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Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia. We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins (proximity extension-based (PEA) immunoassays) in a deeply-phenotyped mixed-memory clinic cohort (n=502, mean age (sd) = 64.1 [8.7] years, 181 female [35.4%]), including patients with Alzheimer's disease (AD, n=213), dementia with Lewy bodies (DLB, n=50) and frontotemporal dementia (FTD, n=93), and controls (n=146). Validation was assessed in independent cohorts (n=99 PEA platform, n=198, MRM-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not. We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P=1.65e-08), ZCWPW1-PILRB (rs1476679, P=2.73e-32), CTSH-CTSH (rs3784539, P=2.88e-24) and HESX1-RETN (rs186108507, P=8.39e-08), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90e-7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for frontotemporal dementia, either for the total sample as for analyses performed within FTD only. pQTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia.
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INTRODUCTION: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269). RESULTS: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10-5) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10-7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10-6) and CSF p-tau levels (P = 4.38 × 10-9). DISCUSSION: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. HIGHLIGHTS: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.
Subject(s)
Alzheimer Disease , Genome-Wide Association Study , Glutathione Peroxidase , tau Proteins , Aged , Aged, 80 and over , Female , Humans , Male , Alzheimer Disease/genetics , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , DNA-Binding Proteins/genetics , Glutathione Peroxidase/genetics , Glutathione Peroxidase/cerebrospinal fluid , Polymorphism, Single Nucleotide/genetics , Proteomics , tau Proteins/cerebrospinal fluid , tau Proteins/geneticsABSTRACT
INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aß]42), T+ (CSF phosphorylated tau181), and N+ or N- based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng-. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng- and A+T+NfL-, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV-, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. HIGHLIGHTS: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.
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INTRODUCTION: Angiotensin-converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and other common dementias is largely unknown. METHODS: We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two-sample Mendelian randomization (MR) approach. RESULTS: Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE [95% confidence interval]; 1.07 [1.04-1.10], P = 5 × 10-07 ) and frontotemporal dementia (1.16 [1.04-1.29], P = 0.01) but not with Lewy body dementia or vascular dementia (P > 0.05). These findings were independently replicated and remained consistent in sensitivity analyses. DISCUSSION: This comprehensive MR study provided genetic evidence for an association between ACE inhibition and the risk for AD and frontotemporal dementias. These results should encourage further studies of the neurocognitive effects of ACE inhibition. HIGHLIGHTS: This study evaluated genetically proxied angiotensin-converting enzyme (ACE) inhibition association with dementias. The results suggest an association between ACE inhibition and Alzheimer's disease. The results suggest an association between ACE inhibition and frontotemporal dementia. Those associations can be interpreted as potentially causal.
Subject(s)
Alzheimer Disease , Dementia, Vascular , Frontotemporal Dementia , Humans , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Frontotemporal Dementia/genetics , AngiotensinsABSTRACT
BACKGROUND: What combination of risk factors for Alzheimer's disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-ß pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals. METHODS: We included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-ß status was assessed by visual read of [18F]flutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-ß status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-ß status, and their interaction on changes in cognitive functioning over time. RESULTS: Fifty-two participants (19%) had abnormal amyloid-ß, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-ß status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-ß status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-ß×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE ß(SE)=-0.05(0.02); AD-PRS ß(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-ß status and AD-PRS predicted a steeper decline in memory functioning (amyloid-ß ß(SE)=-0.07(0.04); AD-PRS ß(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-ß status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-ß abnormal individuals only (ß(SE)=-0.13(0.06); ß(SE)=-0.22(0.07), respectively). CONCLUSION: Our results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-ß only. Furthermore, independent of amyloid-ß status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Female , Humans , Male , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides , Cognitive Dysfunction/complications , Genotype , Apolipoproteins E/genetics , Memory Disorders , Risk Factors , Positron-Emission Tomography , Apolipoprotein E4/geneticsABSTRACT
BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. METHODS: Individuals were classified based on CSF amyloid beta (Aß)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. RESULTS: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. CONCLUSION: The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.
