Publications by authors named "Giuseppe Tosto"

43 Publications

Midlife Vascular Factors and Prevalence of Mild Cognitive Impairment in Late-Life in Mexico.

J Int Neuropsychol Soc 2021 Aug 11:1-11. Epub 2021 Aug 11.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University College of Physicians and Surgeons, New York City, NY, USA.

Objective: To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes and investigate the impact of midlife cardiovascular risk factors on late-life MCI among the aging Mexican population.

Method: Analyses included a sample of non-demented adults over the age of 55 living in both urban and rural areas of Mexico (N = 1807). MCI diagnosis was assigned based on a comprehensive cognitive assessment assessing the domains of memory, executive functioning, language, and visuospatial ability. The normative sample was selected by means of the robust norms approach. Cognitive impairment was defined by a 1.5-SD cut-off per cognitive domain using normative corrections for age, years of education, and sex. Risk factors included age, education, sex, rurality, depression, insurance status, workforce status, hypertension, diabetes, stroke, and heart disease.

Results: The prevalence of amnestic MCI was 5.9%. Other MCI subtypes ranged from 4.2% to 7.7%. MCI with and without memory impairment was associated with older age (OR = 1.01 [1.01, 1.05]; OR = 1.03 [1.01, 1.04], respectively) and residing in rural areas (OR = 1.49 [1.08, 2.06]; OR = 1.35 [1.03, 1.77], respectively). Depression (OR = 1.07 [1.02, 1.12]), diabetes (OR = 1.37 [1.03, 1.82]), and years of education (OR = 0.94 [0.91, 0.97]) were associated with MCI without memory impairment. Midlife CVD increased the odds of MCI in late-life (OR = 1.76 [1.19, 2.59], which was driven by both midlife hypertension and diabetes (OR = 1.70 [1.18, 2.44]; OR = 1.88 [1.19, 2.97], respectively).

Conclusions: Older age, depression, low education, rurality, and midlife hypertension and diabetes were associated with higher risk of late-life MCI among older adults in Mexico. Our findings suggest that the causes of cognitive impairment are multifactorial and vary by MCI subtype.
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http://dx.doi.org/10.1017/S1355617721000539DOI Listing
August 2021

Polygenic Risk Score for Alzheimer's Disease in Caribbean Hispanics.

Ann Neurol 2021 Sep 17;90(3):366-376. Epub 2021 Jun 17.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY.

Objective: Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most PRSs are constructed in European-ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late-onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH).

Methods: We used a CH discovery (n = 4,312) and independent validation sample (n = 1,850) to construct an ancestry-specific PRS ("CH-PRS") and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH-PRS predicted conversion to LOAD in a subsample with longitudinal data (n = 1,239). We also tested the CH-PRS in an independent replication CH cohort (n = 200) and brain autopsy cohort (n = 33). Finally, we tested the effect of ancestry on PRS by using European and African American discovery cohorts to construct alternative PRSs ("EUR-PRS", "AA-PRS").

Results: The full model (LOAD ~ CH-PRS + sex + age + APOE-ɛ4), achieved an AUC = 74% (OR  = 1.51 95%CI = 1.36-1.68), raising to >75% in APOE-ɛ4 non-carriers. CH-PRS alone achieved an AUC = 72% in the autopsy cohort, raising to AUC = 83% in full model. Higher CH-PRS was significantly associated with clinical LOAD in the replication CH cohort (OR = 1.61, 95%CI = 1.19-2.17) and significantly predicted conversion to LOAD (HR = 1.93, CI = 1.70-2.20) in the longitudinal subsample. EUR-PRS and AA-PRS reached lower prediction accuracy (AUC = 58% and 53%, respectively).

Interpretation: Enriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. ANN NEUROL 2021;90:366-376.
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http://dx.doi.org/10.1002/ana.26131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435026PMC
September 2021

Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.

Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk.

Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.

Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.
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http://dx.doi.org/10.1002/alz.12333DOI Listing
May 2021

Genetic and epigenetic study of an Alzheimer's disease family with monozygotic triplets.

Brain 2019 11;142(11):3375-3381

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave, Toronto, ON, Canada.

Age at onset of Alzheimer's disease is highly variable, and its modifiers (genetic or environmental) could act through epigenetic changes, such as DNA methylation at CpG sites. DNA methylation is also linked to ageing-the strongest Alzheimer's disease risk factor. DNA methylation age can be calculated using age-related CpGs and might reflect biological ageing. We conducted a clinical, genetic and epigenetic investigation of a unique Ashkenazi Jewish family with monozygotic triplets, two of whom developed Alzheimer's disease at ages 73 and 76, while the third at age 85 has no cognitive complaints or deficits in daily activities. One of their offspring developed Alzheimer's disease at age 50. Targeted sequencing of 80 genes associated with neurodegeneration revealed that the triplets and the affected offspring are heterozygous carriers of the risk APOE ε4 allele, as well as rare substitutions in APP (p.S198P), NOTCH3 (p.H1235L) and SORL1 (p.W1563C). In addition, we catalogued 52 possibly damaging rare variants detected by NeuroX array in affected individuals. Analysis of family members on a genome-wide DNA methylation chip revealed that the DNA methylation age of the triplets was 6-10 years younger than chronological age, while it was 9 years older in the offspring with early-onset Alzheimer's disease, suggesting accelerated ageing.
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http://dx.doi.org/10.1093/brain/awz289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821163PMC
November 2019

Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease.

