Authors: Santana, Isabel | Baldeiras, Inês | Santiago, Beatriz | Duro, Diana | Freitas, Sandra | Pereira, Miguel Tábuas | Almeida, Maria Rosário | Oliveira, Catarina Resende
Article Type: Research Article
Abstract: The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer’s disease (AD), but this mandatory “amyloid-first pathway” has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% …with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42 , and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1–18.0, p = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7–9.3, p = 0.141; SNAP: HR = 3.1, 95% CI = 1.1–9.6; p = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative “neurodegeneration-first pathway” for further investigation. Show more
Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid biomarkers, mild cognitive impairment, neurodegeneration
DOI: 10.3233/JAD-179908
Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S647-S657, 2018
Authors: Gabriel, António José | Almeida, Maria Rosário | Ribeiro, Maria Helena | Carneiro, Diogo | Valério, Daniela | Pinheiro, Ana Cristina | Pascoal, Rui | Santana, Isabel | Baldeiras, Inês
Article Type: Research Article
Abstract: Background: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited. Objective: To investigate the influence of the BuChE-K variant in MCI progression to AD. Methods: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels of AD biomarkers amyloid-β …42 (Aβ42 ), total and hyperphosphorylated tau (t-tau and p-tau) were also determined. Results: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ 4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ 4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD. Conclusion: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ 4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients. Show more
Keywords: Alzheimer’s disease, butyrylcholinesterase, disease progression, mildcognitive impairment
DOI: 10.3233/JAD-170695
Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1097-1105, 2018
Authors: Cardoso, Remy | Lemos, Carolina | Oliveiros, Bárbara | Almeida, Maria Rosário | Baldeiras, Inês | Pereira, Cláudia Fragão | Santos, Ana | Duro, Diana | Vieira, Daniela | Santana, Isabel | Oliveira, Catarina Resende
Article Type: Research Article
Abstract: Background: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer’s disease (AD) conversion remain controversial. Objective: Evaluate whether TOMM40 poly-T (TOMM40 ′ 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype. Methods: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group of those that remained stable (MCI-S). Results: TOMM40 …′ 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p < 0.001, 95% CI: 2.830 to 24.617). However, when adjusted for the presence of APOE ɛ 4 allele, both the L allele and ɛ 4 allele lost significance in the model (p > 0.05). We then analyzed the APOE ɛ 4-TOMM40′ 523 L haplotype and observed that patients carrying this haplotype had significantly higher risk (OR = 5.83; 95% CI = 2.30–14.83) and mean lower times of conversion to AD (p = 0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p = 0.007). Conclusion: This study shows that the APOE ɛ 4-TOMM40′ 523 L haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction. Show more
Keywords: Age of onset, Alzheimer’s disease, APOE, biomarker, cerebrospinal fluid, haplotype, mild cognitive impairment, poly T, progression, TOMM40
DOI: 10.3233/JAD-200556
Citation: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 587-601, 2020
Authors: Ramos de Matos, Mafalda | Ferreira, Catarina | Herukka, Sanna-Kaisa | Soininen, Hilkka | Janeiro, André | Santana, Isabel | Baldeiras, Inês | Almeida, Maria Rosário | Lleó, Alberto | Dols-Icardo, Oriol | Alcolea, Daniel | Benussi, Luisa | Binetti, Giuliano | Paterlini, Anna | Ghidoni, Roberta | Nacmias, Benedetta | Meulenbroek, Olga | van Waalwijk van Doorn, Linda J.C. | Kuiperi, H. Bea j | Hausner, Lucrezia | Waldemar, Gunhild | Simonsen, Anja Hviid | Tsolaki, Magda | Gkatzima, Olymbia | Resende de Oliveira, Catarina | Verbeek, Marcel M. | Clarimon, Jordi | Hiltunen, Mikko | de Mendonça, Alexandre | Martins, Madalena
Article Type: Research Article
Abstract: Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer’s disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1–42 ), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1–42 is decreased due to the accumulation of Aβ1–42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand …the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42 , t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers. Our results highlighted five genes, APOE , LOC100129500 , PVRL2 , SNAR-I , and TOMM40 , previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D , CD2AP , and CASS4 , showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment. Show more
Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, endophenotypes, European multicenter study, quantitative trait loci
DOI: 10.3233/JAD-180512
Citation: Journal of Alzheimer's Disease, vol. 66, no. 2, pp. 639-652, 2018
Authors: Serpente, Maria | Fenoglio, Chiara | Arcaro, Marina | Carandini, Tiziana | Sacchi, Luca | Pintus, Manuela | Rotondo, Emanuela | Borracci, Vittoria | Ghezzi, Laura | Bouzigues, Arabella | Russell, Lucy L. | Foster, Phoebe H. | Ferry-Bolder, Eve | van Swieten, John C. | Jiskoot, Lize C. | Seelaar, Harro | Sánchez Valle, Raquel | Laforce, Robert | Graff, Caroline | Vandenberghe, Rik | de Mendonça, Alexandre | Tiraboschi, Pietro | Santana, Isabel | Gerhard, Alexander | Levin, Johannes | Sorbi, Sandro | Otto, Markus | Pasquier, Florence | Ducharme, Simon | Butler, Chris R. | Le Ber, Isabelle | Finger, Elizabeth | Tartaglia, Maria Carmela | Masellis, Mario | Rowe, James B. | Synofzik, Matthis | Moreno, Fermin | Borroni, Barbara | Rohrer, Jonathan D. | Arighi, Andrea | Galimberti, Daniela | Alberici, Antonella | Afonso, Sónia | Alves, Patricia | Anderl-Straub, Sarah | Antonell, Anna | Balasa, Mircea | Barandiaran, Myriam | Bargalló, Nuria | Bartha, Robert | Bender, Benjamin | Bernhardt, Alexander Maximilian | Bertoux, Maxime | Bertrand, Anne | Bessi, Valentina | Black, Sandra | Bocca, Giorgio | Bocchetta, Martina | Borrego-Ecija, Sergi | Brice, Alexis | Bruffaerts, Rose | Buccellato, Francesca R | Buratti, Emanuele | Cantoni, Valentina | Caroppo, Paola | Cash, David | Castelo-Branco, Miguel | Colliot, Olivier | Convery, Rhian | Cope, Thomas | Costa-Coelho, Tiago | Croitoru, Ioana | Camuzat, Agnès | D’Anca, Marianna | de Boer, Liset | de Houwer, Julie | Deramecourt, Vincent | Durães, João | Di Fede, Giuseppe | Ferrari, Camilla | Florio, Graziana | Frascotti, Marta | Freedman, Morris | Funkiewiez, Aurélie | Gabilondo, Alazne | Gasparotti, Roberto | Giaccone, Giorgio | Giannini, Lucia | Goldsmith, Sophie | Graf, Lisa | Jelic, Vesna | Keren, Ron | Krüger, Johanna | Kuchcinski, Gregory | Langheinrich, Tobias | Lebouvier, Thibaud | Leitão, Maria João | Lemos, João | Lima, Marisa | Lladó, Albert | Lombardi, Gemma | Lombardi, Jolina | Malpetti, Maura | Maruta, Carolina | Mengel, David | Miltenberger, Gabriel | Mitchell, Sara | Montembault, Maxime | Nacmias, Benedetta | Nilsson, Mattias | Öijerstedt, Linn | Olives, Jaume | Papma, Janne M. | Pijnenburg, Yolande | Poesen, Koen | Polito, Cristina | Poos, Jackie | Premi, Enrico | Prioni, Sara | Prix, Catharina | Redaelli, Veronica | Rittman, Timothy | Rademakers, Rosa | Rinaldi, Daisy | Rogaeva, Ekaterina | Rollin, Adeline | Rosa-Neto, Pedro | Almeida, Maria Rosario | Rossi, Giacomina | Samra, Kiran | Saracino, Dario | Sayah, Sabrina | Scarpini, Elio | Schönecker, Sonja | Shoesmith, Christen | Simões do Couto, Frederico | Stockbauer, Anna | Tábuas-Pereira, Miguel | Tang-Wai, David | Taheri Rydell, Melissa | Tainta, Mikel | Thomas, David L | Vandenbulcke, Mathieu | Van Damme, Philip | van Minkelen, Rick | Verdelho, Ana | Viklund, Henrik | Vimercati, Roberto | Vogels, Annick | Wagemann, Olivia | Wlasich, Elisabeth
Article Type: Research Article
Abstract: Background: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72 ), Microtubule Associated Protein Tau (MAPT ), and Progranulin (GRN ) genes are not well understood. Objective: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI). Methods: Fifty-three lncRNAs were analyzed with the OpenArray Custom panel, in 131 patients with mutations in C9ORF72 , MAPT , and …GRN , including 68 symptomatic mutation carriers (SMC) and 63 presymptomatic mutation carriers (PMC), compared with 40 non-carrier controls (NC). Results: Thirty-eight lncRNAs were detectable; the relative expression of NEAT1 and NORAD was significantly higher in C9ORF72 SMC as compared with NC. GAS5 expression was instead significantly lower in the GRN group versus NC. MAPT carriers showed no significant deregulations. No significant differences were observed in PMC. Disease duration did not correlate with lncRNA expression. Conclusions: NEAT1 and NORAD are upregulated in C9ORF72 SMC and GAS5 levels are downregulated in GRN SMC, underlining lncRNAs’ relevance in FTD and their potential for biomarker development. Further validation and mechanistic studies are crucial for clinical implications. Show more
Keywords: Alzheimer’s disease, chromosome 9 open reading frame 72, frontotemporal dementia, long non-coding RNA, microtubule associated protein tau, progranulin
DOI: 10.3233/JAD-240557
Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S187-S196, 2024