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

Background: Cholinergic 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. Results: The patients had worse cognitive function, higher cortisol level, and lower levels of triiodothyronine-(T-3) 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-T-3 and thyroxin-(T-4) levels were observed. Responders had higher levels of-T-4 than non-responders, followed by a significant reduction after treatment. Conclusions: These results suggest that relatively higher levels of-T-4 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.