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Article ; Online: The Progression of Alzheimer's Disease: Are Fast Decliners Really Fast? A Four-Year Follow-Up.

Barocco, Federica / Spallazzi, Marco / Concari, Letizia / Gardini, Simona / Pelosi, Annalisa / Caffarra, Paolo

2017 Volume 57, Issue 3, Page(s) 775–786

Abstract: Background: The rate of cognitive and functional decline in Alzheimer's disease (AD) changes across individuals.: Objectives: Our purpose was to assess whether the concept of "fast decline" really fits its definition and whether cognitive and ... ...

Abstract	Background: The rate of cognitive and functional decline in Alzheimer's disease (AD) changes across individuals. Objectives: Our purpose was to assess whether the concept of "fast decline" really fits its definition and whether cognitive and functional variables at onset can predict the progression of AD. Methods: 324 AD patients were included. We retrospectively examined their Mini-Mental State Examination (MMSE) total score and sub-items, Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) at baseline and every six months for a 4-year follow-up. Patients were divided into "fast decliners" (n = 62), defined by a loss ≥5 points on the MMSE score within the first year from the baseline; "intermediate decliners" (n = 37), by a loss ≥5 points after the first year and before the 18th month; or "slow decliners" (n = 225), composed of the remaining patients. Results: At baseline, the groups did not differ on demographic, clinical, and cognitive variables. The decline at the end of the 4-year follow-up period seems to be similar among the different decline clusters. Predictors of disease progression have not been identified; only the MMSE total score at 12 months <14/30 was indicative of a poor prognosis. Conclusions: Even with the limitation due to the small sample size, the lack of differences in the disease progression in time in the different clusters suggest the inconsistency of the so-called "fast decliners". This study was unable to show any significant difference among clusters of AD progression within a 4-year time interval. Further studies should better clarify whether a more consistent distinction exists between slow and fast decliners.
MeSH term(s)	Activities of Daily Living ; Aged ; Aged, 80 and over ; Alzheimer Disease/diagnosis ; Alzheimer Disease/physiopathology ; Analysis of Variance ; Cognition Disorders/diagnosis ; Cognition Disorders/physiopathology ; Disease Progression ; Female ; Humans ; Longitudinal Studies ; Male ; Psychiatric Status Rating Scales ; ROC Curve ; Time Factors
Language	English
Publishing date	2017
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-161264
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Article ; Online: Differential patterns of hypoperfusion in subtypes of mild cognitive impairment.

Caffarra, Paolo / Ghetti, Caterina / Concari, Letizia / Venneri, Annalena

The open neuroimaging journal

2008 Volume 2, Page(s) 20–28

Abstract: In this study the regional cerebral blood flow (rCBF) pattern of three Mild Cognitive Impairment (MCI) subtypes was measured with SPECT in 60 patients (nineteen with an amnestic deficit, sixteen with disexecutive deficits, and twenty five with mild ... ...

Abstract	In this study the regional cerebral blood flow (rCBF) pattern of three Mild Cognitive Impairment (MCI) subtypes was measured with SPECT in 60 patients (nineteen with an amnestic deficit, sixteen with disexecutive deficits, and twenty five with mild multidomain deficits) and compared with that of 15 healthy matched older adults. The amnestic MCI subgroup showed significant hypoperfusion in the left hippocampus, parahippocampal gyrus and fronto-parieto-temporal areas. The disexecutive subgroup had significant hypoperfusion of the left superior, medial frontal and cingulate cortex. The multidomain subgroup had similar perfusion deficits to the amnestic subgroup, with an additional deficit in the left posterior cingulate gyrus. This study found differential patterns of hypoperfusion in MCI subtypes. Since all patients who progressed to dementia converted to probable Alzheimer's disease, the different rCBF patterns most likely reflect the neuropathological heterogeneity at onset and differences in disease stage.
Language	English
Publishing date	2008-05-09
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2395976-9
ISSN	1874-4400 ; 1874-4400
ISSN (online)	1874-4400
ISSN	1874-4400
DOI	10.2174/1874440000802010020
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Article ; Online: Visuo-spatial imagery impairment in posterior cortical atrophy: a cognitive and SPECT study.

Gardini, Simona / Concari, Letizia / Pagliara, Salvatrice / Ghetti, Caterina / Venneri, Annalena / Caffarra, Paolo

Behavioural neurology

2011 Volume 24, Issue 2, Page(s) 123–132

Abstract: This study investigated the cognitive profile and the cerebral perfusion pattern in a highly educated 70 year old gentleman with posterior cortical atrophy (PCA). Visuo-perceptual abilities, spatial memory, spatial representation and navigation, visuo- ... ...

