Publications by authors named "John Q Trojanowski"

796 Publications

Detection of β-amyloid positivity in Alzheimer's Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers.

Authors:
Duygu Tosun Dallas Veitch Paul Aisen Clifford R Jack William J Jagust Ronald C Petersen Andrew J Saykin James Bollinger Vitaliy Ovod Kwasi G Mawuenyega Randall J Bateman Leslie M Shaw John Q Trojanowski Kaj Blennow Henrik Zetterberg Michael W Weiner

Brain Commun 2021 2;3(2):fcab008. Epub 2021 Feb 2.

San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.

gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid or the β-amyloid/β-amyloid ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer's disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer's disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer's Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid/β-amyloid, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid/β-amyloid as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly ε4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 0.21-0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04-0.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify β-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, , global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid/β-amyloid may be improved by age and genotype.
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http://dx.doi.org/10.1093/braincomms/fcab008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023542PMC
February 2021

Neurofilament Light Chain Related to Longitudinal Decline in Frontotemporal Lobar Degeneration.

Authors:
Jiasi Vicky Zhang David J Irwin Kaj Blennow Henrik Zetterberg Edward B Lee Leslie M Shaw Katya Rascovsky Lauren Massimo Corey T McMillan Alice Chen-Plotkin Lauren Elman Virginia M-Y Lee Leo McCluskey Jon B Toledo Daniel Weintraub David Wolk John Q Trojanowski Murray Grossman

Neurol Clin Pract 2021 Apr;11(2):105-116

Penn Frontotemporal Degeneration Center (JVZ, DJI, KR, L. Massimo, CTM, MG) and Department of Neurology (DJI, KR, L. Massimo, CTM, AC-P, LE, L. McCluskey, D. Wolk, MG), Department of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease Research (EBL, LMS, VM-YL, JBT, JQT), Department of Psychiatry (D. Weintraub), University of Pennsylvania, Philadelphia; Institute of Neuroscience and Physiology (KB, HZ), Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory (KB, HZ), Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at UCL (HZ); and Department of Neurodegenerative Disease (HZ), UCL Institute of Neurology, UK.

Objective: Accurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology.

Methods: This case-control study evaluated CSF NfL, total tau, phosphorylated tau, and β-amyloid in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148). Regression analyses related CSF analytes to longitudinal cognitive decline (follow-up ∼1 year), controlling for demographic variables and core AD CSF analytes.

Results: In FTLD-TDP with known pathology, CSF NfL is significantly elevated compared with controls and significantly associated with longitudinal decline on specific executive and language measures, after controlling for age, disease duration, and core AD CSF analytes. Similar findings are found in the extended cohort, also including clinically identified likely FTLD-TDP. Although CSF NfL is elevated in FTLD-tau compared with controls, the association between NfL and longitudinal cognitive decline is limited to executive measures.

Conclusion: CSF NfL is associated with longitudinal clinical decline in relevant cognitive domains in patients with FTLD-TDP after controlling for demographic factors and core AD CSF analytes and may also be related to longitudinal decline in executive functioning in FTLD-tau.
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http://dx.doi.org/10.1212/CPJ.0000000000000959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032415PMC
April 2021

PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding.

Authors:
Alberto Carpinteiro Soares Andreia Ferreira Jonas Mariën Charlotte Delay Edward Lee John Q Trojanowski Dieder Moechars Wim Annaert Louis De Muynck

J Biol Chem 2021 Apr 5:100636. Epub 2021 Apr 5.

Neuroscience Department, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340, Beerse, Belgium. Electronic address:

Tauopathies, such as Alzheimer's disease (AD), are neurodegenerative disorders characterized by the deposition of hyperphosphorylated tau aggregates. Proteopathic tau seeds spread through the brain in a temporospatial pattern, indicative of transsynaptic propagation. It is hypothesized that reducing the uptake of tau seeds and subsequent induction of tau aggregation could be a potential approach for abrogating disease progression in AD. Here, we studied to what extent different endosomal routes play a role in the neuronal uptake of pre-formed tau seeds. Using pharmacological and genetic tools we identified dynamin-1, actin and Rac1 as key players. Furthermore, inhibition of PIKfyve, a protein downstream of Rac1, reduced both the trafficking of tau seeds into lysosomes as well as the induction of tau aggregation. Our work shows that tau aggregates are internalized by a specific endocytic mechanism and that their fate once internalized can be pharmacologically modulated to reduce tau seeding in neurons.
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http://dx.doi.org/10.1016/j.jbc.2021.100636DOI Listing
April 2021

LRRK2 Kinase Activity Does Not Alter Cell-Autonomous Tau Pathology Development in Primary Neurons.

Authors:
Michael X Henderson Lakshmi Changolkar John Q Trojanowski Virginia M Y Lee

J Parkinsons Dis 2021 Mar 9. Epub 2021 Mar 9.

Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD) and are also associated with genetic risk in idiopathic PD. Mutations in LRRK2, including the most common p.G2019S lead to elevated kinase activity, making LRRK2 kinase inhibitors prime targets for therapeutic development. However, the role of LRRK2 kinase activity in PD pathogenesis has remained unclear. While essentially all LRRK2-PD patients exhibit dopaminergic neuron loss, many of these patients to not have α-synuclein Lewy bodies in their brains. So, what is the neuropathological substrate of LRRK2-PD? Tau has emerged as a possible candidate due to the presence of tau pathology in the majority of LRRK2 mutation carriers and reports of hyperphosphorylated tau in LRRK2 animal models.

Objective: In the current study, we aim to address whether a mutation in LRRK2 changes the cell-autonomous seeding of tau pathology in primary neurons. We also aim to assess whether LRRK2 kinase inhibitors are able to modulate tau pathology.

Methods/results: Treatment of primary neurons with LRRK2 kinase inhibitors leads to prolonged kinase inhibition but does not alter tau pathology induction. The lack of an effect of LRRK2 kinase activity was further confirmed in primary neurons expressing LRRK2G2019S and with two different forms of pathogenic tau. In no case was there more than a minor change in tau pathology induction.

