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Targeting the Hallmarks of Aging with Vitamin D: Starting to Decode the Myth.
Ruggiero, C, Tafaro, L, Cianferotti, L, Tramontana, F, Macchione, IG, Caffarelli, C, Virdis, A, Ferracci, M, Rinonapoli, G, Mecocci, P, et al
Nutrients. 2024;(6)
Abstract
Aging is the result of several complex and multifactorial processes, where several agents contribute to an increased intrinsic vulnerability and susceptibility to age-related diseases. The hallmarks of aging are a set of biological mechanisms that are finely regulated and strictly interconnected, initiating or contributing to biological changes and anticipating several age-related diseases. The complex network of cellular and intercellular connections between the hallmarks might represent a possible target for the research of agents with pleiotropic effects. Vitamin D (VitD) is known to have a positive impact not only on muscle and bone health but also on several extra-skeletal districts, due to the widespread presence of Vitamin D Receptors (VDRs). VitD and VDR could be molecules potentially targeting the hallmarks of the aging network. To date, evidence about the potential effects of VitD on the hallmarks of aging is scarce in humans and mainly based on preclinical models. Although underpowered and heterogeneous, in-human studies seem to confirm the modulatory effect of VitD on some hallmarks of aging and diseases. However, more investigations are needed to clarify the pleiotropic effects of VitD and its impact on the hallmark of aging, hopefully highlighting the courses for translational applications and potential clinical conclusions.
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Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease.
, , Luo, J, Thomassen, JQ, Bellenguez, C, Grenier-Boley, B, de Rojas, I, Castillo, A, Parveen, K, Küçükali, F, Nicolas, A, et al
JAMA network open. 2023;(5):e2313734
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Abstract
IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). CONCLUSIONS AND RELEVANCE This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
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Diabetes-Alzheimer's connection in older age: SGLT2 inhibitors as promising modulators of disease pathways.
Mancinetti, F, Xenos, D, De Fano, M, Mazzieri, A, Porcellati, F, Boccardi, V, Mecocci, P
Ageing research reviews. 2023;:102018
Abstract
Late-onset Alzheimer's disease (LOAD) is the most frequent cause of dementia in older persons. Subjects affected by type 2 diabetes mellitus (T2DM) are at higher risk of vascular disease, cognitive decline, and dementia. LOAD has many characteristics shared with impaired insulin signaling pathways, and substantial evidence has demonstrated a pivotal role in dysregulated glucose metabolism in its pathogenesis. Recent studies have shown that some anti-diabetic drugs, other than regulating the metabolism of peripheral tissues, can also modulate the brain's metabolism, reduce inflammation, and have a direct neuroprotective effect. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a newer class with many pleiotropic effects that may have strong neuroprotective potential. After a summary of the principal "anti-diabetic" drugs acting as suitable candidates in treating LOAD, this narrative review explored the potential role of SGLT2i on cognition from pre-clinical to clinical studies.
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Author Correction: Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
de Rojas, I, Moreno-Grau, S, Tesi, N, Grenier-Boley, B, Andrade, V, Jansen, IE, Pedersen, NL, Stringa, N, Zettergren, A, Hernández, I, et al
Nature communications. 2023;(1):716
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The interdisciplinary fracture liaison service improves health-related outcomes and survival of older adults after hip fracture surgical repair.
Ruggiero, C, Baroni, M, Talesa, GR, Cirimbilli, A, Prenni, V, Bubba, V, Parretti, L, Bogini, R, Duranti, G, Caraffa, A, et al
Archives of osteoporosis. 2022;(1):135
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Abstract
UNLABELLED Due to the high burden of fragility fractures, we developed an interdisciplinary FLS care pathway for early management and monitoring of older adults discharged from a high-volume trauma center after hip fracture repair. Interdisciplinary FLS effectively improves up to 1-year adherence to treatments for secondary prevention of fragility fractures, reduces health facility admission, and improves long-term survival. PURPOSE To compare adherence to secondary fragility fracture prevention, falls, healthcare facility admissions, and mortality between hip fracture older adults who entered the fracture liaison services pathway of care (FLS-CP) and those managed according to the usual traumatologist model of care (U-CP). METHODS Prospective observational study enrolling subjects aged ≥ 65 years discharged by high-volume trauma center after hip fracture repair from February 2016 to February 2017, who consecutively entered FLS-CP or U-CP according to their preference and goals. RESULTS Compared to U-CP, those in FLS-CP had higher initiation rate and up to 1-year adherence to secondary prevention of fragility fracture, including vitamin D and calcium (87.7% vs 36.9%; p < 0.0001), specific anti-osteoporosis drugs (75.1% vs 8.0%; p < 0.0001), and complete anti-fracture therapy (72.3% vs 5.7%; p < 0.0001). Older adults belonging to FLS-CP showed a lower likelihood of healthcare facility admission (RR 0.597; 95% CI 0.398-0.895; p = 0.0125), with a longer re-hospitalization-free survival (176.4 vs 88.7 days; p = 0.0152) than those in U-CP. One-year incidence of falls and fractures was similar between groups, with a lower tendency of the subjects in the FLS-CP to be multiple fallers (19% vs 34.8%; OR 0.057; 95% CI 0.004-0.876; p = 0.0690). The FLS-CP group experienced a lower 1-year (87.2% vs 74.3%; p = 0.001) and 3-year mortality (67.9% vs 55.6%; p = 0.0245) and a lower adjusted 5-year mortality hazard ratio (50.2% vs 58%; HR = 0.76; 95% CI 0.60; 0.96). CONCLUSION The FLS-CP may improve initiation and adherence to secondary prevention of fragility fractures, reduces healthcare facility admission, and improves long-term survival.
