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

Koriath, Carolin; Lashley, Tammaryn; Taylor, William A.; Druyeh, Ronald; Dimitriadis, Athanasios; Denning, Nicola; Williams, Julie; Warren, Jason D.; Fox, Nick C.; Schott, Jonathan M.; Rowe, James B.; Collinge, John; Rohrer, Jonathan D.; Mead, Simon

doi:10.1016/j.dadm.2019.01.010

Cited by 32 publications

(26 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other genetic or environmental factors affecting age at symptom onset and at death in individuals with MAPT mutations have not yet been well studied. 24 Despite being statistically significant, correlation coefficients were low in the GRN group for the com parisons between individual age at symptom onset and parental and mean family age at symptom onset. The variability in age at symptom onset and age at death for individuals with GRN mutations was not accounted for particularly by either the individual mutation or family membership.…”

Section: Discussionmentioning

confidence: 85%

“…Significant differences were also found between the three genetic groups in the variability of interfamily and intrafamily age at death (both p<0•0001; appendix p 49). Family membership explained 74% (95% CI 65-82) of this variability in individuals with MAPT mutations, but only 20% (12-30) in those with GRN mutations and 19% (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) in those with C9orf72 expansions. We also found a significant difference between the GRN and MAPT groups in the betweenmutation variability in age at death (p<0•0001): in the GRN group, only 9% (95% CI 3-21) of the variability was explained by the specific mutation, whereas in the MAPT group, 61% (47-73) of the variability was explained by the specific mutation.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Moore

Nicholas

Grossman

et al. 2020

The Lancet Neurology

Self Cite

222

230

View full text Add to dashboard Cite

Background Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49•5 years (SD 10•0; onset) and 58•5 years (11•3; death) in the MAPT group, 58•2 years (9•8; onset) and 65•3 years (10•9; death) in the C9orf72 group, and 61•3 years (8•8; onset) and 68•8 years (9•7; death) in the GRN group. Mean disease duration was 6•4 years (SD 4•9) in the C9orf72 group, 7•1 years (3•9) in the GRN group, and 9•3 years (6•4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0•45 between individual and parental age at onset, r=0•63 between individual and mean family age at onset, r=0•58 between individual and parental age at death, and r=0•69 between individual and mean family age at death) than in either the C9orf72 group (r=0•32 individual and parental age at onset, r=0•36 individual and mean family age at onset, r=0•38 individual and parental age at death, and r=0•40 individual and mean family age at death) or the GRN group (r=0•22 individual and parental age at onset, r=0•18 individual and mean family age at onset, r=0•22 individual and parental age at death, and r=0•32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even mor...

show abstract

Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Moore

Nicholas

Grossman

et al. 2020

The Lancet Neurology

Self Cite

222

230

View full text Add to dashboard Cite

show abstract

“…In AD, APOEε4 only associates with tau pathology in the presence of amyloid pathology [86]. However, in frontotemporal dementia with MAPT mutations that lead to familial tauopathy, APOEε4 lowers the age of onset independent of amyloid plaques [168]. In contrast, another study found that APOEε2 was associated with increased tau pathology burden in PSP [327].…”

Section: Bidirectional Effects Of Tau Pathology and Microglial Neuroimentioning

confidence: 99%

Intersection of pathological tau and microglia at the synapse

Vogels

Murgoci

Hromádka

2019

acta neuropathol commun

146

141

View full text Add to dashboard Cite

Tauopathies are a heterogenous class of diseases characterized by cellular accumulation of aggregated tau and include diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy and chronic traumatic encephalopathy. Tau pathology is strongly linked to neurodegeneration and clinical symptoms in tauopathy patients. Furthermore, synapse loss is an early pathological event in tauopathies and is the strongest correlate of cognitive decline. Tau pathology is additionally associated with chronic neuroinflammatory processes, such as reactive microglia, astrocytes, and increased levels of pro-inflammatory molecules (e.g. complement proteins, cytokines). Recent studies show that as the principal immune cells of the brain, microglia play a particularly important role in the initiation and progression of tau pathology and associated neurodegeneration. Furthermore, AD risk genes such as Triggering receptor expressed on myeloid cells 2 ( TREM2 ) and Apolipoprotein E ( APOE ) are enriched in the innate immune system and modulate the neuroinflammatory response of microglia to tau pathology. Microglia can play an active role in synaptic dysfunction by abnormally phagocytosing synaptic compartments of neurons with tau pathology. Furthermore, microglia are involved in synaptic spreading of tau – a process which is thought to underlie the progressive nature of tau pathology propagation through the brain. Spreading of pathological tau is also the predominant target for tau-based immunotherapy. Active tau vaccines, therapeutic tau antibodies and other approaches targeting the immune system are actively explored as treatment options for AD and other tauopathies. This review describes the role of microglia in the pathobiology of tauopathies and the mechanism of action of potential therapeutics targeting the immune system in tauopathies.

show abstract

“…For Aβ x-40 ELISA, HJ2 (anti-Aβ [35][36][37][38][39][40] ) was used as a capture antibody and for Aβ x-42 ELISA, HJ7.4 (anti-Aβ [37][38][39][40][41][42] ) was used as a capture antibody. HJ5.1-biotin (anti-Aβ [13][14][15][16][17][18] ) [33,34] was used as the detecting antibody for both Aβ ELISAs.…”

Section: Sandwich Elisamentioning

confidence: 99%

“…Emerging data indicate that APOE not only affects AD risk, but also severity of pathology in dementia with Lewy bodies and neurodegeneration in tauopathies [11][12][13][14]. In particular, microglia-derived apoE appears to regulate the inflammatory response [11,[15][16][17], suggesting that the cellular source of apoE in both the brain and periphery has distinct functions in different diseases.…”

Section: Introductionmentioning

confidence: 99%

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Huynh

Wang

Tran

et al. 2019

Mol Neurodegeneration

View full text Add to dashboard Cite

Background The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown. Methods We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition. Results As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected. Conclusions Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.

show abstract

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

Cited by 32 publications

References 15 publications

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Intersection of pathological tau and microglia at the synapse

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model

Contact Info

Product

Resources

About