scholarly journals EDITORIAL: BLOOD TESTS FOR ALZHEIMER’S DISEASE AND RELATED DISORDERS

2019 ◽  
pp. 1-2
Author(s):  
E.M. Reiman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Task Force ◽  
Neurofibrillary Tangle ◽  
Neuritic Plaque ◽  
Plaque Burden ◽  
Neurofilament Light ◽  
Task Force Report ◽  
Blood Tests ◽  
Wide Range

This issue of the Journal of Prevention of Alzheimer’s Disease (AD) includes a timely Clinical Trials on AD Task Force Report on promising blood tests for AD and related disorders (1). It highlights the promise of recently developed plasma amyloid-β42/40 (Aβ42/40) measurements for the assessment of neuritic plaque burden (e.g., reference 2), ultrasensitive neurofilament light (NfL) measurements for the assessment of ongoing neuroaxonal injury in a wide range of neurological disorders (3), and their potential roles in evaluation of interventions to treat and prevent the clinical onset of AD. It also considers recently developed plasma total-tau measurements, an indicator of neuronal injury and/or Aβ-mediated tau secretion (4), plasma phospho-tau measurements, a potential indicator of neurofibrillary tangle burden, and the ongoing effort to develop high-dimensional plasma genomic, transcriptomic, metabolomic, lipidomic, and proteomic profiles.

scholarly journals PLASMA BIOMARKERS OF AD EMERGING AS ESSENTIAL TOOLS FOR DRUG DEVELOPMENT: AN EU/US CTAD TASK FORCE REPORT

2019 ◽  
pp. 1-5
Author(s):  
R.J. Bateman ◽  
K. Blennow ◽  
R. Doody ◽  
S. Hendrix ◽  
S. Lovestone ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Task Force ◽  
Accurate Estimate ◽  
Current Status ◽  
The European Union ◽  
Neurofilament Light ◽  
Stakeholder Collaboration ◽  
Task Force Report

There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer’s disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer’s Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential.

Alzheimer’s Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort

2021 ◽  
pp. 1-10
Author(s):  
Douglas Barthold ◽  
Laura E. Gibbons ◽  
Zachary A. Marcum ◽  
Shelly L. Gray ◽  
C. Dirk Keene ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sex Education ◽  
Descriptive Analysis ◽  
Neurofibrillary Tangle ◽  
Apoe Genotype ◽  
Severity Index ◽  
Neuritic Plaque ◽  
Braak Stage ◽  
Total N

Background: Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N = 118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ 1–42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ 1–42 (–0.57 (CI: –1.12, –0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ 1–42 compared to nonusers (–0.15 (CI: –0.28, –0.02), –0.31 (CI: –0.54, –0.07), respectively). Conclusion: Some evidence exists that diabetes medications are associated with lower levels of Aβ 1–42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

scholarly journals Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer’s disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Garrett S. Gibbons ◽  
Soo-Jung Kim ◽  
Qihui Wu ◽  
Dawn M. Riddle ◽  
Susan N. Leight ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Monoclonal Antibodies ◽  
Statistical Significance ◽  
Neuritic Plaque ◽  
Plaque Burden ◽  
Primary Neurons ◽  
Tau Pathology ◽  
Model Of Alzheimer’S Disease

Abstract 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.

Alzheimer’s disease therapeutic trials: EU/US task force report on recruitment, retention, and methodology

2012 ◽  
Vol 16 (4) ◽  
pp. 339-345 ◽  
Author(s):  
B. Vellas ◽  
◽  
H. Hampel ◽  
M. E. Rouge-Bugat ◽  
M. Grundman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Task Force ◽  
Task Force Report ◽  
Therapeutic Trials

scholarly journals NON-AMYLOID APPROACHES TO DISEASE MODIFICATION FOR ALZHEIMER’S DISEASE: AN EU/US CTAD TASK FORCE REPORT

2020 ◽  
pp. 1-6
Author(s):  
S. Gauthier ◽  
P.S. Aisen ◽  
J. Cummings ◽  
M.J. Detke ◽  
F.M. Longo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Task Force ◽  
Neurotrophin Receptor ◽  
General Strategy ◽  
Disease Modification ◽  
Task Force Report ◽  
Receptor Modulation ◽  
Alternative Approaches ◽  
Therapy Strategies

