Vitamin D and Its Analogues: From Differences in Molecular Mechanisms to Potential Benefits of Adapted Use in the Treatment of Alzheimer's Disease

Abstract

Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D hypovitaminosis is associated with many diseases, such as Alzheimer's disease (AD), vitamin D supplementation seems to be particularly useful for this vulnerable age population. Importantly, in addition to vitamin D, several analogues are known and used for different medical purposes. These vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol, and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and is commonly represented in the elderly population. It is usually caused by extracellular accumulation of amyloidogenic plaques, consisting of amyloid (Aβ) peptides. Furthermore, the formation of intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D supply and discusses the specifics of administering various vitamin D analogues compared with vitamin D in geriatric patients, especially those suffering from AD.

Keywords: 1,25(OH)2D3; 1,25-dihydroxyvitamin D3; Alzheimer’s disease; vitamin D; vitamin D analogues; vitamin D binding protein; vitamin D derivatives; vitamin D receptor.

Figure 1

Chemical structure of vitamin D₃ derivatives (A) and vitamin D₂ analogues (B). Structural changes between the analogues are highlighted in green or with green circles.

Figure 2

Increasing clinical and environmental relevance of vitamin D and its analogues. (A) Defined daily dose (DDD) of vitamin D and vitamin D analogues prescribed in Germany, which has been increasing since 2015 until 2020. (Source: annual “Arzneiverordnungs-Report” in the publishing company “Springer”, data given in million DDD). (B) Increasing number of publications on PubMed for the search term “vitamin D”, “vitamin D analogues” or “vitamin D derivatives” as of 30 December 2022.

Figure 3

Graphical summary of the activation of vitamin D and vitamin D analogues by the 1- and 25-hydroxylases and potential triggers that may lead to enzyme dysfunction. In hepatic insufficiency or due to the influence of certain drugs, the function of 25-hydroxylases can be impaired [28,29,30]. Renal insufficiency, elevated FGF23 levels, and decreased estrogen levels may affect the functionality of 1-hydroxylase [31,32,33,34]. While cholecalciferol and ergocalciferol are activated by the 1- and 25-hydroxylases, the activation of some synthetic vitamin D analogues occurs independently of renal and extrarenal 1-hydroxylase, because they are already hydroxylated at the first carbon atom. Calcitriol, doxercalciferol, and alfacalcidol need only be activated by 25-hydroxylase. Maxacalcitol and paricalcitol bypass both 1 and 25-hydroxylation since they are already hydroxylated at the 1st and 25th carbon atom [35].

Figure 4

Schematic of an AD brain and the multiple impacts caused by vitamin D and its analogues. Vitamin D and its analogues have an inhibiting influence on Aβ plaques by reducing the amyloidogenic processing and promoting non-amyloidogenic processing and Aβ degradation. Moreover, neurofibrillary tangles, oxidative stress, and neuroinflammation are diminished. The neurotransmitters acetylcholine and dopamine are enhanced, and glutamate is degraded.