Journal of Alzheimer's Disease - Volume 97, issue 3

Authors: Valentin-Escalera, Josue | Leclerc, Manon | Calon, Frédéric

Article Type: Review Article

Abstract: High dietary intake of saturated fatty acids is a suspected risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD). To decipher the causal link behind these associations, high-fat diets (HFD) have been repeatedly investigated in animal models. Preclinical studies allow full control over dietary composition, avoiding ethical concerns in clinical trials. The goal of the present article is to provide a narrative review of reports on HFD in animal models of AD. Eligibility criteria included mouse models of AD fed a HFD defined as > 35% of fat/weight and western diets containing > 1% cholesterol or > 15% sugar. MEDLINE and Embase databases …were searched from 1946 to August 2022, and 32 preclinical studies were included in the review. HFD-induced obesity and metabolic disturbances such as insulin resistance and glucose intolerance have been replicated in most studies, but with methodological variability. Most studies have found an aggravating effect of HFD on brain Aβ pathology, whereas tau pathology has been much less studied, and results are more equivocal. While most reports show HFD-induced impairment on cognitive behavior, confounding factors may blur their interpretation. In summary, despite conflicting results, exposing rodents to diets highly enriched in saturated fat induces not only metabolic defects, but also cognitive impairment often accompanied by aggravated neuropathological markers, most notably Aβ burden. Although there are important variations between methods, particularly the lack of diet characterization, these studies collectively suggest that excessive intake of saturated fat should be avoided in order to lower the incidence of AD. Show more

Keywords: Alzheimer’s disease, cognition, fatty acids, high-fat diet, metabolism, neuropathology

DOI: 10.3233/JAD-230118

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 977-1005, 2024

Authors: Asiamah, Ernest Amponsah | Feng, Baofeng | Guo, Ruiyun | Yaxing, Xu | Du, Xiaofeng | Liu, Xin | Zhang, Jinyu | Cui, Huixian | Ma, Jun

Article Type: Review Article

Abstract: Apolipoprotein E4 (APOE4 ), although yet-to-be fully understood, increases the risk and lowers the age of onset of Alzheimer’s disease (AD), which is the major cause of dementia among elderly individuals. The endosome-lysosome and autophagy pathways, which are necessary for homeostasis in both neurons and glia, are dysregulated even in early AD. Nonetheless, the contributory roles of these pathways to developing AD-related pathologies in APOE4 individuals and models are unclear. Therefore, this review summarizes the dysregulations in the endosome-lysosome and autophagy pathways in APOE4 individuals and non-human models, and how these anomalies contribute to developing AD-relevant pathologies. The …available literature suggests that APOE4 causes endosomal enlargement, increases endosomal acidification, impairs endosomal recycling, and downregulates exosome production. APOE4 impairs autophagy initiation and inhibits basal autophagy and autophagy flux. APOE4 promotes lysosome formation and trafficking and causes ApoE to accumulate in lysosomes. APOE4 -mediated changes in the endosome, autophagosome and lysosome could promote AD-related features including Aβ accumulation, tau hyperphosphorylation, glial dysfunction, lipid dyshomeostasis, and synaptic defects. ApoE4 protein could mediate APOE4 -mediated endosome-lysosome-autophagy changes. ApoE4 impairs vesicle recycling and endosome trafficking, impairs the synthesis of autophagy genes, resists being dissociated from its receptors and degradation, and forms a stable folding intermediate that could disrupt lysosome structure. Drugs such as molecular correctors that target ApoE4 molecular structure and enhance autophagy may ameliorate the endosome-lysosome-autophagy-mediated increase in AD risk in APOE4 individuals. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, endosomes, lysosomes

DOI: 10.3233/JAD-230658

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1007-1031, 2024

Authors: Han, Yuru | Huang, Congying | Pan, Yuhui | Gu, Xuefeng

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) involves degeneration of cells in the brain. Due to insidious onset and slow progression, AD is often not diagnosed until it gets progressed to a more severe stage. The diagnosis and treatment of AD has been a challenge. In recent years, high-throughput sequencing technologies have exhibited advantages in exploring the pathogenesis of diseases. However, the types of cells of the central nervous system are complex and traditional bulk sequencing cannot reflect their heterogeneity. Single-cell sequencing technology enables study at the individual cell level and has an irreplaceable advantage in the study of complex diseases. In recent years, …this field has expanded rapidly and several types of single-cell sequencing technologies have emerged, including transcriptomics, epigenomics, genomics and proteomics. This review article provides an overview of these single-cell sequencing technologies and their application in AD. Show more

Keywords: Alzheimer’s disease, heterogeneity, multi-omics, single-cell sequencing technology

DOI: 10.3233/JAD-230861

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1033-1050, 2024

Authors: Du, Pengyang | Zhang, Xiaomin | Lian, Xia | Hölscher, Christian | Xue, Guofang

Article Type: Review Article

Abstract:  As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation’s roles in several neurodegenerative disorders …such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Machado-Joseph’s disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, neurodegenerative diseases, O-GlcNAc transferase, O-GlcNAcase inhibitors, O-GlcNAcylation, Parkinson’s disease

DOI: 10.3233/JAD-230955

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1051-1068, 2024

Authors: Stone, Jonathan | Mitrofanis, John | Johnstone, Daniel M. | Robinson, Stephen R.

