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Authors: Nacmias, Benedetta | Bagnoli, Silvia | Piaceri, Irene | Sorbi, Sandro

Article Type: Review Article

Abstract: Studies on the genetics of Alzheimer’s disease (AD) have revealed the complexity and heterogeneity of the disease. All our studies have supported this evidence and contribute to the current understanding of the genetic architecture of AD. This report reviews the success of our investigations, focusing on the implications and importance of the genetics of AD, and demonstrates the relevance of research strategies embracing partnerships.

Keywords: Alzheimer‘s disease, autosomal dominant, genetic mutation, genetic risk factor

DOI: 10.3233/JAD-170570

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 903-911, 2018

Authors: Lombardi, Gemma | Polito, Cristina | Berti, Valentina | Bagnoli, Silvia | Nacmias, Benedetta | Pupi, Alberto | Sorbi, Sandro

Article Type: Short Communication

Abstract: Bilingualism is an independent component of cognitive reserve that permits to delay dementia onset up to 5 years. We describe a case of a bilingual Italian man affected by mild cognitive impairment with high cognitive reserve that, despite the presence of multiple risk factors (ApoE ɛ 4/ɛ 4 genotype, older age, untreated Obstructive Sleep Apnea Syndrome, AD-like biomarker alterations) did not convert to Alzheimer’s disease up to 5 years follow-up. The present case confirms the role of bilingualism as a strong protective factor for dementia, even in the occurrence of multiple risk factors.

Keywords: Alzheimer’s disease, bilingualism, cognitive reserve, obstructive sleep apnea, prevention

DOI: 10.3233/JAD-180736

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1389-1395, 2018

Authors: Piaceri, Irene | Raspanti, Beatrice | Tedde, Andrea | Bagnoli, Silvia | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Short Communication

Abstract: Alzheimer's disease (AD) is a multifactorial disorder induced by a combination of genetic and environmental factors, and epigenetic modifications could be the key to understand the pathogenesis of AD. We performed a methylation study of the promoter regions of the three AD principal causative genes in 60 late-onset AD patients and 60 controls. The studied regions in the three causative genes were strongly unmethylated in both groups, but in AD patients the methylation resulted significantly increased. Our study adds new insights to previous ones by showing the involvement of epigenetic changes in AD, which influence the pathogenesis of the disease.

Keywords: Alzheimer's disease, AβPP, DNA methylation, epigenetics, PSEN1, PSEN2

DOI: 10.3233/JAD-141452

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1169-1173, 2015

Authors: Nacmias, Benedetta | Tedde, Andrea | Bagnoli, Silvia | Cellini, Elena | Guarnieri, Bianca Maria | Piacentini, Silvia | Sorbi, Sandro

Article Type: Short Communication

Abstract: A common polymorphism (rs2373115) in the GRB-associated binding protein 2 (GAB2) gene has been recently associated with the risk of developing Alzheimer's disease (AD) in 644 apolipoprotein E (ApoE) ε4 carriers. In order to assess the involvement of the GAB2 polymorphism in the risk of developing AD, we analyzed the genotype and allele distributions of the GAB2 rs2373115 polymorphism in 579 Italian subjects. Our results support a possible implication of GAB2 genetic variant in AD. However, the observed association was confined to ApoE ε4 non-carriers, thus suggesting a possible role of GAB2 as an independent risk factor for AD.

Keywords: Alzheimer's disease, apolipoprotein E, genetic determinant, GRB-associated binding protein 2

DOI: 10.3233/JAD-2009-1005

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 513-515, 2009

Authors: Tedde, Andrea | Piaceri, Irene | Bagnoli, Silvia | Lucenteforte, Ersilia | Piacentini, Silvia | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Short Communication

Abstract: Apoptosis is correlated with various forms of dementia. Death-associated protein kinase 1 (DAPK1) plays an important role in neuronal apoptosis and could influence the pathology of late-onset Alzheimer's disease (LOAD) and frontotemporal dementia (FTD). It has been reported that two common polymorphisms (rs4878104 and rs4877365) are associated with LOAD, thus we examined the genotype and allele distributions of the above polymorphisms in 681 Italian subjects, including patients with LOAD and FTD. We showed a positive association between rs4878104 and FTD, suggesting a possible implication of the DAPK1 genetic variant in the susceptibility to FTD.

Keywords: Alzheimer's disease, DAPK1, frontotemporal dementia, SNP

DOI: 10.3233/JAD-2012-120556

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 13-17, 2012

Authors: Ferrari, Camilla | Polito, Cristina | Berti, Valentina | Lombardi, Gemma | Lucidi, Giulia | Bessi, Valentina | Bagnoli, Silvia | Piaceri, Irene | Nacmias, Benedetta | Sorbi, Sandro

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) has been described as a neurodegenerative language disorder mainly affecting the left hemisphere. Few cases of right hemisphere damage in right-handed PPA subjects have been reported. This condition, named crossed aphasia in dextral (CAD), is relatively rare and probably related to an alteration during neurodevelopment of language networks. Objective: To explore the prevalence of CAD in an Italian cohort of 68 PPA patients, in order to evaluate whether right hemisphere language lateralization could be a risk factor for PPA. Methods: Clinical-demographic and cerebral [18 F]-fluorodeoxyglucose positron emission tomography ([18 F]FDG-PET) scan were analyzed, resulting in …23 logopenic variant (lvPPA) patients, 26 non-fluent variant (nfvPPA) patients, and 19 semantic variant (svPPA) patients. SPM single subject routine was performed for diagnostic purposes in order to identify the hypometabolic pattern of each patient. Based on brain metabolic profile, PPA patients were divided in right and left lvPPA, nfvPPA, and svPPA. [18 F]FDG-PET group analyses were performed with SPM two-sample t -test routine. Results: 26% of lvPPA cases were identified as CAD based on right hypometabolic pattern. CAD patients did not differ from left lvPPA regarding demographic features and general cognitive performance; however, they performed better in specific working memory tasks and showed brain hypometabolism limited to the superior, middle, and supramarginal temporal gyri. Conclusion: Atypical lateralization of language function could determine a vulnerability of the phonological language loop and in that way could be a risk factor for lvPPA. Show more

