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Background: To date, there is no high throughput proteomic study in the context of Autosomal Dominant Alzheimer's disease (ADAD). Here, we aimed to characterize early CSF proteome changes in ADAD and leverage them as potential biomarkers for disease monitoring and therapeutic strategies. Methods: We utilized Somascan® 7K assay to quantify protein levels in the CSF from 291 mutation carriers (MCs) and 185 non-carriers (NCs). We employed a multi-layer regression model to identify proteins with different pseudo-trajectories between MCs and NCs. We replicated the results using publicly available ADAD datasets as well as proteomic data from sporadic Alzheimer's disease (sAD). To biologically contextualize the results, we performed network and pathway enrichment analyses. Machine learning was applied to create and validate predictive models. Findings: We identified 125 proteins with significantly different pseudo-trajectories between MCs and NCs. Twelve proteins showed changes even before the traditional AD biomarkers (Aß42, tau, ptau). These 125 proteins belong to three different modules that are associated with age at onset: 1) early stage module associated with stress response, glutamate metabolism, and mitochondria damage; 2) the middle stage module, enriched in neuronal death and apoptosis; and 3) the presymptomatic stage module was characterized by changes in microglia, and cell-to-cell communication processes, indicating an attempt of rebuilding and establishing new connections to maintain functionality. Machine learning identified a subset of nine proteins that can differentiate MCs from NCs better than traditional AD biomarkers (AUC>0.89). Interpretation: Our findings comprehensively described early proteomic changes associated with ADAD and captured specific biological processes that happen in the early phases of the disease, fifteen to five years before clinical onset. We identified a small subset of proteins with the potentials to become therapy-monitoring biomarkers of ADAD MCs. Funding: Proteomic data generation was supported by NIH: RF1AG044546.
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INTRODUCTION: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS: AD polygenic risk scores (PRS) were tested for association with DS-related traits. RESULTS: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE , p = 2.84 × 10-4 ; PRS excluding APOE, PRSnonAPOE , p = 1.60 × 10-2 ). PRSAPOE exhibited significant associations with Aß42, tTau, pTau, and Aß42/40 ratio in DS. DISCUSSION: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. HIGHLIGHTS: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Down Syndrome , Adult , Humans , Alzheimer Disease/diagnosis , Down Syndrome/genetics , Genetic Risk Score , Apolipoproteins E/genetics , Phenotype , Cognitive Dysfunction/diagnosis , Biomarkers/cerebrospinal fluid , Cognition , Memory Disorders , Amyloid beta-Peptides/cerebrospinal fluidABSTRACT
Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P < 0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7â pg/ml, P = 0.005), but no significant differences were found for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.
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INTRODUCTION: Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm-FINGERS) is the first non-pharmacological multicenter randomized clinical trial (RCT) to prevent cognitive impairment in Latin America (LA). Our aim is to present the study design and discuss the strategies used for multicultural harmonization. METHODS: This 1-year RCT (working on a 1-year extension) investigates the feasibility of a multi-domain lifestyle intervention in LA and the efficacy of the intervention, primarily on cognitive function. An external harmonization process was carried out to follow the FINGER model, and an internal harmonization was performed to ensure this study was feasible and comparable across the 12 participating LA countries. RESULTS: Currently, 1549 participants have been screened, and 815 randomized. Participants are ethnically diverse (56% are Nestizo) and have high cardiovascular risk (39% have metabolic syndrome). DISCUSSION: LatAm-FINGERS overcame a significant challenge to combine the region's diversity into a multi-domain risk reduction intervention feasible across LA while preserving the original FINGER design.
Subject(s)
Cognitive Dysfunction , Humans , Latin America , Cognitive Dysfunction/prevention & control , Life Style , Cognition , Research DesignABSTRACT
Human induced pluripotent stem cell (hiPSC) line INEUi001-A was reprogrammed from peripheral blood mononuclear cells (PBMC) using the lentiviral-hSTEMCCA-loxP vector. PBMCs were obtained from a 75- year-old female ALS/FTD disease patient carrying a heterozygous deletion within the C9ORF72 hexanucleotide repeat region resulting in a GGGGCCG sequence (â¼1.16 repeats). C9ORF72 genotype was maintained and stemness and pluripotency confirmed in INEUi001-A hiPSC line.