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AIMS: Several factors are known to increase risk for cerebrovascular disease and dementia, but there is limited evidence on associations between multiple vascular risk factors (VRFs) and detailed aspects of brain macrostructure and microstructure in large community-dwelling populations across middle and older age. METHODS AND RESULTS: Associations between VRFs (smoking, hypertension, pulse pressure, diabetes, hypercholesterolaemia, body mass index, and waist-hip ratio) and brain structural and diffusion MRI markers were examined in UK Biobank (N = 9722, age range 44-79 years). A larger number of VRFs was associated with greater brain atrophy, lower grey matter volume, and poorer white matter health. Effect sizes were small (brain structural R2 ≤1.8%). Higher aggregate vascular risk was related to multiple regional MRI hallmarks associated with dementia risk: lower frontal and temporal cortical volumes, lower subcortical volumes, higher white matter hyperintensity volumes, and poorer white matter microstructure in association and thalamic pathways. Smoking pack years, hypertension and diabetes showed the most consistent associations across all brain measures. Hypercholesterolaemia was not uniquely associated with any MRI marker. CONCLUSION: Higher levels of VRFs were associated with poorer brain health across grey and white matter macrostructure and microstructure. Effects are mainly additive, converging upon frontal and temporal cortex, subcortical structures, and specific classes of white matter fibres. Though effect sizes were small, these results emphasize the vulnerability of brain health to vascular factors even in relatively healthy middle and older age, and the potential to partly ameliorate cognitive decline by addressing these malleable risk factors.
Subject(s)
Brain/diagnostic imaging , Brain/pathology , Cerebrovascular Disorders/epidemiology , Magnetic Resonance Imaging , Adult , Aged , Biological Specimen Banks , Female , Humans , Male , Middle Aged , Risk Factors , United KingdomABSTRACT
Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44-77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function.
Subject(s)
Biological Specimen Banks , Brain Mapping , Brain/physiology , Sex Characteristics , Adult , Aged , Biological Specimen Banks/statistics & numerical data , Brain/diagnostic imaging , Community Health Planning , Connectome , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle Aged , Oxygen/blood , Rest , United Kingdom , White Matter/diagnostic imagingABSTRACT
BACKGROUND: Dupuytren disease (DD) is a common complex trait, with varying severity and incompletely understood cause. Genome-wide association studies (GWAS) have identified risk loci. In this article, we examine whether genetic risk profiles of DD in patients are associated with clinical variation and disease severity and with patient genetic risk profiles of genetically correlated traits, including body mass index (BMI), triglycerides, high-density lipoproteins, type 2 diabetes mellitus, and endophenotypes fasting glucose and glycated hemoglobin. METHODS: The authors used a well-characterized cohort of 1461 DD patients with available phenotypic and genetic data. Phenotype data include age at onset, recurrence, and family history of disease. Polygenic risk scores (PRSs) of DD, BMI, triglycerides, high-density lipoprotein, type 2 diabetes, fasting glucose, and hemoglobin A1c using various significance thresholds were calculated with PRSice using the most recent GWAS summary statistics. Control data from LifeLines were used to determine P value cutoffs for PRS generation explaining most variance. RESULTS: The PRS for DD was significantly associated with a positive family history for DD, age at onset, disease onset before the age of 50, and recurrence. We also found a significant negative correlation between the PRSs for DD and BMI. CONCLUSIONS: Although GWAS studies of DD are designed to identify genetic risk factors distinguishing case/control status, we show that the genetic risk profile for DD also explains part of its clinical variation and disease severity. The PRS may therefore aid in accurate prognostication, choosing initial treatment and in personalized medicine in the future. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.
Subject(s)
Diabetes Mellitus, Type 2 , Dupuytren Contracture , Humans , Diabetes Mellitus, Type 2/complications , Dupuytren Contracture/genetics , Genome-Wide Association Study , Multifactorial Inheritance/genetics , Risk Factors , Glycated Hemoglobin , Glucose , Triglycerides , Genetic Predisposition to DiseaseABSTRACT
Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/genetics , ProteomicsABSTRACT
Social dysfunction represents one of the most common signs of neuropsychiatric disorders, such as Schizophrenia (SZ) and Alzheimer's disease (AD). Perturbed socioaffective neural processing is crucially implicated in SZ/AD and generally linked to social dysfunction. Yet, transdiagnostic properties of social dysfunction and its neurobiological underpinnings remain unknown. As part of the European PRISM project, we examined whether social dysfunction maps onto shifts within socioaffective brain systems across SZ and AD patients. We probed coupling of social dysfunction with socioaffective neural processing, as indexed by an implicit facial emotional processing fMRI task, across SZ (N = 46), AD (N = 40) and two age-matched healthy control (HC) groups (N = 26 HC-younger and N = 27 HC-older). Behavioural (i.e., social withdrawal, interpersonal dysfunction, diminished prosocial or recreational activity) and subjective (i.e., feelings of loneliness) aspects of social dysfunction were assessed using the Social Functioning Scale and De Jong-Gierveld loneliness questionnaire, respectively. Across SZ/AD/HC participants, more severe behavioural social dysfunction related to hyperactivity within fronto-parieto-limbic brain systems in response to sad emotions (P = 0.0078), along with hypoactivity of these brain systems in response to happy emotions (P = 0.0418). Such relationships were not found for subjective experiences of social dysfunction. These effects were independent of diagnosis, and not confounded by clinical and sociodemographic factors. In conclusion, behavioural aspects of social dysfunction across SZ/AD/HC participants are associated with shifts within fronto-parieto-limbic brain systems. These findings pinpoint altered socioaffective neural processing as a putative marker for social dysfunction, and could aid personalized care initiatives grounded in social behaviour.