Conclusion: Together, our results indicate that LRRK2 kinase activity is not playing a major role in the induction of tau pathology in individual neurons. Understanding the impact of LRRK2 kinase inhibitors on pathology generation is important as kinase inhibitors move forward in clinical trials.
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http://dx.doi.org/10.3233/JPD-212562DOI Listing
March 2021

COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI).

Authors:
Douglas H Smith Jean-Pierre Dollé Kamar E Ameen-Ali Abigail Bretzin Etty Cortes John F Crary Kristen Dams-O'Connor Ramon Diaz-Arrastia Brian L Edlow Rebecca Folkerth Lili-Naz Hazrati Sidney R Hinds Diego Iacono Victoria E Johnson C Dirk Keene Julia Kofler Gabor G Kovacs Edward B Lee Geoffrey Manley David Meaney Thomas Montine David O Okonkwo Daniel P Perl John Q Trojanowski Douglas J Wiebe Kristine Yaffe Thomas McCabe William Stewart

Acta Neuropathol Commun 2021 03 1;9(1):32. Epub 2021 Mar 1.

Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK.

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.
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http://dx.doi.org/10.1186/s40478-021-01122-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919306PMC
March 2021

Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor.

Authors:
Jun Maeda Takeharu Minamihisamatsu Masafumi Shimojo Xiaoyun Zhou Maiko Ono Yukio Matsuba Bin Ji Hideki Ishii Masanao Ogawa Hiroyasu Akatsu Daita Kaneda Yoshio Hashizume John L Robinson Virginia M-Y Lee Takashi Saito Takaomi C Saido John Q Trojanowski Ming-Rong Zhang Tetsuya Suhara Makoto Higuchi Naruhiko Sahara

Brain Commun 2021 29;3(1):fcab011. Epub 2021 Jan 29.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer's disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (). However, it is yet to be clarified in Alzheimer's disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer's disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer's disease and non-Alzheimer's disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and mice). By contrast, neuritic plaques in Alzheimer's disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer's disease-related neurodegenerative processes.
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http://dx.doi.org/10.1093/braincomms/fcab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901060PMC
January 2021

Frontotemporal lobar degeneration proteinopathies have disparate microscopic patterns of white and grey matter pathology.

Authors:
Lucia A A Giannini Claire Peterson Daniel Ohm Sharon X Xie Corey T McMillan Katya Raskovsky Lauren Massimo EunRah Suh Vivianna M Van Deerlin David A Wolk John Q Trojanowski Edward B Lee Murray Grossman David J Irwin

Acta Neuropathol Commun 2021 02 23;9(1):30. Epub 2021 Feb 23.

Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau) or TDP-43 inclusions (FTLD-TDP) are associated with clinically similar phenotypes. However, these disparate proteinopathies likely differ in cellular severity and regional distribution of inclusions in white matter (WM) and adjacent grey matter (GM), which have been understudied. We performed a neuropathological study of subcortical WM and adjacent GM in a large autopsy cohort (n = 92; FTLD-Tau = 37, FTLD-TDP = 55) using a validated digital image approach. The antemortem clinical phenotype was behavioral-variant frontotemporal dementia (bvFTD) in 23 patients with FTLD-Tau and 42 with FTLD-TDP, and primary progressive aphasia (PPA) in 14 patients with FTLD-Tau and 13 with FTLD-TDP. We used linear mixed-effects models to: (1) compare WM pathology burden between proteinopathies; (2) investigate the relationship between WM pathology burden and WM degeneration using luxol fast blue (LFB) myelin staining; (3) study regional patterns of pathology burden in clinico-pathological groups. WM pathology burden was greater in FTLD-Tau compared to FTLD-TDP across regions (beta = 4.21, SE = 0.34, p < 0.001), and correlated with the degree of WM degeneration in both FTLD-Tau (beta = 0.32, SE = 0.10, p = 0.002) and FTLD-TDP (beta = 0.40, SE = 0.08, p < 0.001). WM degeneration was greater in FTLD-Tau than FTLD-TDP particularly in middle-frontal and anterior cingulate regions (p < 0.05). Distinct regional patterns of WM and GM inclusions characterized FTLD-Tau and FTLD-TDP proteinopathies, and associated in part with clinical phenotype. In FTLD-Tau, WM pathology was particularly severe in the dorsolateral frontal cortex in nonfluent-variant PPA, and GM pathology in dorsolateral and paralimbic frontal regions with some variation across tauopathies. Differently, FTLD-TDP had little WM regional variability, but showed severe GM pathology burden in ventromedial prefrontal regions in both bvFTD and PPA. To conclude, FTLD-Tau and FTLD-TDP proteinopathies have distinct severity and regional distribution of WM and GM pathology, which may impact their clinical presentation, with overall greater severity of WM pathology as a distinguishing feature of tauopathies.
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http://dx.doi.org/10.1186/s40478-021-01129-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901087PMC
February 2021

Cognitive Profile and Markers of Alzheimer Disease-Type Pathology in Patients With Lewy Body Dementias.

Authors:
Erica Howard David J Irwin Katya Rascovsky Naomi Nevler Sanjana Shellikeri Thomas F Tropea Meredith Spindler Andres Deik Alice Chen-Plotkin Andrew Siderowf Nabila Dahodwala Daniel Weintraub Leslie M Shaw John Q Trojanowski Sanjeev N Vaishnavi David A Wolk Dawn Mechanic-Hamilton James F Morley John E Duda Murray Grossman Katheryn A Q Cousins

Neurology 2021 04 16;96(14):e1855-e1864. Epub 2021 Feb 16.

From the Department of Neurology (E.H., D.J.I., K.R., N.N., S.S., T.F.T., M.S., A.D., A.C.-P., A.S., N.D., D.W., S.N.V., D.A.W., D.M.-H., J.F.M., J.E.D., M.G., K.A.Q.C.), Frontotemporal Degeneration Center (E.H., D.J.I., K.R., N.N., S.S., M.G., K.A.Q.C.), Parkinson's Disease and Movement Disorders Center (T.F.T., M.S., A.D., A.C.-P., A.S., N.D., D.W.), Digital Neuropathology Laboratory (D.J.I.), Alzheimer's Disease Center (J.Q.T., S.N.V., D.A.W., D.M.-H.), Center for Neurodegenerative Disease Research (L.M.S., J.Q.T.), and Department of Pathology and Laboratory Medicine (L.M.S., J.Q.T., D.A.W.), Perelman School of Medicine at the University of Pennsylvania; and Michael J. Crescenz VA Medical Center (D.W., J.F.M., J.E.D.), Parkinson's Disease Research, Education, and Clinical Center, Philadelphia, PA.

