Journal of Alzheimer's Disease Reports - Volume 7, issue 1

Authors: Loeffler, David A.

Article Type: Review Article

Abstract: Immunotherapeutic efforts to slow the clinical progression of Alzheimer’s disease (AD) by lowering brain amyloid-β (Aβ) have included Aβ vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aβ monoclonal antibodies. Neither Aβ vaccination nor IVIG slowed disease progression. Despite conflicting phase III results, the monoclonal antibody Aducanumab received Food and Drug Administration (FDA) approval for treatment of AD in June 2021. The only treatments unequivocally demonstrated to slow AD progression to date are the monoclonal antibodies Lecanemab and Donanemab. Lecanemab received FDA approval in January 2023 based on phase II results showing lowering of PET-detectable Aβ; phase III results released at that …time indicated slowing of disease progression. Topline results released in May 2023 for Donanemab’s phase III trial revealed that primary and secondary end points had been met. Antibody binding to Aβ facilitates its clearance from the brain via multiple mechanisms including promoting its microglial phagocytosis, activating complement, dissolving fibrillar Aβ, and binding of antibody-Aβ complexes to blood-brain barrier receptors. Antibody binding to Aβ in peripheral blood may also promote cerebral efflux of Aβ by a peripheral sink mechanism. According to the amyloid hypothesis, for Aβ targeting to slow AD progression, it must decrease downstream neuropathological processes including tau aggregation and phosphorylation and (possibly) inflammation and oxidative stress. This review discusses antibody-mediated mechanisms of Aβ clearance, findings in AD trials involving Aβ vaccination, IVIG, and anti-Aβ monoclonal antibodies, downstream effects reported in those trials, and approaches which might improve the Aβ-clearing ability of monoclonal antibodies. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid hypothesis, antibodies, clearance, clinical trials, downstream effects, intravenous immunoglobulin

DOI: 10.3233/ADR-230025

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 873-899, 2023

Authors: Wang, Mengxue | Wang, Yanjuan | Wang, Zan | Ren, Qingguo

Article Type: Systematic Review

Abstract: Background: Cognitive impairment (CI) is an important extrapulmonary complication in patients with chronic obstructive pulmonary disease (COPD). Multimodal Neuroimaging Examination can display changes in brain structure and functions in patients with COPD. Objective: The purpose of this systematic review is to provide an overview of the variations in brain imaging in patients with COPD and their potential relationship with CI. Furthermore, we aim to provide new ideas and directions for future research. Methods: Literature searches were performed using the electronic databases PubMed, Scopus, and ScienceDirect. All articles published between January 2000 and November 2021 that met …the eligibility criteria were included. Results: Twenty of the 23 studies focused on changes in brain structure and function. Alterations in the brain’s macrostructure are manifested in the bilateral frontal lobe, hippocampus, right temporal lobe, motor cortex, and supplementary motor area. The white matter microstructural changes initially appear in the bilateral frontal subcortical region. Regarding brain function, patients with COPD exhibited reduced frontal cerebral perfusion and abnormal alterations in intrinsic brain activity in the bilateral posterior cingulate cortex, precuneus, right lingual gyrus, and left anterior central gyrus. Currently, there is limited research related to brain networks. Conclusion: CI in patients with COPD may present as a type of dementia different from Alzheimer’s disease, which tends to manifest as frontal cognitive decline early in the disease. Further studies are required to clarify the neurobiological pathways of CI in patients with COPD from the perspective of brain connectomics based on the whole-brain system in the future. Show more

Keywords: Alzheimer’s disease, brain imaging, chronic obstructive pulmonary disease, cognitive impairment, mechanism

DOI: 10.3233/ADR-220083

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 901-919, 2023

Authors: Volloch, Vladimir | Rits-Volloch, Sophia

Article Type: Other

Abstract: With the Amyloid Cascade Hypothesis (ACH) largely discredited, the ACH2.0 theory of Alzheimer’s disease (AD) has been recently introduced. Within the framework of the ACH2.0, AD is triggered by amyloid-β protein precursor (AβPP)-derived intraneuronal Aβ (i Aβ) and is driven by i Aβ produced in the AβPP-independent pathway and retained intraneuronally. In this paradigm, the depletion of extracellular Aβ or suppression of Aβ production by AβPP proteolysis, the two sources of AβPP-derived i Aβ, would be futile in symptomatic AD, due to its reliance on i Aβ generated independently of AβPP, but effective in preventing AD and treating Aging-Associated …Cognitive Decline (AACD) driven, in the ACH2.0 framework, by AβPP-derived i Aβ. The observed effect of lecanemab and donanemab, interpreted in the ACH2.0 perspective, supports this notion and mandates AD-preventive clinical trials. Such trials are currently in progress. They are likely, however, to fail or to yield deceptive results if conducted conventionally. The present study considers concepts of design of clinical trials of lecanemab, donanemab, or any other drug, targeting the influx of AβPP-derived i Aβ, in prevention of AD and treatment of AACD. It analyzes possible outcomes and explains why selection of high-risk asymptomatic participants seems reasonable but is not. It argues that outcomes of such AD preventive trials could be grossly misleading, discusses inevitable potential problems, and proposes feasible solutions. It advocates the initial evaluation of this type of drugs in clinical trials for treatment of AACD. Whereas AD protective trials of these drugs are potentially of an impractical length, AACD clinical trials are expected to yield unequivocal results within a relatively short duration. Moreover, success of the latter, in addition to its intrinsic value, would constitute a proof of concept for the former. Furthermore, this study introduces concepts of the active versus passive i Aβ depletion, contends that targeted degradation of i Aβ is the best therapeutic strategy for both prevention and treatment of AD and AACD, proposes potential i Aβ-degrading drugs, and describes their feasible and unambiguous evaluation in clinical trials. Show more

