Digital Commons Network^™

The Performance Of Plasma Amyloid Beta Measurements In Identifying Amyloid Plaques In Alzheimer's Disease: A Literature Review, Abby L Brand, Paige E Lawler, James G Bollinger, Yan Li, Suzanne E Schindler, Melody Li, Samir Lopez, Vitaliy Ovod, Akinori Nakamura, Leslie M Shaw, Henrik Zetterberg, Oskar Hansson, Randall J Bateman

2020-Current year OA Pubs

The extracellular buildup of amyloid beta (Aβ) plaques in the brain is a hallmark of Alzheimer's disease (AD). Detection of Aβ pathology is essential for AD diagnosis and for identifying and recruiting research participants for clinical trials evaluating disease-modifying therapies. Currently, AD diagnoses are usually made by clinical assessments, although detection of AD pathology with positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis can be used by specialty clinics. These measures of Aβ aggregation, e.g. plaques, protofibrils, and oligomers, are medically invasive and often only available at specialized medical centers or not covered by medical insurance, and PET …

Trem2 Dependent And Independent Functions Of Microglia In Alzheimer's Disease, Jinchao Hou, Yun Chen, Gary Grajales-Reyes, Marco Colonna

2020-Current year OA Pubs

Microglia are central players in brain innate immunity and have been the subject of extensive research in Alzheimer's disease (AD). In this review, we aim to summarize the genetic and functional discoveries that have advanced our understanding of microglia reactivity to AD pathology. Given the heightened AD risk posed by rare variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2), we will focus on the studies addressing the impact of this receptor on microglia responses to amyloid plaques, tauopathy and demyelination pathologies in mouse and human. Finally, we will discuss the implications of recent discoveries on microglia …

Lecanemab In Patients With Early Alzheimer's Disease: Detailed Results On Biomarker, Cognitive, And Clinical Effects From The Randomized And Open-Label Extension Of The Phase 2 Proof-Of-Concept Study, Eric Mcdade, Jeffrey L Cummings, Shobha Dhadda, Chad J Swanson, Larisa Reyderman, Michio Kanekiyo, Akihiko Koyama, Michael Irizarry, Lynn D Kramer, Randall J Bateman

2020-Current year OA Pubs

BACKGROUND: Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab.

METHODS: The lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly …

Differential Roles Of Aβ42/40, P-Tau231 And P-Tau217 For Alzheimer's Trial Selection And Disease Monitoring, Nicholas J Ashton, Yan Li, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio …

Transferability Of Alzheimer Disease Polygenic Risk Score Across Populations And Its Association With Alzheimer Disease-Related Phenotypes, Sang-Hyuk Jung, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry.

OBJECTIVE: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases …

Vascular Endothelial-Cadherin As A Marker Of Endothelial Injury In Preclinical Alzheimer Disease, Rawan Tarawneh, Rachel S Kasper, Jessie Sanford, Chia-Ling Phuah, Jason Hassenstab, Carlos Cruchaga

2020-Current year OA Pubs

OBJECTIVE: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD.

METHODS: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Aβ42/Aβ40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) …

Gantenerumab: An Anti-Amyloid Monoclonal Antibody With Potential Disease-Modifying Effects In Early Alzheimer's Disease, Randall J Bateman, Jeffrey Cummings, Scott Schobel, Stephen Salloway, Bruno Vellas, Mercè Boada, Sandra E Black, Kaj Blennow, Paulo Fontoura, Gregory Klein, Sheila Seleri Assunção, Janice Smith, Rachelle S Doody

2020-Current year OA Pubs

BACKGROUND: This review describes the research and development process of gantenerumab, a fully human anti-amyloid monoclonal antibody in development to treat early symptomatic and asymptomatic Alzheimer's disease (AD). Anti-amyloid monoclonal antibodies can substantially reverse amyloid plaque pathology and may modify the course of the disease by slowing or stopping its clinical progression. Several molecules targeting amyloid have failed in clinical development due to drug-related factors (e.g., treatment-limiting adverse events, low potency, poor brain penetration), study design/methodological issues (e.g., disease stage, lack of AD pathology confirmation), and other factors. The US Food and Drug Administration's approval of aducanumab, an anti-amyloid monoclonal …

Csf Tau Microtubule-Binding Region Identifies Pathological Changes In Primary Tauopathies, Kanta Horie, Nicolas R Barthélemy, Yingxin He, Albert A Davis, Celeste M Karch, Richard J Perrin, Rama K Koppisetti, Faris Shaikh, Nupur Ghoshal, Randall J Bateman, Chihiro Sato, Et Al.