JAMA Neurol 2019 Aug;76(8):942-948

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York.

Importance: Genetic causes of late-onset Alzheimer disease (LOAD) are not completely explained by known genetic loci. Whole-exome and whole-genome sequencing can improve the understanding of the causes of LOAD and provide initial steps required to identify potential therapeutic targets.

Objective: To identify the genetic loci for LOAD across different ethnic groups.

Design, Setting, And Participants: This multicenter cohort study was designed to analyze whole-exome sequencing data from a multiethnic cohort using a transethnic gene-kernel association test meta-analysis, adjusted for sex, age, and principal components, to identify genetic variants associated with LOAD. A meta-analysis was conducted on the results of 2 independent studies of whole-exome and whole-genome sequence data from individuals of European ancestry. This group of European American, African American, and Caribbean Hispanic individuals participating in an urban population-based study were the discovery cohort; the additional cohorts included affected individuals and control participants from 2 publicly available data sets. Replication was achieved using independent data sets from Caribbean Hispanic families with multiple family members affected by LOAD and the International Genetics of Alzheimer Project.

Main Outcomes And Measures: Late-onset Alzheimer disease.

Results: The discovery cohort included 3595 affected individuals, while the additional cohorts included 5931 individuals with LOAD and 5504 control participants. Of 3916 individuals in the discovery cohort, we included 3595 individuals (1397 with LOAD and 2198 cognitively healthy controls; 2451 [68.2%] women; mean [SD] age, 80.3 [6.83] years). Another 321 individuals (8.2%) were excluded because of non-LOAD diagnosis, age younger than 60 years, missing covariates, duplicate data, or genetic outlier status. Gene-based tests that compared affected individuals (n = 7328) and control participants (n = 7702) and included only rare and uncommon variants annotated as having moderate-high functional effect supported PINX1 (8p23.1) as a locus with gene-wide significance (P = 2.81 × 10-6) after meta-analysis across the 3 studies. The PINX1 finding was replicated using data from the family-based study and the International Genetics of Alzheimer Project. Full meta-analysis of discovery and replication cohorts reached a P value of 6.16 × 10-7 for PINX1 (in 7620 affected individuals vs 7768 control participants). We also identified TREM2 in an annotation model that prioritized highly deleterious variants with a combined annotation dependent depletion greater than 20 (P= 1.0 × 10-7).

Conclusions And Relevance: This gene-based, transethnic approach identified PINX1, a gene involved in telomere integrity, and TREM2, a gene with a product of an immune receptor found in microglia, as associated with LOAD. Both genes have well-established roles in aging and neurodegeneration.
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http://dx.doi.org/10.1001/jamaneurol.2019.1066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503572PMC
August 2019

Rare Variants Imputation in Admixed Populations: Comparison Across Reference Panels and Bioinformatics Tools.

Front Genet 2019 3;10:239. Epub 2019 Apr 3.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States.

Background: Imputation has become a standard approach in genome-wide association studies (GWAS) to infer untyped markers. Although feasibility for common variants imputation is well established, we aimed to assess rare and ultra-rare variants' imputation in an admixed Caribbean Hispanic population (CH).

Methods: We evaluated imputation accuracy in CH ( = 1,000), focusing on rare (0.1% ≤ minor allele frequency (MAF) ≤ 1%) and ultra-rare (MAF < 0.1%) variants. We used two reference panels, the Haplotype Reference Consortium (HRC; = 27,165) and 1000 Genome Project (1000G phase 3; = 2,504) and multiple phasing (SHAPEIT, Eagle2) and imputation algorithms (IMPUTE2, MACH-Admix). To assess imputation quality, we reported: (a) high-quality variant counts according to imputation tools' internal indexes (e.g., IMPUTE2 "Info" ≥ 80%). (b) Wilcoxon Signed-Rank Test comparing imputation quality for genotyped variants that were masked and imputed; (c) Cohen's kappa coefficient to test agreement between imputed and whole-exome sequencing (WES) variants; (d) imputation of G206A mutation in the (ultra-rare in the general population an more frequent in CH) followed by confirmation genotyping. We also tested ancestry proportion (European, African and Native American) against WES-imputation mismatches in a Poisson regression fashion.

Results: SHAPEIT2 retrieved higher percentage of imputed high-quality variants than Eagle2 (rare: 51.02% vs. 48.60%; ultra-rare 0.66% vs. 0.65%, Wilcoxon -value < 0.001). SHAPEIT-IMPUTE2 employing HRC outperformed 1000G (64.50% vs. 59.17%; 1.69% vs. 0.75% for high-quality rare and ultra-rare variants, respectively, Wilcoxon -value < 0.001). SHAPEIT-IMPUTE2 outperformed MaCH-Admix. Compared to 1000G, HRC-imputation retrieved a higher number of high-quality rare and ultra-rare variants, despite showing lower agreement between imputed and WES variants (e.g., rare: 98.86% for HRC vs. 99.02% for 1000G). High Kappa ( = 0.99) was observed for both reference panels. Twelve G206A mutation carriers were imputed and all validated by confirmation genotyping. African ancestry was associated with higher imputation errors for uncommon and rare variants (-value < 1e-05).

