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Introduction: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies., Methods: We present the phenotype and whole-exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712). Western blotting was conducted of the wild-type and mutant protein of the final candidate., Results: Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism., Discussion: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases., Highlights: A TRIM25 nonsense mutation (p.C168*) is associated with autosomal dominant early-onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease. TRIM25 protein studies support that the mutation exerts its effect through loss of function. TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration. The role of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Frontotemporal lobar degeneration caused by GRN mutations is mainly associated with a TDP-43 type A proteinopathy. We present a family with autosomal dominant frontotemporal lobar degeneration caused by a novel GRN nonsense mutation (c.5G>A: p.Trp2*) in which the proband's brain also showed prominent glial tauopathy consistent with an aging-related tau astrogliopathy. Astrocytic tauopathy, 4R(+) and 3R(-) immunoreactive, was characterized by thorn-shaped astrocytes present in subpial, subependymal, and perivascular areas, and in gray matter; plus granular or fuzzy tau immunoreactivity in astrocytic processes in gray matter, either solitary or clustered in different regions. Some neurofibrillary tangles and pretangles, both 3R and 4R(+), were present in the medial temporal lobe but did not exhibit the characteristic distribution of Alzheimer's type pathology. This 4R-tau aging-related tau astrogliopathy is likely a co-occurring pathology, although an interaction between progranulin and tau proteins within the neurodegenerative process should not be ruled out., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13-1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated., (© 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.)

Meta-analysis of existing genome-wide association studies on Alzheimer's disease (AD) showed subgenome-wide association of an intronic variant in the sequestosome 1 (SQSTM1) gene with AD. We performed targeted resequencing of SQSTM1 in Flanders-Belgian AD patients selected to be enriched for a genetic background (n = 435) and geographically matched nonaffected individuals (n = 872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European early-onset dementia cohorts (926 early-onset Alzheimer's disease [EOAD] patients and 1476 nonaffected individuals). Of the 61 detected exonic variants in SQSTM1, the majority were rare (n = 57). Rare variant (minor allele frequency <0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (odds ratiop.D292= = 1.11 [95% confidence interval = 1-1.22], p = 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin-related receptor 1 (SORL1), have been suggested to be potentially causative. To identify AD causative variants, we performed whole-exome sequencing on five individuals from a family with EOAD and a missense variant, p.Arg1303Cys (c.3907C > T) was identified in SORL1 which segregated with disease and was further characterized with immunohistochemistry on two post mortem autopsy cases from the same family. In a targeted re-sequencing effort on independent index patients from 35 EOAD-families, a second SORL1 variant, c.3050-2A > G, was found which segregated with the disease in 3 affected and was absent in one unaffected family member. The c.3050-2A > G variant is located two nucleotides upstream of exon 22 and was shown to cause exon 22 skipping, resulting in a deletion of amino acids Gly1017-Glu1074 of SORL1. Furthermore, a third SORL1 variant, c.5195G > C, recently identified in a Swedish case control cohort included in the European Early-Onset Dementia (EU EOD) consortium study, was detected in two affected siblings in a third family with familial EOAD. The finding of three SORL1-variants that segregate with disease in three separate families with EOAD supports the involvement of SORL1 in AD pathology. The cause of these rare monogenic forms of EOAD has proven difficult to find and the use of exome and genome sequencing may be a successful route to target them. [ABSTRACT FROM AUTHOR]

Published descriptions of the neuropathology of clinically defined primary lateral sclerosis (PLS) are reviewed in order to clarify the pathogenesis and the relationship between PLS and classical amyotrophic lateral sclerosis (ALS). Degeneration of the primary motor cortex and corticospinal tracts with preservation of lower motor neurons (LMN) has been reported in most cases. Studies that employed immunohistochemistry found ubiquitin and/or TDP-43-positive neuronal inclusions in the motor cortex and often in the extramotor neocortex. Ubiquitin/TDP-43-immunoreactive inclusions in LMN have been reported in just over half of cases; however, these have never been numerous. The finding of TDP-43 pathology in most cases indicates that PLS and ALS are closely related conditions; however, the fact that cases of PLS consistently show minimal involvement of LMN suggests that PLS represents a distinct entity, rather than an early stage of ALS. [ABSTRACT FROM AUTHOR]

