Journal of Alzheimer's Disease - Volume 95, issue 4

Authors: Xu, Xuan | Wang, Hui | Zhang, Qing-Ye | Meng, Xiang-Yu | Li, Xin-Xing | Zhang, Hong-Yu

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the leading cause of dementia, with its prevalence increasing as the global population ages. AD is a multifactorial and intricate neurodegenerative disease with pathological changes varying from person to person. Because the mechanism of AD is highly controversial, effective treatments remain a distant prospect. Currently, one of the most promising hypotheses posits mitochondrial dysfunction as an early event in AD diagnosis and a potential therapeutic target. Objective: Here, we adopted a systems medicine strategy to explore the mitochondria-related mechanisms of AD. Then, its implications for discovering nutrients combatting the disease were …demonstrated. Methods: We employed conditional mutual information (CMI) to construct AD gene dependency networks. Furthermore, the GeneRank algorithm was applied to prioritize the gene importance of AD patients and identify potential anti-AD nutrients targeting crucial genes. Results: The results suggested that two highly interconnected networks of mitochondrial ribosomal proteins (MRPs) play an important role in the regulation of AD pathology. The close association between mitochondrial ribosome dysfunction and AD was identified. Additionally, we proposed seven nutrients with potential preventive and ameliorative effects on AD, five of which have been supported by experimental reports. Conclusions: Our study explored the important regulatory role of MRP genes in AD, which has significant implications for AD prevention and treatment. Show more

Keywords: Alzheimer’s disease, biomarker, drug discovery, gene dependency network, mitochondria, nutrients

DOI: 10.3233/JAD-230366

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1709-1722, 2023

Authors: Guieysse, Thomas | Lamothe, Roxane | Houot, Marion | Razafimahatratra, Solofo | Medani, Takfarinas | Lejeune, François-Xavier | Dreyfus, Gérard | Klarsfeld, André | Pantazis, Dimitrios | Koechlin, Etienne | Andrade, Katia

Article Type: Research Article

Abstract: Background: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer’s disease (AD). Objectives: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could …add additional support for detecting anosognosia. Methods: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects’ estimation of their performances in a computerized experiment. Results: The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods. Conclusions: The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis. Show more

Keywords: Alzheimer’s disease, anosognosia assessment, caregiver burden, error-monitoring, HABC-M, timely diagnosis

DOI: 10.3233/JAD-230552

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1723-1733, 2023

Authors: Witucki, Łukasz | Borowczyk, Kamila | Suszyńska-Zajczyk, Joanna | Warzych, Ewelina | Pawlak, Piotr | Jakubowski, Hieronim

Article Type: Research Article

Abstract: Background: Bleomycin hydrolase (BLMH), a homocysteine (Hcy)-thiolactone detoxifying enzyme, is attenuated in Alzheimer’s disease (AD) brains. Blmh loss causes astrogliosis in mice while the loss of histone demethylase Phf8, which controls mTOR signaling, causes neuropathy in mice and humans. Objective: To examine how Blmh gene deletion affects the Phf8/H4K20me1/mTOR/autophagy pathway, amyloid-β (Aβ) accumulation, and cognitive/neuromotor performance in mice. Methods: We generated a new mouse model of AD, the Blmh -/- 5xFAD mouse. Behavioral assessments were conducted by cognitive/neuromotor testing. Blmh and Phf8 genes were silenced in mouse neuroblastoma N2a-APPswe cells …by RNA interference. mTOR- and autophagy-related proteins, and AβPP were quantified by western blotting and the corresponding mRNAs by RT-qPCR. Aβ was quantified by western blotting (brains) and by confocal microscopy (cells). Results: Behavioral testing showed cognitive/neuromotor deficits in Blmh -/- and Blmh -/- 5xFAD mice. Phf8 was transcriptionally downregulated in Blmh -/- and Blmh -/- 5xFAD brains. H4K20me1, mTOR, phospho-mTOR, and AβPP were upregulated while autophagy markers Becn1, Atg5, and Atg7 were downregulated in Blmh -/- and Blmh -/- 5xFAD brains. Aβ was elevated in Blmh -/- 5xFAD brains. These biochemical changes were recapitulated in Blmh -silenced N2a-APPswe cells, which also showed increased H4K20me1-mTOR promoter binding and impaired autophagy flux (Lc3-I, Lc3-II, p62). Phf8 -silencing or treatments with Hcy-thiolactone or N -Hcy-protein, metabolites elevated in Blmh -/- mice, induced biochemical changes in N2a-APPswe cells like those induced by the Blmh -silencing. However, Phf8 -silencing elevated Aβ without affecting AβPP. Conclusions: Our findings show that Blmh interacts with AβPP and the Phf8/H4K20me1/mTOR/autophagy pathway, and that disruption of those interactions causes Aβ accumulation and cognitive/neuromotor deficits. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, autophagy, bleomycin hydrolase, Blmh-/-5xFAD mouse, H4K20me1, homocysteine thiolactone, mTOR, N2a-APPswe mouse neuroblastoma cells, Phf8