Conclusion: Reference panels with larger numbers of haplotypes can improve imputation quality for rare and ultra-rare variants in admixed populations such as CH. Ethnic composition is an important predictor of imputation accuracy, with higher African ancestry associated with poorer imputation accuracy.
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http://dx.doi.org/10.3389/fgene.2019.00239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456789PMC
April 2019

Plasma microRNA profiling distinguishes patients with frontotemporal dementia from healthy subjects.

Neurobiol Aging 2019 12 5;84:240.e1-240.e12. Epub 2019 Feb 5.

Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy. Electronic address:

The purpose of this study was to develop an easy and minimally invasive assay to detect a plasma miRNA profile in frontotemporal dementia (FTD) patients, with the final aim of discriminating between FTD patients and healthy controls (HCs). After a global miRNA profiling, significant downregulation of miR-663a, miR-502-3p, and miR-206 (p = 0.0001, p = 0.0002, and p = 0.02 respectively) in FTD patients was confirmed when compared with HCs in a larger case-control sample. Moreover, miR-663a and miR-502-3p showed significant differences in both genders, whereas miR-206, only in male subjects. To obtain a discriminating measure between FTD patients and HCs, we calculated a combined score of the 3 miRNAs by applying a Bayesian approach and obtaining a classifier with an accuracy of 84.4%. Moreover, for men, combined miRNA levels showed an excellent sensitivity (100%) and a good specificity (87.5%) in distinguishing FTD patients from HCs. All these findings open new hypotheses in the pathophysiology and new perspectives in the diagnosis of a complex pathology as FTD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.024DOI Listing
December 2019

An MRI measure of degenerative and cerebrovascular pathology in Alzheimer disease.

Neurology 2018 10 14;91(15):e1402-e1412. Epub 2018 Sep 14.

From the Taub Institute for Research on Alzheimer's Disease and the Aging Brain (A.M.B., G.T., H.A., Y.G., A.N., B.R., V.G., J.J.M., J.P.V., N.S., R.M.), The Gertrude H. Sergievsky Center (A.M.B., G.T., H.A., Y.G., J.J.M., N.S., R.M.), and the Departments of Neurology (A.M.B., G.T., J.G., Y.G., J.J.M., N.S., R.M.), Pathology and Cell Biology (J.P.V.), and Psychiatry (R.M.), College of Physicians and Surgeons, and Departments of Biostatistics (H.A.) and Epidemiology (N.S., R.M.), Mailman School of Public Health, Columbia University, New York, NY.

Objective: To develop, replicate, and validate an MRI-based quantitative measure of both cerebrovascular and neurodegeneration in Alzheimer disease (AD) for clinical and potentially research purposes.

Methods: We used data from a cross-sectional and longitudinal community-based study of Medicare-eligible residents in northern Manhattan followed every 18-24 months (n = 1,175, mean age 78 years). White matter hyperintensities, infarcts, hippocampal volumes, and cortical thicknesses were quantified from MRI and combined to generate an MRI measure associated with episodic memory. The combined MRI measure was replicated and validated using autopsy data, clinical diagnoses, and CSF biomarkers and amyloid PET from the Alzheimer's Disease Neuroimaging Initiative.

Results: The quantitative MRI measure was developed in a group of community participants (n = 690) and replicated in a similar second group (n = 485). Compared with healthy controls, the quantitative MRI measure was lower in patients with mild cognitive impairment and lower still in those with clinically diagnosed AD. The quantitative MRI measure correlated with neurofibrillary tangles, neuronal loss, atrophy, and infarcts at postmortem in an autopsy subset and was also associated with PET amyloid imaging and CSF levels of total tau, phosphorylated tau, and β-amyloid 42. The MRI measure predicted conversion to MCI and clinical AD among healthy controls.

Conclusion: We developed, replicated, and validated an MRI measure of cerebrovascular and neurodegenerative pathologies that are associated with clinical and neuropathologic diagnosis of AD and related to established biomarkers.
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http://dx.doi.org/10.1212/WNL.0000000000006310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177275PMC
October 2018

Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia.

J Alzheimers Dis 2018 ;65(4):1417-1425

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Background: Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-β42 (Aβ42) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer's disease (AD).

Objective: The goal was to determine the overall accuracy of CSF Aβ42, tTau, pTau, and the Aβ42/total tau index (ATI) in a non-research, clinical setting for the diagnosis of AD.

Methods: From medical records in 1,016 patients that had CSF studies for dementia over a 12-year period (2005 to 2017), we calculated the sensitivity and specificity of CSF Aβ42, tTau, and pTau and the ATI in relation to the final clinical diagnosis.

Results: Compared with non-demented patients and patients with other dementias or mild cognitive impairment (MCI), the sensitivity and specificity of the recommended ATI and pTau cut-offs (ATI < 1.0 and pTau >61 pg/ml) for the diagnosis of AD were 0.88 and 0.72, respectively. Similar results were obtained comparing AD with non-demented patients only (0.88, 0.82) and AD with other types of dementia (0.81, 0.77). A subgroup of patients with presumed normal pressure hydrocephalus (n = 154) were biopsied at the time of shunt placement. Using the pathological manifestations of AD as the standard, the sensitivity was 0.83 while the specificity was 0.72.

