Browsing by Author "Dickson, Dennis W."

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    A multiethnic transcriptome for Alzheimer Disease identifies cross‐ancestry and ancestry‐specific expression profiles
    (Wiley, 2025-01-03) Yang, Zikun; Cieza, Basilio; Reyes-Dumeyer, Dolly; Lee, Annie J.; Dugger, Brittany N.; Jin, Lee-Way; Murray, Melissa E.; Dickson, Dennis W.; Pericak-Vance, Margaret A.; Vance, Jeffery M.; Foroud, Tatiana M.; Teich, Andrew F.; Mayeux, Richard; Tosto, Giuseppe; Neurology, School of Medicine
    Background: Alzheimer’s Disease (AD) presents complex molecular heterogeneity, influenced by a variety of factors including heterogeneous phenotypic, genetic, and neuropathologic presentations. Regulation of gene expression mechanisms is a primary interest of investigations aiming to uncover the underlying disease mechanisms and progression. Method: We generated bulk RNA‐sequencing in prefrontal cortex from 565 AD brain samples (non‐Hispanic Whites, n = 399; Hispanics, n = 113; African American, n = 12) across six U.S. brain banks, and conducted differential gene expression and enrichment analyses. We sought to identify cross‐ancestry and ancestry‐specific differentially expressed genes (DEG) and pathways across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We validated our findings using the Religious Orders Study/Memory and Aging Project study (ROS/MAP, n = 1,095). Lastly, we validated top DEG using publically‐available human single‐nucleus RNA sequencing (snRNAseq) data. Result: AD‐known genes VGF (LFC = ‐0.661, padj = 3.78) and ADAMTS2 (padj = 1.21) were consistently differentially expressed across statistical models, ethnic groups, and replicated in ROS/MAP (Figure 1). Genes from the heat shock protein (HSP) family, e.g. HSPB7 (padj = 3.78), were the top DEG, also replicated in ROS/MAP. Ethnic‐stratified analyses prioritized TNFSF14 and SPOCD1 as top DEG in Hispanic samples. Gene set enrichment analysis highlighted several significantly pathways, including “TYROBP causal network in microglia” (WP3945; padj = 1.68) and “Alzheimer Disease” (WP5124; padj = 4.24). snRNAseq validated several DEG, including VGF downregulated in neurons (padj = 1.1). Conclusion: To our knowledge, this is the largest diverse transcriptome study for AD in post‐mortem tissue. We identified perturbated genes and pathways resulting in cross‐ethnic and ethnic‐specific findings, ultimately highlighting the importance of diversity in AD investigations.
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    Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease
    (Wiley, 2014-05) Nuytemans, Karen; Inchausti, Vanessa; Beecham, Gary W.; Wang, Liyong; Dickson, Dennis W.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Mash, Deborah C.; Frosch, Matthew P.; Foroud, Tatiana M.; Honig, Lawrence S.; Montine, Thomas J.; Dawson, Ted M.; Martin, Eden R.; Scott, William K.; Vance, Jeffery M.; Medical & Molecular Genetics, School of Medicine
    BACKGROUND: We have reported that intermediate repeat lengths of the C9ORF72 repeat are a risk factor for Parkinson's disease (PD) in a clinically diagnosed data set. Because 10% to 25% of clinically diagnosed PD have different diagnoses upon autopsy, we hypothesized that this may reflect phenotypic heterogeneity or concomitant pathology of other neurodegenerative disorders. METHODS: We screened 488 autopsy-confirmed PD cases for expansion haplotype tag rs3849942T. In 196 identified haplotype carriers, the C9ORF72 repeat was genotyped using the repeat-primed polymerase chain reaction assay. RESULTS: No larger (intermediate or expanded) repeats were found in these autopsy-confirmed PD samples. This absence of larger repeats is significantly different from the frequency in clinically diagnosed datasets (P = 0.002). CONCLUSIONS: Our results suggest that expanded or intermediate C9ORF72 repeats in clinically diagnosed PD or parkinsonism might be an indication of heterogeneity in clinically diagnosed PD cases. Further studies are needed to elucidate the potential contribution of the C9ORF72 repeat to autopsy-confirmed PD.