Objective: To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)-type copathology are more impaired on confrontation naming than those without likely AD-type copathology.

Methods: We selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aβ ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD - AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD - AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes.

Results: Patients with LBD + AD performed worse on BNT than patients with LBD - AD ( = 4.80, = 0.03); both groups performed similarly on LF, RDS, and MMSE (all > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = -0.28, < 0.05) and p-tau (ρ = -0.26, = 0.05) but not Aβ ( > 0.1).

Conclusion: Markers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.
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http://dx.doi.org/10.1212/WNL.0000000000011699DOI Listing
April 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Authors:
Ruth Chia Marya S Sabir Sara Bandres-Ciga Sara Saez-Atienzar Regina H Reynolds Emil Gustavsson Ronald L Walton Sarah Ahmed Coralie Viollet Jinhui Ding Mary B Makarious Monica Diez-Fairen Makayla K Portley Zalak Shah Yevgeniya Abramzon Dena G Hernandez Cornelis Blauwendraat David J Stone John Eicher Laura Parkkinen Olaf Ansorge Lorraine Clark Lawrence S Honig Karen Marder Afina Lemstra Peter St George-Hyslop Elisabet Londos Kevin Morgan Tammaryn Lashley Thomas T Warner Zane Jaunmuktane Douglas Galasko Isabel Santana Pentti J Tienari Liisa Myllykangas Minna Oinas Nigel J Cairns John C Morris Glenda M Halliday Vivianna M Van Deerlin John Q Trojanowski Maurizio Grassano Andrea Calvo Gabriele Mora Antonio Canosa Gianluca Floris Ryan C Bohannan Francesca Brett Ziv Gan-Or Joshua T Geiger Anni Moore Patrick May Rejko Krüger David S Goldstein Grisel Lopez Nahid Tayebi Ellen Sidransky Lucy Norcliffe-Kaufmann Jose-Alberto Palma Horacio Kaufmann Vikram G Shakkottai Matthew Perkins Kathy L Newell Thomas Gasser Claudia Schulte Francesco Landi Erika Salvi Daniele Cusi Eliezer Masliah Ronald C Kim Chad A Caraway Edwin S Monuki Maura Brunetti Ted M Dawson Liana S Rosenthal Marilyn S Albert Olga Pletnikova Juan C Troncoso Margaret E Flanagan Qinwen Mao Eileen H Bigio Eloy Rodríguez-Rodríguez Jon Infante Carmen Lage Isabel González-Aramburu Pascual Sanchez-Juan Bernardino Ghetti Julia Keith Sandra E Black Mario Masellis Ekaterina Rogaeva Charles Duyckaerts Alexis Brice Suzanne Lesage Georgia Xiromerisiou Matthew J Barrett Bension S Tilley Steve Gentleman Giancarlo Logroscino Geidy E Serrano Thomas G Beach Ian G McKeith Alan J Thomas Johannes Attems Christopher M Morris Laura Palmer Seth Love Claire Troakes Safa Al-Sarraj Angela K Hodges Dag Aarsland Gregory Klein Scott M Kaiser Randy Woltjer Pau Pastor Lynn M Bekris James B Leverenz Lilah M Besser Amanda Kuzma Alan E Renton Alison Goate David A Bennett Clemens R Scherzer Huw R Morris Raffaele Ferrari Diego Albani Stuart Pickering-Brown Kelley Faber Walter A Kukull Estrella Morenas-Rodriguez Alberto Lleó Juan Fortea Daniel Alcolea Jordi Clarimon Mike A Nalls Luigi Ferrucci Susan M Resnick Toshiko Tanaka Tatiana M Foroud Neill R Graff-Radford Zbigniew K Wszolek Tanis Ferman Bradley F Boeve John A Hardy Eric J Topol Ali Torkamani Andrew B Singleton Mina Ryten Dennis W Dickson Adriano Chiò Owen A Ross J Raphael Gibbs Clifton L Dalgard Bryan J Traynor Sonja W Scholz

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Nasal vaccine delivery attenuates brain pathology and cognitive impairment in tauopathy model mice.

Authors:
Hiroki Takeuchi Keiko Imamura Bin Ji Kayoko Tsukita Takako Enami Keizo Takao Tsuyoshi Miyakawa Masato Hasegawa Naruhiko Sahara Nobuhisa Iwata Makoto Inoue Hideo Hara Takeshi Tabira Maiko Ono John Q Trojanowski Virginia M-Y Lee Ryosuke Takahashi Tetsuya Suhara Makoto Higuchi Haruhisa Inoue

NPJ Vaccines 2020 Mar 25;5(1):28. Epub 2020 Mar 25.

Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto, Kyoto, 606-8507, Japan.

Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer's disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy.
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http://dx.doi.org/10.1038/s41541-020-0172-yDOI Listing
March 2020

Association of Mitochondrial DNA Genomic Variation With Risk of Pick Disease.

Authors:
Rebecca R Valentino Michael G Heckman Patrick W Johnson Matthew C Baker Alexandra I Soto-Beasley Ronald L Walton Shunsuke Koga Shanu F Roemer EunRan Suh Ryan J Uitti John Q Trojanowski Murray Grossman Vivianna M Van Deerlin Rosa Rademakers Zbigniew K Wszolek Dennis W Dickson Owen A Ross

Neurology 2021 03 10;96(13):e1755-e1760. Epub 2021 Feb 10.

From the Department of Neuroscience (R.R.V., M.C.B., A.I.S.-B., R.L.W., S.K., S.F.R., R.R., D.W.D., O.A.R.), Division of Biomedical Statistics and Informatics (M.G.H., P.W.J.), Department of Neurology (R.J.U., Z.K.W.), and Department of Clinical Genomics (O.A.R.), Mayo Clinic, Jacksonville, FL; Perelman School of Medicine (E.S., J.Q.T., V.M.V.D.) and Department of Neurology (M.G.), University of Pennsylvania, Philadelphia; and VIB-UAntwerp Center for Molecular Neurology (R.R.), University of Antwerp, Belgium.