Abstract	This study investigated the cognitive profile and the cerebral perfusion pattern in a highly educated 70 year old gentleman with posterior cortical atrophy (PCA). Visuo-perceptual abilities, spatial memory, spatial representation and navigation, visuo-spatial mental imagery, semantic and episodic-autobiographical memory were assessed. Regional cerebral blood flow (rCBF) was imaged with SPECT. Cognitive testing showed visual-perceptual impairment, apperceptive visual and landmark agnosia, topographical disorientation with way-finding deficits, impaired map learning and poor mental image generation. Semantic memory was normal, while episodic-autobiographical memory was impaired. Reduced rCBF was found mainly in the right hemisphere, in the precentral gyrus, posterior cingulate and middle temporal gyri, cuneus and precuneus, in the left superior temporal and lingual gyri and in the parahippocampus bilaterally. Hypoperfusion in occipito-parietal regions was associated with visuo-spatial deficits, whereas deficits in visuo-spatial mental imagery might reflect dysfunction related to hypoperfusion in the parahippocampus and precuneus, structures which are responsible for spatial and imagery processing. Dissociating performance between preserved semantic memory and poor episodic-autobiographical recall is consistent with a pattern of normal perfusion in frontal and anterior temporal regions but abnormal rCBF in the parahippocampi. The present findings indicate that PCA involves visuo-spatial imagery deficits and provide further validation to current neuro-cognitive models of spatial representation and topographical disorientation.
MeSH term(s)	Aged ; Atrophy/diagnostic imaging ; Atrophy/physiopathology ; Atrophy/psychology ; Brain Mapping ; Cerebral Cortex/diagnostic imaging ; Cerebral Cortex/physiopathology ; Cerebrovascular Circulation ; Cognition/physiology ; Dementia/diagnostic imaging ; Dementia/physiopathology ; Dementia/psychology ; Humans ; Image Processing, Computer-Assisted ; Imagination/physiology ; Male ; Mental Recall/physiology ; Neurodegenerative Diseases/diagnostic imaging ; Neurodegenerative Diseases/physiopathology ; Neurodegenerative Diseases/psychology ; Neuropsychological Tests ; Tomography, Emission-Computed, Single-Photon
Language	English
Publishing date	2011-05-23
Publishing country	Netherlands
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1001896-7
ISSN	1875-8584 ; 0953-4180
ISSN (online)	1875-8584
ISSN	0953-4180
DOI	10.3233/BEN-2011-0279
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Article ; Online: The qualitative scoring MMSE pentagon test (QSPT): a new method for differentiating dementia with Lewy Body from Alzheimer's disease.

Caffarra, Paolo / Gardini, Simona / Dieci, Francesca / Copelli, Sandra / Maset, Laura / Concari, Letizia / Farina, Elisabetta / Grossi, Enzo

Behavioural neurology

2013 Volume 27, Issue 2, Page(s) 213–220

Abstract: The differential diagnosis across different variants of degenerative diseases is sometimes controversial. This study aimed to validate a qualitative scoring method for the pentagons copy test (QSPT) of Mini-Mental State Examination (MMSE) based on the ... ...

Abstract	The differential diagnosis across different variants of degenerative diseases is sometimes controversial. This study aimed to validate a qualitative scoring method for the pentagons copy test (QSPT) of Mini-Mental State Examination (MMSE) based on the assessment of different parameters of the pentagons drawing, such as number of angles, distance/intersection, closure/opening, rotation, closing-in, and to verify its efficacy to differentiate dementia with Lewy Body (DLB) from Alzheimer's disease (AD). We established the reliability of the qualitative scoring method through the inter-raters and intra-subjects analysis. QSPT was then applied to forty-six AD and forty-six DLB patients, using two phases statistical approach, standard and artificial neural network respectively. DLB patients had significant lower total score in the copy of pentagons and number of angles, distance/intersection, closure/opening, rotation compared to AD. However the logistic regression did not allow to establish any suitable modeling, whereas using Auto-Contractive Map (Auto-CM) the DLB was more strongly associated with low scores in some qualitative parameters of pentagon copying, i.e. number of angles and opening/closure and, for the remaining subitems of the MMSE, in naming, repetition and written comprehension, and for demographic variables of gender (male) and education (6-13 years). Twist system modeling showed that the QSPT had a good sensitivity (70.29%) and specificity (78.67%) (ROC-AUC 0.74). The proposed qualitative method of assessment of pentagons copying used in combination with non-linear analysis, showed to be consistent and effective in the differential diagnosis between Lewy Body and Alzheimer's dementia.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/diagnosis ; Diagnosis, Differential ; Female ; Humans ; Lewy Body Disease/diagnosis ; Male ; Neuropsychological Tests ; Reproducibility of Results ; Sensitivity and Specificity
Language	English
Publishing date	2013-02-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1001896-7
ISSN	1875-8584 ; 0953-4180
ISSN (online)	1875-8584
ISSN	0953-4180
DOI	10.3233/BEN-120319
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Article ; Online: Degenerative jargon aphasia: unusual progression of logopenic/phonological progressive aphasia?

