Journal of Alzheimer's Disease - Volume 80, issue 3

Authors: Zhang, Guimei | Zhang, Yaru | Shen, Yanxin | Wang, Yongchun | Zhao, Meng | Sun, Li

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most prevalent cause of dementia, accounting for approximately 60%–80%of all cases. Although much effort has been made over the years, the precise mechanism of AD has not been completely elucidated. Recently, great attention has shifted to the roles of iron metabolism, lipid peroxidation, and oxidative stress in AD pathogenesis. We also note that these pathological events are the vital regulators of a novel regulatory cell death, termed ferroptosis—an iron-dependent, oxidative, non-apoptotic cell death. Ferroptosis differs from apoptosis, necrosis, and autophagy with respect to morphology, biochemistry, and genetics. Mounting evidence suggests that ferroptosis may be involved …in neurological disorders, including AD. Here, we review the underlying mechanisms of ferroptosis; discuss the potential interaction between AD and ferroptosis in terms of iron metabolism, lipid peroxidation, and the glutathione/glutathione peroxidase 4 axis; and describe some associated studies that have explored the implication of ferroptosis in AD. Show more

Keywords: Alzheimer’s disease, ferroptosis, glutathione, glutathione peroxidase 4, iron overload, lipid peroxidation

DOI: 10.3233/JAD-201369

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 907-925, 2021

Authors: Indorewalla, Khushnoo K. | O’Connor, Maureen K. | Budson, Andrew E. | Guess (DiTerlizzi), Christina | Jackson, Jonathan

Article Type: Review Article

Abstract: Clinical Alzheimer’s disease (AD) trials currently face a critical shortfall of thousands of eligible participants, which inflates the duration and cost of the clinical study as well as threatens the scientific merit of promising clinical interventions. This recruitment crisis is further compounded by the fact that underrepresented and marginalized populations—particularly those identifying as a racial or ethnic minority, those with low socioeconomic status, or living in rural areas—have been historically underrepresented in ongoing AD clinical trials despite overwhelming evidence that such populations are at increased risk for developing dementia. As a result of various recruitment barriers, current AD clinical studies …frequently reflect a decreasingly representative segment of the US population, which threatens the overall generalizability of these findings. The current narrative review provides an updated examination and critique of common recruitment barriers and potential solutions, as well as a discussion of theoretical approaches that may address barriers disproportionately experienced by underrepresented communities. AD clinical researchers are encouraged to take purposive action aimed at increasing diversity of enrolled AD clinical trial cohorts by actively identifying and quantifying barriers to research participation—especially recruitment barriers and health disparities that disproportionately prevent underrepresented and marginalized populations from participating in research. Furthermore, researchers are encouraged to closely track which individuals who express interest in AD research ultimately enroll in research studies to examine whether AD research participation is appropriately representative of the intended population for whom these new and novel AD interventions are being designed. Show more

Keywords: Alzheimer’s disease, modifiable barriers, recruitment, recruitment interventions, retention, underrepresented minorities

DOI: 10.3233/JAD-201081

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 927-940, 2021

Authors: Chung, Mijoo | Rhee, Hak Young | Chung, Weon Kuu

Article Type: Review Article

Abstract: Our research team recently published two relevant papers. In one study, we have seen the acute effect of low-dose ionizing irradiation (LDIR) did not reduce the amyloid-β (Aβ) protein concentration in brain tissue, yet significantly improved synaptic degeneration and neuronal loss in the hippocampus and cerebral cortex. Surprisingly, in another study, we could see late effect that the LDIR-treated mice showed significantly improved learning and memory skills compared with those in the sham group. In addition, Aβ concentrations were significantly decreased in brain tissue. Furthermore, the pro-inflammatory cytokine tumor necrosis factor-α was decreased and the anti-inflammatory cytokine transforming growth factor-β …was increased in the brain tissue of 5xFAD mice treated with LDIR. Definitive clinical results for the safety and efficacy of LDIR have not yet been published and, despite the promising outcomes reported during preclinical studies, LDIR can only be applied to patients with Alzheimer’s disease dementia when clinical results are made available. In addition, in the case of LDIR, additional large-scale clinical studies are necessary to determine the severity of Alzheimer’s disease dementia, indications for LDIR, the total dose to be irradiated, fraction size, and intervals of LDIR treatment. The purpose of this review is to summarize the mechanism of LDIR based on existing preclinical results in a way that is useful for conducting subsequent clinical research. Show more

Keywords: Alzheimer’s disease, clinical research, cognitive function, low-dose ionizing radiation (LDIR), neurodegeneration

DOI: 10.3233/JAD-210042

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 941-947, 2021

Authors: Wang, Yang-Yang | Huang, Zhen-Ting | Yuan, Ming-Hao | Jing, Feng | Cai, Ruo-Lan | Zou, Qian | Pu, Yin-Shuang | Wang, Sheng-Yuan | Chen, Fei | Yi, Wen-Min | Zhang, Hui-Ji | Cai, Zhi-You

Article Type: Review Article

Abstract: Amyloid-β (Aβ) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer’s disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AβPP processing and Aβ generation by promoting β/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, …HIF-1α could resist the toxic effect of Aβ, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, HIF-1α, neuroinflammation, oxidative stress, tau hyperphosphorylation

DOI: 10.3233/JAD-201448

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 949-961, 2021

Authors: Jin, He | Wang, Rong

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the leading cause of dementia. With aging societies, the prevalence of AD is increasing dramatically worldwide. The onset of AD is often not identified, and currently no available treatments are capable of stopping the disease process and its effect on cognitive decline. Thus, well-validated biomarkers of the preclinical stages of AD are needed. Alzheimer-associated neuronal thread protein (AD7c-NTP) is a member of the neuronal thread protein family and has a molecular weight of approximately 41 kD. AD7c-NTP has been identified as a biomarker for its specifically elevated levels in putative brain domains, cerebrospinal fluid (CSF), and the …urine of AD and mild cognitive impairment (MCI) patients. Since the urine test is non-invasive, easy to perform, and patients accept it more easily than other methods, the urinary AD7c-NTP concentration has been recommended as a practical diagnostic tool for diagnosing AD and MCI. AD7c-NTP has undergone nearly 25 years of research course from its initial discovery to pathological verification, multi-center clinical evaluation, improvement of detection methods, epidemiological investigation, and combined application with other biomarkers. However, as a fluid biomarker, AD7c-NTP can be detected in urine instead of the traditional biomarker sources—CSF or blood, which has made the use of AD7c-NTP as a biomarker controversial. In this article, we review the research course of AD7c-NTP and suggest directions for future research. Show more

Keywords: Alzheimer’s disease, Alzheimer-associated neuronal thread protein, biomarker, urine

DOI: 10.3233/JAD-201273

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 963-971, 2021

Authors: Khodadadi, Hesam | Salles, Évila Lopes | Jarrahi, Abbas | Costigliola, Vincenzo | Khan, MB | Yu, Jack C. | Morgan, John C. | Hess, David C. | Vaibhav, Kumar | Dhandapani, Krishnan M. | Baban, Babak

Article Type: Short Communication

Abstract: There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive …decline. Show more

Keywords: Alzheimer’s disease, cannabidiol, CBD, dementia, ILC2, innate lymphoid cells

DOI: 10.3233/JAD-210026

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 973-977, 2021

Authors: Cieri, Filippo | Yang, Zhengshi | Cordes, Dietmar | Caldwell, Jessica Z.K. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Short Communication

Abstract: We applied graph theory analysis on resting-state functional magnetic resonance imaging data to evaluate sex differences of brain functional topography in normal controls (NCs), early mild cognitive impairment (eMCI), and AD patients. These metrics were correlated with RAVLT verbal learning and memory scores. The results show NCs have better functional connectivity (FC) metrics than eMCI and AD, and NC women show worse FC metrics compared to men, despite performing better on the RAVLT. FC differences between men and women diminished in eMCI and disappeared in AD. Within women, better FC metrics relate to better RAVLT learning in NCs and eMCI …groups. Show more

Keywords: Alzheimer’s disease, brain imaging, functional connectivity, graph theory, mild cognitive impairment, rey auditory verbal learning test, sex differences

DOI: 10.3233/JAD-201596

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 979-984, 2021

Authors: Pytel, Vanesa | Hernández-Lorenzo, Laura | Torre-Fuentes, Laura | Sanz, Raúl | González, Nieves | Cabrera-Martín, María Nieves | Delgado-Álvarez, Alfonso | Gómez-Pinedo, Ulises | Matías-Guiu, Jorge | Matias-Guiu, Jordi A