Objective: To determine whether stable polymorphisms that define mitochondrial haplogroups in mitochondrial DNA (mtDNA) are associated with Pick disease risk, we genotyped 52 pathologically confirmed cases of Pick disease and 910 neurologically healthy controls and performed case-control association analysis.

Methods: Fifty-two pathologically confirmed cases of Pick disease from Mayo Clinic Florida (n = 38) and the University of Pennsylvania (n = 14) and 910 neurologically healthy controls collected from Mayo Clinic Florida were genotyped for unique mtDNA haplogroup-defining variants. Mitochondrial haplogroups were determined, and in a case-control analysis, associations of mtDNA haplogroups with risk of Pick disease were evaluated with logistic regression models that were adjusted for age and sex.

Results: No individual mtDNA haplogroups or superhaplogroups were significantly associated with risk of Pick disease after adjustment for multiple testing ( < 0.0021, considered significant). However, nominally significant ( < 0.05) associations toward an increased risk of Pick disease were observed for mtDNA haplogroup W (5.8% cases vs 1.6% controls, odds ratio [OR] 4.78, = 0.020) and subhaplogroup H4 (5.8% cases vs 1.2% controls, OR 4.82, = 0.021).

Conclusion: Our findings indicate that mtDNA variation is not a disease driver but may influence disease susceptibility. Ongoing genetic assessments in larger cohorts of Pick disease are currently underway.
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http://dx.doi.org/10.1212/WNL.0000000000011649DOI Listing
March 2021

α-Synuclein Spread from Olfactory Bulb Causes Hyposmia, Anxiety, and Memory Loss in BAC-SNCA Mice.

Authors:
Norihito Uemura Jun Ueda Toru Yoshihara Masashi Ikuno Maiko T Uemura Hodaka Yamakado Masahide Asano John Q Trojanowski Ryosuke Takahashi

Mov Disord 2021 Feb 6. Epub 2021 Feb 6.

Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Patients with Parkinson's disease (PD) show motor symptoms as well as various non-motor symptoms. Postmortem studies of PD have suggested that initial alpha-synuclein (α-Syn) pathology develops independently in the olfactory bulb and lower brainstem, spreading from there stereotypically. However, it remains unclear how these two pathological pathways contribute to the clinicopathological progression of PD.

Objective: The objective of this study was to examine the clinicopathological contribution of α-Syn spread from the olfactory bulb.

Methods: We conducted pathological and behavioral analyses of human α-Syn bacterial artificial chromosome transgenic mice injected with α-Syn preformed fibrils into the bilateral olfactory bulb up to 10 months postinjection.

Results: α-Syn preformed fibril injections induced more widespread α-Syn pathology in the transgenic mice than that in wild-type mice. Severe α-Syn pathology in the transgenic mice injected with α-Syn preformed fibrils was initially observed along the olfactory pathway and later in the brain regions that are included in the limbic system and have connections with it. The α-Syn pathology was accompanied by regional atrophy, neuron loss, reactive astrogliosis, and microglial activation, which were remarkable in the hippocampus. Behavioral analyses revealed hyposmia, followed by anxiety-like behavior and memory impairment, but not motor dysfunction, depression-like behavior, or circadian rhythm disturbance.

Conclusion: Our data suggest that α-Syn spread from the olfactory bulb mainly affects the olfactory pathway and limbic system as well as its related regions, leading to the development of hyposmia, anxiety, and memory loss in PD. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28512DOI Listing
February 2021

Hippocampal subfield pathologic Burden in Lewy body diseases versus Alzheimer's disease.

Authors:
David G Coughlin Murray Grossman John Q Trojanowski David J Irwin

Neuropathol Appl Neurobiol 2021 Jan 25. Epub 2021 Jan 25.

Penn Digital Neuropathology Laboratory at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

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http://dx.doi.org/10.1111/nan.12698DOI Listing
January 2021

The development and convergence of co-pathologies in Alzheimer's disease.

Authors:
John L Robinson Hayley Richardson Sharon X Xie EunRan Suh Vivianna M Van Deerlin Brian Alfaro Nicholas Loh Matias Porras-Paniagua Jeffrey J Nirschl David Wolk Virginia M-Y Lee Edward B Lee John Q Trojanowski

Brain 2021 Apr;144(3):953-962

Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Cerebral amyloid angiopathy (CAA), limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) and Lewy bodies occur in the absence of clinical and neuropathological Alzheimer's disease, but their prevalence and severity dramatically increase in Alzheimer's disease. To investigate how plaques, tangles, age and apolipoprotein E ε4 (APOE ε4) interact with co-pathologies in Alzheimer's disease, we analysed 522 participants ≥50 years of age with and without dementia from the Center for Neurodegenerative Disease Research (CNDR) autopsy program and 1340 participants in the National Alzheimer's Coordinating Center (NACC) database. Consensus criteria were applied for Alzheimer's disease using amyloid phase and Braak stage. Co-pathology was staged for CAA (neocortical, allocortical, and subcortical), LATE-NC (amygdala, hippocampal, and cortical), and Lewy bodies (brainstem, limbic, neocortical, and amygdala predominant). APOE genotype was determined for all CNDR participants. Ordinal logistic regression was performed to quantify the effect of independent variables on the odds of having a higher stage after checking the proportional odds assumption. We found that without dementia, increasing age associated with all pathologies including CAA (odds ratio 1.63, 95% confidence interval 1.38-1.94, P < 0.01), LATE-NC (1.48, 1.16-1.88, P < 0.01), and Lewy bodies (1.45, 1.15-1.83, P < 0.01), but APOE ε4 only associated with CAA (4.80, 2.16-10.68, P < 0.01). With dementia, increasing age associated with LATE-NC (1.30, 1.15-1.46, P < 0.01), while Lewy bodies associated with younger ages (0.90, 0.81-1.00, P = 0.04), and APOE ε4 only associated with CAA (2.36, 1.52-3.65, P < 0.01). A longer disease course only associated with LATE-NC (1.06, 1.01-1.11, P = 0.01). Dementia in the NACC cohort associated with the second and third stages of CAA (2.23, 1.50-3.30, P < 0.01), LATE-NC (5.24, 3.11-8.83, P < 0.01), and Lewy bodies (2.41, 1.51-3.84, P < 0.01). Pathologically, increased Braak stage associated with CAA (5.07, 2.77-9.28, P < 0.01), LATE-NC (5.54, 2.33-13.15, P < 0.01), and Lewy bodies (4.76, 2.07-10.95, P < 0.01). Increased amyloid phase associated with CAA (2.27, 1.07-4.80, P = 0.03) and Lewy bodies (6.09, 1.66-22.33, P = 0.01). In summary, we describe widespread distributions of CAA, LATE-NC and Lewy bodies that progressively accumulate alongside plaques and tangles in Alzheimer's disease dementia. CAA interacted with plaques and tangles especially in APOE ε4 positive individuals; LATE-NC associated with tangles later in the disease course; most Lewy bodies associated with moderate to severe plaques and tangles.
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http://dx.doi.org/10.1093/brain/awaa438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041349PMC
April 2021