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Genomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological mechanisms in vivo , measuring 5,543 CSF metabolites, the largest panel in CSF to date, in 977 individuals of European ancestry. Individuals originated from two separate cohorts including cognitively healthy subjects (n=490) and a well-characterized memory clinic sample, the Amsterdam Dementia Cohort (ADC, n=487). We performed metabolite quantitative trait loci (mQTL) mapping on CSF metabolomics and found 126 significant mQTLs, representing 65 unique CSF metabolites across 51 independent loci. To better understand the role of CSF mQTLs in brain-related disorders, we performed a metabolome-wide association study (MWAS), identifying 40 associations between CSF metabolites and brain traits. Similarly, over 90% of significant mQTLs demonstrated colocalized associations with brain-specific gene expression, unveiling potential neurobiological pathways.
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BACKGROUND: In people with cognitive impairment, loss of social interactions has a major impact on well-being. Therefore, patients would benefit from early detection of symptoms of social withdrawal. Current measurement techniques such as questionnaires are subjective and rely on recall, in contradiction to smartphone apps, which measure social behavior passively and objectively. OBJECTIVE: This study uses the remote monitoring smartphone app Behapp to assess social behavior, and aims to investigate (1) the association between social behavior, demographic characteristics, and neuropsychiatric symptoms in cognitively normal (CN) older adults, and (2) if social behavior is altered in cognitively impaired (CI) participants. In addition, we explored in a subset of individuals the association between Behapp outcomes and neuropsychiatric symptoms. METHODS: CN, subjective cognitive decline (SCD), and CI older adults installed the Behapp app on their own Android smartphone for 7 to 42 days. CI participants had a clinical diagnosis of mild cognitive impairment (MCI) or Alzheimer-type dementia. The app continuously measured communication events, app use and location. Neuropsychiatric Inventory (NPI) total scores were available for 20 SCD and 22 CI participants. Linear models were used to assess group differences on Behapp outcomes and to assess the association of Behapp outcomes with the NPI. RESULTS: We included CN (n=209), SCD (n=55) and CI (n=22) participants. Older cognitively normal participants called less frequently and made less use of apps (P<.05). No sex effects were found. Compared to the CN and SCD groups, CI individuals called less unique contacts (ß=-0.7 [SE 0.29], P=.049) and contacted the same contacts relatively more often (ß=0.8 [SE 0.25], P=.004). They also made less use of apps (ß=-0.83 [SE 0.25], P=.004). Higher total NPI scores were associated with further traveling (ß=0.042 [SE 0.015], P=.03). CONCLUSIONS: CI individuals show reduced social activity, especially those activities that are related to repeated and unique behavior, as measured by the smartphone app Behapp. Neuropsychiatric symptoms seemed only marginally associated with social behavior as measured with Behapp. This research shows that the Behapp app is able to objectively and passively measure altered social behavior in a cognitively impaired population.
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OBJECTIVES: Social dysfunction is one of the most common signs of major neuropsychiatric disorders. The Default Mode Network (DMN) is crucially implicated in both psychopathology and social dysfunction, although the transdiagnostic properties of social dysfunction remains unknown. As part of the pan-European PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project, we explored cross-disorder impact of social dysfunction on DMN connectivity. METHODS: We studied DMN intrinsic functional connectivity in relation to social dysfunction by applying Independent Component Analysis and Dual Regression on resting-state fMRI data, among schizophrenia (SZ; N = 48), Alzheimer disease (AD; N = 47) patients and healthy controls (HC; N = 55). Social dysfunction was operationalised via the Social Functioning Scale (SFS) and De Jong-Gierveld Loneliness Scale (LON). RESULTS: Both SFS and LON were independently associated with diminished DMN connectional integrity within rostromedial prefrontal DMN subterritories (pcorrected range = 0.02-0.04). The combined effect of these indicators (Mean.SFS + LON) on diminished DMN connectivity was even more pronounced (both spatially and statistically), independent of diagnostic status, and not confounded by key clinical or sociodemographic effects, comprising large sections of rostromedial and dorsomedial prefrontal cortex (pcorrected=0.01). CONCLUSIONS: These findings pinpoint DMN connectional alterations as putative transdiagnostic endophenotypes for social dysfunction and could aid personalised care initiatives grounded in social behaviour.