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    Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes
    (medRxiv, 2024-02-28) Wang, Hui; Chang, Timothy S.; Dombroski, Beth A.; Cheng, Po-Liang; Si, Ya-Qin; Tucci, Albert; Patil, Vishakha; Valiente-Banuet, Leopoldo; Farrell, Kurt; Mclean, Catriona; Molina-Porcel, Laura; Alex, Rajput; De Deyn, Peter Paul; Le Bastard, Nathalie; Gearing, Marla; Donker Kaat, Laura; Van Swieten, John C.; Dopper, Elise; Ghetti, Bernardino F.; Newell, Kathy L.; Troakes, Claire; de Yébenes, Justo G.; Rábano-Gutierrez, Alberto; Meller, Tina; Oertel, Wolfgang H.; Respondek, Gesine; Stamelou, Maria; Arzberger, Thomas; Roeber, Sigrun; Müller, Ulrich; Hopfner, Franziska; Pastor, Pau; Brice, Alexis; Durr, Alexandra; Le Ber, Isabelle; Beach, Thomas G.; Serrano, Geidy E.; Hazrati, Lili-Naz; Litvan, Irene; Rademakers, Rosa; Ross, Owen A.; Galasko, Douglas; Boxer, Adam L.; Miller, Bruce L.; Seeley, Willian W.; Van Deerlin, Vivianna M.; Lee, Edward B.; White, Charles L., III; Morris, Huw R.; de Silva, Rohan; Crary, John F.; Goate, Alison M.; Friedman, Jeffrey S.; Leung, Yuk Yee; Coppola, Giovanni; Naj, Adam C.; Wang, Li-San; PSP genetics study group; Dickson, Dennis W.; Höglinger, Günter U.; Tzeng, Jung-Ying; Geschwind, Daniel H.; Schellenberg, Gerard D.; Lee, Wan-Ping; Pathology and Laboratory Medicine, School of Medicine
    Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, β, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, β, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, β, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and β were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1β1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1β1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1β1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1β1γ4. Moreover, H1β1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1β1γ1 to 77% in H1β1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.
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    Biomarker-Based Approach to α-Synucleinopathies: Lessons from Neuropathology
    (Wiley, 2024) Kovacs, Gabor G.; Grinberg, Lea T.; Halliday, Glenda; Alafuzoff, Irina; Dugger, Brittany N.; Murayama, Shigeo; Forrest, Shelley L.; Martinez-Valbuena, Ivan; Tanaka, Hidetomo; Kon, Tomoya; Yoshida, Koji; Jaunmuktane, Zane; Spina, Salvatore; Nelson, Peter T.; Gentleman, Steve; Alegre-Abarrategui, Javier; Serrano, Geidy E.; Paes, Vitor Ribeiro; Takao, Masaki; Wakabayashi, Koichi; Uchihara, Toshiki; Yoshida, Mari; Saito, Yuko; Kofler, Julia; Diehl Rodriguez, Roberta; Gelpi, Ellen; Attems, Johannes; Crary, John F.; Seeley, William W.; Duda, John E.; Keene, C. Dirk; Woulfe, John; Munoz, David; Smith, Colin; Lee, Edward B.; Neumann, Manuela; White, Charles L., III; McKee, Ann C.; Thal, Dietmar R.; Jellinger, Kurt; Ghetti, Bernardino; Mackenzie, Ian R. A.; Dickson, Dennis W.; Beach, Thomas G.; Pathology and Laboratory Medicine, School of Medicine
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    C9orf72 Intermediate Repeats are Associated with Corticobasal Degeneration, Increased C9orf72 Expression and Disruption of Autophagy
    (Springer, 2019-11) Cali, Christopher P.; Patino, Maribel; Tai, Yee Kit; Ho, Wan Yun; McLean, Catriona A.; Morris, Christopher M.; Seeley, William W.; Miller, Bruce L.; Gaig, Carles; Vonsattel, Jean Paul G.; White, Charles L.; Roeber, Sigrun; Kretzschmar, Hans; Troncoso, Juan C.; Troakes, Claire; Gearing, Marla; Ghetti, Bernardino; Van Deerlin, Vivianna M.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Mok, Kin Y.; Ling, Helen; Dickson, Dennis W.; Schellenberg, Gerard D.; Ling, Shuo-Chien; Lee, Edward B.; Pathology and Laboratory Medicine, School of Medicine
    Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson’s disease patients, but the association was not found in autopsy confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson’s but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n=354 cases, odds ratio=3.59, p-value=0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.