2020-Current year OA Pubs

Despite recent advances in fluid biomarker research in Alzheimer's disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau

Β-Amyloid Pet Harmonisation Across Longitudinal Studies: Application To Aibl, Adni And Oasis3, Pierrick Bourgeat, Manu Goyal, Pamela Lamontagne, John C Morris, Et Al.

2020-Current year OA Pubs

INTRODUCTION: The Centiloid scale was developed to harmonise the quantification of β-amyloid (Aβ) PET images across tracers, scanners, and processing pipelines. However, several groups have reported differences across tracers and scanners even after centiloid conversion. In this study, we aim to evaluate the impact of different pre and post-processing harmonisation steps on the robustness of longitudinal Centiloid data across three large international cohort studies.

METHODS: All Aβ PET data in AIBL (N = 3315), ADNI (N = 3442) and OASIS3 (N = 1398) were quantified using the MRI-based Centiloid standard SPM pipeline and the PET-only pipeline CapAIBL. SUVR were converted …

Genome-Wide Meta-Analysis For Alzheimer's Disease Cerebrospinal Fluid Biomarkers, Iris E Jansen, Muhammad Ali, Yun Ju Sung, Carlos Cruchaga, Duber Gomez-Fonseca, Et Al.

2020-Current year OA Pubs

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for …

Covariance-Based Vs. Correlation-Based Functional Connectivity Dissociates Healthy Aging From Alzheimer Disease, Jeremy F. Strain, Matthew R. Brier, Aaron Tanenbaum, Brian A. Gordon, John E. Mccarthy, Aylin Dincer, Daniel S. Marcus, Richard J. Perrin, John C. Morris, Tammie L. S. Benzinger, Randall J. Bateman, Beau M. Ances, Abraham Z. Snyder, Et Al.

2020-Current year OA Pubs

Prior studies of aging and Alzheimer disease have evaluated resting state functional connectivity (FC) using either seed-based correlation (SBC) or independent component analysis (ICA), with a focus on particular functional systems. SBC and ICA both are insensitive to differences in signal amplitude. At the same time, accumulating evidence indicates that the amplitude of spontaneous BOLD signal fluctuations is physiologically meaningful. We systematically compared covariance-based FC, which is sensitive to amplitude, vs. correlation-based FC, which is not, in affected individuals and controls drawn from two cohorts of participants including autosomal dominant Alzheimer disease (ADAD), late onset Alzheimer disease (LOAD), and age-matched …

Herpes Simplex Virus And Rates Of Cognitive Decline Or Whole Brain Atrophy In The Dominantly Inherited Alzheimer Network, Charlotte Warren-Gash, Brian A Gordon, Eric Mcdade, Randall J Bateman, John C Morris, Et Al.

2020-Current year OA Pubs

OBJECTIVE: To investigate whether herpes simplex virus type 1 (HSV-1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN).

METHODS: Among two subsets of the DIAN cohort (age range 19.6-66.6 years; median follow-up 3.0 years) we examined (i) rate of cognitive decline (N = 164) using change in mini-mental state examination (MMSE) score, (ii) rate of whole brain atrophy (N = 149), derived from serial MR imaging, calculated using the boundary shift integral (BSI) method. HSV-1 antibodies were assayed in baseline sera collected from 2009-2015. Linear mixed-effects models …

Comparison Of Plasma And Csf Biomarkers In Predicting Cognitive Decline, Andrew J Aschenbrenner, Yan Li, Rachel L Henson, Katherine Volluz, Jason Hassenstab, Philip Verghese, Tim West, Matthew R Meyer, Kristopher M Kirmess, Anne M Fagan, Chengjie Xiong, David Holtzman, John C Morris, Randall J Bateman, Suzanne E Schindler

2020-Current year OA Pubs

OBJECTIVES: Concentrations of amyloid-β peptides (Aβ42/Aβ40) and neurofilament light (NfL) can be measured in plasma or cerebrospinal fluid (CSF) and are associated with Alzheimer's disease brain pathology and cognitive impairment. This study directly compared plasma and CSF measures of Aβ42/Aβ40 and NfL as predictors of cognitive decline.

