Journal of Alzheimer's Disease - Volume 100, issue 3

Authors: LoBue, Christian | McClintock, Shawn M. | Chiang, Hsueh-Sheng | Helphrey, Jessica | Thakkar, Vishal J. | Hart, John

Article Type: Review Article

Abstract: Multiple pharmacologic agents now have been approved in the United States and other countries as treatment to slow disease and clinical progression for Alzheimer’s disease. Given these treatments have not been proven to lessen the cognitive deficits already manifested in the Alzheimer’s Clinical Syndrome (ACS), and none are aimed for another debilitating dementia syndrome identified as primary progressive aphasia (PPA), there is an urgent need for new, safe, tolerable, and efficacious treatments to mitigate the cognitive deficits experienced in ACS and PPA. Noninvasive brain stimulation has shown promise for enhancing cognitive functioning, and there has been interest in its potential …therapeutic value in ACS and PPA. This review critically examines the evidence of five technologies in ACS and PPA: transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), repetitive transcranial magnetic stimulation (rTMS), and noninvasive vagus nerve stimulation (nVNS). Many randomized controlled trials of tDCS and rTMS report positive treatment effects on cognition in ACS and PPA that persist out to at least 8 weeks, whereas there are few trials for tACS and none for tRNS and nVNS. However, most positive trials did not identify clinically meaningful changes, underscoring that clinical efficacy has yet to be established in ACS and PPA. Much is still to be learned about noninvasive brain stimulation in ACS and PPA, and shifting the focus to prioritize clinical significance in addition to statistical significance in trials could yield greater success in understanding its potential cognitive effects and optimal parameters. Show more

Keywords: Alzheimer’s disease, primary progressive aphasia, randomized controlled trial, semantic dementia, transcranial electrical stimulation, transcranial magnetic stimulation

DOI: 10.3233/JAD-240230

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 743-760, 2024

Authors: Cassard, Lydia | Honari, Golara | Tousi, Babak

Article Type: Review Article

Abstract: This manuscript reviews the significant skin manifestations of Lewy body disease, including Parkinson’s disease and dementia with Lewy bodies, and the diagnostic utility of skin biopsy. Besides classic motor and cognitive symptoms, non-motor manifestations, particularly dermatologic disorders, can play a crucial role in disease presentation and diagnosis. This review explores the intricate relationship between the skin and Lewy body disease. Seborrheic dermatitis, autoimmune blistering diseases (bullous pemphigoid and pemphigus), rosacea, and melanoma are scrutinized for their unique associations with Parkinson’s disease, revealing potential links through shared pathophysiological mechanisms. Advances in diagnostic techniques allow the identification of promising biomarkers such as …α -synuclein in samples obtained by skin punch biopsy. Understanding the dermatologic aspects of Lewy body disease not only contributes to its holistic characterization but also holds implications for innovative diagnostic approaches. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, Lewy body disease, Parkinson’s disease, skin biopsy

DOI: 10.3233/JAD-240198

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 761-769, 2024

Authors: Greenblatt, Charles L. | Bercovier, Herve | Klein, Benjamin Y. | Gofrit, Ofer N.

Article Type: Short Communication

Abstract: The Montreal Cognitive Assessment (MoCA) is a valuable assessment of the patient’s awareness of time and place. We show that bacille Calmette-Guerin (BCG) significantly affects MoCA testing when administered by the intravesical route. MoCA scores were lower with increasing age and higher in more formally educated individuals. Patients receiving BCG tended to maintain their MoCA scores, whereas almost half the control cases tended to show reduced scores. This benefit is supported by reduced pre-amyloid biomarkers in BCG-injected healthy volunteers and a favorable effect on neuronal dendritic development in animal models. Our results suggest that BCG has a beneficial impact on …the cognitive status of older individuals. Show more

Keywords: Alzheimer’s disease, bacille Calmette-Guerin, cognition, Montreal Cognitive Assessment, vaccines

DOI: 10.3233/JAD-240307

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 771-774, 2024

Authors: Lin, Chi-Ying R. | Yonce, Shayla S. | Pacini, Nat J. | Yu, Melissa M. | Bishop, Jeffrey S. | Pavlik, Valory N. | Salas, Ramiro

Article Type: Short Communication

Abstract: The role of the cerebellum in amnestic mild cognitive impairment (aMCI), typically a prodromal stage of Alzheimer’s disease, is not fully understood. We studied the lobule-specific cerebello-cerebral connectivity in 15 cognitively normal and 16 aMCI using resting-state functional MRI. Our analysis revealed weaker connectivity between the cognitive cerebellar lobules and parietal lobe in aMCI. However, stronger connectivity was observed in the cognitive cerebellar lobules with certain brain regions, including the precuneus cortex, posterior cingulate gyrus, and caudate nucleus in participants with worse cognition. Leveraging these measurable changes in cerebello-parietal functional networks in aMCI could offer avenues for future therapeutic interventions.