While amyloid-targeting therapies continue to predominate in the Alzheimer’s disease (AD) drug development pipeline, there is increasing recognition that to effectively treat the disease it may be necessary to target other mechanisms and pathways as well. In December 2019, The EU/US CTAD Task Force discussed these alternative approaches to disease modification in AD, focusing on tau-targeting therapies, neurotrophin receptor modulation, anti-microbial strategies, and the innate immune response; as well as vascular approaches, aging, and non-pharmacological approaches such as lifestyle intervention strategies, photobiomodulation and neurostimulation. The Task Force proposed a general strategy to accelerate the development of alternative treatment approaches, which would include increased partnerships and collaborations, improved trial designs, and further exploration of combination therapy strategies.

scholarly journals Microglia Activation in the Brain as Inflammatory Biomarker of Alzheimer’s Disease Neuropathology and Clinical Dementia

2006 ◽  
Vol 22 (1-2) ◽  
pp. 95-102 ◽  
Author(s):  
Zhongmin Xiang ◽  
Vahram Haroutunian ◽  
Lap Ho ◽  
Dushant Purohit ◽  
Giulio Maria Pasinetti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Layer ◽  
Neurofibrillary Tangle ◽  
Microglia Activation ◽  
Postmortem Brain ◽  
Neuritic Plaque ◽  
Clinical Dementia Rating ◽  
Inflammatory Biomarker ◽  
Hla Dr

The role of microglia-mediated inflammation in the progression of Alzheimer’s disease (AD) neuropathology remains unclear. In this study, postmortem brain sections from AD and control cases were subjected to Human Leukocyte Antigen (HLA)-DR immunohistochemistry to examine microglia activation in the progression of AD assessed by pre-mortem clinical dementia rating (CDR) and postmortem pathological manifestations of neuritic plaque (NP) and neurofibrillary tangle (NT) according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). In both gray and white matter of the entorhinal cortex (EC) and HLA-DR immunostaining increased with the progression of CDR or CERAD NP, and to a lesser degree with CERAD NT. Between CDR stages HLA-DR significance was found in moderate (CDR 2) to severe dementia (CDR 5) where as between CERAD NP stages staining increased significantly from NP 0 (no plaque) to NP 1 (sparse plaques), suggesting increased microglia activation begins with amyloid NP deposition. In the hippocampus, a significant increase in microglia immunostaining was found in the pyramidal cell layer of CA1 as early as CDR 1, and in the upper molecular layer of the dentate gyrus in CDR 0.5. This increase continues with the progression of CDR and reaches maximum in CDR 5. When assessed by CERAD NP stages however, a significant increase in microglia immunostaining was found only in mid-to-late stages (NP 3) and reduced staining was seen in NP 5. These results suggest that microglia activation increases with the progression of AD, with the increase varying depending on the involved brain region.

scholarly journals Vaccine Development to Treat Alzheimer’s Disease Neuropathology in APP/PS1 Transgenic Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
Iván Carrera ◽  
Ignacio Etcheverría ◽  
Lucía Fernández-Novoa ◽  
Valter Lombardi ◽  
Ramón Cacabelos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
T Cell Activation ◽  
Cell Activation ◽  
Vaccine Development ◽  
Senile Plaque ◽  
Neurofibrillary Tangle ◽  
Plaque Burden ◽  
Activation Markers

A novel vaccine addressing the major hallmarks of Alzheimer’s disease (AD), senile plaque-like deposits of amyloid beta-protein (Aβ), neurofibrillary tangle-like structures, and glial proinflammatory cytokines, has been developed. The present vaccine takes a new approach to circumvent failures of previous ones tested in mice and humans, including the Elan-Wyeth vaccine (AN1792), which caused massive T-cell activation, resulting in a meningoencephalitis-like reaction. The EB101 vaccine consists ofAβ1-42delivered in a novel immunogen-adjuvant composed of liposomes-containing sphingosine-1-phosphate (S1P). EB101 was administered to APPswe/PS1dE9 transgenic mice before and after AD-like pathological symptoms were detectable. Treatment with EB101 results in a marked reduction of Aβplaque burden, decrease of neurofibrillary tangle-like structure density, and attenuation of astrocytosis. In this transgenic mouse model, EB101 reduces the basal immunological interaction between the T cells and immune activation markers in the affected hippocampal/cortical areas, consistent with decreased amyloidosis-induced inflammation. Therefore, immunization with EB101 prevents and reverses AD-like neuropathology in a significant manner by halting disease progression without developing behavioral spatial deficits in transgenic mice.

scholarly journals NEXT-GENERATION ALZHEIMER’S THERAPEUTICS: LEVERAGING DEEP BIOLOGY

2020 ◽  
pp. 1-2
Author(s):  
F.M. Longo ◽  
S.M. Massa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Diversity ◽  
Task Force ◽  
Next Generation ◽  
Disease Modification ◽  
Task Force Report ◽  
Field Point

A recent EU/US CTAD Task Force Report focused on non-amyloid approaches to Alzheimer’s disease (AD) modification (1). While the broad range of targets and therapies highlighted is in some ways sobering, several themes and advances in the field point to principles and technologies that are encouraging and will likely accelerate progress. These themes include: the view that amyloid and non-amyloid approaches might ultimately be complementary or synergistic; the biological diversity of approaches; emerging -omics strategies that might help guide such options; and finally, the incorporation of aging biology into perspectives of target prioritization and disease modification.