Conclusions: In a non-research setting, CSF biomarkers for AD showed a high sensitivity in accordance with previous studies, but modest specificity differentiating AD from other types of dementia or MCI. This study of unselected patients provides a valid and realistic assessment of the diagnostic accuracy of these CSF biomarkers in clinical practice.
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http://dx.doi.org/10.3233/JAD-180548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218126PMC
August 2019

Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

Mol Psychiatry 2020 08 14;25(8):1859-1875. Epub 2018 Aug 14.

McDonnell Genome Institute, Washington University, St. Louis, MO, USA.

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
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http://dx.doi.org/10.1038/s41380-018-0112-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375806PMC
August 2020

Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease.

Ann Clin Transl Neurol 2018 Jul 24;5(7):832-842. Epub 2018 May 24.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain College of Physicians and Surgeons Columbia University The New York Presbyterian Hospital New York New York.

Objective: The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer's disease, using whole-exome sequencing in 20,197 individuals.

Methods: We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.

Results: We identified 19 cases carrying extremely rare loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( = 2.17 × 10; OR: 36.2 [95% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including , and were among candidates for follow-up studies.

Interpretation: This study implicates ultra-rare, loss-of-function variants in as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in and Alzheimer's disease in a large whole-exome study of unrelated cases and controls.
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http://dx.doi.org/10.1002/acn3.582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043775PMC
July 2018

Analysis of pedigree data in populations with multiple ancestries: Strategies for dealing with admixture in Caribbean Hispanic families from the ADSP.

Genet Epidemiol 2018 09 3;42(6):500-515. Epub 2018 Jun 3.

Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.

Multipoint linkage analysis is an important approach for localizing disease-associated loci in pedigrees. Linkage analysis, however, is sensitive to misspecification of marker allele frequencies. Pedigrees from recently admixed populations are particularly susceptible to this problem because of the challenge of accurately accounting for population structure. Therefore, increasing emphasis on use of multiethnic samples in genetic studies requires reevaluation of best practices, given data currently available. Typical strategies have been to compute allele frequencies from the sample, or to use marker allele frequencies determined by admixture proportions averaged over the entire sample. However, admixture proportions vary among pedigrees and throughout the genome in a family-specific manner. Here, we evaluate several approaches to model admixture in linkage analysis, providing different levels of detail about ancestral origin. To perform our evaluations, for specification of marker allele frequencies, we used data on 67 Caribbean Hispanic admixed families from the Alzheimer's Disease Sequencing Project. Our results show that choice of admixture model has an effect on the linkage analysis results. Variant-specific admixture proportions, computed for individual families, provide the most detailed regional admixture estimates, and, as such, are the most appropriate allele frequencies for linkage analysis. This likely decreases the number of false-positive results, and is straightforward to implement.
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http://dx.doi.org/10.1002/gepi.22133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160322PMC
September 2018

White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer's disease.

PLoS One 2018 9;13(5):e0195838. Epub 2018 May 9.

Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States of America.

Introduction: White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer's disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD.

Participants And Methods: Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds.

Results: Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds.

Discussion: Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195838PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942789PMC
August 2018

Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease.

Ann Clin Transl Neurol 2018 Apr 13;5(4):406-417. Epub 2018 Mar 13.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain New York.

Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families.

Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.

Results: A variant in p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07-30.9, = 0.041). In addition, missense mutations in and under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant ( < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including ( = 0.049), ( = 0.0098) and ( = 0.040).

Conclusions And Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.
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http://dx.doi.org/10.1002/acn3.537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899906PMC
April 2018

The effect of white matter hyperintensities on cognition is mediated by cortical atrophy.

Neurobiol Aging 2018 04 16;64:25-32. Epub 2017 Dec 16.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address:

White matter hyperintensities (WMH) have been linked to cognitive dysfunction and dementia, although the reasons are unclear. One possibility is that WMH promote neurodegeneration, which, in turn, affects cognition. We examined whether cortical thickness, a marker of neurodegeneration, mediates the relationship between WMH and cognition among 519 older adults. Using conditional process analysis modeling techniques, we examined the association between WMH volume and global cognition and tested whether cortical thickness mediates this relationship statistically. We also tested specific regional hypotheses to determine whether cortical thickness or volume in the medial temporal lobe mediates the relationship between WMH volume and memory. Increased total WMH volume was associated with poorer global cognition and memory. Global cortical thickness and medial temporal lobe thickness/volume mediated the relationship of WMH volume on global cognition and memory functioning. The mediating relationship was similar across racial and ethnic groups and across diagnostic groups (i.e., mild cognitive impairment/Alzheimer's disease). The findings suggest that WMH promote atrophy, which, in turn, drives cognitive decline and highlight a potential pathway in which small vessel cerebrovascular disease affects cognition by promoting neurodegenerative changes directly.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831564PMC
April 2018

Prosodic Impairment in Dementia: Review of the Literature.