Primary lateral sclerosis (PLS) is a controversial form of motor neuron disease (MND), with uncertainty whether it represents a distinct clinico-pathological entity or is simply a variant of classical amyotrophic lateral sclerosis (ALS). Neuropathological studies provide an opportunity to investigate these issues; however, there have been very few published descriptions of postmortem findings in clinically defined PLS, using modern techniques. Here, we report the neuropathological features of seven cases of PLS with age at onset ranging from 47 to 73 years and disease duration from 3.5 to 35 years. All cases showed chronic degeneration of the primary motor cortex and/or the corticospinal tracts with preservation of lower motor neurons (LMN). All five cases, in which motor cortex was available, had TDP-43 immunoreactive (TDP-ir) cortical pathology. In all seven cases, TDP-ir inclusions were also present in LMN; however, these were always rare, averaging less than one inclusion per tissue section. The finding of TDP-ir pathology in all our cases suggests that PLS and ALS are closely related conditions. Importantly however, the extremely minor involvement of LMN, even after very long disease duration in some cases, suggests that PLS is a distinct form of MND in which LMN are spared or protected. [ABSTRACT FROM AUTHOR]

With age, the presence of multiple neuropathologies in a single individual becomes increasingly common. Given that traumatic brain injury and the repetitive head impacts (RHIs) that occur in contact sports have been associated with the development of many neurodegenerative diseases, including chronic traumatic encephalopathy (CTE), Alzheimer's disease, Lewy body disease, and amyotrophic lateral sclerosis, it is becoming critical to understand the relationship and interactions between these pathologies. In fact, comorbid pathology is common in CTE and likely influenced by both age and the severity and type of exposure to RHI as well as underlying genetic predisposition. Here, we review the major comorbid pathologies seen with CTE and in former contact sports athletes and discuss what is known about the associations between RHI, age, and the development of neuropathologies. In addition, we examine the distinction between CTE and age-related pathology including primary age-related tauopathy and age-related tau astrogliopathy. [ABSTRACT FROM AUTHOR]

Previous studies have implicated common and rare genetic variants as risk factors for late‐onset Alzheimer's disease (LOAD). Here, weighted burden analysis was applied to over 10,000 exome‐sequenced subjects from the Alzheimer's Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7, and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R, and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10−6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Because PIK3R1 variants are expected to impair PI3K/Akt/GSK‐3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models, suggesting that this pathway is protective against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

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Background: Primary lateral sclerosis (PLS) is considered a rare variant of motor neuron disease (MND) characterized by selective upper motor neuron dysfunction leading to limb weakness, spasticity, and even bulbar symptoms. Previous studies have demonstrated that mutations in ALSIN, spastic paraplegia 7 (SPG7), TBK1, ALS2, ERLIN2, and FIG4 are responsible for PLS. Most of them occurred in childhood to young-adult onset patients. The aim of this study was to identify the genetic lesion of patients with adult-onset PLS. Methods: We applied whole-exome sequencing (WES) and MND and ataxia-related genes filtering strategies to discover the genetic factors in a Chinese adult-onset PLS family. Sanger sequencing was used in the cosegregation analysis in the affected family members. Results: A mutation (c.2219A>G/p.Y740C) in exon 17 of SPG7 was identified in an adult-onset PLS patient and cosegregated with the affected members in this family. Meanwhile, the mutation was predicted to be deleterious by 3 bioinformatics programs (Polymorphism phenotyping-2, sorting intolerant from tolerant and MutationTaster). This variant may cause the structure changes of paraplegin protein. Conclusions: We employed WES to detect a missense mutation of SPG7 gene in a PLS family. This finding expands the spectrum of known SPG7 mutations, and it may contribute to novel approaches to genetic diagnosis and counseling of families with PLS. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. The majority of cases, however, derive from complex interactions between a number of genetic and environmental factors. Gene variants may act as risk or protective factors. Their combination with a variety of environmental exposures may result in increased susceptibility to these diseases or may influence their course. The scenario is even more complicated considering the effect of epigenetics, which encompasses mechanisms able to alter the expression of genes without altering the DNA sequence. In this review, an overview of the current genetic and epigenetic progresses in AD and FTD will be provided, with particular focus on 1) causative genes, 2) genetic risk factors and disease modifiers, and 3) epigenetics, including methylation, non-coding RNAs and chromatin remodeling. [ABSTRACT FROM AUTHOR]

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene ( ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment ( p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD. [ABSTRACT FROM AUTHOR]

ABSTRACT We investigated the mutation spectrum of the TANK-Binding Kinase 1 ( TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles ( P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease-specific 'seed' proteins; however, roles of other co-aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control-subject pools using magnetic-bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high-resolution proteomics. Although total detergent-insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1-42 pulldown, the protein constituents of Alzheimer-derived aggregates were more abundant, diverse, and post-translationally modified than those from controls. Tau- and Aβ-containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer-specific protein enrichment in tau-containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co-aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co-localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer-specific enrichment in tau-containing aggregates, were assessed for aggregation-promoting roles in C. elegans by RNA-interference 'knockdown'. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1-42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate-mediated cross-talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention. [ABSTRACT FROM AUTHOR]