Subject(s)
Amyotrophic Lateral Sclerosis , Frontotemporal Dementia , Induced Pluripotent Stem Cells , Female , Humans , Aged , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Frontotemporal Dementia/genetics , Induced Pluripotent Stem Cells/metabolism , C9orf72 Protein/genetics , Leukocytes, Mononuclear/metabolism , GenotypeABSTRACT
BACKGROUND: In recent years, there has been an increase in the number of case reports of families with autosomal dominant Alzheimer's disease (ADAD) in Latin America (LA). Nevertheless, little is known about the clinical phenotypes and demographic characteristics of mutations in each country. Past literature has proved that variants in LA have different and unique characteristics than those reported in Asia, North America, and Europe. Clinical heterogeneity in ADAD supports the need to study clinical phenotypes, especially in preclinical stages, to develop cognitive and clinical markers of the disease. We aimed to describe clinical and cognitive characteristics at baseline assessment of an Argentina PSEN1 p.M146L family enrolled at DIAN. METHOD: Fifteen Dian Participants living in Buenos Aires and its suburbs and in Taco Pozo, a rural and isolated community from the Province of Salta, positive for the PSEN1 p.M146L mutation, were recruited. DNA was obtained from peripheral blood leukocytes according to standard protocols. In addition, exon 5 of the PSEN1 gene was PCR-amplified, and Sanger sequencing was performed. NACC Uniform Data Set clinical assessment, including the 2.0 UDS Neuropsychological Battery, was administered. Two groups were used to compare cognitive data: Patients with CDR:0 (n:10) and patients with CDR>0 (n:5). RESULT: The mean age at symptom onset reported in this cohort was 42,90 (SD: 4,62). Significant differences were found in several cognitive measures: Logical Memory Immediate, TMT B and Digit Backward (<0,001); MMSE, Category Fluency Animals, TMT A and Digit Symbol(<0,05). In neurological signs, paraplegia was reported in one of the patients. CONCLUSION: As expected, differences in neuropsychological tests showed a prevalence of memory deficits, however, dysexecutive symptoms were also present for this mutation. Paraplegia in PSEN1 p.M146L has not been reported in the literature so far. Ongoing longitudinal work will be important in tracking changes in this cohort. Other characteristics, proper of underrepresented groups, such as socioeconomic status, education, race, and ethnicity, deserve appropriate follow-up. Future studies are planned, comparing urban and rural populations in this cohort with the same mutation.
Subject(s)
Alzheimer Disease , Neuropsychological Tests , Presenilin-1 , Humans , Alzheimer Disease/genetics , Male , Female , Argentina , Middle Aged , Presenilin-1/genetics , Neuropsychological Tests/statistics & numerical data , Mutation/genetics , Aged , Adult , PhenotypeABSTRACT
BACKGROUND: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. METHODS: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. RESULTS: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. CONCLUSIONS: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.
Subject(s)
Alzheimer Disease , Frontotemporal Lobar Degeneration , Neurodegenerative Diseases , Alzheimer Disease/genetics , Colombia , Founder Effect , Frontotemporal Lobar Degeneration/genetics , Humans , Mutation , Neurodegenerative Diseases/geneticsABSTRACT
OBJECTIVE: Increased life expectancy and exponential growth of adults suffering from Alzheimer's disease (AD) worldwide, has led to biomarkers incorporation for diagnosis in early stages. Use of neuropsychological testing remains limited. This study aimed to identify which neuropsychological tests best indicated underlying AD pathophysiology. METHODS: One hundred and forty-one patients with MCI (Mild Cognitive Impairment) were studied. A neuropsychological test battery based on the Uniform Data Set (UDS) from the Alzheimer's Disease Centers program of the National Institute on Aging (NIA) was performed and amyloid markers recorded; according to presence or absence of amyloid identified by positive PIB-PET findings, or low CSF Aß42 levels, patients were separated into MCI amyloid-(n:58) and MCI amyloid + (n = 83) cases. RESULTS: Statistical differences were found in all memory tests between groups. Delayed recall score at thirty minutes on the Rey Auditory Verbal Learning Test (AVLT) was the best predictor of amyloid pathology presence (AUC 0.68), followed by AVLT total learning (AUC 0.66) and AVLT Recognition (AUC 0.59) scores, providing useful cut off values in the clinical setting. CONCLUSIONS: Use of neuropsychological testing, specifically AVLT scores with cutoff values, contributed to the correct diagnosis of MCI due to AD in this SouthAmerican cohort.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Adult , Alzheimer Disease/complications , Alzheimer Disease/diagnosis , Amyloid beta-Peptides , Biomarkers , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/etiology , Cognitive Dysfunction/psychology , Humans , Neuropsychological Tests , Peptide Fragments , South AmericaABSTRACT
Human induced pluripotent stem cells (hiPSC) line FLENIi001-A was reprogrammed from dermal fibroblasts using the lentiviral-hSTEMCCA-loxP vector. Fibroblasts were obtained from a skin biopsy of a 72-year-old Caucasian male familial Alzheimer's disease patient carrying the T119I mutation in the PSEN1 gene. PSEN1 genotype was maintained and stemness and pluripotency confirmed in the FLENIi001-A hiPSC line.