METHODS: Participants were 65 years or older and cognitively normal at baseline with at least one follow-up cognitive assessment. Analytes were measured with the following types of assays: plasma Aβ42/Aβ40, immunoprecipitation-mass spectrometry; plasma NfL, Simoa; CSF Aβ42/Aβ40, automated immunoassay; CSF NfL plate-based immunoassay. Mixed effects models evaluated the global cognitive composite score over …

Amyloid Β, Lipid Metabolism, Basal Cholinergic System, And Therapeutics In Alzheimer's Disease, Victoria Campos-Peña, Pavel Pichardo-Rojas, Talía Sánchez-Barbosa, Emma Ortíz-Islas, Citlali Ekaterina Rodríguez-Pérez, Pedro Montes, Gerardo Ramos-Palacios, Daniela Silva-Adaya, Rafael Valencia-Quintana, Jorge Francisco Cerna-Cortes, Danira Toral-Rios

2020-Current year OA Pubs

The presence of insoluble aggregates of amyloid β (Aβ) in the form of neuritic plaques (NPs) is one of the main features that define Alzheimer's disease. Studies have suggested that the accumulation of these peptides in the brain significantly contributes to extensive neuronal loss. Furthermore, the content and distribution of cholesterol in the membrane have been shown to have an important effect on the production and subsequent accumulation of Aβ peptides in the plasma membrane, contributing to dysfunction and neuronal death. The monomeric forms of these membrane-bound peptides undergo several conformational changes, ranging from oligomeric forms to beta-sheet structures, each …

The Metabolism Of Human Soluble Amyloid Precursor Protein Isoforms Is Quantifiable By A Stable Isotope Labeling-Tandem Mass Spectrometry Method, Justyna A Dobrowolska Zakaria, Randall J Bateman, Monika Lysakowska, Ammaarah Khatri, Dinorah Jean-Gilles, Matthew E Kennedy, Robert Vassar

2020-Current year OA Pubs

Evidence suggests that β-secretase (BACE1), which cleaves Amyloid Precursor Protein (APP) to form sAPPβ and amyloid-β, is elevated in Alzheimer's disease (AD) brains and biofluids and, thus, BACE1 is a therapeutic target for this devastating disease. The direct product of BACE1 cleavage of APP, sAPPβ, serves as a surrogate marker of BACE1 activity in the central nervous system. This biomarker could be utilized to better understand normal APP processing, aberrant processing in the disease setting, and modulations to processing during therapeutic intervention. In this paper, we present a method for measuring the metabolism of sAPPβ and another APP proteolytic product, …

Corpora Amylacea Are Associated With Tau Burden And Cognitive Status In Alzheimer's Disease, Connor M Wander, Tamy Harumy Moraes Tsujimoto, John F Ervin, Chanung Wang, Spencer M Maranto, Vanya Bhat, Julian D Dallmeier, Shih-Hsiu Jerry Wang, Feng-Chang Lin, William K Scott, David M Holtzman, Todd J Cohen

2020-Current year OA Pubs

Corpora amylacea (CA) and their murine analogs, periodic acid Schiff (PAS) granules, are age-related, carbohydrate-rich structures that serve as waste repositories for aggregated proteins, damaged cellular organelles, and other cellular debris. The structure, morphology, and suspected functions of CA in the brain imply disease relevance. Despite this, the link between CA and age-related neurodegenerative diseases, particularly Alzheimer's disease (AD), remains poorly defined. We performed a neuropathological analysis of mouse PAS granules and human CA and correlated these findings with AD progression. Increased PAS granule density was observed in symptomatic tau transgenic mice and APOE knock-in mice. Using a cohort of …

Discovery And Validation Of Dominantly Inherited Alzheimer's Disease Mutations In Populations From Latin America, Leonel Tadao Takada, Bhagyashri D Burgute, Ellen Ziegemeier, Jennifer Petranek, Carlos Cruchaga, Maria Victoria Fernández, Eric Mcdade, Randall J Bateman, Celeste M Karch, Jorge J Llibre-Guerra, Et Al.

2020-Current year OA Pubs

BACKGROUND: In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations.