Curr Alzheimer Res 2018 ;15(2):157-163

G.H. Sergievsky Center, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY. United States.

Objective: Prosody, an important aspect of spoken language, is defined as the emphasis placed on certain syllables, changes in tempo or timing, and variance in pitch and intonation. Most studies investigating expression and comprehension of prosody have focused primarily on emotional prosody and less extensively on supralexical prosody. The distinction is indeed important, as the latter conveys information such as interrogative or assertive mode, whereas the former delivers emotional connotation, such as happiness, anger, and sadness. These functions appear to rely on distinct neuronal networks, supported by functional neuroimaging studies that show activation of the right hemisphere, specifically in the right inferior frontal area during emotional detection.

Conclusion: This review summarizes the studies conducted on prosody impairment in Alzheimer's disease and other dementias, with emphasis on experiments designed to investigate the emotional vs. the supralexical aspect of speech production. We also discussed the available tools validated to test and quantify the prosodic impairment.
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http://dx.doi.org/10.2174/1567205014666171030115624DOI Listing
March 2019

Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.

Alzheimers Dement 2018 02 21;14(2):205-214. Epub 2017 Sep 21.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Objective: To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD).

Methods: Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.

Results: We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10) and sLOAD (OR = 1.40; P = 1.21 × 10). The PRS was associated with cerebrospinal fluid ptau-Aβ on eADAD (P = 4.36 × 10).

Conclusion: Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.
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http://dx.doi.org/10.1016/j.jalz.2017.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803427PMC
February 2018

Ultra-rare mutations in segregate in Caribbean Hispanic families with Alzheimer disease.

Neurol Genet 2017 Oct 24;3(5):e178. Epub 2017 Aug 24.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.N.V., G.T., R. Lefort, P.L.D.J., S.B., D.R.-D., J.H.L., R.C., R. Lantigua, R.M.); Gertrude H. Sergievsky Center (B.N.V., G.T., S.B., D.R.-D., J.H.L., R.C., R.M.); Department of Neurology (P.L.D.J., S.B., R.M.), Department of Psychiatry (R.M.), Department of Systems Biology (B.N.V.), Department of Medicine (R. Lantigua), and Department of Pathology and Cell Biology (R. Lefort, P.L.N.), College of Physicians and Surgeons, Columbia University, New York Presbyterian Hospital; Department of Epidemiology (J.H.L., R.M.), School of Public Health, Columbia University, New York; Tanz Centre for Research in Neurodegenerative Diseases (E.R., P.S.G.-H.) and Department of Medicine (E.R., P.S.G.-H.), University of Toronto, Krembil Discovery Tower, ON, Canada; Department of Clinical Neurosciences (P.S.G.-H.), Cambridge Institute for Medical Research, University of Cambridge, UK; Rush Alzheimer's Disease Center (L.Y., D.A.B.), Rush University Medical Center, Chicago, IL; Program in Medical and Population Genetics (P.L.D.J.), Broad Institute, Cambridge, MA; and School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic.

Objective: To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families.

Methods: Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia.

Results: Ten ultra-rare missense mutations in the Snf2-related , activator protein (), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of mutations among Caribbean Hispanic patients with LOAD was significantly enriched ( = 1.19e-16). mRNA expression of in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes.

Conclusions: WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in , a gene expressed in the brain and mutated in Floating-Harbor syndrome. is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers.
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http://dx.doi.org/10.1212/NXG.0000000000000178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570674PMC
October 2017

Genetics of Alzheimer's Disease: the Importance of Polygenic and Epistatic Components.

Curr Neurol Neurosci Rep 2017 Aug 21;17(10):78. Epub 2017 Aug 21.

The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 622 W. 168th Street PH 19-314, New York, NY, 10032, USA.

Purpose Of Review: We aimed to summarize the recent advances in genetic findings of Alzheimer's disease (AD), focusing on traditional single-marker and gene approaches and non-traditional ones, i.e., polygenic and epistatic components.

Recent Findings: Genetic studies have progressed over the last few decades from linkage to genome-wide association studies (GWAS), and most recently studies utilizing high-throughput sequencing. So far, GWASs have identified several common variants characterized by small effect sizes (besides APOE-ε4). Sequencing has facilitated the study of rare variants with larger effects. Nevertheless, missing heritability for AD remains extensive; a possible explanation might lie in the existence of polygenic and epistatic components. We review findings achieved by single-marker approaches, but also polygenic and epistatic associations. The latter two are critical, yet-underexplored mechanisms. Genes involved in complex diseases are likely regulated by mechanisms and pathways involving many other genes, an aspect potentially missed by traditional approaches.
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http://dx.doi.org/10.1007/s11910-017-0787-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699909PMC
August 2017

Polygenic risk scores in familial Alzheimer disease.

Neurology 2017 Mar 17;88(12):1180-1186. Epub 2017 Feb 17.

