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  • br Potential and established risk factor

    2024-02-22


    Potential and established risk factor for Alzheimer’s Disease The only way to overcome the above mentioned limitations is the identification of risk factors, which, taken together, can reliable predict the development of AD. Age and ApoE4 are established non-modifiable risk factors for AD. The risk of developing the disease doubles every 5 years after 65 years of age [13], and about 50% of AD patients carry the ε4 gene encoding for ApoE4. Among the modifiable risk factors of AD, recent meta-analyses have highlighted the importance of diet, physical activity, cognitive reserve, and stress [14], [15]. In this review, we will discuss data that support a role for stress and glucocorticoids as risk factors for AD.
    Hypothalamic-pituitary-adrenal axis and stress response Internal and external (stressor) signals trigger the activation of the hypothalamic-pituitary-adrenal (HPA) axis, which results into substantial sch772984 elevations of plasma ACTH and glucocorticoids levels (cortisol in humans and corticosterone in rodents). Adrenocortical activation plays an essential role in the adaptive response to physical and psychogenic stressors. Glucocorticoids restrain the activity of the HPA axis via negative feed-back mechanisms mediated by glucocorticoid receptors at the level of hippocampus, hypothalamus, and anterior pituitary. Glucocorticoids activate two types of cytosolic receptors: mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). Upon ligand binding, the hormone-ligand receptor complex translocates from the cytosol to the nucleus where MRs and GRs act as transcription factor regulating gene transcription [16]. Landmark studies have shown that GRs have one order of magnitude lower affinity for glucocorticoids than MRs, and are fully occupied by glucocorticoid hormones only under conditions of stress or at the peaks of the circadian rhythm of the HAP axis. On the contrary, MRs are extensively occupied when levels of circulating concentrations of glucocorticoids are low [17]. It is pertinent with the aim of this review to highlight that MRs and GRs are colocalized in CA1 and CA2 pyramidal neurons and dentate gyrus granule sch772984 of the hippocampus [18], which, again, is particularly vulnerable to AD pathology [19]. Pioneer studies by Bruce McEwen and his Associates have demonstrated that prolonged activation of GRs by high levels of glucocorticoids associated with stress causes neuronal damage in the hippocampus [20]. This cause-to-effect relationship between stress and neurodegeneration fits nicely with the current belief that neurodegeneration contributes to the pathophysiology of most, if not all, psychiatric disorders. Indeed, a positive correlation between severe or protracted stress exposure in vulnerable individuals is thought to increase the risk to develop post-traumatic stress disorder (PTSD), affective disorders and schizophrenia [21].
    Hypothalamic-pituitary-adrenal axis in Alzheimer’s Disease patients Increased cortisol levels in biological fluids (e.g., plasma, saliva and cerebrospinal fluid) have been found in patients affected by AD [22], [23], [24], [25], [26], [27], [28]. This is not surprising at early and late times after the clinical diagnosis of AD because of the suffering conditions related to the early awareness of memory impairment and the progressively invalidating course of the disease. Of note, increased levels of cortisol might also be associated with medical risk factors that may occur during the prodromic phase or even years prior to the onset of AD. For example, a dysregulation of the axis is associated with depression, diabetes and metabolic syndrome, all conditions considered as risk factors for AD. [29], [30], [31]. Genetic studies support a role for glucocorticoids as risk factors in AD. de Quervain and colleagues [32] have found that a rare haplotype in the 5′ regulatory region of the gene encoding 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) was associated with an increased risk to develop AD. 11ß-HSD1, also known as cortisone reductase, catalyzes the conversion of cortisol into the biologically inert 11 keto-product (cortisone). Thus, it is likely that subjects carrying a loss-of-function polymorphism of 11ß-HSD1, are more prone to develop AD as a result of the increased levels of cortisol at the target sites, including the hippocampus. In contrast, subjects bearing loss-of-function polymorphisms of the GR gene (NR3C1) are at lower risk to develop AD [33]. For example, this has been shown with subjects carrying the ER22/23EK polymorphism (approximatively 7% of the entire population), which decreases the sensitivity of GRs to glucocorticoids [34].