METHODS: Clinical data was collected from LatAm families at risk …

Predicting Brain Age From Functional Connectivity In Symptomatic And Preclinical Alzheimer Disease, Peter R. Millar, Patrick H. Luckett, Brian A. Gordon, Tammie L. S. Benzinger, Suzanne E. Schindler, Anne M. Fagan, Carlos Cruchaga, Randall J. Bateman, Ricardo Allegri, Mathias Jucker, Jae-Hong Lee, Hiroshi Mori, Stephen P. Salloway, Igor Yakushev, John C. Morris, Beau M. Ances, Dominantly Inherited Alzheimer Network

2020-Current year OA Pubs

"Brain-predicted age" quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18-89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and …

Sex Differences In The Genetic Architecture Of Cognitive Resilience To Alzheimer's Disease, Jaclyn M Eissman, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts …

Effect Of Race On Prediction Of Brain Amyloidosis By Plasma Aβ42/Aβ40, Phosphorylated Tau, And Neurofilament Light, Suzanne E Schindler, Rachel L Henson, Yan Li, Benjamin Saef, Krista L Moulder, David Bradford, Anne M Fagan, Brian A Gordon, Tammie L S Benzinger, Joyce Balls-Berry, Randall J Bateman, Chengjie Xiong, John C Morris, Et Al

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.

METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age,

RESULTS: There were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were

DISCUSSION: Models predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and …

Csf Tau Phosphorylation At Thr205 Is Associated With Loss Of White Matter Integrity In Autosomal Dominant Alzheimer Disease, Jeremy F. Strain, Nicolas Barthelemy, Kanta Horie, Brian A. Gordon, Collin Kilgore, Andrew Aschenbrenner, Carlos Cruchaga, Chengjie Xiong, Nelly Joseph-Mathurin, Jason Hassenstab, Anne M. Fagan, Yan Li, Celeste M. Karch, Richard J. Perrin, Sarah B. Berman, Jasmeer P. Chhatwal, Neill R. Graff-Radford, Hiroshi Mori, Johannes Levin, James M. Noble, Ricardo Allegri, Peter R. Schofield, Daniel S. Marcus, David M. Holtzman, John C. Morris, Tammie L. S. Benzinger, Eric M. Mcdade, Randall J. Bateman, Beau M. Ances

2020-Current year OA Pubs

BACKGROUND: Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s).

METHODS: In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD.

RESULTS: The …

Peripheral Monocyte-Derived Cells Counter Amyloid Plaque Pathogenesis In A Mouse Model Of Alzheimer's Disease, Ping Yan, Ki-Wook Kim, Qingli Xiao, Xiucui Ma, Leah R. Czerniewski, Haiyan Liu, David R. Rawnsley, Yan Yan, Gwendalyn J. Randolph, Slava Epelman, Jin-Moo Lee, Abhinav Diwan

Open Access Publications

Microglia, the parenchymal tissue macrophages in the brain, surround amyloid plaques in brains of individuals with Alzheimer's disease (AD) but are ineffective at clearing amyloid to mitigate disease progression. Recent studies in mice indicate that microglia are derived exclusively from primitive yolk sac hematopoiesis and self-renew without contribution from ontogenically distinct monocytes/macrophages of definitive adult hematopoietic origin. Using a genetic fate-mapping approach to label cells of definitive hematopoietic origin throughout life span, we discovered that circulating monocytes contribute 6% of plaque-associated macrophages in aged AD mice. Moreover, peripheral monocytes contributed to a higher fraction of macrophages in the choroid plexus, …

Cerebrospinal Fluid Neurofilament Light Chain Is A Marker Of Aging And White Matter Damage, Karin L Meeker, Omar H Butt, Brian A Gordon, Anne M Fagan, Suzanne E Schindler, John C Morris, Tammie L S Benzinger, Beau M Ances

2020-Current year OA Pubs

BACKGROUND: Cerebrospinal fluid (CSF) neurofilament light chain (NfL) reflects neuro-axonal damage and is increasingly used to evaluate disease progression across neurological conditions including Alzheimer disease (AD). However, it is unknown how NfL relates to specific types of brain tissue. We sought to determine whether CSF NfL is more strongly associated with total gray matter, white matter, or white matter hyperintensity (WMH) volume, and to quantify the relative importance of brain tissue volume, age, and AD marker status (i.e., APOE genotype, brain amyloidosis, tauopathy, and cognitive status) in predicting CSF NfL.

METHODS: 419 participants (Clinical Dementia Rating [CDR] Scale > 0, N …

Proposed Research Criteria For Prodromal Behavioural Variant Frontotemporal Dementia, Megan S Barker, Jill Goldman, Et Al.