Keywords: Alzheimer’s disease, cerebellum, functional MRI, mild cognitive impairment, resting state functional connectivity

DOI: 10.3233/JAD-240368

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 775-782, 2024

Authors: Puzzo, Daniela

Article Type: Article Commentary

Abstract: This commentary critically examines the long-standing emphasis on amyloid-β (Aβ)-based therapies in Alzheimer’s disease (AD), despite numerous clinical trial failures. It highlights the urgency to reassess research methodologies and challenges the initiation of anti-Aβ trials in preclinical stages of the disease without conclusive proofs of their safety and efficacy. Instead, a comprehensive approach that considers Aβ’s physiological roles and addresses AD complex nature is suggested, encouraging the idea that clinical trial failures may result from targeting the wrong mechanism. Evidence-based scientific research is needed to advance with AD treatment, moving beyond the current conception of Aβ hypothesis.

Keywords: Amyloid-β, BACE1 inhibitors, clinical trials, physiology

DOI: 10.3233/JAD-240406

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 783-786, 2024

Authors: Bocti, Christian

Article Type: Article Commentary

Abstract: Alzheimer’s disease (AD) research has been dominated by the single-factor amyloid hypothesis in the last decades. Several other hypotheses have been proposed and increasingly attract attention considering the limited success of amyloid-based therapeutic strategies. Surprisingly, most published alternative etiological hypotheses for AD are similarly single-factor hypotheses, such as vascular, metabolic, mitochondrial, infectious, and inflammatory hypotheses, but the existence of so many different hypotheses suggests that AD is most likely a complex, multifactorial disorder. This inventory of different etiological hypotheses will hopefully help the field to move forward with explanatory models that consider the multifaceted aspects of this devastating disorder.

Keywords: Alzheimer’s disease, amyloid hypothesis, biomarkers, dementia, diagnostic criteria, etiological hypothesis, multiple etiologies, neuropathology

DOI: 10.3233/JAD-240488

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 787-789, 2024

Authors: Tan, Stephanie | Kelty, Erin | Page, Amy | Etherton-Beer, Christopher | Sanfilippo, Frank | Almeida, Osvaldo P.

Article Type: Research Article

Abstract: Background: Evidence from previous observational studies suggest that infection by herpes simplex virus (HSV) and varicella zoster virus (VZV) increase the risk of dementia. Objective: To investigate if older adults exposed to HSV treatment have lower risk of dementia than the rest of the population. Methods: We used the 10% Australian Pharmaceutical Benefits Scheme (PBS) database from 2013 to 2022 to ascertain the cross-sectional, time-series and longitudinal association between exposure to HSV treatment and the dispensing of antidementia medicines. Participants were men and women aged 60 years or older. We used Anatomical Therapeutic Chemical (ATC) codes …to identify medicines dispensed for the treatment of HSV and dementia. Results: During the year 2022 6,868 (1.2%) of 559,561 of participants aged 60 years or over were dispensed antidementia agent. The odds ratio (OR) of being dispensed an antidementia agent among individuals dispensed treatment for HSV was 0.73 (99% CI = 0.56–0.95). Multilevel logistic regression for the 2013–2022 period for those dispensed HSV treatment was 0.87 (99% CI = 0.75–1.00). Split-time span series from 2013 was associated with hazard ratio of 0.98 (99% CI = 0.89–1.07) for individuals dispensed relative to those not dispensed HSV treatment. All analyses were adjusted for age, sex, and the dispensing of medicines for the treatment of diabetes, hyperlipidemia, hypertension, and ischemic heart disease. Conclusions: The dispensing of antiviral medicines for the treatment of HSV and VZV is consistently, but not conclusively, associated with decreased dispensing of antidementia medicines. This suggests that treatment of HSV and VZV infections may contribute to reduce the risk of dementia. Show more

Keywords: Keywords: Alzheimer’s disease, dementia, herpes simplex virus, varicella zoster virus

DOI: 10.3233/JAD-240391

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 791-797, 2024

Authors: Yu, Wenzhen | Zhuang, Shuting | Zhan, Mengxiong | Chen, Yong | Zhang, Jieping | Chen, Ling | Tu, Chunxiang | Zheng, Linfei | Chen, Shi

Article Type: Research Article

Abstract: Background: Ferroptosis is extremely relevant to the progression of neurodegenerative pathologies such as Alzheimer’s disease (AD). Ubiquitin-specific proteases (USP) can affect the NADPH oxidase family. Objective: Our study aimed to elucidate the potential role and molecular basis of a certain USP19 in reducing ferroptosis and mitochondrial injury in AD cells by targeting NOX4 stability. Methods: The deubiquitinase USP family gene USP19, which affects the stability of NOX4 protein, was first screened. The cell model of AD was constructed after interfering with SH-SY5Y cells by Aβ1-40 , and then SH-SY5Y cells were infected with lentiviral vectors to …knock down USP19 and overexpress NOX4, respectively. Finally, the groups were tested for cell viability, changes in cellular mitochondrial membrane potential, lipid reactive oxygen species, intracellular iron metabolism, and NOX4, Mf1, Mf2, and Drp1 protein expression. Results: 5 μmol/L Aβ1-40 intervened in SH-SY5Y cells for 24 h to construct a cell model of AD. Knockdown of USP19 decreased the expression of NOX4 protein, promoted the expression of mitochondrial fusion proteins Mnf1 and Mnf2, and inhibited the expression of the splitting protein Drp1. Furthermore, USP19 knockdown decreased mitochondrial membrane potential, SOD, MDA, intracellular iron content and increased GSH/GSSG ratio in SH-SY5Y cells. Our study revealed that NOX4 protein interacts with USP19 and knockdown of USP19 enhanced ubiquitination to maintain NOX4 protein stability. Conclusions: USP19 attenuates mitochondrial damage in SH-SY5Y cells by targeting NOX4 protein with Aβ1-40 . Show more