Keywords: Aging-associated cognitive decline, Alzheimer’s disease, Amyloid Cascade Hypothesis 2.0 (ACH2.0), BACE1 and BACE2 activators, clinical trial design, donanemab, intraneuronal Aβ , lecanemab, verubecestat

DOI: 10.3233/ADR-230037

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 921-955, 2023

Authors: Patel, Ashay O. | Caldwell, Andrew B. | Ramachandran, Srinivasan | Subramaniam, Shankar

Article Type: Research Article

Abstract: Background: While Alzheimer’s disease (AD) pathology is associated with altered brain structure, it is not clear whether gene expression changes mirror the onset and evolution of pathology in distinct brain regions. Deciphering the mechanisms which cause the differential manifestation of the disease across different regions has the potential to help early diagnosis. Objective: We aimed to identify common and unique endotypes and their regulation in tangle-free neurons in sporadic AD (SAD) across six brain regions: entorhinal cortex (EC), hippocampus (HC), medial temporal gyrus (MTG), posterior cingulate (PC), superior frontal gyrus (SFG), and visual cortex (VCX). Methods: …To decipher the states of tangle-free neurons across different brain regions in human subjects afflicted with AD, we performed analysis of the neural transcriptome. We explored changes in differential gene expression, functional and transcription factor target enrichment, and co-expression gene module detection analysis to discern disease-state transcriptomic variances and characterize endotypes. Additionally, we compared our results to tangled AD neuron microarray-based study and the Allen Brain Atlas. Results: We identified impaired neuron function in EC, MTG, PC, and VCX resulting from REST activation and reversal of mature neurons to a precursor-like state in EC, MTG, and SFG linked to SOX2 activation. Additionally, decreased neuron function and increased dedifferentiation were linked to the activation of SUZ12. Energetic deficit connected to NRF1 inactivation was found in HC, PC, and VCX. Conclusions: Our findings suggest that SAD manifestation varies in scale and severity in different brain regions. We identify endotypes, such as energetic shortfalls, impaired neuronal function, and dedifferentiation. Show more

Keywords: Alzheimer’s disease, dedifferentiation, endotype, energetics, NRF1, REST, SOX2, sporadic Alzheimer’s disease, SUZ12, transcriptome

DOI: 10.3233/ADR-220098

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 957-972, 2023

Authors: Yu, Ruan-Ching | Lai, Jen-Chieh | Hui, Esther K. | Mukadam, Naaheed | Kapur, Narinder | Stott, Joshua | Livingston, Gill

Article Type: Systematic Review

Abstract: Background: Chinese is the most commonly spoken world language; however, most cognitive tests were developed and validated in the West. It is essential to find out which tests are valid and practical in Chinese speaking people with suspected dementia. Objective: We therefore conducted a systematic review and meta-analysis of brief cognitive tests adapted for Chinese-speaking populations in people presenting for assessment of suspected dementia. Methods: We searched electronic databases for studies reporting brief (≤20 minutes) cognitive test’s sensitivity and specificity as part of dementia diagnosis for Chinese-speaking populations in clinical settings. We assessed …quality using Centre for Evidence Based Medicine (CEBM) criteria and translation and cultural adaptation using the Manchester Translation Reporting Questionnaire (MTRQ), and Manchester Cultural Adaptation Reporting Questionnaire (MCAR). We assessed heterogeneity and combined sensitivity in meta-analyses. Results: 38 studies met inclusion criteria and 22 were included in meta-analyses. None met the highest CEBM criteria. Five studies met the highest criteria of MTRQ and MCAR. In meta-analyses of studies with acceptable heterogeneity (I2  <  75%), Addenbrooke’s Cognitive Examination Revised &III (ACE-R & ACE-III) had the best sensitivity and specificity; specifically, for dementia (93.5% & 85.6%) and mild cognitive impairment (81.4% & 76.7%). Conclusions: Current evidence is that the ACE-R and ACE-III are the best brief cognitive assessments for dementia and mild cognitive impairment in Chinese-speaking populations. They may improve time taken to diagnosis, allowing people to access interventions and future planning. Show more

Keywords: Alzheimer’s disease, cognitive assessment, dementia, diagnosis, mild cognitive impairment

DOI: 10.3233/ADR-230024

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 973-987, 2023

Authors: Aborode, Abdullahi Tunde | Idowu, Nike Jesutofunmi | Tundealao, Samuel | Jaiyeola, Joseph | Ogunware, Adedayo Emmanuel

Article Type: Article Commentary

Abstract: This paper explores the emerging field of neuroscience in Africa, considering the unique genetic diversity, socio-cultural determinants, and health inequalities in the continent. It presents numerous brain research initiatives, such as ABDRN, AMARI, APCDR, and H3Africa, aimed at understanding genetic and environmental factors influencing brain disorders in Africa. Despite numerous challenges like the brain drain phenomenon, inadequate infrastructure, and scarce research expertise, significant progress has been achieved. The paper proposes solutions, including international collaboration, capacity-building efforts, and policies to promote neuroscience research, to enhance the understanding of brain function and address brain-related health issues within the African context.