Subject(s)
Alzheimer Disease , Schizophrenia , Humans , Schizophrenia/diagnostic imaging , Alzheimer Disease/diagnostic imaging , Neural Pathways/diagnostic imaging , Default Mode Network , Magnetic Resonance Imaging , Brain/diagnostic imaging , Brain Mapping , Nerve Net/diagnostic imagingABSTRACT
BACKGROUND: Social functioning is often impaired in schizophrenia (SZ) and Alzheimer's disease (AD). However, commonalities and differences in social dysfunction among these patient groups remain elusive. MATERIALS AND METHODS: Using data from the PRISM study, behavioral (all subscales and total score of the Social Functioning Scale) and affective (perceived social disability and loneliness) indicators of social functioning were measured in patients with SZ (N = 56), probable AD (N = 50) and age-matched healthy controls groups (HC, N = 29 and N = 28). We examined to what extent social functioning differed between disease and age-matched HC groups, as well as between patient groups. Furthermore, we examined how severity of disease and mood were correlated with social functioning, irrespective of diagnosis. RESULTS: As compared to HC, both behavioral and affective social functioning seemed impaired in SZ patients (Cohen's d's 0.81-1.69), whereas AD patients mainly showed impaired behavioral social function (Cohen's d's 0.65-1.14). While behavioral indices of social functioning were similar across patient groups, SZ patients reported more perceived social disability than AD patients (Cohen's d's 0.65). Across patient groups, positive mood, lower depression and anxiety levels were strong determinants of better social functioning (p's <0.001), even more so than severity of disease. CONCLUSIONS: AD and SZ patients both exhibit poor social functioning in comparison to age- and sex matched HC participants. Social dysfunction in SZ patients may be more severe than in AD patients, though this may be due to underreporting by AD patients. Across patients, social functioning appeared as more influenced by mood states than by severity of disease.
Subject(s)
Alzheimer Disease , Schizophrenia , Humans , Loneliness , Schizophrenia/diagnosis , Social Adjustment , Social InteractionABSTRACT
BACKGROUND: Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. METHODS: We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. RESULTS: We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. CONCLUSIONS: CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.
Subject(s)
Alzheimer Disease , Neuronal Plasticity , tau Proteins , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/pathology , Biomarkers/cerebrospinal fluid , Humans , Proteomics , tau Proteins/cerebrospinal fluidABSTRACT
Late-onset Alzheimer's disease (AD) has a significant genetic component, but the molecular mechanisms through which genetic risk factors contribute to AD pathogenesis are unclear. We screened for genetic sharing between AD and the blood levels of 615 metabolites to elucidate how the polygenic architecture of AD affects metabolomic profiles. We retrieved summary statistics from genome-wide association studies of AD and the metabolite blood levels and assessed for shared genetic etiology, using a polygenic risk score-based approach. For the blood levels of 31 metabolites, all of which were lipids, we identified and replicated genetic sharing with AD. We also found a positive genetic concordance - implying that genetic risk factors for AD are associated with higher blood levels - for 16 of the 31 replicated metabolites. In the brain, lipids and their intermediate metabolites have essential structural and functional roles, such as forming and dynamically regulating synaptic membranes. Our results imply that genetic risk factors for AD affect lipid levels, which may be leveraged to develop novel treatment strategies for AD.
Subject(s)
Alzheimer Disease/genetics , Genome-Wide Association Study , Lipids/blood , Multifactorial Inheritance/genetics , Aged , Brain/metabolism , Brain/pathology , Female , Humans , Male , Metabolomics , Risk , Synaptic Membranes/metabolism , Synaptic Membranes/pathologyABSTRACT
BACKGROUND: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. METHODS: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. RESULTS: We identified 73 significant gene-tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. CONCLUSIONS: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.
Subject(s)
Frontotemporal Dementia , Frontotemporal Dementia/genetics , Gene Expression , HumansABSTRACT
BACKGROUND: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. OBJECTIVE: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort. METHODS: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; nâ=â654), non-fluent variant primary progressive aphasia (nfvPPA; nâ=â99), semantic variant primary progressive aphasia (svPPA; nâ=â117), and right temporal variant frontotemporal dementia (rtvFTD; nâ=â40). We compared sex distribution between genetic and sporadic FTD using χ2-tests. RESULTS: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, pâ=â0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, pâ=â0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases the sex distribution was somewhat equal. CONCLUSION: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research.
Subject(s)
Aphasia, Primary Progressive , Frontotemporal Dementia , Sex Distribution , Female , Frontotemporal Dementia/classification , Frontotemporal Dementia/genetics , Humans , Internationality , Male , Middle Aged , Retrospective Studies , SemanticsABSTRACT
Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 × 10-9, rs117204439: OR = 4.9, P = 6.0 × 10-9) and replication analysis (P < 1.1 × 10-3). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 G4C2 repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (~22% versus ~2%; P = 7.70 × 10-58). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 × 10-260). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G4C2. These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.