From the Taub Institute for Research on Alzheimer's Disease and the Aging Brain (G.T., J.M., R.O., N.S., Y.S., R.M.), Gertrude H. Sergievsky Center (G.T., J.M., N.S., Y.S., R.M.), and Department of Neurology (G.T., J.M., R.O., N.S., Y.S.), Columbia University College of Physicians and Surgeons, New York; New York Presbyterian Hospital (G.T., J.M., R.O., N.S., Y.S.), NY; Departments of Neurology and Medicine (T.D.B., D.T.), University of Washington, Seattle; Rush Alzheimer's Disease Center (D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN; Hope Center for Neurological Disorders (C.C.), Washington University, St Louis, MO; Department of Medical and Molecular Genetics (K.F., T.M.F.), Indiana University; Department of Neurology (M.F.), Indiana University Center for Alzheimer's Disease and Related Disorders, Indianapolis; Department of Neuroscience (A.M.G., S.B.), Mount Sinai School of Medicine, New York, NY; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; School of Medicine (M.M., R.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; Department of Medicine (R.L.) and Department of Epidemiology, Mailman School of Public Health (R.O., N.S.), Columbia University, New York; Division of Epidemiology (R.O.), New York State Psychiatric Institute, New York; Department of Neurology and Neurotherapeutics (R.R.), The University of Texas Southwestern Medical Center, Dallas; Department of Health Sciences Research (D.J.S.), Mayo Clinic, Rochester, MN; and Department of Psychiatry, Neurology and Epidemiology (R.A.S.), University of Pittsburgh, PA.

Objective: To investigate the association between a genetic risk score (GRS) and familial late-onset Alzheimer disease (LOAD) and its predictive value in families multiply affected by the disease.

Methods: Using data from the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease (National Institute on Aging-Late-Onset Alzheimer's Disease Family Study), mixed regression models tested the association of familial LOAD with a GRS based on single nucleotide polymorphisms (SNPs) previously associated with LOAD. We modeled associations using unweighted and weighted scores with estimates derived from the literature. In secondary models, we adjusted subsequent models for presence of the ε4 allele and further tested the interaction between ε4 and the GRS. We constructed a similar GRS in a cohort of Caribbean Hispanic families multiply affected by LOAD by selecting the SNP with the strongest value within the same regions.

Results: In the NIA-LOAD families, the GRS was significantly associated with LOAD (odds ratio [OR] 1.29; 95% confidence interval 1.21-1.37). The results did not change after adjusting for ε4. In Caribbean Hispanic families, the GRS also significantly predicted LOAD (OR 1.73; 1.57-1.93). Higher scores were associated with lower age at onset in both cohorts.

Conclusions: High GRS increases the risk of familial LOAD and lowers the age at onset, regardless of ethnic group.
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http://dx.doi.org/10.1212/WNL.0000000000003734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373783PMC
March 2017

Association of Cardiovascular Risk Factors and Stroke With Alzheimer Disease-Reply.

JAMA Neurol 2017 01;74(1):129-130

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, New York2The Gertrude H. Sergievsky Center, Columbia University College of Physicians and Surgeons, New York, New York3Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York4New York Presbyterian Hospital, New York5Department of Epidemiology, Columbia University, New York, New York.

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http://dx.doi.org/10.1001/jamaneurol.2016.4384DOI Listing
January 2017

Genomics of Alzheimer's disease: Value of high-throughput genomic technologies to dissect its etiology.

Mol Cell Probes 2016 12 13;30(6):397-403. Epub 2016 Sep 13.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA; The Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA; The Department of Neurology, Columbia University, New York, NY, USA; The Dept. of Epidemiology, Columbia University, New York, NY, USA. Electronic address:

Late-onset Alzheimer's disease (AD), the most common neurodegenerative disorder in western countries, is clinically defined by progressive worsening in cognitive functions along with function and behavioral impairment. This ultimately results in complete incapacity and death. AD is a clinically and pathologically heterogeneous disease, and this is reflected by the numerous genetic findings that point to several diverse molecular mechanisms and pathways. Linkage, genome-wide association and next-generation sequencing studies have led to the identification of more than 20 novel susceptibility loci for AD. While these observations have significantly increased the knowledge of pathogenic mechanisms and potential therapeutic targets, a large part of the genetic component underlying AD is still unexplained. This review will summarize and discuss the major genetic findings and their potential impact on AD diagnosis and prediction of prognosis.
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http://dx.doi.org/10.1016/j.mcp.2016.09.001DOI Listing
December 2016

The Role of Cardiovascular Risk Factors and Stroke in Familial Alzheimer Disease.

JAMA Neurol 2016 Oct;73(10):1231-1237

Taub Institute for Research on Alzheimer's Disease, The Aging Brain and the Gertrude H. Sergievsky Center, Columbia University College of Physicians and Surgeons, New York, New York2Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York3New York Presbyterian Hospital in New York City14Department of Epidemiology, Columbia University, New York, New York.

Importance: The contribution of cardiovascular disease (CV) and cerebrovascular disease to the risk for late-onset Alzheimer disease (LOAD) has been long debated. Investigations have shown that antecedent CV risk factors increase the risk for LOAD, although other investigations have failed to validate this association.

Objective: To study the contribution of CV risk factors (type 2 diabetes, hypertension, and heart disease) and the history of stroke to LOAD in a data set of large families multiply affected by LOAD.

