Higher levels of thyroxine may predict a favorable response to donepezil treatment in patients with Alzheimer disease: a prospective, case–control study

Abstract

BackgroundCholinergic hypothesis has been advanced as an etiology of Alzheimer disease (AD) on the basis of the presynaptic deficit found in the diseased brains, and cholinesterase inhibitors (ChEIs) are the treatment of choice for these patients. However, only about half of treatment efficacy was found. Because increasing evidence supports an extensive interrelationship between thyroid hormones (THs), cortisol level and the cholinergic system, the aim of the present study was to evaluate thyroid function and cortisol level in patients with mild to moderate AD before and after ChEIs treatment, and to identify possible variations in response. This was a prospective, case–control, follow-up study. Levels of cortisol and THs were evaluated in 21 outpatients with mild to moderate AD and 20 normal controls. All patients were treated with 5 mg/day of donepezil (DPZ) and were reevaluated after 24–26 weeks of treatment. ResultsThe patients had worse cognitive function, higher cortisol level, and lower levels of triiodothyronine (T3) and its free fraction than the controls. There were no significant differences in global cognitive function or cortisol level after treatment, however, significant reductions in T3 and thyroxin (T4) levels were observed. Responders had higher levels of T4 than non-responders, followed by a significant reduction after treatment. ConclusionsThese results suggest that relatively higher levels of T4 may predict a favorable response to DPZ treatment. Further studies are warranted to confirm the relationship between THs and ChEIs therapy in AD and to explore new therapeutic strategies. On the other hand, cortisol levels are more likely to respond to interventions for stress-related neuropsychiatric symptoms in patients with AD rather than ChEIs treatment. Further studies are warranted to investigate the association between cortisol level and the severity of stress-related neuropsychiatric symptoms in patients with AD.

Effect of Donepezil and Vitamin B12 Supplement on Serum Thyroid Profile in Alzheimer’s Disease

“…A study conducted by Yu San Chang et al 2018 has shown that the responders had a higher level of T4 than the nonresponders, followed by a significant reduction after donepezil treatment. These results indicate that relatively higher levels of T4 may predict a favorable response to donepezil treatment [3]. In our study, no beneficial effects of the donepezil and Vit B 12 therapy were observed on the thyroid profile in a duration of 6 months.…”

“…The most widely recognized association between endocrine and cognitive functions involves the thyroid hormone supported by increasing pieces of evidence about an extensive inter-relationship between thyroid hormones and the cholinergic system. Thyroxin (T4) has been shown to modulate choline acetyltransferase activity, and triiodothyronine (T3) has been shown to negatively regulate the expression of amyloid precursor protein (APP) in the brain [3,4]. Although the progressive cognitive decline is a critical clinical feature of AD, mood disturbance and behavioral symptoms are very common in patients.…”

An acetylcholinesterase inhibitor, donepezil, increases anxiety and cortisol levels in adult zebrafish

“…In the present study, donepezil dose-dependently increased whole-body cortisol levels in zebrafish (Figure 2), consistent with its putative acute anxiogenic-like behavioral effects described here (Figure 1). However, while AD patients demonstrate elevated cortisol, donepezil treatment is ineffective (Furiya et al, 2018; San Chang et al, 2018), as is another AChE inhibitor, pyridostigmine, unaltering adrenocorticotropin and cortisol in men (Freeman et al, 1990), or corticosterone in rodents (Kant et al, 2001). Importantly, elevated whole-body cortisol levels have been linked to increased anxiety-like behaviors in various zebrafish models (Demin et al, 2020; Egan et al, 2009; Song et al, 2018).…”

Nasal delivery of donepezil HCl-loaded hydrogels for the treatment of Alzheimer’s disease

“…According to this hypothesis, reducing the production of acetylcholine, as a neurotransmitter, leads to AD. Therefore, cholinesterase inhibitors (ChEIs) can be considered as potential targets for the treatment of AD 3 . Donepezil HCl (DH) is one of the ChEIs developed for AD treatment 4 .…”