Science

Bryan J. Neth and Suzanne Craft

Metabolic dysfunction is a well-established feature of Alzheimer’s disease (AD),
evidenced by brain glucose hypometabolism that can be observed potentially decades
prior to the development of AD symptoms. Furthermore, there is mounting support
for an association between metabolic disease and the development of AD and
related dementias. Individuals with insulin resistance, type 2 diabetes mellitus (T2D),
hyperlipidemia, obesity, or other metabolic disease may have increased risk for the
development of AD and similar conditions, such as vascular dementia. This association
may in part be due to the systemic mitochondrial dysfunction that is common to
these pathologies. Accumulating evidence suggests that mitochondrial dysfunction is
a significant feature of AD and may play a fundamental role in its pathogenesis. In fact,
aging itself presents a unique challenge due to inherent mitochondrial dysfunction and
prevalence of chronic metabolic disease. Despite the progress made in understanding
the pathogenesis of AD and in the development of potential therapies, at present we
remain without a disease-modifying treatment. In this review, we will discuss insulin
resistance as a contributing factor to the pathogenesis of AD, as well as the metabolic
and bioenergetic disruptions linking insulin resistance and AD. We will also focus on
potential neuroimaging tools for the study of the metabolic dysfunction commonly seen
in AD with hopes of developing therapeutic and preventative targets.