Exploring Alzheimer Disease as the Hyperthyroid Brain


A small study finds that thyroid function may meditate treatment efficacy in patients with AD.



Thyroid function may meditate donepezil efficacy in patients with Alzheimer disease (AD), according to a team of researchers from the Kaohsiung Municipal Kai-Syuan Psychiatric Hospital in Kaohsiung, Taiwan.1 The results of their small a prospective, case-control, 24- to 26-week follow-up study suggest that  higher levels of thyroxin (T4 ) may predict a favorable response to donepezil therapy.

Acetylcholinesterase inhibition using donepezil or rivastigmine has become a major therapeutic strategy for symptomatic relief and disease modification of AD, but effects are generally mild and response is not guaranteed. Further, response reportedly gradually declines after 24 to 36 weeks of treatment.2

A recently updated Cochrane Review of 13 studies inclusive of nearly 4000 patients confirmed that donepezil at a dosage of 10 mg/d provides some relief of AD symptoms for at least up to 24 weeks.3 Adverse effects seen in the study were dose-dependent, and higher dosages were not more effective than the 10 mg/d regimen: whereas a 5-mg/d dosage was associated with slightly better quality of life and fewer adverse events but slightly worse cognitive function on one of 3 rating scales applied (Alzheimer’s Disease Assessment Scale-Cognitive, Mini-Mental State Examination [MMSE], and Severe Impairment Battery) than 10 mg/d, a dosage of 23 mg/d was less tolerable and not more effective than 10 mg/d.

Evidence supports an extensive interrelationship between thyroid hormones, cortisol level, and the cholinergic system, according to the researchers. Chang and colleagues1 sought to evaluate thyroid function and cortisol level in patients with mild to moderate AD before and after donepezil therapy and evaluate variations in response. The study group consisted of 21 patients with mild to moderate AD and 20 age-matched healthy controls. Neuropsychological assessments, thyroid function tests, and serum cortisol measures were conducted at baseline and after 24 to 26 weeks of donepezil therapy at a dosage of 5 mg/d.

At baseline, patients with AD had a higher cortisol level (P <.05), lower levels of triiodothyronine (T3;  P = .003), and lower MMSE scores (P < .001) compared with controls. No significant differences in MMSE scores and cortisol level were seen at the 24-to-26‒week follow-up; however, significant reductions in T3 and T4 levels were seen (P <.05). The study authors noted that no significant difference in baseline or follow-up T3 levels was evident between responders (62% of the cohort), but responders had a higher baseline T4 level compared with the nonresponders (P <.05) and a significant reduction in T4 level after 24 to 26 weeks of donepezil therapy (P = .003).

The authors explained that findings from laboratory studies have suggested a relationship between thyroid hormones and AD pathogenesis, withT3 having an inhibiting regulatory effect on expression of the amyloid precursor protein gene and T4 modulating choline acetyltransferase activity. This and additional supporting data suggest that brain hypothyroidism may be at play in AD.

The team acknowledged that the study had several limitations, including but not limited to small sample size and lack of documentation of body mass or concomitant illness that might affect cortisol level or thyroid function. The team described its study as a preliminary attempt at exploring the relationship between thyroid hormones and cholinesterase inhibitor therapy as a means to discover new therapeutic strategies for treatment of AD.


1. Chang YS, Wu YH, Wang CJ, et al. Higher levels of thyroxine may predict a favorable response to donepezil treatment in patients with Alzheimer disease: a prospective, case-control study. BMC Neurosci. 2018;19(1):36.

2. Rocca P, Cocuzza E, Marchiaro L, Bogetto F. Donepezil in the treatment of Alzheimer’s disease long-term efficacy and safety. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:369-73.

3. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD001190. Updated June 18, 2018. http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD001190.pub3/full.

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