Gradual, consistent cognitive declines commonly found with advancing age, even in the absence of clinical disease, are often ascribed to normal aging processes in the brain. Age-related differences in cognition have also been attributed to physiological mechanisms beyond the aging process, including degenerative diseases such as Alzheimer's disease (AD). Yet until recently the pathophysiological brain differences associated with preclinical AD have been difficult to study in vivo directly, and the effects of such preclinial biomarkers on cognition have received limited investigation in normal cognitive aging. With the advent of positron emission tomography (PET) ligands that bind biomarkers of the AD pathological cascade (e.g., tau, amyloid-beta [A?]), tools now exist to permit direct examination. We hypothesize that, among cognitively normal elderly, preclinical biomarker differences associated with AD are linked with disrupted glucose metabolism and cognition. In particular, increased age and increased fibrillar A? accumulation in diffuse neocortical regions will influence tau accumulation in and beyond MTL subregions, respectively, and tau will directly affect brain metabolism measured using FDG PET, and indirectly affect cognitive function. We will also examine, using approaches including mediation and path analysis, how tau may mediate the effect of A? on cognition, and how glucose metabolism may mediate the effect of tau accumulation on cognitive performance. Preclinical progression along the AD pathological cascade may be inadvertently conflated with normal aging processes in many studies investigating gradual cognitive decline late in life. Therefore, our goal is to investigate effectsof tau and A? accumulation on cerebral glucose metabolism, which itself is known to change in preclinical AD, and the relative effects of these brain differences on cognitive performance across multiple domains. The proposed research will contribute to a model of how preclinical AD-related differences, in otherwise normal elderly, disrupt brain function and cognitive performance. This research holds promise for impacting public health, through eventual clinical applications to age-related cognitive decline and disorders associated with A? and tau accumulation. My proposed research will provide training integral to my development as a translational cognitive neuroscientist of aging and dementia. I will gain valuable experience in PET and MRI imaging and in cognitive aging research during my training with Dr. William Jagust, and gain valuable mentorship from the collaborators whose letters are included with this application, taking advantage of the rich academic resources available through UC Berkeley and Lawrence Berkeley National Laboratory and through collaboration with UC San Francisco.
The risk for Alzheimer's disease (AD), a progressive condition associated with debilitating cognitive losses, increases with age, and there is growing consensus among researchers that treatment of AD needs to occur years before the onset of clinically obvious symptoms. However, the successful identification of seemingly healthy older adult patients with so-called 'preclinical AD' requires further research into the brain differences that are detectable prior to clinical onset. An improved understanding of these brain differences, achieved by combining established biomarker methods with newer techniques that measure the accumulation of AD-related molecules in the living human brain, will both inform basic neuroscience research and provide useful knowledge to clinicians.