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    Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders
    (Springer Nature, 2025-03-12) Sheth, Udit; Öijerstedt, Linn; Heckman, Michael G.; White, Launia J.; Heuer, Hilary W.; Lago, Argentina Lario; Forsberg, Leah K.; Faber, Kelley M.; Foroud, Tatiana M.; Rademakers, Rosa; Ramos, Eliana Marisa; Appleby, Brian S.; Bozoki, Andrea C.; Darby, R. Ryan; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Galasko, Douglas R.; Ghoshal, Nupur; Graff-Radford, Neill R.; Grant, Ian M.; Hales, Chadwick M.; Hsiung, Ging-Yuek Robin; Huey, Edward D.; Irwin, David; Kwan, Justin Y.; Litvan, Irene; Mackenzie, Ian R.; Masdeu, Joseph C.; Mendez, Mario F.; Onyike, Chiadi U.; Pascual, Belen; Pressman, Peter S.; Roberson, Erik D.; Snyder, Allison; Tartaglia, M. Carmela; Seeley, William W.; Dickson, Dennis W.; Rosen, Howard J.; Boeve, Bradley F.; Boxer, Adam L.; Petrucelli, Leonard; Gendron, Tania F.; Medical and Molecular Genetics, School of Medicine
    Background: Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing to inconsistent findings. Therefore, we evaluated plasma GFAP as a FTD biomarker and compared its performance to that of neurofilament light (NfL) protein, a leading FTD biomarker. Methods: We availed ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources to conduct a comprehensive cross-sectional and longitudinal examination of the susceptibility/risk, prognostic, and predictive performance of GFAP and NfL in the largest series of well-characterized presymptomatic FTD mutation carriers and participants with sporadic or familial FTD syndromes. Utilizing single molecule array technology, we measured GFAP and NfL in plasma from 161 controls, 127 presymptomatic mutation carriers, 702 participants with a FTD syndrome, and 67 participants with mild behavioral and/or cognitive changes. We used multivariable linear regression and Cox proportional hazard models adjusted for co-variates to examine the biomarker utility of baseline GFAP and NfL concentrations or their rates of change. Results: Compared to controls, GFAP and NfL were elevated in each FTD syndrome but GFAP, unlike NfL, poorly discriminated controls from participants with mild symptoms. Similarly, both baseline GFAP and NfL were higher in presymptomatic mutation carriers who later phenoconverted, but NfL better distinguished non-converters from phenoconverters. We additionally observed that GFAP and NfL were associated with disease severity indicators and survival, but NfL far outperformed GFAP. Nevertheless, we validated findings that the GFAP/NfL ratio may discriminate frontotemporal lobar degeneration with tau versus TDP-43 pathology. Conclusions: Our head-to-head comparison of plasma GFAP and NfL as biomarkers for FTD indicate that NfL consistently outmatched GFAP as a prognostic and predictive biomarker for participants with a FTD syndrome, and as a susceptibility/risk biomarker for people at genetic risk of FTD. Our findings underscore the need to include leading biomarkers in investigations evaluating new biomarkers if the field is to fully ascertain their performance and clinical value.