Caffarra, Paolo / Gardini, Simona / Cappa, Stefano / Dieci, Francesca / Concari, Letizia / Barocco, Federica / Ghetti, Caterina / Ruffini, Livia / Prati, Guido Dalla Rosa

Behavioural neurology

2012 Volume 26, Issue 1-2, Page(s) 89–93

Abstract: Primary progressive aphasia (PPA) corresponds to the gradual degeneration of language which can occur as nonfluent/agrammatic PPA, semantic variant PPA or logopenic variant PPA. We describe the clinical evolution of a patient with PPA presenting jargon ... ...

Abstract	Primary progressive aphasia (PPA) corresponds to the gradual degeneration of language which can occur as nonfluent/agrammatic PPA, semantic variant PPA or logopenic variant PPA. We describe the clinical evolution of a patient with PPA presenting jargon aphasia as a late feature. At the onset of the disease (ten years ago) the patient showed anomia and executive deficits, followed later on by phonemic paraphasias and neologisms, deficits in verbal short-term memory, naming, verbal and semantic fluency. At recent follow-up the patient developed an unintelligible jargon with both semantic and neologistic errors, as well as with severe deficit of comprehension which precluded any further neuropsychological assessment. Compared to healthy controls, FDG-PET showed a hypometabolism in the left angular and middle temporal gyri, precuneus, caudate, posterior cingulate, middle frontal gyrus, and bilaterally in the superior temporal and inferior frontal gyri. The clinical and neuroimaging profile seems to support the hypothesis that the patient developed a late feature of logopenic variant PPA characterized by jargonaphasia and associated with superior temporal and parietal dysfunction.
MeSH term(s)	Aged ; Aphasia, Primary Progressive/complications ; Aphasia, Primary Progressive/diagnostic imaging ; Aphasia, Primary Progressive/psychology ; Aphasia, Wernicke/complications ; Aphasia, Wernicke/diagnostic imaging ; Aphasia, Wernicke/physiopathology ; Aphasia, Wernicke/psychology ; Brain/diagnostic imaging ; Brain/physiopathology ; Disease Progression ; Female ; Fluorodeoxyglucose F18 ; Functional Neuroimaging/methods ; Functional Neuroimaging/psychology ; Humans ; Language Tests/statistics & numerical data ; Neuropsychological Tests/statistics & numerical data ; Positron-Emission Tomography/methods ; Positron-Emission Tomography/psychology
Chemical Substances	Fluorodeoxyglucose F18 (0Z5B2CJX4D)
Language	English
Publishing date	2012-06-19
Publishing country	Netherlands
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1001896-7
ISSN	1875-8584 ; 0953-4180
ISSN (online)	1875-8584
ISSN	0953-4180
DOI	10.3233/BEN-2012-110218
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Article ; Online: Thrombolysis after dabigatran reversal: A nation-wide Italian multicentre study, systematic review and meta-analysis.

Romoli, Michele / Matteo, Eleonora / Migliaccio, Ludovica / Gentile, Mauro / Mosconi, Maria Giulia / Scura, Giuseppe Maria / Naccarato, Marcello / Colangeli, Enrico / Candelaresi, Paolo / Andreone, Vincenzo / Giammello, Fabrizio / Fortunata Musolino, Rosa / Dell'Aera, Cristina / Sepe, Federica Nicoletta / Pronello, Edoardo / Barbarini, Leonardo / Caggiula, Marcella / Rizzo, Federica / Petruzzellis, Marco /

European stroke journal

2022 Volume 8, Issue 1, Page(s) 117–124

Abstract: Introduction: Recent anticoagulant intake represents a contraindication for thrombolysis in acute ischemic stroke. Idarucizumab reverses the anticoagulant effect of dabigatran, potentially allowing for thrombolysis. This nation-wide observational cohort ...

