Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series

Koriath, Carolin; Kenny, Joanna; Adamson, Gary; Druyeh, Ronald; Taylor, William A.; Beck, Jon; Quinn, Liam; Mok, Tze How; Dimitriadis, Athanasios; Norsworthy, Penny J.; Bass, Nick; Carter, J.; Walker, Zuzana; Kipps, Christopher; Coulthard, Elizabeth; Polke, James M.; Bernal-Quirós, Manuel; Denning, Nicola; Thomas, Rebecca; Raybould, Rachel; Williams, Julie; Mummery, Catherine J.; Wild, Edward J.; Houlden, Henry; Tabrizi, Sarah J.; Rossor, Martin N.; Hummerich, Holger; Warren, Jason D.; Rowe, James B.; Rohrer, Jonathan D.; Schott, Jonathan M.; Fox, Nick C.; Collinge, John; Mead, Simon

doi:10.1038/s41380-018-0224-0

Cited by 41 publications

(67 citation statements)

References 31 publications

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“…We found that the ApoE4 genotype lowered age at clinical onset in patients with dementia and tau pathology, and was a particularly strong effect once the confounding effects of amyloid b pathology were taken into account. The patients in this FTD cohort were previously tested for causative genetic mutations [12] and are described in Table 1. Patients with causative mutations in genes not typically associated with FTD were excluded from the present analysis.…”

supporting

confidence: 75%

ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid‐β copathology

Koriath

Lashley

Taylor

et al. 2019

Alz & Dem Diag Ass & Dis Mo

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Introduction Apolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer's disease (AD), with ApoE4 thought to enhance and accelerate amyloid‐β (Aβ) pathology. ApoE4 has recently been described to increase neurodegeneration in a mouse model of frontotemporal dementia (FTD), in vitro, and in patients, demonstrating that ApoE4 modifies tauopathy independently of Aβ. This raises the question whether ApoE genotype also modifies the clinical phenotype in patients with FTD with tau pathology. Methods We analyzed 704 patients with FTD, including a genetically and neuropathologically confirmed subset, and 452 healthy elderly controls. We compared ApoE4 genotype frequency and age at onset in tau+ or TDP43+ FTD patients with or without Aβ copathology. Results The ApoE4 genotype lowered age at onset in patients with FTD and tau pathology, particularly once accounting for confounding effects of Aβ pathology. Discussion We conclude that ApoE4 accelerates neurodegeneration in FTD patients with MAPT mutations or FTLD‐tau pathology, independent of Aβ.

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supporting

confidence: 75%

ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid‐β copathology

Koriath

Lashley

Taylor

et al. 2019

Alz & Dem Diag Ass & Dis Mo

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“…in FTD as in other dementias [12]. Genetic modifiers such as TMEM106B [52], APOE [53], have also been identified. Further work, with larger cohorts, will be able to test the potential effect of these moderators on the relationships between brain structure, functional networks and cognition.…”

Section: Discussionmentioning

confidence: 99%

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Tsvetanov

Gazzina

Jones

et al. 2019

Preprint

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INTRODUCTION: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial Frontotemporal dementia (FTD). METHODS: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. RESULTS: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviourally-relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. DISCUSSION: Our findings suggest that maintenance of functional network connectivity enables carriers to maintain cognitive performance.

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“…Based on the CSF biomarker analyses performed, some of the PSENs VUS mutations analysed showed biomarker levels comparable to the known pathogenic mutations: for instance, the PSEN1 p.40del, which was described for the first time in an EOAD patient with prominent frontal features and no family history of dementia [51]. This variant was considered "most likely benign" or causing a small increase in risk based on its frequency in gnomAD [52].…”

Section: Mutation Screeningmentioning

confidence: 94%

Amyloid-β1–43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations

et al. 2020

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Background Alzheimer’s disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ1–43 is more prone to aggregation and has higher toxic properties than the long-known Aβ1–42. However, a direct effect on Aβ1–43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined. Methods N = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ1–43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ1–42 and Aβ1–40 CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers. Results A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ1–43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ1–43 levels positively correlated with CSF Aβ1–42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ1–43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ1–43 and Aβ1–42 levels, we could re-classify as “likely pathogenic” 3 of the unclear mutations. Conclusion This is the first time that Aβ1–43 levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ1–43 in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ1–43 could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.

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Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series

Cited by 41 publications

References 31 publications

ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid‐β copathology

ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid‐β copathology

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Amyloid-β1–43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations

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