Keywords: Crossed-aphasia in dextral, dementia, language, lateralization, logopenic variant, primary progressive aphasia, risk factor

DOI: 10.3233/JAD-190677

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1089-1096, 2019

Authors: Piaceri, Irene | Imperiale, Daniele | Ghidoni, Enrico | Atzori, Cristiana | Bagnoli, Silvia | Ferrari, Camilla | Ungari, Silvana | Ambrogio, Luca | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Research Article

Abstract: Background: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer’s disease or psychiatric disorders, jeopardizing care and research. Objective: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer’s disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein). Methods: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s. Results: Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN …genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature. Conclusion: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, GRN, mutation

DOI: 10.3233/JAD-170989

Citation: Journal of Alzheimer's Disease, vol. 62, no. 4, pp. 1683-1689, 2018

Authors: Piaceri, Irene | Bagnoli, Silvia | Lucenteforte, Ersilia | Mancuso, Michelangelo | Tedde, Andrea | Siciliano, Gabriele | Piacentini, Silvia | Bracco, Laura | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Short Communication

Abstract: A common polymorphism (rs3851179) in the PICALM (phosphatidylinositol-binding clathrin assembly protein) gene has been recently associated with reduced risk of developing late-onset Alzheimer's disease (LOAD). We analyzed the genotype and allele distributions of the PICALM polymorphism in 813 Italian subjects, including LOAD patients and centenarians. The segregation of the PICALM rs3851179 showed no statistically significant difference between LOAD cases and controls. The implication of a genetic variant at PICALM is confirmed for the first time, in centenarians, thus suggesting a possible role in longevity.

Keywords: Alzheimer's disease, apolipoprotein E, centenarian, genetic variation, PICALM

DOI: 10.3233/JAD-2011-101791

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 409-413, 2011

Authors: Evangelisti, Elisa | Zampagni, Mariagioia | Cascella, Roberta | Becatti, Matteo | Fiorillo, Claudia | Caselli, Anna | Bagnoli, Silvia | Nacmias, Benedetta | Cecchi, Cristina

Article Type: Research Article

Abstract: Increasing evidence indicates that interaction of amyloid-β peptide (Aβ) with the cell membrane is a primary step in Alzheimer's disease (AD) neurotoxicity. In particular, it has been demonstrated that lipid rafts are key sites of Aβ production, aggregation, and interaction with the cell membrane. In this study we show that Aβ42 oligomers are recruited to lipid rafts, leading to plasma membrane perturbation and Ca2+ dyshomeostasis in primary fibroblasts from familial AD patients bearing APPVal717Ile, PS-1Leu392Val, or PS-1Met146Leu gene mutations. In contrast, a moderate increase in membrane cholesterol content precluded the interaction of Aβ42 oligomers with the plasma membrane and resulting …cell damage. Moreover, the recruitment of amyloid assemblies to lipid raft domains of cholesterol-depleted fibroblasts was significantly increased, thus triggering an earlier and sharper increase in intracellular Ca2+ levels and plasma membrane permeabilization. Our findings suggest a protective role for raft cholesterol against amyloid toxicity in AD. Show more

Keywords: Aβ42-GM1 colocalization, Alzheimer's disease fibroblasts, calcium dysregulation, lipid rafts, membrane cholesterol, membrane permeabilization, prion

DOI: 10.3233/JAD-131406

Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 289-300, 2014

Authors: Ingannato, Assunta | Bessi, Valentina | Chiari, Annalisa | Salvatori, Davide | Bagnoli, Silvia | Bedin, Roberta | Ferrari, Camilla | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Research Article

Abstract: Background: Progranulin protein (GRN) is a growth factor, encoded by the GRN (Granulin precursor) gene, involved in several functions including inflammation, wound repair, signal transduction, proliferation, and tumorigenesis. Mutations in GRN gene are usually the genetic etiology of frontotemporal dementia (FTD), but different studies reported GRN mutations in Alzheimer ’s disease (AD) patients. Objective: Here, we analyzed FTD linked gene GRN in 23 patients with a clinical diagnosis of AD and a family history of AD (FAD), not carrying mutations in AD candidate genes (PSEN 1, PSEN 2 , and APP ). In addition, Microtubule-associated protein tau (MAPT ) gene …was studied too. All patients underwent an extensive neuropsychological battery. Methods: Genetic analyses were performed thought PCR assay and sequencing. Variants were annotated with ANNOVAR and allele frequency was checked on population databases. In silico prediction tools were consulted to check nonsynonymous variants and their effect on protein function and structure. The clinical data were retrospectively collected from medical records. Results: Genetic screening of MAPT and GRN in 23 FAD patients highlighted two rare different variants in two probands (2/23 = 8,7%) located in GRN gene: R433W (p.Arg433Trp) and C521Y (p.Cys521Tyr). The R433W and C521Y are variants with uncertain significant, that are predicted to affect GRN protein structure and function, with a possible damaging effect. Conclusions: Our data provide evidence of the importance of GRN genetic analysis also in the study of familial AD. Show more

Keywords: Alzheimer’s disease, genetic variants, GRN, Progranulin

DOI: 10.3233/JAD-230689

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 767-775, 2023