DOI: 10.3233/JAD-230578

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1735-1755, 2023

Authors: Tang, Hao | Sun, Yuhong | Fachim, Helene A. | Cheung, To Ka Dorcas | Reynolds, Gavin P. | Harte, Michael K.

Article Type: Research Article

Abstract: Introduction: Tandem pore domain halothane-inhibited K + channel 1 (THIK-1, coded by KCNK13 ) provides an upstream regulation of the activation of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which has been suggested as one of the key mechanisms of the pathological process in neurodegeneration mainly from in vitro and in vivo model systems studies. However, unequivocal evidence from neurodegenerative disorders has been lacking. Objective: To investigate the involvement of the THIK-1/NLRP3 pathway in the pathological process of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Methods: This study investigated …gene expression of markers in the THIK-1/NLRP3 pathway in an animal model representing AD as well as in human postmortem brains of AD and PD by quantitative real-time PCR. THIK-1 protein expression was determined using automated capillary electrophoresis immunoblotting. Furthermore, DNA methylation of KCNK13 was analysed in AD cohort by pyrosequencing. Results: A substantial upregulation of KCNK13 , glial activation markers, NLRP3 inflammasome components, and IL1B was observed in the animal study. Increased expression of KCNK13 support an inflammatory glial cell activation in both advanced AD and PD. The increase in KCNK13 expression was also supported by downregulation in DNA methylation of KCNK13 in AD. Conclusions: The association between THIK-1 K + channels expression and pathology changes indicates a THIK-1-induced activation of this glial subtype in AD and PD. Therefore, specific blocks of the microglial THIK-1 K + channels at the early stage of AD and PD may be beneficial for the patients. Show more

Keywords: Alzheimer’s disease, DNA methylation, neuroinflammation, NLRP3 inflammasome, Parkinson’s disease, THIK-1 potassium channel

DOI: 10.3233/JAD-230616

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1757-1769, 2023

Authors: Musyimi, Christine | Ndetei, David | Muyela, Levi Abisai | Masila, Joe | Mutunga, Elizabeth | Farina, Nicolas

Article Type: Research Article

Abstract: Background: In Kenya, many people are currently living with dementia without a formal diagnosis or support; often attributing symptoms to normal aging or as a consequence of past behaviors. Dementia screening is not commonplace within Kenya. Improving the supply (or opportunity) of dementia screening within the region may promote uptake, thus leading to more people to seek a formal diagnosis and subsequently receive support within the Kenyan healthcare system. Community Healthcare Workers (CHWs) have successfully demonstrated their value in delivering health interventions within Kenya and have strong links within local communities. Objective: To integrate and evaluate …a community-level dementia screening program among older adults in rural Kenya. Methods: Through leveraging this resource, we will deliver dementia screening to older adults (≥60 years) within Makueni County, Kenya over a 6-month period. Here, we present a protocol for the process evaluation of a dementia screening program in Kenya — DEM-SKY. The process evaluation seeks to understand the adoption, implementation, continuation, and implementation determinants, using quantitative and qualitative measures. Conclusions: Gaining perspectives of different participants involved in the program (i.e., older adults, CHWs, hospital staff, and trainers), will ensure that we understand the reason for successful (or unsuccessful) delivery of DEM-SKY. Show more

Keywords: Africa, Alzheimer’s disease, dementia, diagnosis, evaluation, implementation, middle-income

DOI: 10.3233/JAD-230107

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1771-1776, 2023

Authors: Dinnerstein, Eric

Article Type: Correction

DOI: 10.3233/JAD-239010

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1777-1777, 2023