Keywords: Alzheimer’s disease, deubiquitinating enzyme, ferroptosis, NADPH Oxidase 4, oxidative stress

DOI: 10.3233/JAD-231193

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 799-808, 2024

Authors: Schwerthöffer, Dirk | Haselwarter, Tim | Grimmer, Timo

Article Type: Research Article

Abstract: Background: Obstructive sleep apnea (OSA) is associated with cognitive disorders, but little is known about prevalence of co-occurring OSA and mild cognitive impairment (MCI) as well as about co-occurring OSA and Alzheimer’s disease (AD). Pathophysiological models integrating OSA, cognitive deficits and neurodegeneration remain speculative. Findings in this area could contribute to the knowledge about pathophysiological processes in cognitive disorders and neurodegenerative processes, be helpful for the diagnosis of cognitive disorders and provide approaches for the treatment of cognitive disorders. Objective: Examining the prevalence of OSA and patterns of cognitive deficits as well as AD biomarker profiles associated with …OSA in a cohort of 104 MCI patients. Methods: Assessments used include: respiratory polygraphy, The Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD NB), Tau, phosphoTau181, amyloid-β-1–42/1–40, 18F-fluorodeoxyglucose positron emission tomography (F18-FDG-PET). Results: Prevalence of OSA of any severity: 58,7% (Apnea Hypopnea Index (AHI)≥5/h), OSA in a moderate-to-severe extent (AHI≥15/h): 25%. Only 13.1% of MCI patients with OSA reported daytime sleepiness. MCI-OSA patients showed no specific neuropsychological pattern. Presence of OSA was not associated with specific AD biomarker profiles in the whole study group besides a positive association between AD positivity in an AD biomarker sub cohort. Conclusions: OSA is highly prevalent in patients with MCI. It might often remain undiagnosed as only a small number of MCI-OSA patients report daytime sleepiness. OSA could contribute to MCI symptoms and even to AD pathology. Further research is needed to validate these findings and to investigate possible pathophysiological relationships between OSA and MCI as well as between OSA and AD. Show more

Keywords: Alzheimer’s disease, daytime sleepiness, mild cognitive impairment, obstructive sleep apnea

DOI: 10.3233/JAD-240251

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 809-823, 2024

Authors: Deng, Chengeng | Cai, Qingyuan | Zhang, Jiani | Chang, Kexin | Peng, Tiantian | Liu, Xiaoge | Cao, Feng | Yan, Xinyuan | Cheng, Junshi | Wang, Xu | Tan, Yan | Hua, Qian

Article Type: Research Article

Abstract: Background: Presenilin (PSEN, PS) is essential for γ-secretase function, and mutations can disrupt amyloid-β (Aβ) production in familial Alzheimer’s disease. Targeting γ-secretase is complex due to its broad involvement in physiological processes. Objective: Our aim was to create a novel knockin (KI) mouse model expressing PSEN1 D385A mutation and investigate the efficacy of a Geniposide and Ginsenoside Rg1 combination (NeuroProtect modified formula, NP-2) in restoring γ-secretase activity. Methods: Using gene manipulation, we established the PS1 D385A KI mouse model and confirmed the mutation, mRNA, and protein levels using Southern blotting, northern blotting, and western blotting, respectively. …In vitro γ-secretase assay was conducted to measure γ-secretase activity, while histological analyses examined neurogenesis effects. NP-2 administration evaluated its impact on γ-secretase activity. Results: The PS1 D385A KI homozygotes displayed severe cerebral hemorrhage, postnatal lethality, developmental disorders, reduced proliferation of neural progenitor cells, and disrupted γ-secretase function. The mutation abolished PS1 protein self-shearing, leading to compromised γ-secretase activity. NP-2 intervention effectively restored γ-secretase activity in the heterozygous mice. Conclusions: PS1 D385A mutant disrupted PS1 protein self-cleaving, impairing γ-secretase activity in KI mice. NP-2 restored γ-secretase function, offering potential for novel AD treatment strategies despite the challenges posed by γ-secretase’s complex role in physiological processes. Show more

Keywords: Alzheimer’s disease, amyloid-β, D385A, geniposide, ginsenoside Rg1, presenilin, γ-secretase

DOI: 10.3233/JAD-231148

Citation: Journal of Alzheimer's Disease, vol. 100, no. 3, pp. 825-841, 2024