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Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
de Rojas, I, Moreno-Grau, S, Tesi, N, Grenier-Boley, B, Andrade, V, Jansen, IE, Pedersen, NL, Stringa, N, Zettergren, A, Hernández, I, et al
Nature communications. 2021;(1):3417
Abstract
Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.
DeMichele-Sweet, MAA, Klei, L, Creese, B, Harwood, JC, Weamer, EA, McClain, L, Sims, R, Hernandez, I, Moreno-Grau, S, Tárraga, L, et al
Molecular psychiatry. 2021;(10):5797-5811
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Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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Beta-carotene, telomerase activity and Alzheimer's disease in old age subjects.
Boccardi, V, Arosio, B, Cari, L, Bastiani, P, Scamosci, M, Casati, M, Ferri, E, Bertagnoli, L, Ciccone, S, Rossi, PD, et al
European journal of nutrition. 2020;(1):119-126
Abstract
PURPOSE Advancing age represents the strongest risk factor for Alzheimer's disease (AD), and the identification of biomarkers able to define what characterizes physiological aging from AD may represent a potential starting point for novel preventive strategies. Among these biomarkers, telomeres seem to be a promising target. Interestingly, high intake of carotenoid-rich food may play a role in protecting telomeres by oxidative stress reduction. Accordingly, low plasma β-carotene concentrations have been found in AD subjects when compared with cognitively healthy subjects. In this study, we aim at investigating the hypothesis that low β-carotene might be associated with markers of accelerated cellular aging, including leucocyte telomere length (LTL) and peripheral mononuclear cell (PBMC) telomerase activity in a cohort of old age subjects. METHODS The study was conducted in 68 old age subjects, 37 AD, and 31 age-matched healthy controls. In all subjects, β-carotene plasma level, LTL and peripheral telomerase activity were measured. RESULTS In all populations, β-carotene significantly and positively (r = 0.320, p = 0.008) correlated with telomerase activity, independent of gender. A model having telomerase activity levels as the dependent variable, and age, gender, smoking habit, and β-carotene as independent variables, confirmed that β-carotene was independently associated with telomerase activity (β = 0.319, p = 0.012). Subjects affected by AD had significantly lower plasmatic levels of β-carotene (448 ± 66 mg/ml vs 497 ± 59 mg/ml, p = 0.001) and LTL (0.53 ± 0.25 vs 0.69 ± 0.29; p = 0.009) as compared with healthy controls. Β-carotene plasma level was associated with AD diagnosis (OR 0.988; IC95% 0.978-0.997; p = 0.013) independently of age, gender, smoking habit, ApoE genotype, and LTL. CONCLUSION Our data show that β-carotene may modulate telomerase activity in old age. Moreover, lower plasma β-carotene levels, correlating with peripheral telomerase activity, are associated with AD diagnosis independent of multiple covariates.
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Cachexia and advanced dementia.
Minaglia, C, Giannotti, C, Boccardi, V, Mecocci, P, Serafini, G, Odetti, P, Monacelli, F
Journal of cachexia, sarcopenia and muscle. 2019;(2):263-277
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Cachexia is a complex metabolic process that is associated with several end-stage organ diseases. It is known to be also associated with advanced dementia, although the pathophysiologic mechanisms are still largely unknown. The present narrative review is aimed at presenting recent insights concerning the pathophysiology of weight loss and wasting syndrome in dementia, the putative mechanisms involved in the dysregulation of energy balance, and the interplay among the chronic clinical conditions of sarcopenia, malnutrition, and frailty in the elderly. We discuss the clinical implications of these new insights, with particular attention to the challenging question of nutritional needs in advanced dementia and the utility of tube feeding in order to optimize the management of end-stage dementia.
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Effects of Weekly Supplementation of Cholecalciferol and Calcifediol Among the Oldest-Old People: Findings From a Randomized Pragmatic Clinical Trial.
Ruggiero, C, Baroni, M, Bini, V, Brozzetti, A, Parretti, L, Zengarini, E, Lapenna, M, Antinolfi, P, Falorni, A, Mecocci, P, et al
Nutrients. 2019;(11)
Abstract
Vitamin D inadequacy is pervasive in the oldest-old. Many vitamin D metabolites are available for supplementation, their effects on the recovery of adequate serum levels remain unknown. We investigate the effects of supplementation with cholecalciferol (D3) and calcifediol (25D3) on serum levels of 25(OH)D, 1-25(OH)D, bone and inflammatory markers, ultimately identifying clinical predictors of successful treatment. Sixty-seven oldest-old individuals were randomized to weekly administration of 150 mcg of 25D3 or D3, from hospital admission to 7 months after discharge. Supplementation of 25D3 and D3 were associated with increasing serum levels of 25(OH)D (p < 0.001) and 1-25(OH)D (p = 0.01). Participants on 25D3 experienced a steeper rise than those on D3 (group*time interaction p = 0.01), after adjustment for intact parathyroid hormone (iPTH) levels the differences disappeared (intervention*iPTH interaction p = 0.04). Vitamin D supplementation was associated with a decreasing trend of iPTH and C-reactive protein (CRP) (p < 0.001). Polypharmacy and low handgrip strength were predictors of failure of intervention, independent of vitamin D metabolites. In conclusion, D3 and 25D3 supplementation significantly increase vitamin D serum levels in the oldest-old individuals, with a tendency of 25D3 to show a faster recovery of acceptable iPTH levels than D3. Polypharmacy and low muscle strength weaken the recovery of adequate vitamin D serum levels.