Abstract	Introduction: Recent anticoagulant intake represents a contraindication for thrombolysis in acute ischemic stroke. Idarucizumab reverses the anticoagulant effect of dabigatran, potentially allowing for thrombolysis. This nation-wide observational cohort study, systematic review, and meta-analysis evaluated the efficacy and safety of thrombolysis preceded by dabigatran-reversal in people with acute ischemic stroke. Patients and methods: We recruited people undergoing thrombolysis following dabigatran-reversal at 17 stroke centers in Italy (reversal-group), people on dabigatran treated with thrombolysis without reversal (no-reversal group), and age, sex, hypertension, stroke severity, and reperfusion treatment-matched controls in 1:7 ratio (control-group). We compared groups for symptomatic intracranial hemorrhage (sICH, main outcome), any brain hemorrhage, good functional outcome (mRS 0-2 at 3 months), and death. The systematic review followed a predefined protocol (CRD42017060274), and odds ratio (OR) meta-analysis was implemented to compare groups. Results: Thirty-nine patients in dabigatran-reversal group and 300 matched controls were included. Reversal was associated with a non-significant increase in sICH (10.3% vs 6%, aOR = 1.32, 95% CI = 0.39-4.52), death (17.9% vs 10%, aOR = 0.77, 95% CI = 0.12-4.93) and good functional outcome (64.1% vs 52.8%, aOR = 1.41, 95% CI = 0.63-3.19). No hemorrhagic events or deaths were registered in no-reversal group (n = 12). Pooling data from 3 studies after systematic review (n = 1879), reversal carried a non-significant trend for sICH (OR = 1.53, 95% CI = 0.67-3.50), death (OR = 1.53, 95% CI = 0.73-3.24) and good functional outcome (OR = 2.46, 95% CI = 0.85-7.16). Discussion and conclusion: People treated with reperfusion strategies after dabigatran reversal with idarucizumab seem to have a marginal increase in the risk of sICH but comparable functional recovery to matched patients with stroke. Further studies are needed to define treatment cost-effectiveness and potential thresholds in plasma dabigatran concentration for reversal.
MeSH term(s)	Humans ; Dabigatran/adverse effects ; Antithrombins/adverse effects ; Ischemic Stroke/complications ; Brain Ischemia/drug therapy ; Thrombolytic Therapy/adverse effects ; Stroke/drug therapy ; Anticoagulants/therapeutic use ; Intracranial Hemorrhages/chemically induced ; Observational Studies as Topic ; Multicenter Studies as Topic
Chemical Substances	Dabigatran (I0VM4M70GC) ; Antithrombins ; Anticoagulants
Language	English
Publishing date	2022-10-29
Publishing country	England
Document type	Meta-Analysis ; Systematic Review ; Journal Article
ZDB-ID	2851287-X
ISSN	2396-9881 ; 2396-9873
ISSN (online)	2396-9881
ISSN	2396-9873
DOI	10.1177/23969873221131635
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Article ; Online: Influence of APOE status on lexical-semantic skills in mild cognitive impairment.

Biundo, Roberta / Gardini, Simona / Caffarra, Paolo / Concari, Letizia / Martorana, Davide / Neri, Tauro Maria / Shanks, Michael F / Venneri, Annalena

Journal of the International Neuropsychological Society : JINS

2011 Volume 17, Issue 3, Page(s) 423–430

Abstract: This study characterized the relationship between apolipoprotein E (APOE) status and residual semantic abilities in amnestic mild cognitive impairment (MCI). APOE status (ε4 carrier/non ε4 carrier) was determined in 30 amnestic MCIs and in 22 healthy ... ...

