Alzheimer neuropathology without frontotemporal lobar degeneration hallmarks (<scp>TAR DNA</scp>‐binding protein 43 inclusions) in missense progranulin mutation <scp>C</scp>ys139<scp>A</scp>rg

Redaelli, Veronica; Rossi, Giacomina; Maderna, Emanuela; Kovács, Gábor G.; Piccoli, Elena; Caroppo, Paola; Cacciatore, Francesca; Spinello, Sonia; Grisoli, Marina; Sozzi, G.; Salmaggi, Andrea; Tagliavini, Fabrizio; Giaccone, Giorgio

doi:10.1111/bpa.12480

Cited by 17 publications

(5 citation statements)

References 17 publications

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“…114 GRN and 63 MAPT mutations currently identified in total. This number excludes the majority of missense variants in GRN , many of which may be risk factors for Alzheimer’s disease rather than a Mendelian cause of FTD, although identifying pathogenicity is not always easy [16].…”

Section: Heritability Genes and Phenotypementioning

confidence: 99%

An update on genetic frontotemporal dementia

2019

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Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, with around 30% of patients having a strong family history. The majority of that heritability is accounted for by autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) genes, with mutations more rarely seen in a number of other genes. This review will discuss the recent updates in the field of genetic FTD. Age at symptom onset in genetic FTD is variable with recently identified genetic modifiers including TMEM106B (in GRN carriers particularly) and a polymorphism at a locus containing two overlapping genes LOC101929163 and C6orf10 (in C9orf72 carriers). Behavioural variant FTD (bvFTD) is the most common diagnosis in each of the genetic groups, although in C9orf72 carriers amyotrophic lateral sclerosis either alone, or with bvFTD, is also common. An atypical neuropsychiatric presentation is also seen in C9orf72 carriers and family members of carriers are at greater risk of psychiatric disorders including schizophrenia and autistic spectrum disorders. Large natural history studies of presymptomatic genetic FTD are now underway both in Europe/Canada (GENFI-the Genetic FTD Initiative) and in the US (ARTFL/LEFFTDS study), collaborating together under the banner of the FTD Prevention Initiative (FPI). These studies are taking forward the validation of cognitive, imaging and fluid biomarkers that aim to robustly measure disease onset, staging and progression in genetic FTD. Grey matter changes on MRI and hypometabolism on FDG-PET are seen at least 10 years before symptom onset with white matter abnormalities seen earlier, but the pattern and exact timing of changes differ between different genetic groups. In contrast, tau PET has yet to show promise in genetic FTD. Three key fluid biomarkers have been identified so far that are likely to be helpful in clinical trials-CSF or blood neurofilament light chain levels (in all groups), CSF or blood progranulin levels (in GRN carriers) and CSF poly(GP) dipeptide repeat protein levels (in C9orf72 carriers). Increased knowledge about genetic FTD has led to more clinical presymptomatic genetic testing but this has not yet been mirrored in the development of either an accepted FTD-specific testing protocol or provision of appropriate psychological support mechanisms for those living through the at-risk phase. This will become even more relevant as disease-modifying therapy trials start in each of the genetic groups over the next few years.

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Section: Heritability Genes and Phenotypementioning

confidence: 99%

An update on genetic frontotemporal dementia

2019

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“…10 In addition, progranulin levels are also associated with cortical thinning on brain MRI 50 and AD neuropathology. 51…”

Section: Discussionmentioning

confidence: 99%

“…Progranulin levels in CSF are associated with the progression of early and late onset, clinically diagnosed AD 10 . In addition, progranulin levels are also associated with cortical thinning on brain MRI 50 and AD neuropathology 51 . Future studies should attempt to relate CSF progranulin levels, GRN variants, neurofibrillary tangle pathology, and Braak stage.…”

Section: Discussionmentioning

confidence: 99%

Progranulin mutations in clinical and neuropathological Alzheimer's disease

Vardarajan

Reyes‐Dumeyer

Piriz

et al. 2022

Alzheimer's & Dementia

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Introduction: Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology. Methods:We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers.Results: Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for associationThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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“…The variant is known to cause FTD [ 33 , 39 ] and has not been associated with clinical AD, although one family was described with profound AD neuropathology (reported as UBC11, Braak stage VI) [ 40 ]. Although FTD- GRN patients may show coexistent AD pathology [ 41 ], certain GRN variants have been suggested as the direct cause of AD [ 42 ] through several proposed mechanisms (i.e., Aβ clearance, tau phosphorylation, neuroinflammation), indicating shared pathways between AD and progranulin [ 43 ]. As such, we propose that the identified variant — possibly in concert with an AD polygenic risk profile (OR = 1.84) — plays a causal role in this family and should be reported in genetic counseling.…”

Section: Discussionmentioning

confidence: 99%

Mapping the genetic landscape of early-onset Alzheimer’s disease in a cohort of 36 families

et al. 2022

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Background Many families with clinical early-onset Alzheimer’s disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we evaluated the possible polygenic architecture in a large series of families, to assess if genetic testing of familial EOAD could be expanded. Methods Thirty-six pedigrees (77 patients) were ascertained from a larger cohort of patients, with relationships determined by genetic data (exome sequencing data and/or SNP arrays). All families included at least one AD patient with symptom onset <70 years. We evaluated segregating rare variants in known dementia-related genes, and other genes or variants if shared by multiple families. APOE was genotyped and duplications in APP were assessed by targeted test or using SNP array data. We computed polygenic risk scores (PRS) compared with a reference population-based dataset, by imputing SNP arrays or exome sequencing data. Results In eight families, we identified a pathogenic variant, including the genes APP, PSEN1, SORL1, and an unexpected GRN frameshift variant. APOE-ε4 homozygosity was present in eighteen families, showing full segregation with disease in seven families. Eight families harbored a variant of uncertain significance (VUS), of which six included APOE-ε4 homozygous carriers. PRS was not higher in the families combined compared with the population mean (beta 0.05, P = 0.21), with a maximum increase of 0.61 (OR = 1.84) in the GRN family. Subgroup analyses indicated lower PRS in six APP/PSEN1 families compared with the rest (beta −0.22 vs. 0.10; P = 0.009) and lower APOE burden in all eight families with monogenic cause (beta 0.29 vs. 1.15, P = 0.010). Nine families remained without a genetic cause or risk factor identified. Conclusion Besides monogenic causes, we suspect a polygenic disease architecture in multiple families based on APOE and rare VUS. The risk conveyed by PRS is modest across the studied families. Families without any identified risk factor render suitable candidates for further in-depth genetic evaluation.

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Alzheimer neuropathology without frontotemporal lobar degeneration hallmarks (TAR DNA‐binding protein 43 inclusions) in missense progranulin mutation Cys139Arg

Cited by 17 publications

References 17 publications

An update on genetic frontotemporal dementia

An update on genetic frontotemporal dementia

Progranulin mutations in clinical and neuropathological Alzheimer's disease

Mapping the genetic landscape of early-onset Alzheimer’s disease in a cohort of 36 families

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