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    Correction: Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
    (Springer Nature, 2024-10-14) Wang, Hui; Chang, Timothy S.; Dombroski, Beth A.; Cheng, Po-Liang; Patil, Vishakha; Valiente-Banuet, Leopoldo; Farrell, Kurt; Mclean, Catriona; Molina-Porcel, Laura; Rajput, Alex; De Deyn, Peter Paul; Le Bastard, Nathalie; Gearing, Marla; Donker Kaat, Laura; Van Swieten, John C.; Dopper, Elise; Ghetti, Bernardino F.; Newell, Kathy L.; Troakes, Claire; de Yébenes, Justo G.; Rábano-Gutierrez, Alberto; Meller, Tina; Oertel, Wolfgang H.; Respondek, Gesine; Stamelou, Maria; Arzberger, Thomas; Roeber, Sigrun; Müller, Ulrich; Hopfner, Franziska; Pastor, Pau; Brice, Alexis; Durr, Alexandra; Le Ber, Isabelle; Beach, Thomas G.; Serrano, Geidy E.; Hazrati, Lili-Naz; Litvan, Irene; Rademakers, Rosa; Ross, Owen A.; Galasko, Douglas; Boxer, Adam L.; Miller, Bruce L.; Seeley, Willian W.; Van Deerlin, Vivanna M.; Lee, Edward B.; White, Charles L., III; Morris, Huw; de Silva, Rohan; Crary, John F.; Goate, Alison M.; Friedman, Jeffrey S.; Leung, Yuk Yee; Coppola, Giovanni; Naj, Adam C.; Wang, Li-San; P. S. P. genetics study group; Dalgard, Clifton; Dickson, Dennis W.; Höglinger, Günter U.; Schellenberg, Gerard D.; Geschwind, Daniel H.; Lee, Wan-Ping; Pathology and Laboratory Medicine, School of Medicine
    Correction : Mol Neurodegeneration 19, 61 (2024) https://doi.org/10.1186/s13024-024-00747-3 The original article [1] erroneously gives a wrong affiliation for Ulrich Müller. His correct affiliation is Institute of Human Genetics, Justus-Liebig University Giessen, 35392 Giessen, Germany.
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    Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease
    (medRxiv, 2023-04-24) Valentino, Rebecca R.; Scotton, William J.; Roemer, Shanu F.; Lashley, Tammaryn; Heckman, Michael G.; Shoai, Maryam; Martinez-Carrasco, Alejandro; Tamvaka, Nicole; Walton, Ronald L.; Baker, Matthew C.; Macpherson, Hannah L.; Real, Raquel; Soto-Beasley, Alexandra I.; Mok, Kin; Revesz, Tamas; Warner, Thomas T.; Jaunmuktane, Zane; Boeve, Bradley F.; Christopher, Elizabeth A.; DeTure, Michael; Duara, Ranjan; Graff-Radford, Neill R.; Josephs, Keith A.; Knopman, David S.; Koga, Shunsuke; Murray, Melissa E.; Lyons, Kelly E.; Pahwa, Rajesh; Parisi, Joseph E.; Petersen, Ronald C.; Whitwell, Jennifer; Grinberg, Lea T.; Miller, Bruce; Schlereth, Athena; Seeley, William W.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, EunRan; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Wolk, David A.; Connors, Theresa R.; Dooley, Patrick M.; Frosch, Matthew P.; Oakley, Derek H.; Aldecoa, Iban; Balasa, Mircea; Gelpi, Ellen; Borrego-Écija, Sergi; de Eugenio Huélamo, Rosa Maria; Gascon-Bayarri, Jordi; Sánchez-Valle, Raquel; Sanz-Cartagena, Pilar; Piñol-Ripoll, Gerard; Molina-Porcel, Laura; Bigio, Eileen H.; Flanagan, Margaret E.; Gefen, Tamar; Rogalski, Emily J.; Weintraub, Sandra; Redding-Ochoa, Javier; Chang, Koping; Troncoso, Juan C.; Prokop, Stefan; Newell, Kathy L.; Ghetti, Bernardino; Jones, Matthew; Richardson, Anna; Robinson, Andrew C.; Roncaroli, Federico; Snowden, Julie; Allinson, Kieren; Green, Oliver; Rowe, James B.; Singh, Poonam; Beach, Thomas G.; Serrano, Geidy E.; Flowers, Xena E.; Goldman, James E.; Heaps, Allison C.; Leskinen, Sandra P.; Teich, Andrew F.; Black, Sandra E.; Keith, Julia L.; Masellis, Mario; Bodi, Istvan; King, Andrew; Sarraj, Safa-Al; Troakes, Claire; Halliday, Glenda M.; Hodges, John R.; Kril, Jillian J.; Kwok, John B.; Piguet, Olivier; Gearing, Marla; Arzberger, Thomas; Roeber, Sigrun; Attems, Johannes; Morris, Christopher M.; Thomas, Alan J.; Evers, Bret M.; White, Charles L.; Mechawar, Naguib; Sieben, Anne A.; Cras, Patrick P.; De Vil, Bart B.; De Deyn, Peter Paul P. P.; Duyckaerts, Charles; Le Ber, Isabelle; Seihean, Danielle; Turbant-Leclere, Sabrina; MacKenzie, Ian R.; McLean, Catriona; Cykowski, Matthew D.; Ervin, John F.; Wang, Shih-Hsiu J.; Graff, Caroline; Nennesmo, Inger; Nagra, Rashed M.; Riehl, James; Kovacs, Gabor G.; Giaccone, Giorgio; Nacmias, Benedetta; Neumann, Manuela; Ang, Lee-Cyn; Finger, Elizabeth C.; Blauwendraat, Cornelis; Nalls, Mike A.; Singleton, Andrew B.; Vitale, Dan; Cunha, Cristina; Carvalho, Agostinho; Wszolek, Zbigniew K.; Morris, Huw R.; Rademakers, Rosa; Hardy, John A.; Dickson, Dennis W.; Rohrer, Jonathan D.; Ross, Owen A.; Pathology and Laboratory Medicine, School of Medicine
    Background: Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD. Methods: We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521). Findings: Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65). Interpretation: The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.