Abstract	This study characterized the relationship between apolipoprotein E (APOE) status and residual semantic abilities in amnestic mild cognitive impairment (MCI). APOE status (ε4 carrier/non ε4 carrier) was determined in 30 amnestic MCIs and in 22 healthy matched non ε4 carrier controls. The lexical characteristics (age of acquisition, typicality, familiarity) of words produced in a category fluency task were determined. MCIs produced fewer words than controls and these were also earlier acquired and more familiar. The words produced by MCI ε4 carriers were earlier acquired than those of non ε4 carriers. Analyses limited to the first 10 words produced by patients and controls showed similar findings and also revealed that MCI subgroups retrieved first more typical words than controls. Follow up showed higher conversion to Alzheimer's disease (AD) in MCI ε4 carriers than in non ε4 carriers. These findings show that a significant proportion of phenotype variability in performance on category fluency in people at increased AD risk is influenced by genetic factors. These findings explain why category fluency deficits, together with episodic memory deficits, are the only consistent early deficits in MCI patients who convert to AD.
MeSH term(s)	Aged ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/genetics ; Apolipoproteins E/genetics ; Case-Control Studies ; Cognitive Dysfunction/genetics ; Cognitive Dysfunction/physiopathology ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Radionuclide Imaging ; Recognition (Psychology) ; Semantics ; Verbal Learning
Chemical Substances	Apolipoproteins E
Language	English
Publishing date	2011-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1230632-0
ISSN	1469-7661 ; 1355-6177
ISSN (online)	1469-7661
ISSN	1355-6177
DOI	10.1017/S135561771100021X
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Article ; Online: Italian norms for the Freedman version of the Clock Drawing Test.

Caffarra, Paolo / Gardini, Simona / Zonato, Fabrizio / Concari, Letizia / Dieci, Francesca / Copelli, Sandra / Freedman, Morris / Stracciari, Andrea / Venneri, Annalena

Journal of clinical and experimental neuropsychology

2011 Volume 33, Issue 9, Page(s) 982–988

Abstract: Background: The Clock Drawing Test (CDT) is a valid screening tool for the evaluation of cognitive decline. This study aimed to compute standardized norms for the Freedman version of the CDT in a population of 248 healthy Italian individuals aged from ... ...

Abstract	Background: The Clock Drawing Test (CDT) is a valid screening tool for the evaluation of cognitive decline. This study aimed to compute standardized norms for the Freedman version of the CDT in a population of 248 healthy Italian individuals aged from 20 to 89 years. Method: The effects of age, education, and gender on performance were assessed. Three conditions were administered: free-drawn clock (FD), which required participants to draw the contour, numbers, hands, and center of the clock; predrawn clock (PD), in which numbers, hands, and center had to be included in a predrawn contour; examiner-drawn clock (ED), in which only hands and center had to be inserted in a template including a predrawn contour and numbers. Scores for each of the single conditions and a total score were calculated. Results: Age had no effect on the FD condition, whereas a significant effect of age was found for the PD and ED conditions and the total score. Gender and education had no influence on any of the scores. Correction grids, cutoffs, and equivalent scores were computed. Conclusion: Standardized norms for the Freedman version of the CDT were collected in a large sample of healthy individuals. No adjustments were required for scores on the free-drawn condition, whereas raw scores on the predrawn and examiner-drawn conditions and the total score needed adjustments to account for age effects. The availability of standardized norms for this version of the CDT could increase the use of this comprehensive tool in the detection of dementia.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Aging/physiology ; Cognition/physiology ; Female ; Humans ; Italy ; Male ; Middle Aged ; Neuropsychological Tests/standards ; Psychomotor Performance ; Reference Values ; Regression Analysis ; Young Adult
Language	English
Publishing date	2011-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605982-x
ISSN	1744-411X ; 0168-8634 ; 1380-3395
ISSN (online)	1744-411X
ISSN	0168-8634 ; 1380-3395
DOI	10.1080/13803395.2011.589373
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Article ; Online: Recovery from transient global amnesia following restoration of hippocampal and fronto - cingulate perfusion.

Caffarra, Paolo / Concari, Letizia / Gardini, Simona / Spaggiari, Sabrina / Dieci, Francesca / Copelli, Sandra / Ghetti, Caterina / Venneri, Annalena

Behavioural neurology

2010 Volume 22, Issue 3-4, Page(s) 131–139

Abstract: A patient who suffered a transient global amnesia (TGA) attack underwent regional cerebral blood flow (rCBF) SPECT imaging and neuropsychological testing in the acute phase, after one month and after one year. Neuropsychological testing in the acute ... ...

