Browsing by Subject "Autosomal dominant Alzheimer's disease"

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    Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer's disease brains
    (Wiley, 2023) Novotny, Brenna C.; Fernandez, Maria Victoria; Wang, Ciyang; Budde, John P.; Bergmann, Kristy; Eteleeb, Abdallah M.; Bradley, Joseph; Webster, Carol; Ebl, Curtis; Norton, Joanne; Gentsch, Jen; Dube, Umber; Wang, Fengxian; Morris, John C.; Bateman, Randall J.; Perrin, Richard J.; McDade, Eric; Xiong, Chengjie; Chhatwal, Jasmeer; Dominantly Inherited Alzheimer Network (DIAN) Study Group; Alzheimer's Disease Neuroimaging Initiative; Alzheimer's Disease Metabolomics Consortium (ADMC); Goate, Alison; Farlow, Martin; Schofield, Peter; Chui, Helena; Karch, Celeste M.; Cruchaga, Carlos; Benitez, Bruno A.; Harari, Oscar; Neurology, School of Medicine
    Introduction: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. Highlights: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.
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    Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease
    (Wiley, 2021-07-05) Keret, Ophir; Staffaroni, Adam M.; Ringman, John M.; Cobigo, Yann; Goh, Sheng-Yang M.; Wolf, Amy; Allen, Isabel Elaine; Salloway, Stephen; Chhatwal, Jasmeer; Brickman, Adam M.; Reyes-Dumeyer, Dolly; Bateman, Randal J.; Benzinger, Tammie L.S.; Morris, John C.; Ances, Beau M.; Joseph-Mathurin, Nelly; Perrin, Richard J.; Gordon, Brian A.; Levin, Johannes; Vöglein, Jonathan; Jucker, Mathias; la Fougère, Christian; Martins, Ralph N.; Sohrabi, Hamid R.; Taddei, Kevin; Villemagne, Victor L.; Schofield, Peter R.; Brooks, William S.; Fulham, Michael; Masters, Colin L.; Ghetti, Bernardino; Saykin, Andrew J.; Jack, Clifford R.; Graff-Radford, Neill R.; Weiner, Michael; Cash, David M.; Allegri, Ricardo F.; Chrem, Patricio; Yi, Su; Miller, Bruce L.; Rabinovici, Gil D.; Rosen, Howard J.; Pathology and Laboratory Medicine, School of Medicine
    Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment. Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally. Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset. Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.
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    Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease
    (Wiley, 2023) Aguillon, David; Langella, Stephanie; Chen, Yinghua; Sanchez, Justin; Su, Yi; Vila-Castelar, Clara; Vasquez, Daniel; Zetterberg, Henrik; Hansson, Oskar; Dage, Jeffrey L.; Janelidze, Shorena; Chen, Kewei; Fox-Fuller, Joshua T.; Aduen, Paula; Martinez, Jairo E.; Garcia, Gloria; Baena, Ana; Guzman, Claudia; Johnson, Keith; Sperling, Reisa A.; Blennow, Kaj; Reiman, Eric M.; Lopera, Francisco; Quiroz, Yakeel T.; Neurology, School of Medicine
    Introduction: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD. Methods: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members. Results: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function. Discussion: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials. Highlights: Non-demented presenilin-1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p-tau217) than do age-matched non-carriers. Higher baseline p-tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden. Higher baseline p-tau217 is associated with greater future tau PET pathology burden. Higher baseline p-tau217 is associated with worse future memory performance.
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    Sex differences in blood biomarkers and cognitive performance in individuals with autosomal dominant Alzheimer’s disease
    (Wiley, 2023) Vila-Castelar, Clara; Chen, Yinghua; Langella, Stephanie; Lopera, Francisco; Zetterberg, Henrik; Hansson, Oskar; Dage, Jeffrey L.; Janelidzde, Shorena; Su, Yi; Chen, Kewei; Pluim McDowell, Celina; Martinez, Jairo E.; Ramirez-Gomez, Liliana; Garcia, Gloria; Aguillon, David; Baena, Ana; Giraldo-Chica, Margarita; Protas, Hillary D.; Ghisays, Valentina; Rios-Romenets, Silvia; Tariot, Pierre N.; Blennow, Kaj; Reiman, Eric M.; Quiroz, Yakeel T.; Neurology, School of Medicine
    Introduction: Plasma tau phosphorylated at threonine 217 (P-tau217) and neurofilament light (NfL) have emerged as markers of Alzheimer's disease (AD) pathology. Few studies have examined the role of sex in plasma biomarkers in sporadic AD, yielding mixed findings, and none in autosomal dominant AD. Methods: We examined the effects of sex and age on plasma P-tau217 and NfL, and their association with cognitive performance in a cross-sectional study of 621 Presenilin-1 E280A mutation carriers (PSEN1) and non-carriers. Results: As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. Yet, as disease progresses, female carriers had a greater plasma NfL increase than male carriers. There were no sex differences in the association between age and plasma biomarkers among non-carriers. Discussion: Our findings suggest that, among PSEN1 mutation carriers, females had a greater rate of neurodegeneration than males, yet it did not predict cognitive performance. Highlights: We examined sex differences in plasma P-tau217 and NfL in Presenilin-1 E280A (PSEN1) mutation carriers and non-carriers. Female carriers had a greater plasma NfL increase, but not P-tau217, than male carriers. As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. The interaction effect of sex by plasma NfL levels did not predict cognition among carriers.