Design, Setting, And Participants: The National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease family study (hereinafter referred to as NIA-LOAD study) is a longitudinal study of families with multiple members affected with LOAD. A multiethnic community-based longitudinal study (Washington Heights-Inwood Columbia Aging Project [WHICAP]) was used to replicate findings. The 6553 participants in the NIA-LOAD study were recruited from 23 US Alzheimer disease centers with ongoing data collection since 2003; the 5972 WHICAP participants were recruited at Columbia University with ongoing data collection since 1992. Data analysis was performed from 2003 to 2015.

Main Outcomes And Measures: Generalized mixed logistic regression models tested the association of CV risk factors (primary association) with LOAD. History of stroke was used for the secondary association. A secondary model adjusted for the presence of an apolipoprotein E (APOE) ε4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE ε4 effect. Mediation analyses evaluated stroke as a mediating factor between the primary association and LOAD.

Results: A total of 6553 NIA-LOAD participants were included in the analyses (4044 women [61.7%]; 2509 men [38.3%]; mean [SD] age, 77.0 [9] years), with 5972 individuals from the WHICAP study included in the replication sample (4072 women [68.2%]; 1900 men [31.8%]; mean [SD] age, 76.5 [7.0] years). Hypertension was associated with decreased LOAD risk (odds ratio [OR], 0.63; 95% CI, 0.55-0.72); type 2 diabetes and heart disease were not. History of stroke conferred greater than 2-fold increased risk for LOAD (OR, 2.23; 95% CI, 1.75-2.83). Adjustment for APOE ε4 did not alter results. The genetic risk score was associated with LOAD (OR, 2.85; 95% CI, 2.05-3.97) but did not change the independent association of LOAD with hypertension or stroke. In the WHICAP sample, hypertension was not associated with LOAD (OR, 0.99; 95% CI, 0.88-1.11), whereas history of stroke increased the risk for LOAD (OR, 1.96; 95% CI, 1.56-2.46). The effect of hypertension on LOAD risk was also mediated by stroke in the NIA-LOAD and the WHICAP samples.

Conclusions And Relevance: In familial and sporadic LOAD, a history of stroke was significantly associated with increased disease risk and mediated the association between selected CV risk factors and LOAD, which appears to be independent of the LOAD-related genetic background.
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http://dx.doi.org/10.1001/jamaneurol.2016.2539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155512PMC
October 2016

White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network.

Ann Neurol 2016 Jun 27;79(6):929-39. Epub 2016 Apr 27.

Department of Neurology, Washington University School of Medicine, St. Louis, MO.

Objective: White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD.

Methods: The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO.

Results: Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset.

Interpretation: Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939.
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http://dx.doi.org/10.1002/ana.24647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884146PMC
June 2016

Promising Therapies for Alzheimer's Disease.

Curr Pharm Des 2016 ;22(14):2050-6

Dipartmento Biologia e Biotecnologie Charles Darwin, Centro di ricerca in Neurobiologia Daniel Bovet, "Sapienza", Università di Roma, P.le A. Moro, 5 - 00185 Roma, Italy.

Background: Alzheimer's disease (AD) is the most frequent progressive neurodegenerative disease. Cholinergic dysfunction is one of the major pathological alteration, although depletion of cholinergic neurons is caused by the well-established toxicity of the beta-amyloid plaques and neurofibrillary tangles. Cholinergic dysfunctions are consequences of the decrease in acetylcholine synthesis and release, and altered function of muscarinic and nicotinic cholinergic receptors. In addition, a direct correlation between cholinergic alteration, amyloidbeta production and tau phosphorylation, two main AD-pathology hallmarks, has been identified.

Methods: In the present review we focused our discussion on the identification of new allosteric or bitopic ligands able to modulate the cholinergic receptor activity. Moreover drug delivery methodology (nanoparticeles, liposomes, etc.) that might contribute to drive the drug in the brain, reducing their toxicity and potential side effects have been also discussed.

Results: Many drugs are currently in use for AD (e.g. donepezil, rivastigmine etc.) and several of those in development such as muscarininc and nicotinic agonists, target specifically the cholinergic system; the main mechanism aims to rescue the cholinergic dysfunction, to reduce neurotoxic protein accumulation and improve the cholinergic impairments responsible of the cognitive deficits. Promising approaches aim to either improve drug delivery into the brain or develope new compounds targeting known or new molecular pathways. Nanoparticles and liposomes are also described as new nanotechnology tools that overcome traditional routes of administration, with a particular focus on their employment for compounddelivery that targets the cholinergic system. Ultimately, a new fields of research is emerging as the use of induced pluripotent stem cells, a technology that allows to obtain cells directly from the patients that can be propagated indefinetely and differentiated into the susceptible neuronal subtypes. This may significantly contribute to improve the understanding of AD pathological processes and enhance current AD pharmacology beyond the cholinergic dysfunction.

Conclusion: From the topics discussed in the present review, emerges that the combination between pharmacological studies and nanotechnological approaches for drug delivery and the identification of new specific models may largely enhance and improve the therapeutic strategies for different neurological disease including AD.
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http://dx.doi.org/10.2174/1381612822666160215154218DOI Listing
November 2017

Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates.

J Alzheimers Dis 2016 ;49(4):1085-93

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.

Background: Extrapyramidal signs (EPS) are frequent in Alzheimer's disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson's disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions.