Abstract	A patient who suffered a transient global amnesia (TGA) attack underwent regional cerebral blood flow (rCBF) SPECT imaging and neuropsychological testing in the acute phase, after one month and after one year. Neuropsychological testing in the acute phase showed a pattern of anterograde and retrograde amnesia, whereas memory was within age normal limits at follow up. SPECT data were analysed with a within subject comparison and also compared with those of a group of healthy controls. Within subject comparison between the one month follow up and the acute phase detected increases in rCBF in the hippocampus bilaterally; further rCBF increases in the right hippocampus were detected after one year. Compared to controls, significant hypoperfusion was found in the right precentral, cingulate and medial frontal gyri in the acute phase; after one month significant hypoperfusion was detected in the right precentral and cingulate gyri and the left postcentral gyrus; after one year no significant hypoperfusion appeared. The restoration of memory was paralleled by rCBF increases in the hippocampus and fronto-limbic-parietal cortex; after one year neither significant rCBF differences nor cognitive deficits were detectable. In conclusion, these data indicate that TGA had no long lasting cognitive and neural alterations in this patient.
MeSH term(s)	Acute Disease ; Amnesia, Transient Global/diagnostic imaging ; Amnesia, Transient Global/physiopathology ; Brain/blood supply ; Brain/diagnostic imaging ; Brain/physiopathology ; Brain Mapping ; Case-Control Studies ; Cerebrovascular Circulation ; Female ; Follow-Up Studies ; Humans ; Male ; Memory/physiology ; Middle Aged ; Neuropsychological Tests ; Recovery of Function ; Regional Blood Flow ; Time Factors ; Tomography, Emission-Computed, Single-Photon
Language	English
Publishing date	2010-07-01
Publishing country	Netherlands
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1001896-7
ISSN	1875-8584 ; 0953-4180
ISSN (online)	1875-8584
ISSN	0953-4180
DOI	10.3233/ben-2009-0253
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Article ; Online: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Kunkle, Brian W / Grenier-Boley, Benjamin / Sims, Rebecca / Bis, Joshua C / Damotte, Vincent / Naj, Adam C / Boland, Anne / Vronskaya, Maria / van der Lee, Sven J / Amlie-Wolf, Alexandre / Bellenguez, Céline / Frizatti, Aura / Chouraki, Vincent / Martin, Eden R / Sleegers, Kristel / Badarinarayan, Nandini / Jakobsdottir, Johanna / Hamilton-Nelson, Kara L / Moreno-Grau, Sonia /

Olaso, Robert / Raybould, Rachel / Chen, Yuning / Kuzma, Amanda B / Hiltunen, Mikko / Morgan, Taniesha / Ahmad, Shahzad / Vardarajan, Badri N / Epelbaum, Jacques / Hoffmann, Per / Boada, Merce / Beecham, Gary W / Garnier, Jean-Guillaume / Harold, Denise / Fitzpatrick, Annette L / Valladares, Otto / Moutet, Marie-Laure / Gerrish, Amy / Smith, Albert V / Qu, Liming / Bacq, Delphine / Denning, Nicola / Jian, Xueqiu / Zhao, Yi / Del Zompo, Maria / Fox, Nick C / Choi, Seung-Hoan / Mateo, Ignacio / Hughes, Joseph T / Adams, Hieab H / Malamon, John / Sanchez-Garcia, Florentino / Patel, Yogen / Brody, Jennifer A / Dombroski, Beth A / Naranjo, Maria Candida Deniz / Daniilidou, Makrina / Eiriksdottir, Gudny / Mukherjee, Shubhabrata / Wallon, David / Uphill, James / Aspelund, Thor / Cantwell, Laura B / Garzia, Fabienne / Galimberti, Daniela / Hofer, Edith / Butkiewicz, Mariusz / Fin, Bertrand / Scarpini, Elio / Sarnowski, Chloe / Bush, Will S / Meslage, Stéphane / Kornhuber, Johannes / White, 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Nature genetics

2019 Volume 51, Issue 3, Page(s) 414–430

Abstract: Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We ... ...

Abstract	Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10
MeSH term(s)	Aged ; Alzheimer Disease/genetics ; Amyloid beta-Peptides/genetics ; Case-Control Studies ; Female ; Genetic Loci/genetics ; Genetic Predisposition to Disease/genetics ; Genetic Testing/methods ; Genome-Wide Association Study/methods ; Haplotypes/genetics ; Humans ; Immunity/genetics ; Lipid Metabolism/genetics ; Lipids/genetics ; Male ; tau Proteins/genetics
Chemical Substances	Amyloid beta-Peptides ; Lipids ; tau Proteins
Language	English
Publishing date	2019-02-28
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-019-0358-2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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