In this study, the patients with AD had a statistically significantly higher cortisol level, lower levels of T3 and FT3, and a decline in global cognition compared with the controls. There were no significant differences in global cognitive function as measured by the MMSE and cortisol level after treatment, however significant reductions in T3 and T4 levels were observed. In addition, the responders had a higher level of T4 than the non-responders, followed by a significant reduction after treatment.
Laboratory studies have implicated a relationship between THs and factors associated with the pathogenesis of AD, including β-amyloid (Aβ) deposition and neuronal apoptosis. Circulation T4 are the major form of the THs which be transported into the brain by transthyretin . T4 is then converted to the active formT3 and inactive rT3 by deiodinase. T3 has been shown to negatively regulate the expression of the amyloid precursor protein gene , T4 has been shown to modulate choline acetyltransferase activity , and transthyretin has been shown to create soluble Aβ complexes . Compared with age-matched controls , the level of transthyretin has been reported to be lower in the cerebrospinal fluid (CSF) of patients with AD, suggesting a possible reduction in T4 transport into the brain in patients with AD. However, most T3 within the brain is produced locally by the intracerebral conversion of T4 to T3 . In addition, increased rT3 levels and an increased rT3 to T4 ratio were also found in the CSF of AD patients . Taken together, these findings suggest abnormal intracerebral THs metabolism and possibly brain hypothyroidism in AD . Even though circulating THs do not properly reflect the bioactive portion of CNS activity, the lower levels of T3 and FT3 in our results also suggest a link between abnormalities in the hypothalamic–pituitary–thyroid axis and dementia.
High levels of glucocorticoid receptors have been reported in the hippocampus where is supposed to engage in the negative-feedback of glucocorticoid secretion . However degeneration of the hippocampus is a prominent characteristic of AD , the loss of hippocampal cells can lead to hypercortisolemia, and this can increase degeneration of the hippocampus as the disease progresses. We also found higher levels of cortisol in the patients with AD than in the controls.
In the current, significant reductions in T3 and T4 levels were observed 24–26 weeks after DPZ treatment, indicating a relationship between THs and treatment. Thyroid glands are known to secrete about 80–90% of T4 and about 10–20% of T3, and that this process is regulated by TSH which is released by the anterior pituitary gland. Deiodinase enzymes in peripheral tissues convert T4 to T3 and rT3, and this is a major source of both rT3 (95%) and T3 (87%) in peripheral tissues . However, thyroid activity is influenced by both neuroendocrine control of TSH release and also various neurotransmitters including Ach. Maayan et al.  reported that Ach possible involved of muscarinic receptors in the thyroid to inhibit TSH- induced T4 release. In addition, numerous acetylcholinesterase-positive nerve fibers, probably cholinergic, were found in the thyroid . Therefore, our results of decreased T3 and T4 levels after treatment implicated the effect of Ach on the thyroid gland. However, there were no significant changes in TSH level after treatment in our study.
ChEIs treatment in AD has been reported to be most beneficial with regards to cognition after 3–4 months of administration , followed by a gradual decline after 24–36 weeks of treatment [6, 24]. DPZ is a ChEIs that has also been shown to exhibit a significantly greater improvement in cognitive function within 3 months of 5 mg/day administration, and to maintain a response defined by stabilization of cognitive function for 1 year . Accordingly, the global cognitive function was improved after treatment in this study but did not have statistically significant. This may be because of the small sample size, or because we did not perform evaluations during the period of maximum benefit.
Many studiers have reported interactions between glucocorticoids and Ach in the brain [26,27,28]. Stress-induced responses not only activate the hypothalamic–pituitary–adrenal (HPA) axis but also the septo-hippocampal cholinergic pathway. Activation of the HPA axis leads to the release of corticosterone, and activation of the septo-hippocampal cholinergic pathway results in an increase in Ach in the hippocampus. Ach also mediates neuroendocrine, emotional, and physiological responses by stimulating the HPA axis. Thus, the hippocampus in tandem with basal forebrain cholinergic pathways is involved in regulating HPA axis stress responses. Hence, neurodegeneration of cholinergic neurons in patients with AD makes them vulnerable to stress, resulting in cognitive impairment.
In this study, we found no statistical difference in cortisol levels after DPZ treatment. A previous large prospective study did not find a relationship between cortisol levels and the risk of developing AD, and concluded that dysregulation of the HPA axis in patients with AD seemed to be a consequence rather than a cause of AD [29, 30]. In addition, other studies have reported that chronic exposure to high levels of endocrine glucocorticoids probably contributes to the intensification of neuropsychiatric symptoms, particularly in stress-related symptoms such as depression and anxiety [31,32,33]. It is therefore possible that cortisol levels in patients with AD would be more likely to respond to interventions for stress-related neuropsychiatric symptoms rather than ChEIs treatment. This may be why we did not find a relationship between cortisol levels and the effect of DPZ treatment in patients with AD.
In our results, the responders had a higher level of T4 than the non-responders, followed by a significant reduction after treatment. Although THs in the CNS depend almost entirely on the uptake of T4 and its intracellular deiodination to the active compound T3 , deiodinase enzymes have also been shown to convert T4 to T3 in peripheral tissues . Thus, the reduction of serum T4 levels, as seen during DPZ treatment, may not only be due to enhanced conversion of T4 to T3 in the CNS. However, many neurotropic medications such as antidepressants, anticonvulsants, neuroleptics and benzodiazepines may affect deiodinase activity and THs concentration in the CNS . Therefore, the effect of DPZ beyond that of ChEIs may involve the upregulation of deiodinase activity in the brain. Alternatively, the responders to DPZ presented with higher baseline T4 levels before treatment and showed a significant reduction after treatment, which may indicate that a higher level of T4 characterizes a subgroup of AD patients who would be expected to benefit from ChEIs treatment.
There are several limitations to the present study. First, the small sample size limits the interpretation of the findings. Second, circulating hormone assessments do not properly reflect the bioactive portion involved in the CNS. Third, we did not record body mass index or concomitant diseases such as diabetes mellitus and hypertension, all of which could have affected the levels of THs and cortisol. Fourth, the study lacks supporting epidemiological data to make an association between THs and the expected favorable therapeutic response to DPZ treatment. However, the clinical relevance of the preliminary findings provide information to identify possible variations in response. Finally, the study was restricted to DPZ, and thus the findings cannot be extrapolated to other ChEIs.