TRIANGULATING HETEROGENEITY IN DEMENTIA:An interaction between genetic variation, biological correlates and clinical symptoms

The goal of this thesis was to increase our understanding of the clinical and biological nature of Alzheimer’s disease (AD) and frontotemporal dementia (FTD), with the following three aims. First, we aimed to examine how patient characteristics (e.g., clinical symptoms, biomarker profiles) relate to disease development in AD and FTD (chapter 2). Second, we investigated the genetic architecture of FTD (chapter 3). Lastly, we aimed to identify biological processes through which genetic variants increase the risk of developing dementia (chapter 4). In chapter 2.1, we reviewed literature on personality characteristics as predictor or consequence of dementia. We found that neuroticism was associated with increased risk to develop dementia. In chapter 2.2, we compared longitudinal differences over a period of 3 years between disorders that can present with behavioural changes, including the behavioural variant of FTD (bvFTD), other neurodegenerative disorders and primary psychiatric disorders. Only bvFTD patients presented with worsening of frontal behavioural symptoms (e.g., disinhibition, apathy) over time, indicating that longitudinal monitoring of these symptoms might aid in differentiating bvFTD from other disorders. In chapter 2.3, we examined whether AD biomarker profiles showing abnormal and normal CSF total tau within the AD clinical spectrum were related to different clinical characteristics and biological factors. Individuals with abnormal tau (n=788, 57%) showed increased levels of proteins involved in neuronal plasticity (hyperplasticity), and individuals with normal tau (n=592, 43%) showed a decrease in neuronal plasticity proteins and an increase in blood-brain barrier dysfunction proteins (hypoplasticity). Our second aim was to improve our understanding of the genetic architecture underlying C9ORF72-FTD. We first performed a genome-wide association study (GWAS) on FTD, comparing frequencies of rare and common variants between FTD patients and controls in chapter 3.1. Here, we identified two genetic risk variants for FTD nearby the C9ORF72 gene that tag a rare C9ORF72 sub-haplotype of the Finnish founder haplotype of the repeat expansion. In chapter 3.2, we performed a transcriptome-wide association study (TWAS) on FTD, by integrating FTD summary statistics with cis gene expression panels on 53 tissue types (five consortia). Here, we identified 44 genes for which their predicted gene expression, mostly in the prefrontal cortex, was associated with an increased disease risk for FTD. Identified genes could function as potential candidates for functional follow-up studies. Lastly, in chapter 4, we aimed to identify which biological processes associated with measurements of genetic risk for AD, FTD and dementia with Lewy bodies (DLB). In chapter 4.1 we used a polygenic risk scores (PGRS)-based approach to assess the shared genetic overlap between AD and 615 unique metabolite blood levels. Most of the metabolites with a significant association with AD were lipids, including lipoproteins, glycerophospholipids, fatty acyls and sterols. A modest proportion of these associations were dependent on APOE-ε4-status. In chapter 4.2, we examined the association between the genetic liability for AD and CSF proteomic profiles in individuals with normal cognition, mild cognitive impairment and AD-type dementia. Out of 412 proteins, 201 were associated with polygenic risk scores (PGRS) for AD. We identified three clusters on proteins associated with PGRS, a protein cluster: (1) correlated with highly significant genetic variants, associated with amyloid-beta pathology; (2) including variants contributing to modest risk, involved in neural injury; (3) that also included less strongly associated variants, enriched with cytokine-cytokine interactions and cell adhesion molecules. In chapter 4.3 we aimed to identify which genetic risk loci for AD, FTD and DLB influence protein CSF levels, through so-called protein quantitative trait loci (pQTLs) analyses. We identified four pQTLS, of which three pQTLs related to AD and one pQTL related to DLB. No pQTLs for FTD were observed

Diagnostic Instability Over Time in the Late-Onset Frontal Lobe Syndrome: When Can We Say it's FTD?

OBJECTIVES: Distinguishing sporadic behavioral variant of frontotemporal dementia (bvFTD) from late-onset primary psychiatric disorders (PPD) remains challenging with the lack of robust biomarkers. An early bvFTD misdiagnosis in PPD cases and vice-versa is common. Little is known about diagnostic (in)stability over longer period of time. We investigated diagnostic instability in a neuropsychiatric cohort up to 8 years after baseline visit and identified which clinical hallmarks contribute to diagnostic instability. DESIGN: Diagnoses of participants of the late-onset frontal lobe (LOF) study were collected from the baseline visit (T0) and the 2-year follow-up visit (T2). Clinical outcomes were retrieved 5-8 years after baseline visit (T final). Endpoint diagnoses were categorized into bvFTD, PPD and other neurological disorders (OND). We calculated the total amount of participants that switched diagnosis between T0-T2 and T2-T final. Clinical records of participants that switched diagnosis were assessed. RESULTS: Of the 137 patients that were included in the study, the final diagnoses at T final were bvFTD 24.1% (n = 33), PPD 39.4% (n = 54), OND 33.6% (n = 46) and unknown 2.9% (n = 4). Between T0 and T2, a total of 29 (21.2%) patients switched diagnosis. Between T2 and T final, 8 (5.8%) patients switched diagnosis. Prolonged follow-up identified few cases with diagnostic instability. Major contributors to diagnostic instability where a nonconverting diagnosis of possible bvFTD and a probable bvFTD diagnosis based on informant-based history and an abnormal FDG-PET scan whilst having a normal MRI. CONCLUSION: Considering these lessons, a FTD diagnosis remains stable enough to conclude that 2 years is sufficient to say if a patient with late-life behavioral disorder has FTD

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex

Diagnostic Instability Over Time in the Late-Onset Frontal Lobe Syndrome: When Can We Say it's FTD?

Objectives: Distinguishing sporadic behavioral variant of frontotemporal dementia (bvFTD) from late-onset primary psychiatric disorders (PPD) remains challenging with the lack of robust biomarkers. An early bvFTD misdiagnosis in PPD cases and vice-versa is common. Little is known about diagnostic (in)stability over longer period of time. We investigated diagnostic instability in a neuropsychiatric cohort up to 8 years after baseline visit and identified which clinical hallmarks contribute to diagnostic instability. Design: Diagnoses of participants of the late-onset frontal lobe (LOF) study were collected from the baseline visit (T0) and the 2-year follow-up visit (T2). Clinical outcomes were retrieved 5–8 years after baseline visit (Tfinal). Endpoint diagnoses were categorized into bvFTD, PPD and other neurological disorders (OND). We calculated the total amount of participants that switched diagnosis between T0-T2 and T2-Tfinal. Clinical records of participants that switched diagnosis were assessed. Results: Of the 137 patients that were included in the study, the final diagnoses at Tfinal were bvFTD 24.1% (n = 33), PPD 39.4% (n = 54), OND 33.6% (n = 46) and unknown 2.9% (n = 4). Between T0 and T2, a total of 29 (21.2%) patients switched diagnosis. Between T2 and Tfinal, 8 (5.8%) patients switched diagnosis. Prolonged follow-up identified few cases with diagnostic instability. Major contributors to diagnostic instability where a nonconverting diagnosis of possible bvFTD and a probable bvFTD diagnosis based on informant-based history and an abnormal FDG-PET scan whilst having a normal MRI. Conclusion: Considering these lessons, a FTD diagnosis remains stable enough to conclude that 2 years is sufficient to say if a patient with late-life behavioral disorder has FTD

Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer's disease

Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment

Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

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

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex