Browsing by Subject "Late-onset Alzheimer's disease"

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    APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease
    (Wiley, 2023) Polsinelli, Angelina J.; Logan, Paige E.; Lane, Kathleen A.; Manchella, Mohit K.; Nemes, Sára; Sanjay, Apoorva Bharthur; Gao, Sujuan; Apostolova, Liana G.; Neurology, School of Medicine
    Background: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on rates of cognitive decline in early- (EO) and late- (LO) onset Alzheimer's disease (AD). Method: We ran mixed-effects models with longitudinal cognitive measures as dependent variables, and sex, APOE ε4 carrier status, and interaction terms as predictor variables in 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center. Results: APOE ε4 carriers showed accelerated cognitive decline relative to non-carriers in both EOAD and LOAD, although the patterns of specific cognitive domains that were affected differed. Female participants showed accelerated cognitive decline relative to male participants in EOAD only. The effect of APOE ε4 was greater in EOAD for executive functioning (p < 0.0001) and greater in LOAD for language (p < 0.0001). Conclusion: We found APOE ε4 effects on cognitive decline in both EOAD and LOAD and female sex in EOAD only. The specific patterns and magnitude of decline are distinct between the two disease variants. Highlights: Apolipoprotein E (APOE) ε4 carrier status and sex differentiate rates of cognitive decline in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD). APOE ε4 in EOAD accelerated decline in memory, executive, and processing speed domains. Female sex in EOAD accelerated decline in language, memory, and global cognition. The effect of APOE ε4 was stronger for language in LOAD and for executive function in EOAD. Sex effects on language and executive function decline differed between EOAD and LOAD.
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    APOE-ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD
    (Wiley, 2023) Polsinelli, Angelina J.; Lane, Kathleen A.; Manchella, Mohit K.; Logan, Paige E.; Gao, Sujuan; Apostolova, Liana G.; Neurology, School of Medicine
    Background: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on age of symptom onset (AO) in early- (EO) and late- (LO) onset Alzheimer's disease (AD). Method: A total of 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center (NACC) were included. We used analysis of variance to examine AO differences between sexes and APOE genotypes and the effect of APOE ε4, sex, and their interaction on AO in EOAD and LOAD, separately. Results: APOE ε4 carriers in LOAD had younger AO and in EOAD had older AO. Female EOAD APOE ε4 carriers had older AO compared to non-carriers (P < 0.0001). There was no difference for males. Both male and female LOAD APOE ε4 carriers had younger AO relative to non-carriers (P < 0.0001). Conclusion: The observed earlier AO in EOAD APOE ε4 non-carriers relative to carriers, particularly in females, suggests the presence of additional AD risk variants.
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    Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease
    (Elsevier, 2016-01) Kunkle, Brian W.; Jaworski, James; Barral, Sandra; Vardarajan, Badri; Beecham, Gary W.; Martin, Eden R.; Cantwell, Laura S.; Partch, Amanda; Bird, Thomas D.; Raskind, Wendy H.; DeStefano, Anita L.; Carney, Regina M.; Cuccaro, Michael; Vance, Jeffrey M.; Farrer, Lindsay A.; Goate, Alison M.; Foroud, Tatiana; Mayeux, Richard P.; Schellenberg, Gerard D.; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Department of Medical and Molecular Genetics, IU School of Medicine
    INTRODUCTION: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. METHODS: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. RESULTS: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. DISCUSSION: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.
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    Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease
    (Elsevier, 2015-12) Barral, Sandra; Cheng, Rong; Reitz, Christiane; Vardarajan, Badri; Lee, Joseph; Kunkle, Brian; Beecham, Gary; Cantwell, Laura S.; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Haines, Jonathan L.; Goate, Alison M.; Foroud, Tatiana; Boerwinkle, Eric; Schellenberg, Gerard D.; Mayeux, Richard; Department of Medical and Molecular Genetics, IU School of Medicine
    INTRODUCTION: We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. METHODS: We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. RESULTS: We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). DISCUSSION: Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.
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    Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease
    (Wiley, 2023) Chang, Rui; Trushina, Eugenia; Zhu, Kuixi; Zaidi, Syed Shujaat Ali; Lau, Branden M.; Kueider-Paisley, Alexandra; Moein, Sara; He, Qianying; Alamprese, Melissa L.; Vagnerova, Barbora; Tang, Andrew; Vijayan, Ramachandran; Liu, Yanyun; Saykin, Andrew J.; Brinton, Roberta D.; Kaddurah-Daouk, Rima; Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium; Radiology and Imaging Sciences, School of Medicine
    Introduction: Late-onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E (APOE) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine. Methods: Sex- and APOE-specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort. Results: Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient-specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine-focused profile overriding sex-specific differences in serum metabolites of AD patients. Discussion: These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.