation National Alzheimer's Project Act (NAPA). Goals of NAPA include the creation of a national plan to overcome AD, development of treatments to prevent, halt, or reverse AD, and improvements in early diagnosis and care of AD patients.

Our team has been at the forefront research to characterize the impact of exercise on AD prevention and progression. The investigator has shown that an exercise program improves cognitive (primarily executive) function in nondemented (ND) subjects in an exercise dose-dependent manner. The investigator has further shown that there is a positive relationship between cardiorespiratory fitness change and memory change in individuals with AD who participate in 6 months of aerobic exercise and are currently investigating these effects in subjects with preclinical AD (ClinicalTrials.gov ID NCT02000583). However, not all individuals benefit from exercise, and the precise mechanisms by which exercise elicits a beneficial effect are unclear. The investigator is currently exploring a variety of approaches ranging from molecular to neuroimaging studies to investigate these effects. One of the great knowledge gaps, however, is how little the field knows about the acute effects of exercise in AD. Most clinical trials, including our own, have been designed to assess metabolic outcomes at two fasting timepoints, before and after the intervention. However, the effects of each acute exercise bout on brain metabolism, and potential mechanisms by which cognition and memory may be affected, remain unclear. The investigator will explore these factors in the current application. Few groups are as well-positioned as ours to integrate cardiorespiratory fitness measures, acute exercise interventions, and advanced neuroimaging techniques.

Exercise benefits the brain: rationale for understanding the acute exercise response in AD Longitudinal observational studies show a relationship between self-reported exercise and cognitive decline, and higher physical activity in midlife and late life is associated with a reduced risk of developing late-onset AD. Furthermore, intervention studies have shown cognitive improvement following exercise in ND and MCI subjects. Cardiorespiratory fitness decline tracks with brain atrophy and progression of dementia severity in AD and hippocampal volume has improved with a physical activity intervention in some studies of older adults. In our recent study of exercise in AD subjects, the investigator did not see an overall improvement in memory in the intervention group but change in cardiorespiratory fitness was positively correlated with change in memory. The finding that cardiorespiratory fitness change is important in achieving memory effects in AD is consistent with work that shows a positive relationship between exercise-related cardiorespiratory fitness change and markers of cortical thickness and brain volume in ND, MCI, and AD subjects. It is also consistent with work from our group and others that shows physical activity and fitness levels are associated with larger brain volume.

Importantly, the investigator postulate that cardiorespiratory fitness change is likely driven by the repeated, acute effects of each single, acute exercise bout that is additive over time. These acute effects include changes in peripheral biomarkers that readily cross the blood brain barrier but return to normal within a few hours. However, the effects of acute exercise on the brain are not well understood, especially in aged and AD populations, and at the intensities that are often used in exercise intervention programs. This presents a knowledge gap in the study of the beneficial effects of exercise in aging and dementia populations.

Why study lactate? The terms "lactate" and "lactic acid" are often used interchangeably and differ by only one proton. Lactic acid is still considered by some to be a waste product generated during exercise, and although controversy still remains regarding the role of lactic acid in muscle acidification, there is substantial evidence that lactate plays a critical and beneficial role in a variety of tissues. The production of lactate from pyruvate generates NAD+, a necessary intermediate for glycolysis. Peripheral lactate is transported to the liver for regeneration of pyruvate via the Cori cycle; however, lactate is transported throughout the entire body, and during physical exercise, lactate provides a key source of energy for muscle and brain. Because lactate is used efficiently by the brain even at rest, the investigator hypothesize that lactate is a critical energy source for the brain, and that generation of lactate during acute exercise directly impacts glucose metabolism in the brain. The investigator will explore the effects of acute exercise on brain glucose metabolism as well as the dynamics of acute exercise biomarkers, including lactate and related substances that may affect brain metabolism.