Astroglial tau pathology alone preferentially concentrates at sulcal depths in chronic traumatic encephalopathy neuropathologic change.

Authors:
John D Arena Victoria E Johnson Edward B Lee Garrett S Gibbons Douglas H Smith John Q Trojanowski William Stewart

Brain Commun 2020 3;2(2):fcaa210. Epub 2020 Dec 3.

Department of Neuropathology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.

Current diagnostic criteria for the neuropathological evaluation of the traumatic brain injury-associated neurodegeneration, chronic traumatic encephalopathy, define the pathognomonic lesion as hyperphosphorylated tau-immunoreactive neuronal and astroglial profiles in a patchy cortical distribution, clustered around small vessels and showing preferential localization to the depths of sulci. However, despite adoption into diagnostic criteria, there has been no formal assessment of the cortical distribution of the specific cellular components defining chronic traumatic encephalopathy neuropathologic change. To address this, we performed comprehensive mapping of hyperphosphorylated tau-immunoreactive neurofibrillary tangles and thorn-shaped astrocytes contributing to chronic traumatic encephalopathy neuropathologic change. From the Glasgow Traumatic Brain Injury Archive and the University of Pennsylvania Center for Neurodegenerative Disease Research Brain Bank, material was selected from patients with known chronic traumatic encephalopathy neuropathologic change, either following exposure to repetitive mild (athletes  = 17; non-athletes  = 1) or to single moderate or severe traumatic brain injury ( = 4), together with material from patients with previously confirmed Alzheimer's disease neuropathologic changes ( = 6) and no known exposure to traumatic brain injury. Representative sections were stained for hyperphosphorylated or Alzheimer's disease conformation-selective tau, after which stereotypical neurofibrillary tangles and thorn-shaped astrocytes were identified and mapped. Thorn-shaped astrocytes in chronic traumatic encephalopathy neuropathologic change were preferentially distributed towards sulcal depths [sulcal depth to gyral crest ratio of thorn-shaped astrocytes 12.84 ± 15.47 (mean ± standard deviation)], with this pathology more evident in material from patients with a history of survival from non-sport injury than those exposed to sport-associated traumatic brain injury ( = 0.009). In contrast, neurofibrillary tangles in chronic traumatic encephalopathy neuropathologic change showed a more uniform distribution across the cortex in sections stained for either hyperphosphorylated (sulcal depth to gyral crest ratio of neurofibrillary tangles 1.40 ± 0.74) or Alzheimer's disease conformation tau (sulcal depth to gyral crest ratio 1.64 ± 1.05), which was comparable to that seen in material from patients with known Alzheimer's disease neuropathologic changes ( = 0.82 and  = 0.91, respectively). Our data demonstrate that in chronic traumatic encephalopathy neuropathologic change the astroglial component alone shows preferential distribution to the depths of cortical sulci. In contrast, the neuronal pathology of chronic traumatic encephalopathy neuropathologic change is distributed more uniformly from gyral crest to sulcal depth and echoes that of Alzheimer's disease. These observations provide new insight into the neuropathological features of chronic traumatic encephalopathy that distinguish it from other tau pathologies and suggest that current diagnostic criteria should perhaps be reviewed and refined.
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http://dx.doi.org/10.1093/braincomms/fcaa210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784042PMC
December 2020

Evaluation of the Structure-Activity Relationship of Microtubule-Targeting 1,2,4-Triazolo[1,5-]pyrimidines Identifies New Candidates for Neurodegenerative Tauopathies.

Authors:
Killian Oukoloff Goodwell Nzou Carmine Varricchio Bobby Lucero Thibault Alle Jane Kovalevich Ludovica Monti Anne-Sophie Cornec Yuemang Yao Michael J James John Q Trojanowski Virginia M-Y Lee Amos B Smith Andrea Brancale Kurt R Brunden Carlo Ballatore

J Med Chem 2021 01 7;64(2):1073-1102. Epub 2021 Jan 7.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.

Studies in tau and Aβ plaque transgenic mouse models demonstrated that brain-penetrant microtubule (MT)-stabilizing compounds, including the 1,2,4-triazolo[1,5-]pyrimidines, hold promise as candidate treatments for Alzheimer's disease and related neurodegenerative tauopathies. Triazolopyrimidines have already been investigated as anticancer agents; however, the antimitotic activity of these compounds does not always correlate with stabilization of MTs in cells. Indeed, previous studies from our laboratories identified a critical role for the fragment linked at C6 in determining whether triazolopyrimidines promote MT stabilization or, conversely, disrupt MT integrity in cells. To further elucidate the structure-activity relationship (SAR) and to identify potentially improved MT-stabilizing candidates for neurodegenerative disease, a comprehensive set of 68 triazolopyrimidine congeners bearing structural modifications at C6 and/or C7 was designed, synthesized, and evaluated. These studies expand upon prior understanding of triazolopyrimidine SAR and enabled the identification of novel analogues that, relative to the existing lead, exhibit improved physicochemical properties, MT-stabilizing activity, and pharmacokinetics.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01605DOI Listing
January 2021

Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study.

