Metabolic and Non-Cognitive Manifestations of Alzheimer's Disease: The Hypothalamus as Both Culprit and Target of Pathology

Abstract

Alzheimer's disease (AD) is increasingly recognized as a complex neurodegenerative disease beginning decades prior to the cognitive decline. While cognitive deficits remain the cardinal manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in body weight and neuroendocrine functions, are also present, often preceding the cognitive decline. Furthermore, hypothalamic dysfunction can also be a driver of AD pathology. Here we offer a brief appraisal of hypothalamic dysfunction in AD and provide insight into an underappreciated dual role of the hypothalamus as both a culprit and target of AD pathology, as well as into new opportunities for therapeutic interventions and biomarker development.

Figure 1. Hypothalamic nuclei: structure and function

Coronal brain images illustrate the hypothalamus and the location of its nuclei (lettered) in order from most rostral (left) to caudal (right) with a description of key functions and neurotransmitters/neuropeptides associated with each hypothalamic nuclei. Abbreviations: AgRP – agouti related peptide; BDNF – brain-derived neurotrophic factor; CART – cocaine and amphetamine related transcript; CRH – corticotropin releasing hormone; GI: gastrointestinal; GnRH – gonadotropin releasing hormone; MCH – melanin concentrating hormone; NPY – neuropeptide Y; POMC – proopiomelanocortin; TRH – thyrotropin releasing hormone; VIP – vasoactive intestinal peptide.

Figure 2. Hypothalamic-pituitary pathways affected in Alzheimer’s disease

The normal homeostatic regulation of the hypothalamic-pituitary pathways due to stimulatory (+) and inhibitory (−) signals is shown. i.e., for the hypothalamic-pituitary-adrenal pathway, the hypothalamus releases CRH, which stimulates (+) the secretion of ACTH from the pituitary gland. The ACTH then stimulates (+) release of cortisol from the adrenal glands. The cortisol would then send negative feedback signals (−) to both the hypothalamus and pituitary gland to inhibit the any further release of CRH and ACTH respectively. Similar homeostastic regulation occurs with the hypothalamic-pituitary-thyroid and hypothalamic-pituitary-gonadal axes. Abbreviations: ACTH - adrenocorticotroic hormone, CRH - corticotropin-releasing hormone, FSH – follicle-stimulating hormone, LH - luteinizing hormone, TSH - thyroid-stimulating hormone, T₃ - triiodothyronine, T₄ - thyroxine. Figure was adapted and modified from original (Ishii, 2014).

Figure 3. The hypothalamus: target and culprit of AD pathology?

Proposed mechanism depicting how abnormal accumulation of amyloid-beta and tau in the hypothalamus can result in decreased hypothalamic signaling and insensitivity to the normal hormonal feedback signals. Reduced hypothalamic signaling in turn leads to alterations in critical physiological functions including neuroendocrine axis, systemic metabolism, and sleep/circadian rhythm, which can potentially contribute to worsening amyloid and tau pathology and cognitive/mental decline.