Subject(s)
Alzheimer Disease , Induced Pluripotent Stem Cells , Aged , Alzheimer Disease/genetics , Cell Differentiation , Fibroblasts , Humans , Male , Presenilin-1/geneticsABSTRACT
INTRODUCTION: A growing number of dominantly inherited Alzheimer's disease (DIAD) cases have become known in Latin American (LatAm) in recent years. However, questions regarding mutation distribution and frequency by country remain open. METHODS: A literature review was completed aimed to provide estimates for DIAD pathogenic variants in the LatAm population. The search strategies were established using a combination of standardized terms for DIAD and LatAm. RESULTS: Twenty-four DIAD pathogenic variants have been reported in LatAm countries. Our combined dataset included 3583 individuals at risk; countries with highest DIAD frequencies were Colombia (n = 1905), Puerto Rico (n = 672), and Mexico (n = 463), usually attributable to founder effects. We found relatively few reports with extensive documentation on biomarker profiles and disease progression. DISCUSSION: Future DIAD studies will be required in LatAm, albeit with a more systematic approach to include fluid biomarker and imaging studies. Regional efforts are under way to extend the DIAD observational studies and clinical trials to Latin America.
Subject(s)
Alzheimer Disease , Genes, Dominant/genetics , Genetic Heterogeneity , Genetic Predisposition to Disease , Phenotype , Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , Humans , Latin America/epidemiology , Mutation/geneticsABSTRACT
PURPOSE: To describe results of the Amyloid, Tau, Neurodegeneration (ATN) research framework classification in the Argentine-Alzheimer's Disease Neuroimaging Initiative (arg-ADNI) cohort. METHODS: Twenty-three patients with mild cognitive impairment (MCI), 12 dementia of Alzheimer's type (DAT), and 14 normal controls were studied following the ADNI2 protocol. Patients were categorized according to presence or absence of the biomarkers for amyloid beta (Aß; A: amyloid positron emission tomography [PET] scan or cerebrospinal fluid [CSF] Aß42), tau (T: CSF phosphorylated-tau), and neurodegeneration (N: CSF total-tau, fluorodeoxyglucose [FDG]-PET scan, or structural magnetic resonance imaging [MRI] scan). RESULTS: A+T+N+ biomarker profile was identified at baseline in 91% of mild dementia patients, 20% of early MCI patients, 46% of late MCI patients, and 14% of control subjects. Suspected non-AD pathophysiology (SNAP, A-T-N+) was found in 8% of mild dementia, 20% of early MCI, 15% of late MCI, and 7% of control subjects. Conversion rates to dementia after 5-year follow-up were 85% in A+T+N+ MCI patients and 50% in A-T-N+ patients. CONCLUSIONS: We present initial 5-year follow-up results of a regional ADNI based on AD biomarkers and the ATN classification.
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Mutations in PSEN1 are the most common cause of early-onset Alzheimer's disease (AD). In this article, we present an Argentine family with autosomal dominant early- and late-onset AD. The proband and 6 family members were available for genetic testing and clinical and neuropsychological assessments. Cerebrospinal fluid biomarkers were analyzed in the proband and a cousin (mutation carrier), who also underwent positron emission tomography using F-18-2-fluoro-2-deoxy-D-glucose and Pittsburgh compound B. Exon sequencing of PSEN1, PSEN2, and APP revealed a novel heterozygous variant in PSEN1 (c.356C>T; p.T119I). Median age of onset in the family was 56 years. However, the proband's uncle showed initial symptoms at age 71. Although no DNA was available, he was an obligate carrier because his daughter (proband's cousin) carried the mutation. Both the proband and his cousin exhibited biomarker evidence (cerebrospinal fluid or imaging) of underlying Alzheimer's pathology. Overall, our results support that the PSEN1 p.T119I variant is likely pathogenic.
Subject(s)
Alzheimer Disease/genetics , Family , Mutation , Presenilin-1/genetics , Age of Onset , Aged , Alzheimer Disease/diagnosis , Alzheimer Disease/diagnostic imaging , Argentina , Biomarkers/cerebrospinal fluid , Female , Humans , Male , Middle Aged , Positron-Emission Tomography , Presenilin-1/cerebrospinal fluidABSTRACT
Alzheimer disease (AD) is one of the major unresolved health burdens accompanying the increase in life expectancy. The great paradigm shift for this disease has resulted from finding amyloid deposition and neurobrillary degeneration 20 years and 10 years, respectively, prior to onset of the typical clinical memory loss symptoms. The advent of AD biomarkers has enabled a molecular definition of AD, making the clinical definition almost dispensable. Various types of AD biomarkers are available in our country. Each biomarker reflects a particular process and stage of the disease. Although costs restrict their use, the biomarker analysis may be justified in certain clinical scenarios, such as an early onset or an atypical presentation of the disease. Today, the usefulness of biomarkers in AD clinical research is beyond question. Furthermore, the introduction of biomarkers into medical practice has led to significant changes in therapeutic interventions, even in the absence of disease-modifying drugs.
