Primary Hypothyroidism and Alzheimer's Disease: A Tale of Two

Abstract

Hypothyroidism (HPT) HPT could be a risk factor for the development and progression of Alzheimer's disease (AD). In addition, progressive neurodegeneration in AD may affect the metabolism of thyroid hormones (THs) in the brain causing local brain HPT. Hence, the present review aimed to clarify the potential association between HPT and AD. HPT promotes the progression of AD by inducing the production of amyloid beta (Aβ) and tau protein phosphorylation with the development of synaptic plasticity and memory dysfunction. Besides, the metabolism of THs is dysregulated in AD due to the accumulation of Aβ and tau protein phosphorylation leading to local brain HPT. Additionally, HPT can affect AD neuropathology through various mechanistic pathways including dysregulation of transthyretin, oxidative stress, ER stress, autophagy dysfunction mitochondrial dysfunction, and inhibition of brain-derived neurotrophic factor. Taken together there is a potential link between HPT and AD, as HPT adversely impacts AD neuropathology and the reverse is also true.

Keywords: Alzheimer’s disease; Hypothyroidism; Mitochondrial dysfunction; Oxidative stress; Thyroid-stimulating hormone.

Fig. 1

Systemic effects of hypothyroidism (HPT): In primary HPT, both free T3 and T4 are reduced leading to impairment of lipid metabolism, expansion of visceral fat and the development of systemic inflammatory disorders. These metabolic changes increase hepatic triglyceride accumulation, augmentation of lipogenesis and leptin with a reduction of anti-inflammatory adiponectin. Besides, increasing the release of thyroid-stimulating hormone from adenohypophysis due to PHT induces the accumulation of hepatic triglyceride

Fig. 2

Effect of thyroid-stimulating hormone (TSH): Thyrotropin-releasing hormone (TRH) from the hypothalamus activates the release of TSH from the anterior pituitary which activate the release of thyroid hormones (THs) in a positive feedback loop. Increasing levels of THs inhibit the release of both TRH and TSH in a negative feedback loop. Leptin activates the release of TRH from the hypothalamus; somatostatin (SS) and dopamine (DA) inhibit TSH release from the pituitary. Glucocorticoids and pro-inflammatory cytokines inhibit TSH release

Fig. 3

Effects of AD on thyroid function: In the early phase of AD, accumulation of Aβ induces dysregulation of the hypothalamic-pituitary-thyroid axis leading to a reduction of thyroid hormones (THs) and an increase in TSH level. In AD, both thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) are reduced with subsequent reduction of THs release due to a reduction in the sensitivity of the pituitary to the effect of hypothalamic TRH. In advanced AD, degeneration of the hypothalamus and anterior pituitary reduced circulating levels of TRH and TSH with subsequent reduction of circulating THs

Fig. 4

Effect of hypothyroidism (HPT) on Alzheimer’s disease. HPT-induced transthyretin (TTR) and autophagy dysfunction lead to the accumulation of amyloid beta (Aβ) that induce cognitive dysfunction and the progression of AD neuropathology by increasing neuronal degeneration. Additionally, HPT-induced ER stress and mitochondrial dysfunction with subsequent development of oxidative stress that enhances the expression of beta-secretase and generation of Aβ. HPT is associated with a decrease in BDNF levels leading to synaptic and cognitive dysfunction