Keywords: Africa, Alzheimer’s disease, brain drain, brain research, collaboration, global partnerships, health inequities, infrastructure, neuroscience, research capacity

DOI: 10.3233/ADR-230062

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 989-992, 2023

Authors: Kropf, Mario

Article Type: Research Article

Abstract: Dementia currently affects more than 55 million people worldwide, and scientists predict that this number will continue to rise. The most common form is Alzheimer’s disease (AD), which is triggered, among other things, by dysfunctional cells in the human brain. Stem cell research attempts to counteract neurodegenerative processes, for example by replacing or treating diseased cells. In addition to human embryonic stem cells, since the successes of Takahashi and Yamanaka in 2006, there has been an increased focus on human induced pluripotent stem cells (hiPS cells). These cells avoid ethically challenging questions about the moral status of human embryos, but …there are numerous problems, such as high production costs, side effects from the reprogramming process, or a potentially new moral status. These ethical issues will be examined primarily in relation to AD. The first part will be a discussion of hiPS cells and their importance for stem cell research, after which the focus turns to AD. Based on scientific studies, the relationship between hiPS cells and AD will be outlined as well as ethical implications presented. While potential limitations of hiPS cells have been discussed by numerous authors, an ethical perspective on the link between hiPS cells and AD seems to be neglected in the scientific community. The following risk analysis aims to identify a possible research agenda. In conclusion, the focus on individuals with AD may help to adopt an ethical stance that recognizes existing limitations and constructively engages with the possibilities of research. Show more

Keywords: Alzheimer’s disease, ethics, human induced pluripotent stem cells, moral issues, stem cells

DOI: 10.3233/ADR-230018

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 993-1006, 2023

Authors: Alves-Borba, Laryssa | Espinosa-Fernández, Verónica | Canseco-Rodríguez, Ania | Sánchez-Pérez, Ana María

Article Type: Short Communication

Abstract: Insulin resistance underlies Alzheimer’s disease (AD) by affecting neuroinflammation and brain-derived neurotrophic factor (BDNF) expression. Here, we evaluated the effect of early and late-start abscisic acid (ABA) intervention on hippocampal BDNF, tumor necrosis factor α (TNFα), and insulin receptors substrates (IRS) 1/2 mRNA levels in a triple-transgenic mice model of AD. Transgenic mice displayed lower BDNF and IRS2, equal IRS1, and higher TNFα expression compared to wild-type mice. Late ABA treatment could rescue TNFα and increased IRS1/2 expression. However, early ABA administration was required to increase BDNF expression. Our data suggests that early intervention with ABA can prevent AD, via …rescuing IRS1/2 and BDNF expression. Show more

Keywords: Alzheimer’s disease, hippocampus, insulin signal, neuroinflammation, neuroprotector, neurotrophic factor, phytohormones

DOI: 10.3233/ADR-230056

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1007-1013, 2023

Authors: Willis, Brian A. | Lo, Albert C. | Dage, Jeffrey L. | Shcherbinin, Sergey | Chinchen, Louise | Andersen, Scott W. | LaBell, Elizabeth S. | Perahia, David G.S. | Hauck, Paula M. | Lowe, Stephen L.

Article Type: Research Article

Abstract: Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer’s disease (AD). Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. …Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed. Clinicaltrials.gov: NCT03019536 Show more

Keywords: Aggregated tau, Alzheimer’s disease, antibody, safety pharmacokinetics, zagotenemab

DOI: 10.3233/ADR-230012

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1015-1024, 2023

Authors: Franks, Katherine H. | Cribb, Lachlan | Bransby, Lisa | Buckley, Rachel | Yassi, Nawaf | Chong, Trevor T.-J. | Lim, Yen Ying | Pase, Matthew P.

Article Type: Short Communication

Abstract: Psychological stress is associated with dementia risk. However, the underlying mechanisms are unclear. This cross-sectional study examined the association between self-reported psychological stress and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease and neurodegeneration in 73 cognitively unimpaired middle-aged adults from the Healthy Brain Project (mean age = 58±7 years). Linear regression analyses did not reveal any significant associations of psychological stress with CSF amyloid-β42 , phosphorylated tau-181, total tau, or neurofilament light chain. Cohen’s f2 effect sizes were small in magnitude (f2 ≤0.08). Further research is needed to replicate our findings, particularly given that the sample reported on average low levels …of stress. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, dementia, psychological stress

DOI: 10.3233/ADR-230052

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 1025-1031, 2023