Authors:
Johannes Attems Jon B Toledo Lauren Walker Ellen Gelpi Steve Gentleman Glenda Halliday Tibor Hortobagyi Kurt Jellinger Gabor G Kovacs Edward B Lee Seth Love Kirsty E McAleese Peter T Nelson Manuela Neumann Laura Parkkinen Tuomo Polvikoski Beata Sikorska Colin Smith Lea Tenenholz Grinberg Dietmar R Thal John Q Trojanowski Ian G McKeith

Acta Neuropathol 2021 02 5;141(2):159-172. Epub 2021 Jan 5.

Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., "absent" vs. "present") and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff's α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff's α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.
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http://dx.doi.org/10.1007/s00401-020-02255-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847437PMC
February 2021

Psychometric Properties of the Clinical Dementia Rating Scale Sum of Boxes in Parkinson's Disease.

Authors:
Julia Gallagher Jacqueline Rick Sharon X Xie Pablo Martinez-Martin Eugenia Mamikonyan Alice Chen-Plotkin Nabila Dahodwala James Morley John E Duda John Q Trojanowski Andrew Siderowf Daniel Weintraub

J Parkinsons Dis 2020 Dec 29. Epub 2020 Dec 29.

Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Background: A composite measure that assesses both cognitive and functional abilities in Parkinson's disease (PD) would be useful for diagnosing mild cognitive impairment (MCI) and PD dementia (PDD) and as an outcome measure in randomized controlled trials. The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) was designed to assess both cognition and basic-instrumental activities of daily living in Alzheimer's disease but has not yet been validated in PD.

Objective: To validate the CDR-SOB as a composite cognitive-functional measure for PD patients, as well as to assess its sensitivity to change.

Methods: The CDR-SOB and a comprehensive cognitive and functional battery was administered to 101 PD patients at baseline (39 normal cognition [NC], 41 MCI and 21 PDD by expert consensus panel), and re-administered to 64 patients after 1-2 years follow-up (32 NC and 32 cognitive impairment [CI] at baseline).

Results: Cross-sectionally, CDR-SOB and domain scores were correlated with corresponding neuropsychological or functional measures and were significantly different between cognitive subgroups both at baseline and at follow-up. In addition, CDR-SOB ROC curves distinguished between normal cognition and dementia with high sensitivity, but did not distinguish well between NC and MCI. Longitudinal changes in the CDR-SOB and domain scores were not significant and were inconsistent in predicting change in commonly-used cognitive and functional tests.

Conclusion: The CDR-SOB detects dementia-level cognitive impairment in PD but may not be appropriate for predicting longitudinal combined cognitive-functional changes in patients without significant cognitive impairment at baseline.
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http://dx.doi.org/10.3233/JPD-202390DOI Listing
December 2020

In vitro amplification of pathogenic tau conserves disease-specific bioactive characteristics.

Authors:
Hong Xu Mia O'Reilly Garrett S Gibbons Lakshmi Changolkar Jennifer D McBride Dawn M Riddle Bin Zhang Anna Stieber Jeffrey Nirschl Soo-Jung Kim Kevt-Her Hoxha Kurt R Brunden Gerard D Schellenberg John Q Trojanowski Virginia M-Y Lee

Acta Neuropathol 2021 02 1;141(2):193-215. Epub 2021 Jan 1.

Department of Pathology and Laboratory Medicine, Institute On Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.

The microtubule-associated protein tau (tau) forms hyperphosphorylated aggregates in the brains of tauopathy patients that can be pathologically and biochemically defined as distinct tau strains. Recent studies show that these tau strains exhibit strain-specific biological activities, also referred to as pathogenicities, in the tau spreading models. Currently, the specific pathogenicity of human-derived tau strains cannot be fully recapitulated by synthetic tau preformed fibrils (pffs), which are generated from recombinant tau protein. Reproducing disease-relevant tau pathology in cell and animal models necessitates the use of human brain-derived tau seeds. However, the availability of human-derived tau is extremely limited. Generation of tau variants that can mimic the pathogenicity of human-derived tau seeds would significantly extend the scale of experimental design within the field of tauopathy research. Previous studies have demonstrated that in vitro seeding reactions can amplify the beta-sheet structure of tau protein from a minute quantity of human-derived tau. However, whether the strain-specific pathogenicities of the original, human-derived tau seeds are conserved in the amplified tau strains has yet to be experimentally validated. Here, we used biochemically enriched brain-derived tau seeds from Alzheimer's disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) patient brains with a modified seeding protocol to template the recruitment of recombinant 2N4R (T40) tau in vitro. We quantitatively interrogated efficacy of the amplification reactions and the pathogenic fidelity of the amplified material to the original tau seeds using recently developed sporadic tau spreading models. Our data suggest that different tau strains can be faithfully amplified in vitro from tau isolated from different tauopathy brains and that the amplified tau variants retain their strain-dependent pathogenic characteristics.
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http://dx.doi.org/10.1007/s00401-020-02253-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847465PMC
February 2021

Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy.

Authors:
Jamie M Walker Timothy E Richardson Kurt Farrell Megan A Iida Chan Foong Ping Shang Johannes Attems Gai Ayalon Thomas G Beach Eileen H Bigio Andrew Budson Nigel J Cairns María Corrada Etty Cortes Dennis W Dickson Peter Fischer Margaret E Flanagan Erin Franklin Marla Gearing Jonathan Glass Lawrence A Hansen Vahram Haroutunian Patrick R Hof Lawrence Honig Claudia Kawas C Dirk Keene Julia Kofler Gabor G Kovacs Edward B Lee Mirjam I Lutz Qinwen Mao Eliezer Masliah Ann C McKee Corey T McMillan M Marsel Mesulam Melissa Murray Peter T Nelson Richard Perrin Thao Pham Wayne Poon Dushyant P Purohit Robert A Rissman Kenji Sakai Mary Sano Julie A Schneider Thor D Stein Andrew F Teich John Q Trojanowski Juan C Troncoso Jean-Paul Vonsattel Sandra Weintraub David A Wolk Randall L Woltjer Masahito Yamada Lei Yu Charles L White John F Crary

J Neuropathol Exp Neurol 2021 Jan;80(2):102-111

Department of Pathology and Nash Family Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.
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http://dx.doi.org/10.1093/jnen/nlaa153DOI Listing
January 2021

Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis.