Brain lipid homeostasis plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Aggregation of amyloid-β peptide is one of the major events in AD. The complex interplay between lipids and amyloid-β accumulation has been intensively investigated. The proportions of lipid components including phospholipids, sphingolipids, and cholesterol are roughly similar across different brain regions under physiological conditions. However, disruption of brain lipid homeostasis has been described in AD and implicated in disease pathogenesis. Moreover, studies suggest that analysis of lipid composition in plasma and cerebrospinal fluid could improve our understanding of the disease development and progression, which could potentially serve as disease biomarkers and prognostic indicators for AD therapies. Here, we summarize the functional roles of AD risk genes and lipid regulators that modulate brain lipid homeostasis including different lipid species, lipid complexes, and lipid transporters, particularly their effects on amyloid processing, clearance, and aggregation, as well as neuro-toxicities that contribute to AD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD).Objective: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction.Methods: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender.Results: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres.Conclusions: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern. [ABSTRACT FROM AUTHOR]

The article offers information on the 10th International Conference on Frontotemporal Dementias that will be held in Munich, Germany on August 31-September 2, 2016.

The sortilin-related receptor 1 ( SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD. [ABSTRACT FROM AUTHOR]

There is a strong genetic influence on the clinicopathological phenotypes associated with frontotemporal lobar degeneration (FTLD) and frontotemporal dementia (FTD). Intracellular deposition of TDP-43 is the phenotypical hallmark of a frequent subgroup of cases. Mutations in the sequestosome 1 ( SQSTM1) gene have rarely been found in individuals with FTD. Here we provide a comprehensive clinicopathological description of two cases with a SQSTM1 mutation. The clinical phenotype of patient 1 (mutation p.Glu396*) was compatible with the behavioural variant (bv) of FTD. TDP-43 pathology was consistent with the features of type B of FTLD-TDP pathology. However, prominent neuronal granular cytoplasmic TDP-43 immunoreactivity and abundant oligodendroglial inclusions, proven by colocalization with the oligodendroglial-marker TPPP/p25, were also seen. The clinical phenotype of patient 2 was compatible with bvFTD associated with parkinsonism and bulbar symptoms in the later stage. Genetic testing of patient 2 identified a C9orf72 repeat expansion mutation together with a missense mutation (p.Arg212Cys) in SQSTM1. TDP-43 pathology was characterized by neuritic profiles compatible mostly with type A. In contrast to patient 1, p62 pathology was seen to a greater extent as TDP-43 immunoreactivity in neurons. Using an antibody that detects poly(GP) peptides produced via repeat associated non-ATG translation associated with expanded hexanucleotide repeat in the C9orf72 gene, we confirmed the presence of pathognomonic inclusions. The present study supports previous observations on amyotrophic lateral sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43 pathology. The co-presence of C9orf72 mutation may influence the phenotype, thus finding one FTLD (or ALS) related mutation does not exclude the presence of further influential genetic alterations. Oligodendroglial TDP-43 pathology is considerable in some forms of FTLD-TDP, thus their evaluation might be considered to be included in classification systems. [ABSTRACT FROM AUTHOR]

Paget's disease of bone (PDB) is characterized by focal or multifocal increase in bone turnover. One of the most well-established candidate genes for susceptibility to PDB is Sequestosome 1 (SQSTM1). Mutations in SQSTM1 have been documented among Western-European, British and American patients with PDB. However, there is no information on SQSTM1 mutation status in PDB patients from the Central- and Eastern-European regions. In this study, we conducted a mutation screening for SQSTM1 gene variants in 82 PDB patients and 100 control participants in Hungary. Mutations of SQSTM1 were detected in 18 PDB patients (21.95%); associations between genotype and clinical characteristics were also analyzed. Altogether, six different exonic alterations, including two types of UTR variants in the SQSTM1 gene, were observed in our PDB patients. Similarly, to previous genetic studies on Paget's disease, our most commonly detected variant was the c.1175C > T (p.Pro392Leu) in nine cases (four in monostotic and five in polyostotic form). We have surveyed the germline SQSTM1 variant distribution among Hungarian patients with PDB. We also highlighted that the pattern of the analyzed disease-associated pathophysiological parameters could partially discriminate PDB patients with normal or mutant SQSTM1 genotype. However, our findings also underline and strengthen that not solely SQSTM1 stands in the background of the complex PDB etiology.

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology. [ABSTRACT FROM AUTHOR]

The article presents a neuropathological study of a 60-year-old man with frontotemporal lobar degenerations (FTLD) to determine the correlation of TARDBP mutation p.Ile383Val with semantic dementia and complex proteinopathy. The study investigates the temporally accentuated atrophy. The study concludes that the presence of p.Ile383Val mutation in TARDBP indicates a complex clinico-genetic-neuropathological relationships within the continuum FTLD-amyotrophic lateral sclerosis (ALS).