Article Type: Short Communication

Abstract: Primary progressive aphasia (PPA) is mainly considered a sporadic disease and few studies have systematically analyzed its genetic basis. We here report the analyses of C9orf72 genotyping and whole-exome sequencing data in a consecutive and well-characterized cohort of 50 patients with PPA. We identified three pathogenic GRN variants, one of them unreported, and two cases with C9orf72 expansions. In addition, one likely pathogenic variant was found in the SQSTM1 gene. Overall, we found 12%of patients carrying pathogenic or likely pathogenic variants. These results support the genetic role in the pathophysiology of a proportion of patients with …PPA. Show more

Keywords: Alzheimer’s disease, C9orf72 protein, frontotemporal degeneration, genetics, MAPT protein, primary progressive aphasia, progranulin

DOI: 10.3233/JAD-201310

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 985-990, 2021

Authors: Rhodes, Emma | Insel, Philip S. | Butters, Meryl A. | Morin, Ruth | Bickford, David | Tosun, Duygu | Gessert, Devon | Rosen, Howie J. | Aisen, Paul | Raman, Rema | Landau, Susan | Saykin, Andrew | Toga, Arthur | Jack, Clifford R. | Weiner, Michael W. | Nelson, Craig | Mackin, Scott | on behalf of the Alzheimer’s Disease Neuroimaging Initiative | the ADNI Depression Project

Article Type: Research Article

Abstract: Background: Cognitive impairment (CI) is a key feature of late life depression (LLD), but the contribution of underlying neurodegenerative pathology remains unclear. Objective: To evaluate cognitive dysfunction in LLD relative to a sample of nondepressed (ND) older adults with matched levels of memory impairment and amyloid-β (Aβ) burden. Methods: Participants included 120 LLD and 240 ND older adults matched on age, education, sex, Mini-Mental State Exam, mild cognitive impairment diagnosis, and PET Aβ burden. Results: LLD showed higher rates of impairment relative to ND with 54.6% of the LLD sample demonstrating impairment in at …least one cognitive domain compared to 42.9% of controls (H  = 7.13, p  = 0.008). LLD had poorer performance and higher rates of impairment on Rey Auditory Verbal Learning Test learning and memory compared to controls. In the overall sample, Aβ positivity was associated with worse performance on Logical Memory I (p  = 0.044), Logical Memory II (p  = 0.011), and Trail Making Test –B (p  = 0.032), and APOE ɛ 4 genotype was associated with worse performance on Logical Memory I (p  = 0.022); these relationships did not differ between LLD and ND. Conclusion: LLD showed higher rates of CI driven by focal deficits in verbal learning and memory. Alzheimer’s disease (AD) biomarkers were associated with worse performance on timed set-shifting and story learning and memory, and these relationships were not impacted by depression status. These findings suggest that AD may account for a portion of previously reported multi-domain CI in LLD and highlight the potential for AD to confound studies of cognition in LLD. Show more

Keywords: Amyloid, apolipoprotein E, cognitive impairment, late life depression

DOI: 10.3233/JAD-201089

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 991-1002, 2021

Authors: Libard, Sylwia | Walter, Jochen | Alafuzoff, Irina

Article Type: Research Article

Abstract: Background: Stepwise occurrence of biochemically modified amyloid-β (Aβ) in the brain of subjects with Alzheimer’s disease (AD) has been suggested to be of significance for cognitive impairment. Our previous reports have shown that Aβ is observed in 63% of all subjects with idiopathic normal pressure hydrocephalus (iNPH) suggesting that the majority of iNPH subjects with Aβ are indeed also suffering from AD. Objective: We assessed the occurrence of biochemically modified Aβ variants, in vivo, in subjects with iNPH and in a cohort of postmortem brain samples from patients with dementia. Methods: We assessed Aβ proteins …in 127 diagnostic brain biopsies obtained from subjects with iNPH and in a cohort of subjects with dementia by means of immunohistochemistry. Results: The pyroglutamylated Aβ (pyAβ) precedes the aggregation of phosphorylated Aβ (pAβ) during the AD neuropathological change progression; moreover, these modified variants of Aβ correlate with hyperphosphorylated tau in the frontal cortical area of human brain. Our results confirm the existence of the suggested biochemical stages of Aβ aggregation that might be of significance for neurodegeneration leading to cognitive impairment. Conclusion: The observation that both pyAβ and pAβ are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aβ in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aβ is observed in the biopsy, the biochemical characterization is of interest. Show more

Keywords: Alzheimer’s disease neuropathologic change, amyloid-β, biochemical variants, idiopathic normal pressure hydrocephalus

DOI: 10.3233/JAD-201469

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1003-1012, 2021