Abstract and Introduction
Abstract
Objective: Many studies have investigated lower 25-hydroxyvitamin D (25[OH]D) levels in patients with Alzheimer's disease (AD) compared with those in control patients. In the present study, we aimed to evaluate serum free and bioavailable 25(OH)D levels in patients with AD and in healthy control patients.
Methods: The AD group consisted of 85 patients aged >60 years who were diagnosed with possible AD according to National Institute on Aging-Alzheimer's Association criteria and 85 healthy control patients. Serum levels of total 1,25-dihydroxyvitamin D, total 25(OH)D, vitamin D binding protein (VDBP), parathormone, calcium, phosphorus and albumin, free 25(OH)D, bioavailable 25(OH)D, and the bioavailable 25(OH)D/total 25(OH)D ratio were compared in both groups.
Results: Total 25(OH)D, free 25(OH)D, bioavailable 25(OH)D, and the bioavailable 25(OH)D/total 25(OH)D ratio were significantly lower (P <.001, P <.001, P <.001, P <.05, respectively) in the AD group, whereas the VDBP level was significantly higher (P <.05) in the AD than in the control group.
Conclusion: Free and bioavailable 25(OH)D detected at lower levels in patients with AD limit the target central effects of 25(OH)D; this result suggests that reduced levels of the active free form of vitamin D may be a risk factor for AD and dementia.
Introduction
Alzheimer's disease (AD) is a neurodegenerative disease that is the most common cause of dementia.[1] Accounting for 60% to 80% of all dementias,[2] AD is a chronic degenerative and inflammatory brain disorder that leads to inflammation, oxidative injury, neuronal dysfunction, and loss that is linked to the accumulation of fragments amyloid beta fragments (Aβ) and tau protein derivatives.[3]
Vitamin D is a steroid hormone that plays a role in calcium homeostasis, bone mineralization, and immune system differentiation. It is synthesized in the skin by the effect of sunlight from 7-dehydrocholesterol, which is the precursor of cholesterol. Taken from the skin by synthesis or diet, vitamin D binds to the vitamin D binding protein (VDBP) and is transported to the liver, where its 25-hydroxylation occurs with cytochrome P450 enzymes (CYP27A1, CYP2J2, CYP3A4). The main circulating metabolite of vitamin D is 25(OH)D.[4]
In the kidneys, 25(OH)D is rehydroxylated with the other cytochrome P450 enzyme, CYP27B1, and the synthesis of the biologically active form 1,25 dihydroxyvitamin D (1,25[OH]2D) occurs.[5] Renal synthesis of this biologically active form is regulated by whether 25(OH)D is bound to VDBP. The uptake of 25(OH)D-bounded VDBP into renal proximal tubule cells is mediated by the endocytic receptor megalin. In the absence of megalin, the free form of 25(OH)D and 1,25(OH)2D enters the target cell by diffusion. Although vitamin D bounded to VDBP is taken up by megalin in the proximal tubule, the physiological importance of the free form in intestinal absorption is even more prominent. In this case, the level of free vitamin D may be very important for the efficiency of biologically active vitamin D for calcium and phosphate homeostasis and for other important functions such as anti-inflammatory and immunomodulatory effects.
The optimal level of 25(OH)D is unknown; this level is influenced by factors such as binding proteins, vitamin D receptor genetic polymorphisms, and metabolic enzymes. Therefore, 25(OH)D serum levels are insufficient to measure vitamin D activity, but it is important to evaluate them together with free-form and binding proteins.[6–8]
Although the primary function of vitamin D is known to be the maintenance of calcium and phosphate homeostasis, other functions of vitamin D include anti-inflammatory and immunomodulatory effects, control of cell growth, differentiation and apoptosis, and defense against tumorigenesis.[9] Oxidative stress, inflammation, and neuronal calcium signaling defects are known to play an important role in the pathogenesis of AD. Vitamin D shows an anti-inflammatory effect via apolipoprotein A1 and the proinflammatory cytokine tumor necrosis factor-alpha.[10] It protects the brain from oxidative stress by reducing the formation of reactive oxygen species with its antioxidant effect through nitric oxide synthase and glutamyl transpeptidase.[11]
The interaction of vitamin D with Aβ, which is at the center of AD pathology, has made vitamin D an attractive molecule in the pathophysiology of AD.[12] Vitamin D and its metabolites show neuroprotective effects by inhibiting the abnormal accumulation of amyloid fibrils that are responsible for the pathogenesis of AD via amyloid phagocytosis and clearance and by regulating the activation of the phosphatase-2A enzyme that dephosphorylates the tau protein.[13,14] Vitamin D receptors are expressed in several regions of the brain that play a key role in cognition—primarily in the hippocampus, but also in the prefrontal cortex, cingulate gyrus, caudate-putamen, thalamus, substantia nigra, hypothalamus, lateral geniculate ganglion, and cerebellum.[15]
In the present study, our objective was to draw attention particularly to the levels of the effective form of 25(OH)D in AD by measuring serum levels of free and bioavailable 25(OH)D in patients with AD and healthy volunteers.
Lab Med. 2021;52(3):219-225. © 2021 American Society for Clinical Pathology