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    Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease
    (American Society for Biochemistry and Molecular Biology, 2020-07-31) Abskharon, Romany; Seidler, Paul M.; Sawaya, Michael R.; Cascio, Duilio; Yang, Tianxiao P.; Philipp, Stephan; Williams, Christopher Kazu; Newell, Kathy L.; Ghetti, Bernardino; DeTure, Michael A.; Dickson, Dennis W.; Vinters, Harry V.; Felgner, Philip L.; Nakajima, Rie; Glabe, Charles G.; Eisenberg, David S.; Pathology and Laboratory Medicine, School of Medicine
    Soluble oligomers of aggregated tau accompany the accumulation of insoluble amyloid fibrils, a histological hallmark of Alzheimer disease (AD) and two dozen related neurodegenerative diseases. Both oligomers and fibrils seed the spread of Tau pathology, and by virtue of their low molecular weight and relative solubility, oligomers may be particularly pernicious seeds. Here, we report the formation of in vitro tau oligomers formed by an ionic liquid (IL15). Using IL15-induced recombinant tau oligomers and a dot blot assay, we discovered a mAb (M204) that binds oligomeric tau, but not tau monomers or fibrils. M204 and an engineered single-chain variable fragment (scFv) inhibited seeding by IL15-induced tau oligomers and pathological extracts from donors with AD and chronic traumatic encephalopathy. This finding suggests that M204-scFv targets pathological structures that are formed by tau in neurodegenerative diseases. We found that M204-scFv itself partitions into oligomeric forms that inhibit seeding differently, and crystal structures of the M204-scFv monomer, dimer, and trimer revealed conformational differences that explain differences among these forms in binding and inhibition. The efficiency of M204-scFv antibodies to inhibit the seeding by brain tissue extracts from different donors with tauopathies varied among individuals, indicating the possible existence of distinct amyloid polymorphs. We propose that by binding to oligomers, which are hypothesized to be the earliest seeding-competent species, M204-scFv may have potential as an early-stage diagnostic for AD and tauopathies, and also could guide the development of promising therapeutic antibodies.
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    Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study
    (Nature Research, 2020-02-03) Reiman, Eric M.; Arboleda-Velasquez, Joseph F.; Quiroz, Yakeel T.; Huentelman, Matthew J.; Beach, Thomas G.; Caselli, Richard J.; Chen, Yinghua; Su, Yi; Myers, Amanda J.; Hardy, John; Vonsattel, Jean Paul; Younkin, Steven G.; Bennett, David A.; De Jager, Philip L.; Larson, Eric B.; Crane, Paul K.; Keene, C. Dirk; Kamboh, M. Ilyas; Kofler, Julia K.; Duque, Linda; Gilbert, John R.; Gwirtsman, Harry E.; Buxbaum, Joseph D.; Dickson, Dennis W.; Frosch, Matthew P.; Ghetti, Bernardino F.; Lunetta, Kathryn L.; Wang, Li-San; Hyman, Bradley T.; Kukull, Walter A.; Foroud, Tatiana; Haines, Jonathan L.; Mayeux, Richard P.; Pericak-Vance, Margaret A.; Schneider, Julie A.; Trojanowski, John Q.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Beecham, Gary W.; Montine, Thomas J.; Jun, Gyungah R.; Alzheimer’s Disease Genetics Consortium; Pathology and Laboratory Medicine, School of Medicine
    Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.