Bioenergetics and Cognitive Decline

Despite intensive research, no preventive strategies or therapeutic interventions have proven effective for AD dementia. This failure is in large part because AD pathology, including the development of irreversible neurological damage, occurs years before the manifestation of clinical symptoms and cognitive impairment. Therefore, efforts to prevent and countermand AD dementia rely on early detection of presymptomatic pathological changes. A central goal of our research is to identify antecedent biomarkers and risk factors that predict later life AD vulnerability or resilience. We are examining the transitions from normal aging to mild cognitive impairment (MCI) and from MCI to AD and related disorders. In 2004, Swerdlow and Khan promulgated the “mitochondrial cascade hypothesis” for the development of sporadic late-onset AD, proposing that mitochondrial dysfunction is the primary event leading to the deposition of senile plaques and neurofibrillary tangles that are hallmarks of this disease.  An impressive body of work now highlights the central role of mitochondria in AD pathophysiology. Notably, multiple lines of evidence indicate that peripheral mitochondrial dysfunction accompanies changes in brain mitochondria in AD. Based upon this recognition, our team is utilizing peripheral cells to examine mitochondrial bioenergetics in older adults with varying degrees of AD risk and pathology. Blood-based bioenergetic profiling provides a minimally invasive assessment of mitochondrial function that is amenable to longitudinal human studies. Using this approach, we are identifying multi-parameter bioenergetic signatures that are associated with presymptomatic stages of AD and are predictive of AD progression.