2020-Current year OA Pubs

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal …

Soluble Trem2: Innocent Bystander Or Active Player In Neurological Diseases?, Fabia Filipello, Claire Goldsbury, Shih Feng You, Alberto Locca, Celeste M Karch, Laura Piccio

2020-Current year OA Pubs

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by macrophages and microglia in the central nervous system (CNS). TREM2 has attracted a lot of interest in the past decade for its critical role in modulating microglia functions under homeostatic conditions and in neurodegenerative diseases. Genetic variation in TREM2 is sufficient to cause Nasu-Hakola disease, a rare pre-senile dementia with bone cysts, and to increase risk for Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders. Beyond the role played by TREM2 genetic variants in these diseases, TREM2 engagement is a key step in microglia activation …

Soluble Trem2 In Csf And Its Association With Other Biomarkers And Cognition In Autosomal-Dominant Alzheimer's Disease: A Longitudinal Observational Study, Estrella Morenas-Rodríguez, Yan Li, Chengjie Xiong, Anne M. Fagan, Stephanie Schultz, Brian A. Gordon, Tammie L. S. Benzinger, Jason Hassenstab, Eric Mcdade, Celeste M. Karch, John C. Morris, Randall J. Bateman, Et Al.

2020-Current year OA Pubs

BACKGROUND: Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease.

METHODS: We did a longitudinal analysis of data from the Dominantly Inherited …

Sorl1 Polymorphisms In Mexican Patients With Alzheimer's Disease, Danira Toral-Rios, Elizabeth Ruiz-Sánchez, Nancy Lucero Martínez Rodríguez, Marlene Maury-Rosillo, Óscar Rosas-Carrasco, Fernando Becerril-Pérez, Francisco Mena-Barranco, Rosa Carvajal-García, Daniela Silva-Adaya, Yair Delgado-Namorado, Gerardo Ramos-Palacios, Carmen Sánchez-Torres, Victoria Campos-Peña

Open Access Publications

The present study evaluated the risk effect of 12 Single Nucleotide Polymorphisms in the SORL1 gene in the Mexican population using Late-Onset Alzheimer's Disease (LOAD) and control subjects. Considering APOE as the strongest genetic risk factor for LOAD, we conducted interaction analyses between single nucleotide polymorphisms (SNPs) and the APOE genotype.

METHODS: Patients were interviewed during their scheduled visits at neurologic and geriatric clinics from different institutions. The LOAD diagnosis included neurological, geriatric, and psychiatric examinations, as well as the medical history and neuroimaging. Polymorphisms in

RESULTS: The A/A genotype in rs1784933 might be associated with an increased LOAD risk. …

Neutrophil-Vascular Interactions Drive Myeloperoxidase Accumulation In The Brain In Alzheimer's Disease, Leon C D Smyth, Et Al

Open Access Publications

INTRODUCTION: Neutrophil accumulation is a well-established feature of Alzheimer's disease (AD) and has been linked to cognitive impairment by modulating disease-relevant neuroinflammatory and vascular pathways. Neutrophils express high levels of the oxidant-generating enzyme myeloperoxidase (MPO), however there has been controversy regarding the cellular source and localisation of MPO in the AD brain.

MATERIALS AND METHODS: We used immunostaining and immunoassays to quantify the accumulation of neutrophils in human AD tissue microarrays and in the brains of APP/PS1 mice. We also used multiplexed immunolabelling to define the presence of NETs in AD.

RESULTS: There was an increase in neutrophils in AD …

Selective Reduction Of Astrocyte Apoe3 And Apoe4 Strongly Reduces Aβ Accumulation And Plaque-Related Pathology In A Mouse Model Of Amyloidosis, Thomas E Mahan, Chao Wang, Xin Bao, Ankit Choudhury, Jason D Ulrich, David M Holtzman

2020-Current year OA Pubs

BACKGROUND: One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, …

Quantifying Regional Α -Synuclein, Amyloid Β, And Tau Accumulation In Lewy Body Dementia, Rebecca L Miller, Dhruva D Dhavale, Jennifer Y O'Shea, Kristin M Andruska, Jialu Liu, Erin E Franklin, Chandana Buddhala, Susan K Loftin, John R Cirrito, Richard J Perrin, Nigel J Cairns, Meghan C Campbell, Joel S Perlmutter, Paul T Kotzbauer

Open Access Publications

OBJECTIVE: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions.

METHODS: We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 …