La enfermedad de Alzheimer (EA) es uno de los mayores flagelos aún no resueltos que acompañan al aumento de la expectativa de vida. El gran cambio de paradigma en los últimos años fue consecuencia de descubrir que el depósito amiloideo se presenta hasta 20 años antes, y la degeneración neurofibrilar hasta 10 años antes, de que aparezca la sintomatología clínica típica de pérdida de memoria. La aparición de los biomarcadores permitió reestructurar el concepto de la EA, intentándose llegar a una definición molecular de la misma casi prescindiendo de la emblemática clínica. Existen distintos tipos de biomarcadores de EA disponibles en nuestro país. Cada uno nos habla de un proceso y un momento distinto de la enfermedad. Aunque su uso clínico aún se encuentra restringido por cuestiones de costos, existen escenarios particulares en donde sí se justifica, casi siempre en relación a presentaciones clínicas atípicas o de comienzo muy temprano. Sin embargo, hoy en día ya nadie discute que son imprescindibles en investigaciones clínicas sobre EA. La incorporación de biomarcadores en la práctica médica ha generado cambios significativos en la intervención terapéutica de los pacientes, incluso en un contexto en el que todavía no hay medicamentos modificadores de la enfermedad.
Subject(s)
Alzheimer Disease/diagnosis , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Alzheimer Disease/blood , Alzheimer Disease/cerebrospinal fluid , Humans , Magnetic Resonance Imaging , Neuroimaging/methods , Tomography, Emission-Computed, Single-Photon , Tomography, X-Ray ComputedABSTRACT
Systematic evaluation of biomarkers in representative populations is needed to validate their clinical utility. In this work, we assessed the diagnostic performance of cerebrospinal fluid (CSF) neurofilament light chain (NfL) in a neurocognitive clinical setting. A total of 51 patients with different cognitive clinical syndromes and 11 cognitively normal individuals were evaluated in a memory clinic in Argentina. Clinical conditions included mild cognitive impairment (MCI, n = 12), dementia of Alzheimer's type (DAT, n = 14), behavioral variant frontotemporal dementia (bvFTD, n = 13), and primary progressive aphasia (logopenic [n = 6], semantic [n = 2], and nonfluent [n = 4]). We quantified CSF NfL and core Alzheimer's disease biomarkers using commercially available ELISA kits. Cortical thickness was analyzed on brain magnetic resonance imaging scans from 10 controls and 10 patients. CSF NfL was significantly increased in MCI, FTD, and DAT patients compared with controls (Kruskal-Wallis, p < .0001). Interestingly, receiver operating characteristic curve analysis showed the highest area under the curve (AUC) value when analyzing control versus bvFTD patients (AUC = 0.9441). Also, we observed a marginally significant correlation between NfL levels and left orbitofrontal cortex thickness in a small group of patients with FTD. Overall, our results further support CSF NfL as a promising biomarker in the diagnostic workup of bvFTD.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Aphasia, Primary Progressive/cerebrospinal fluid , Cognitive Dysfunction/cerebrospinal fluid , Frontotemporal Dementia/cerebrospinal fluid , Intermediate Filaments/metabolism , Aged , Biomarkers/cerebrospinal fluid , Case-Control Studies , Female , Humans , Male , Middle Aged , ROC CurveABSTRACT
The natural history of preclinical late-onset Alzheimer's disease (LOAD) remains obscure and has received less attention than that of early-onset AD (EOAD), in spite of accounting for more than 99% of cases of AD. With the purpose of detecting early structural and functional traits associated with the disorder, we sought to characterize cortical thickness and subcortical grey matter volume, cerebral metabolism, and amyloid deposition in persons at risk for LOAD in comparison with a similar group without family history of AD. We obtained 3T T1 images for gray matter volume, FDG-PET to evaluate regional cerebral metabolism, and PET-PiB to detect fibrillar amyloid deposition in 30 middle-aged, asymptomatic, cognitively normal individuals with one parent diagnosed with LOAD (O-LOAD), and 25 comparable controls (CS) without family history of neurodegenerative disorders (CS). We observed isocortical thinning in AD-relevant areas including posterior cingulate, precuneus, and areas of the prefrontal and temporoparietal cortex in O-LOAD. Unexpectedly, this group displayed increased cerebral metabolism, in some cases overlapping with the areas of cortical thinning, and no differences in bilateral hippocampal volume and hippocampal metabolism. Given the importance of age in this sample of individuals potentially developing early AD-related changes, we controlled results for age and observed that most differences in cortical thickness and metabolism became nonsignificant; however, greater deposition of ß-amyloid was observed in the right hemisphere including temporoparietal cortex, postcentral gyrus, fusiform inferior and middle temporal and lingual gyri. If replicated, the present observations of morphological, metabolic, and amyloid changes in cognitively normal persons with family history of LOAD may bear important implications for the definition of very early phenotypes of this disorder.