Objective: To identify clusters of EPS progression over time and their clinical and neuropathological correlates.

Methods: 3,502 AD patients with longitudinal assessment from the National Alzheimer's Coordinating Center database were included; 394 provided neuropathological data. k-means algorithm was employed to identify clusters of EPS progression and those were compared in terms of cognitive profile, neuropsychiatric features and neuropathological findings.

Results: Three clusters of EPS progression were identified: no/low (n = 1,583), medium (n = 1,259), and high (n = 660) EPS burden. Compared to those with no/low and medium EPS, those with high EPS had greater cognitive and neuropsychiatric impairment, specifically hallucinations. Despite similar AD-pathology across the three clusters, the high EPS cluster had a significantly number of subjects diagnosed with dementia with Lewy bodies.

Conclusions: Cluster analysis of EPS progression over time identified different subgroups of AD patients with distinct clinical and neuropathological features.
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http://dx.doi.org/10.3233/JAD-150244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779642PMC
October 2016

Sociodemographic and Clinical Changes Over Time of Individuals Evaluated for Cognitive Disturbances: Good or Bad News?

J Am Med Dir Assoc 2015 Dec;16(12):1095-6

Memory Clinic, Department of Neurology and Psychiatry, "Sapienza" University, Rome, Italy.

In recent years, "prevention" and "early diagnosis" have been growingly discussed and explored in the field of cognitive disorders. Such increased attention to cognitive disturbances and neurodegenerative conditions may constitute a key step for achieving early/timely diagnosis of dementing illnesses. At the same time, it may generate possible issues (such as a greater proportion of negative diagnostic procedures with potential misuse of resources) that should be acknowledged by health care systems. In this report, we present exploratory analyses aimed at investigating the sociodemographic and clinical changes over time of all the individuals who have been cognitively assessed in a Memory Clinic between 2002 and 2014. Overall, individuals evaluated for cognitive disturbances have gradually become younger, more educated, and less impaired in cognitive and physical functions at their first cognitive assessment. To date, nearly 1 of 4 individuals completing a neuropsychological evaluation has no objective cognitive deficits, thus presenting subjective cognitive complaints. Based on these findings, the development and implementation of strategies for improving the referral to memory clinics is strongly needed.
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http://dx.doi.org/10.1016/j.jamda.2015.09.013DOI Listing
December 2015

F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease.

Ann Clin Transl Neurol 2015 Aug 18;2(8):810-20. Epub 2015 Jun 18.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, School of Public Health, Columbia University New York, New York ; The Gertrude H. Sergievsky Center, School of Public Health, Columbia University New York, New York ; Department of Neurology, Columbia University New York, New York ; Department of Psychiatry, School of Public Health, Columbia University New York, New York ; Department of Epidemiology, School of Public Health, Columbia University New York, New York.

Objective: In the context of late-onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.

Methods: About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome-wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD-like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non-Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.

Results: A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome-wide significant in the case-control cohort (odd ratio [OR] = 0.61, P = 6.19E-09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E-08). Fbxl7 protein was overexpressed in both AD-like transgenic mice compared to wild-type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single-nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non-Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.

Interpretation: FBXL7, encodes a subcellular protein involved in phosphorylation-dependent ubiquitination processes and displays proapoptotic activity. F-box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
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http://dx.doi.org/10.1002/acn3.223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554442PMC
August 2015

Pattern of extrapyramidal signs in Alzheimer's disease.

J Neurol 2015 Nov 4;262(11):2548-56. Epub 2015 Sep 4.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.

Patients with Alzheimer's disease (AD) often develop extrapyramidal signs (EPS), which increase in frequency as the disease progresses. We aimed to investigate the patterns of presentation of EPS in AD and their correlation with clinical and neuropathological features. 4284 subjects diagnosed with AD from the National Alzheimer's Coordinating Center (NACC) database with at least one abnormal Unified Parkinson's Disease Rating Scale (UPDRS) assessment were included. Individuals were assigned to a discovery sample and a sensitivity analysis sample (moderate and mild dementia, respectively) and a subset of subjects provided neuropathological data (n = 284). Individuals from the Washington Heights and Inwood Columbia Aging Project (WHICAP) served as validation sample. Patterns of presentation of EPS were identified employing categorical principal component analysis (CATPCA). Six principal components were identified in both mild and moderate AD samples: (I) hand movements, alternating movements, finger tapping, leg agility ("limbs bradykinesia"); (II) posture, postural instability, arising from chair, gait and body bradykinesia/hypokinesia ("axial"); (III) limb rigidity ("rigidity"); (IV) postural tremor; (V) resting tremor; (VI) speech and facial expression. Similar results were obtained in the WHICAP cohort. Individuals with hallucinations, apathy, aberrant night behaviors and more severe dementia showed higher axial and limb bradykinesia scores. "Limb bradykinesia" component was associated with a neuropathological diagnosis of Lewy body disease and "axial" component with reduced AD-type pathology. Patterns of EPS in AD show distinct clinical and neuropathological correlates; they share a pattern of presentation similar to that seen in Parkinson's disease, suggesting common pathogenic mechanisms across neurodegenerative diseases.
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http://dx.doi.org/10.1007/s00415-015-7886-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776751PMC
November 2015
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