In 1994, it was shown that that glucose use, lactate production, and lactate release increased with brain activation. This spurred the "lactate shuttle hypothesis" which posits that astrocytes primarily metabolize glucose to lactate, which is shuttled to neurons for use in oxidative phosphorylation. The concept of metabolic compartmentalization between brain cells is supported by expression of specific monocarboxylate transporter (MCT) isoforms, which transport lactate, in neurons compared to glia. Neurons express MCT2, which is characterized by a high affinity for lactate and limited expression profile, while astrocytes primarily express MCT4, which has low lactate affinity and is implicated in efflux of lactate. It is suggested that astrocytes rely more heavily on glycolysis than neurons. Glycolytic enzyme fructose biosphosphatase is degraded in neurons, suggesting a limited ability of neurons to increase glycolysis and further suggests increased shunting of glucose metabolism towards the pentose phosphate pathway. In short, glycolysis in neurons may be more critical for regeneration of antioxidants like glutathione, rather than generation of pyruvate for oxidation within mitochondria. Finally, studies of mice using FRET technology have shown that lactate can permeate both astrocytes and neurons, with evidence of an astrocyte-neuron lactate gradient. Lactate injection has been shown to increase neuronal lactate uptake relative to astrocytes. Taken together, this molecular evidence suggests that interventions which increase peripheral lactate, such as aerobic exercise, may increase flux into neuronal cells.

Lactate dynamics and exercise In humans, there is a linear relationship between systemic lactate concentration and brain lactate uptake at physiological concentrations and lactate can contribute to as much as 60% of cerebral metabolism when transporters are saturated. The kinetics of lactate entry into brain indicate the blood brain barrier is about half as permeable to lactate as glucose, but that intracellular uptake of lactate is greater. Recent evidence suggests that the FDG signal is driven by glial glucose use, and that increased supply of peripheral lactate may reduce the FDG-PET signal. Regardless of source, increased lactate supply should drop the FDG signal due to increased availability to both cell types.

Human studies: To date, most human studies of lactate and the brain have used lactate infusion and/or exercise, and were performed in healthy young men. A study using a lactate clamp and exercise showed that lactate oxidation during moderate exercise was improved by increasing lactate levels, sparing glucose and decreasing glucose production. Two other studies demonstrated that acute exercise improved cognition, and the cognitive improvement positively correlated with cerebral lactate uptake. Finally, exercise at an intensity which increased circulating lactate levels decreased cerebral glucose metabolism (FDG-PET signal), while lower intensity exercise that did not increase peripheral lactate did not. Although the decrease in cerebral glucose metabolism is proposed to be due to glucose sparing, as energy needs are met by lactate, the cellular fates of glucose and lactate have not been measured directly in humans due to technological limitations. Nonetheless, the acute changes in cerebral glucose metabolism may represent an important measure of cerebral responsiveness to exercise. It may also predict changes in resting cerebral glucose metabolism that have been observed in longer exercise intervention studies. However, the effects of acute exercise on brain glucose metabolism have not been assessed in ND elderly or AD populations.

Potential roles of related exercise biomarkers Although a lactate-specific relationship with cerebral glucose metabolism will be our focus for Aim 1, the investigator will also examine five additional exercise-related biomarkers that affect the brain. These biomarkers will include brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF), irisin, and glucose. Our rationale for the selection of these specific exercise-related biomarkers follows. BDNF is a potential mediator of exercise-related brain benefit, but its acute response has not been analyzed in AD. Studies in human cell lines suggest that short-term lactate exposure increases BDNF expression in both cortical astrocytes and SY5Y cells. Lactate is positively linked to both BDNF and VEGF levels following exercise, although it is unclear whether lactate drives these responses. In addition, in rodents, exercise-induced elevation of blood lactate increases TGF in brain CSF. This may be of relevance as TGF is implicated in the mobilization of fat-related energy substrates. The investigators have indirect evidence that energy substrate use during fitness tests may differ based on AD diagnosis, which is discussed later. Furthermore, in rodents, inhibition of TGF signaling decreased memory performance and long-term potentiation. Another modulator of fat metabolism and signaling is irisin. Irisin is a relatively newly-recognized hormone that is induced during moderate intensity exercise and has been linked to cognition in older adults at risk for dementia. The investigators and others have linked glucose to progression of AD and AD-related neuropathology, and in pilot studies the investigators have observed that glucose and insulin are both acutely responsive to exercise, with large variation between individuals. Quantification of these important exercise- and cognition- related biomarkers will enhance our understanding of the acute exercise response in aged and AD populations. The investigators will quantify them during the lactate clamp procedure. This will allow the investigator to determine if lactate itself is performing a function as a signaling molecule and affecting levels of other exercise related biomarkers, or if exercise-mediated change in these biomarkers occurs through other pathways.