Authors:
Katerina Placek Michael Benatar Joanne Wuu Evadnie Rampersaud Laura Hennessy Vivianna M Van Deerlin Murray Grossman David J Irwin Lauren Elman Leo McCluskey Colin Quinn Volkan Granit Jeffrey M Statland Ted M Burns John Ravits Andrea Swenson Jon Katz Erik P Pioro Carlayne Jackson James Caress Yuen So Samuel Maiser David Walk Edward B Lee John Q Trojanowski Philip Cook James Gee Jin Sha Adam C Naj Rosa Rademakers Wenan Chen Gang Wu J Paul Taylor Corey T McMillan

EMBO Mol Med 2021 Jan 3;13(1):e12595. Epub 2020 Dec 3.

Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.
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http://dx.doi.org/10.15252/emmm.202012595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799365PMC
January 2021

ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration.

Authors:
Katheryn A Q Cousins Jeffrey S Phillips David J Irwin Edward B Lee David A Wolk Leslie M Shaw Henrik Zetterberg Kaj Blennow Sarah E Burke Nikolas G Kinney Garrett S Gibbons Corey T McMillan John Q Trojanowski Murray Grossman

Alzheimers Dement 2020 Nov 23. Epub 2020 Nov 23.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Introduction: The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATN ) using CSF total tau (t-tau) to a modified strategy (ATN ) using CSF neurofilament light chain (NfL) in an autopsy cohort.

Methods: ATN and ATN were trained in an independent sample and validated in autopsy-confirmed AD (n = 67) and FTLD (n = 27).

Results: ATN more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATN (sensitivity = 0.44, specificity = 0.97), even in cases with co-occurring AD and FTLD. ATN misclassified fewer AD and FTLD as "Normal" (2%) than ATN (14%).

Discussion: ATN is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co-occur.
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http://dx.doi.org/10.1002/alz.12233DOI Listing
November 2020

Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression.

Authors:
Jessica E Rexach Damon Polioudakis Anna Yin Vivek Swarup Timothy S Chang Tam Nguyen Arjun Sarkar Lawrence Chen Jerry Huang Li-Chun Lin William Seeley John Q Trojanowski Dheeraj Malhotra Daniel H Geschwind

Cell Rep 2020 Nov;33(7):108398

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

To understand how neural-immune-associated genes and pathways contribute to neurodegenerative disease pathophysiology, we performed a systematic functional genomic analysis in purified microglia and bulk tissue from mouse and human AD, FTD, and PSP. We uncover a complex temporal trajectory of microglial-immune pathways involving the type 1 interferon response associated with tau pathology in the early stages, followed by later signatures of partial immune suppression and, subsequently, the type 2 interferon response. We find that genetic risk for dementias shows disease-specific patterns of pathway enrichment. We identify drivers of two gene co-expression modules conserved from mouse to human, representing competing arms of microglial-immune activation (NAct) and suppression (NSupp) in neurodegeneration. We validate our findings by using chemogenetics, experimental perturbation data, and single-cell sequencing in post-mortem brains. Our results refine the understanding of stage- and disease-specific microglial responses, implicate microglial viral defense pathways in dementia pathophysiology, and highlight therapeutic windows.
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http://dx.doi.org/10.1016/j.celrep.2020.108398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842189PMC
November 2020

Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer's disease.

Authors:
Garrett S Gibbons Soo-Jung Kim Qihui Wu Dawn M Riddle Susan N Leight Lakshmi Changolkar Hong Xu Emily S Meymand Mia O'Reilly Bin Zhang Kurt R Brunden John Q Trojanowski Virginia M Y Lee

Mol Neurodegener 2020 11 4;15(1):64. Epub 2020 Nov 4.

Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3600 Spruce St. 3 Maloney, Philadelphia, PA, 19104, USA.

Background: The spread of tau pathology in Alzheimer's disease (AD) is mediated by cell-to-cell transmission of pathological tau seeds released from neurons that, upon internalization by recipient neurons, template the misfolding of naïve cellular tau, thereby propagating fibrillization. We hypothesize that anti-tau monoclonal antibodies (mAbs) that selectively bind to pathological tau seeds will inhibit propagation of tau aggregates and reduce the spread of tau pathology in vivo.

Methods: We inoculated mice with human AD brain-derived extracts containing tau paired helical filaments (AD-tau) and identified two novel mAbs, DMR7 and SKT82, that selectively bind to a misfolded pathological conformation of tau relative to recombinant tau monomer. To evaluate the effects of these mAbs on the spread of pathological tau in vivo, 5xFAD mice harboring significant brain Aβ plaque burden were unilaterally injected with AD-tau in the hippocampus, to initiate the formation of neuritic plaque (NP) tau pathology, and were treated weekly with intraperitoneal (i.p.) injections of DMR7, SKT82, or IgG isotype control mAbs.

Results: DMR7 and SKT82 bind epitopes comprised of the proline-rich domain and c-terminal region of tau and binding is reduced upon disruption of the pathological conformation of AD-tau by chemical and thermal denaturation. We found that both DMR7 and SKT82 immunoprecipitate pathological tau and significantly reduce the seeding of cellular tau aggregates induced by AD-tau in primary neurons by 60.5 + 13.8% and 82.2 + 8.3%, respectively, compared to IgG control. To investigate the mechanism of mAb inhibition, we generated pH-sensitive fluorophore-labeled recombinant tau fibrils seeded by AD-tau to track internalization of tau seeds and demonstrate that the conformation-selective tau mAbs inhibit the internalization of tau seeds. DMR7 and SKT82 treatment reduced hyperphosphorylated NP tau as measured with AT8 immunohistochemistry (IHC) staining, but did not achieve statistical significance in the contralateral cortex and SKT82 significantly reduced tau pathology in the ipsilateral hippocampus by 24.2%; p = 0.044.

Conclusions: These findings demonstrate that conformation-selective tau mAbs, DMR7 and SKT82, inhibit tau pathology in primary neurons by preventing the uptake of tau seeds and reduce tau pathology in vivo, providing potential novel therapeutic candidates for the treatment of AD.
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http://dx.doi.org/10.1186/s13024-020-00404-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643305PMC
November 2020

An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline.