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides/metabolism , Cerebral Cortex , Gray Matter , Adult , Adult Children , Age of Onset , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Female , Gray Matter/diagnostic imaging , Gray Matter/metabolism , Gray Matter/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Positron-Emission TomographyABSTRACT
The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , C9orf72 Protein/genetics , Frontotemporal Dementia/genetics , Gene Expression Regulation/genetics , Age of Onset , Aged , CpG Islands , DNA Methylation , Female , Genotype , Heterozygote , Humans , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
The Argentina-Alzheimer's disease neuroimaging initiative (Arg-ADNI) study is a longitudinal prospective cohort of 50 participants at a single institution in Buenos Aires, Argentina. Longitudinal assessments on a neuropsychological test battery were performed on 15 controls, 24 mild cognitive impairment (MCI) patients and 12 Alzheimer's disease (AD) dementia patients. In our study population, there was a high prevalence of positive AD biomarkers in the AD group, 92.3% (12/13); and a low prevalence in the normal controls, 20%; almost half (48%) of the patients diagnosed with MCI had positive amyloid detection. After a one year, the significant differences found at baseline on neuropsychological testing were similar at the follow-up assessment even though the AD group had significantly altered its functional performance (FAQ and CDR). The exception was semantic fluency, which showed greater impairment between the AD group and MCI and normal controls respectively. For these tests, the addition of AD biomarkers as a variable did not significantly alter the variations previously found for the established clinical group's model. Finally, the one-year conversion rate to dementia was 20% in the MCI cohort.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnostic imaging , Biomarkers/cerebrospinal fluid , Aged , Argentina , Case-Control Studies , Female , Follow-Up Studies , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Male , Positron-Emission Tomography , Severity of Illness IndexABSTRACT
ABSTRACT The Argentina-Alzheimer's disease neuroimaging initiative (Arg-ADNI) study is a longitudinal prospective cohort of 50 participants at a single institution in Buenos Aires, Argentina. Longitudinal assessments on a neuropsychological test battery were performed on 15 controls, 24 mild cognitive impairment (MCI) patients and 12 Alzheimer's disease (AD) dementia patients. In our study population, there was a high prevalence of positive AD biomarkers in the AD group, 92.3% (12/13); and a low prevalence in the normal controls, 20%; almost half (48%) of the patients diagnosed with MCI had positive amyloid detection. After a one year, the significant differences found at baseline on neuropsychological testing were similar at the follow-up assessment even though the AD group had significantly altered its functional performance (FAQ and CDR). The exception was semantic fluency, which showed greater impairment between the AD group and MCI and normal controls respectively. For these tests, the addition of AD biomarkers as a variable did not significantly alter the variations previously found for the established clinical group's model. Finally, the one-year conversion rate to dementia was 20% in the MCI cohort.
RESUMO El estudio de Argentina-Alzheimer's Disease Neuroimaging Initiative (Arg-ADNI) es una cohorte prospectiva de 50 pacientes seguidos en una misma institución. Fueron evaluados cognitivamente 15 controles normales (CN), 24 sujetos con deterioro cognitivo leve (DCL) y 12 con demencia tipo Alzheimer (DTA) leve. En los DTA, 92,3% tuvieron biomarcadores positivos para Alzheimer y 20% en los CN. Casi la mitad de los DCL presentaron biomarcadores positivos. Después de un año de seguimiento, la diferencias significativas halladas en la visita de inicio en las pruebas cognitivas fueron similares al año aunque los DTA tuvieron empeoramiento funcional medido en el FAQ y CDR. La excepción fue la fluencia semántica, la cual mostró mayor declinación entre DTA y los demás grupos. La incorporación de los biomarcadores como variable no alteró significativamente los hallazgos de grupo. La tasa de conversión a demencia anual fue del 20%.