Disorders of Body Weight, Sleep and Circadian Rhythm as Manifestations of Hypothalamic Dysfunction in Alzheimer's Disease.

While cognitive decline and memory loss are the major clinical manifestations of Alzheimer's disease (AD), they are now recognized as late features of the disease. Recent failures in clinical drug trials highlight the importance of evaluating and treating patients with AD as early as possible and the difficulties in developing effective therapies once the disease progresses. Since the pathological hallmarks of AD including the abnormal aggregation of amyloid-beta (Aβ) and tau can occur decades before any significant cognitive decline in the preclinical stage of AD, it is important to identify the earliest clinical manifestations of AD and elucidate their underlying cellular and molecular mechanisms. Importantly, metabolic and non-cognitive manifestations of AD such as weight loss and alterations of peripheral metabolic signals can occur before the onset of cognitive symptoms and worsen with disease progression. Accumulating evidence suggests that the major culprit behind these early metabolic and non-cognitive manifestations of AD is AD pathology causing dysfunction of the hypothalamus, a brain region critical for integrating peripheral signals with essential homeostatic physiological functions. Here, we aim to highlight recent developments that address the role of AD pathology in the development of hypothalamic dysfunction associated with metabolic and non-cognitive manifestations seen in AD. Understanding the mechanisms underlying hypothalamic dysfunction in AD could give key new insights into the development of novel biomarkers and therapeutic targets.