Authors:
Hanna Trzeciakiewicz Deepa Ajit Jui-Heng Tseng Youjun Chen Aditi Ajit Zarin Tabassum Rebecca Lobrovich Claire Peterson Natallia V Riddick Michelle S Itano Ashutosh Tripathy Sheryl S Moy Virginia M Y Lee John Q Trojanowski David J Irwin Todd J Cohen

Nat Commun 2020 11 2;11(1):5522. Epub 2020 Nov 2.

Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, 27599-7260, USA.

Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.
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http://dx.doi.org/10.1038/s41467-020-19317-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606452PMC
November 2020

High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies.

Authors:
Kenji Tagai Maiko Ono Manabu Kubota Soichiro Kitamura Keisuke Takahata Chie Seki Yuhei Takado Hitoshi Shinotoh Yasunori Sano Yasuharu Yamamoto Kiwamu Matsuoka Hiroyuki Takuwa Masafumi Shimojo Manami Takahashi Kazunori Kawamura Tatsuya Kikuchi Maki Okada Haruhiko Akiyama Hisaomi Suzuki Mitsumoto Onaya Takahiro Takeda Kimihito Arai Nobutaka Arai Nobuyuki Araki Yuko Saito John Q Trojanowski Virginia M Y Lee Sushil K Mishra Yoshiki Yamaguchi Yasuyuki Kimura Masanori Ichise Yutaka Tomita Ming-Rong Zhang Tetsuya Suhara Masahiro Shigeta Naruhiko Sahara Makoto Higuchi Hitoshi Shimada

Neuron 2021 01 29;109(1):42-58.e8. Epub 2020 Oct 29.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.
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http://dx.doi.org/10.1016/j.neuron.2020.09.042DOI Listing
January 2021

Tau pathology associates with in vivo cortical thinning in Lewy body disorders.

Authors:
Nicola Spotorno David G Coughlin Christopher A Olm David Wolk Sanjeev N Vaishnavi Leslie M Shaw Nabila Dahodwala James F Morley John E Duda Andres F Deik Meredith A Spindler Alice Chen-Plotkin Edward B Lee John Q Trojanowski Corey T McMillan Daniel Weintraub Murray Grossman David J Irwin

Ann Clin Transl Neurol 2020 12 27;7(12):2342-2355. Epub 2020 Oct 27.

Penn Frontotemporal Degeneration Center, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Objectives: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD).

Methods: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aβ  > 0.3) (LBD+AD, N = 19), and those without AD co-pathology (LBD-AD, N = 53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aβ, and alpha-synuclein using digital histopathology in five representative neocortical regions.

Results: The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE-corrected) relative to LBD-AD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post-mortem tau pathology, while cortical thickness was not significantly associated with Aβ or alpha-synuclein pathology.

Interpretation: LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post-mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD.
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http://dx.doi.org/10.1002/acn3.51183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732256PMC
December 2020

Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer's Disease Neuroimaging Initiative.

Authors:
Thomas K Karikari Andréa L Benedet Nicholas J Ashton Juan Lantero Rodriguez Anniina Snellman Marc Suárez-Calvet Paramita Saha-Chaudhuri Firoza Lussier Hlin Kvartsberg Alexis Moscoso Rial Tharick A Pascoal Ulf Andreasson Michael Schöll Michael W Weiner Pedro Rosa-Neto John Q Trojanowski Leslie M Shaw Kaj Blennow Henrik Zetterberg

Mol Psychiatry 2021 02 26;26(2):429-442. Epub 2020 Oct 26.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4-89.2%), as well as to distinguish between Aβ- and Aβ+ individuals along the Alzheimer's continuum (AUC = 76.9%; 95% CI, 74.0-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.
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http://dx.doi.org/10.1038/s41380-020-00923-zDOI Listing
February 2021

α-Synuclein modulates tau spreading in mouse brains.

Authors:
Fares Bassil Emily S Meymand Hannah J Brown Hong Xu Timothy O Cox Shankar Pattabhiraman Chantal M Maghames Qihui Wu Bin Zhang John Q Trojanowski Virginia M-Y Lee

J Exp Med 2021 Jan;218(1)

The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate-derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.
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http://dx.doi.org/10.1084/jem.20192193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588140PMC
January 2021

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

Authors:
Brian W Kunkle Michael Schmidt Hans-Ulrich Klein Adam C Naj Kara L Hamilton-Nelson Eric B Larson Denis A Evans Phil L De Jager Paul K Crane Joe D Buxbaum Nilufer Ertekin-Taner Lisa L Barnes M Daniele Fallin Jennifer J Manly Rodney C P Go Thomas O Obisesan M Ilyas Kamboh David A Bennett Kathleen S Hall Alison M Goate Tatiana M Foroud Eden R Martin Li-Sao Wang Goldie S Byrd Lindsay A Farrer Jonathan L Haines Gerard D Schellenberg Richard Mayeux Margaret A Pericak-Vance Christiane Reitz Neill R Graff-Radford Izri Martinez Temitope Ayodele Mark W Logue Laura B Cantwell Melissa Jean-Francois Amanda B Kuzma L D Adams Jeffery M Vance Michael L Cuccaro Jaeyoon Chung Jesse Mez Kathryn L Lunetta Gyungah R Jun Oscar L Lopez Hugh C Hendrie Eric M Reiman Neil W Kowall James B Leverenz Scott A Small Allan I Levey Todd E Golde Andrew J Saykin Takiyah D Starks Marilyn S Albert Bradley T Hyman Ronald C Petersen Mary Sano Thomas Wisniewski Robert Vassar Jeffrey A Kaye Victor W Henderson Charles DeCarli Frank M LaFerla James B Brewer Bruce L Miller Russell H Swerdlow Linda J Van Eldik Henry L Paulson John Q Trojanowski Helena C Chui Roger N Rosenberg Suzanne Craft Thomas J Grabowski Sanjay Asthana John C Morris Stephen M Strittmatter Walter A Kukull

JAMA Neurol 2021 Jan;78(1):102-113

National Alzheimer's Coordinating Center, University of Washington, Seattle.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

Design, Setting, And Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

Main Outcomes And Measures: Diagnosis of Alzheimer disease.

Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

Conclusions And Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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http://dx.doi.org/10.1001/jamaneurol.2020.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573798PMC
January 2021