Article Type: Review Article

Abstract: This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer’s disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed …to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens. Show more

Keywords: Acquired resilience, Alzheimer’s disease, brain protection, capillary hemorrhage, dementia, glutamate excitotoxicity, hypoxia, immune-mediated cytotoxicity, neurotoxicity of hemoglobin, vascular aging

DOI: 10.3233/JAD-231202

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1069-1081, 2024

Authors: Robillard, Julie M. | Masellis, Mario | Martin, Susanna E. | Khachaturian, Ara S. | Dixon, Roger A.

Article Type: Review Article

Abstract: Recent research aimed at the discovery, integration, and communication of health outcome measures (or “biomarkers”) in Alzheimer’s disease has raised challenging questions related to whether, how and when results from these investigations should be disclosed to research participants. Reflecting the apparent heterogeneity of many neurodegenerative diseases, biomarker or other risk factor results are often probabilistic, interactive, multi-modal, and selective. Such characteristics make it very complex to summarize and communicate to clinicians, researchers, and research participants. Whereas the format and content of academic literature is well-managed by the peer-review process, reporting individualized results to participants involves complex, sensitive, and ethical considerations. …This paper describes three key factors to consider in decisions about the return of results to research participants: complexity, precision, and responsibility. The paper also presents six practical recommendations for implementing meaningful and ethical communication with research participants. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, disclosure, ethics

DOI: 10.3233/JAD-230359

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1083-1090, 2024

Authors: Fort-Aznar, Laura | Molina-Porcel, Laura | Ramos-Campoy, Oscar | Esteller, Diana | Naranjo, Laura | Lladó, Albert | Balasa, Mircea | Ruiz-García, Raquel | Antonell, Anna | Sánchez-Valle, Raquel

Article Type: Short Communication

Abstract: We analyzed Lewy body (LB) pathology in 18 autosomal dominant Alzheimer’s disease (ADAD) brains via immunohistochemistry. Real-time quaking induced conversion was used to detect misfolded α-synuclein (α-syn) in 18 living ADAD cerebrospinal fluid (CSF) samples. Concomitant LB pathology was present in 44% ADAD brains. Only 6% CSF samples were positive for misfolded α-syn. In an additional AD sample, all patients with confirmed LB presented misfolded α-syn in postmortem CSF regardless of the LB staging. In conclusion, misfolded α-syn in CSF was scarce in symptomatic living ADAD individuals, in contrast to postmortem brain tissue. These results suggest late appearance of LB …pathology in ADAD. Show more

Keywords: α-Synuclein, autosomal dominant Alzheimer’s disease, Lewy body pathology, real-time quaking induced conversion

DOI: 10.3233/JAD-230919

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1091-1096, 2024

Authors: Ottaviani, Silvia | Monacelli, Fiammetta

Article Type: Article Commentary

Abstract: A recent study by Ding et al. explores the integration of artificial intelligence (AI) in predicting dementia risk over a 10-year period using a multimodal approach. While revealing the potential of machine learning models in identifying high-risk individuals through neuropsychological testing, MRI imaging, and clinical risk factors, the imperative of dynamic frailty assessment emerges for accurate late-life dementia prediction. The commentary highlights challenges associated with AI models, including dimensionality and data standardization, emphasizing the critical need for a dynamic, comprehensive approach to reflect the evolving nature of dementia and improve predictive accuracy.

Keywords: Alzheimer’s disease, dementia risk, machine learning, precision medicine

DOI: 10.3233/JAD-231071

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1097-1100, 2024

Authors: Selles, Maria Clara | Oliveira, Mauricio Martins

Article Type: Article Commentary

Abstract: Alzheimer’s disease is a multi-factorial disease that disrupts many aspects of human behavior. In this comment, we highlight the work by Koulousakis et al. published in a recent issue of the Journal of Alzheimer ’s Disease. In this study, the authors tested the therapeutic potential of the neuropeptide oxytocin in a pre-clinical model of Alzheimer’s disease and found positive behavioral outcomes on memory assessments. We discuss these findings in the context of oxytocin research in the field of Alzheimer’s disease and the literature regarding oxytocin-based therapeutics, including administration protocols and potential underlying cellular and molecular mechanisms.

Keywords: Alzheimer’s disease, amyloid-beta, intranasal, memory, oxytocin

DOI: 10.3233/JAD-231127

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1101-1104, 2024

Authors: Martin, Susanna E. | Tam, Mallorie T. | Robillard, Julie M.

Article Type: Article Commentary

Abstract: Technology can support the delivery of care and improve the lives of people living with dementia. However, despite a substantial body of evidence demonstrating the benefits and opportunities afforded by technology, gaps remain in how technology and technology ethics are addressed in dementia care education. Here we discuss disparities in current educational programming and highlight the ethical challenges arising from underdeveloped knowledge exchange about dementia care technology. We put forward that for technology to be ethically deployed and maximized to improve outcomes, it must be embedded into dementia education programs and made widely accessible to the caregiver community.

Keywords: Alzheimer’s disease, delivery of health care, ethics, health education, technology

DOI: 10.3233/JAD-230612

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1105-1109, 2024