Psychotic Symptoms in Alzheimer's Disease Are Not Associated With More Severe Neuropathologic Features

2000 ◽  
Vol 12 (4) ◽  
pp. 547-558 ◽  
Author(s):  
Robert A. Sweet ◽  
Ronald L. Hamilton ◽  
Oscar L. Lopez ◽  
William E. Klunk ◽  
Stephen R. Wisniewski ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Decline ◽  
Neurofibrillary Tangle ◽  
Temporal Cortex ◽  
Lewy Bodies ◽  
Occipital Cortex ◽  
Brain Regions ◽  
Neuritic Plaque ◽  
Psychotic Symptoms

Psychotic symptoms in Alzheimer's disease (AD) have been associated with increased rates of cognitive impairment and functional decline. Prior studies have been conflicting with regard to whether AD patients with psychosis (AD+P) have evidence of more severe neuropathologic findings at postmortem exam. We examined the severity of neuritic plaques and neurofibrillary tangles in six brain regions—middle frontal cortex, hippocampus, inferior parietal cortex, superior temporal cortex, occipital cortex, and transentorhinal cortex—in 24 AD+P subjects and 25 matched AD subjects without psychosis (AD-P). All analyses controlled for the presence of cortical Lewy bodies, and corrected for multiple comparisons. We found no significant associations between neuritic plaque and neurofibrillary tangle severity and AD+P, and no significant associations with any individual psychotic symptom. The association of AD+P with a more rapidly progressive course of AD appears to be mediated by a neuropathologic process other than increased severity of plaque and tangle formation.

scholarly journals ABCA7 polymorphisms correlate with memory impairment and default mode network in patients with APOEε4-associated Alzheimer’s disease

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Ya-Ting Chang ◽  
Shih-Wei Hsu ◽  
Shu-Hua Huang ◽  
Chi-Wei Huang ◽  
Wen-Neng Chang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Connectivity ◽  
Interaction Effect ◽  
Default Mode Network ◽  
Neuritic Plaque ◽  
Plaque Burden ◽  
Significant Interaction Effect ◽  
Default Mode ◽  
With Memory

Abstract Background Since both APOE and ABCA7 protein expression may independently reduce neuritic plaque burden and reorganize fibrillar amyloid burden-mediated disruption of functional connectivity in the default mode network, we aimed to investigate the effect of the APOE-ABCA7 interaction on default mode network in Alzheimer’s disease. Methods Two hundred and eighty-seven individuals with a diagnosis of typical Alzheimer’s disease were included in this study. Memory was characterized and compared between APOE-ε4+ carriers and APOE-ε4 non-carriers within ABCA7 rs3764650T allele homozygous carriers and ABCA7 rs3764650G allele carriers, respectively. Two-way analysis of variance was used to identify a significant interaction effect between APOE (APOE-ε4+ carriers versus APOE-ε4 non-carriers) and ABCA7 (ABCA7 rs3764650T allele homozygous versus ABCA7 rs3764650G allele carriers) on memory scores and functional connectivity in each default mode network subsystem. Results In ABCA7 rs3764650G allele carriers, APOE-ε4+ carriers had lower memory scores (t (159) = − 4.879; P < 0.001) compared to APOE-ε4 non-carriers, but APOE-ε4+ carriers and APOE-ε4 non-carriers did not have differences in memory (P > 0.05) within ABCA7 rs3764650T allele homozygous carriers. There was a significant APOE-ABCA7 interaction effect on the memory (F3, 283 = 4.755, P = 0.030). In the default mode network anchored by the entorhinal seed, the peak neural activity of the cluster that was significantly associated with APOE-ABCA7 interaction effects (P = 0.00002) was correlated with the memory (ρ = 0.129, P = 0.030). Conclusions Genetic-biological systems may impact disease presentation and therapy. Clarifying the effect of APOE-ABCA7 interactions on the default mode network and memory is critical to exploring the complex pathogenesis of Alzheimer’s disease and refining a potential therapy.

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