Journal of Alzheimer's Disease - Volume 96, issue 4

Authors: Lai, Dongbing | Zhang, Michael | Li, Rudong | Zhang, Chi | Zhang, Pengyue | Liu, Yunlong | Gao, Sujuan | Foroud, Tatiana

Article Type: Research Article

Abstract: Background: Except APOE , Alzheimer’s disease (AD) associated genes identified in recent large-scale genome-wide association studies (GWAS) had small effects and explained a small portion of heritability. Many AD-associated genes have even smaller effects thereby sub-threshold p -values in large-scale GWAS and remain to be identified. For some AD-associated genes, drug targeting them may have limited efficacies due to their small effect sizes. Objective: The purpose of this study is to identify AD-associated genes with sub-threshold p -values and prioritize drugs targeting AD-associated genes that have large efficacies. Methods: We developed a gene-based …polygenic risk score (PRS) to identify AD genes. It was calculated using SNPs located within genes and having the same directions of effects in different study cohorts to exclude cohort-specific findings and false positives. Gene co-expression modules and protein-protein interaction networks were used to identify AD-associated genes that interact with multiple other genes, as drugs targeting them have large efficacies via co-regulation or interactions. Results: Gene-based PRS identified 389 genes with 164 of them not previously reported as AD-associated. These 389 genes explained 56.12% –97.46% SNP heritability; and they were enriched in brain tissues and 164 biological processes, most of which are related to AD and other neurodegenerative diseases. We prioritized 688 drugs targeting 64 genes that were in the same co-expression modules and/or PPI networks. Conclusions: Gene-based PRS is a cost-effective way to identify AD-associated genes without substantially increasing the sample size. Co-expression modules and PPI networks can be used to identify drugs having large efficacies. Show more

Keywords: Alzheimer’s disease, gene-based polygenic risk score, gene-targeting drugs, gene co-expression module, protein-protein interaction network, SNP heritability

DOI: 10.3233/JAD-230510

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1639-1649, 2023

Authors: Liu, Yan-Bing | Wang, Xue-Jie | Tan, Lan | Tan, Chen-Chen | Xu, Wei

Article Type: Research Article

Abstract: Background: APOE ɛ4 and PICALM are established genes associated with risk of late-onset Alzheimer’s disease (AD). Previous study indicated interaction of PICALM with APOE ɛ4 in AD patients. Objective: To explore whether PICALM variation could moderate the influences of APOE ɛ4 on AD pathology biomarkers and cognition in pre-dementia stage. Methods: A total of 1,034 non-demented participants (mean age 74 years, 56% females, 40% APOE ɛ4 carriers) were genotyped for PICALM rs3851179 and APOE ɛ4 at baseline and were followed for influences on changes of …cognition and cerebrospinal fluid (CSF) AD markers in six years. The interaction effects were examined via regression models adjusting for age, gender, education, and cognitive diagnosis. Results: The interaction term of rs3851179×APOE ɛ4 accounted for a significant amount of variance in baseline general cognition (p  = 0.039) and memory function (p  = 0.002). The relationships of APOE ɛ4 with trajectory of CSF Aβ42 (p  = 0.007), CSF P-tau181 (p  = 0.003), CSF T-tau (p  = 0.001), and memory function (p  = 0.017) were also moderated by rs3851179 variation. Conclusions: APOE ɛ4 carriers experienced slower clinical and pathological progression when they had more protective A alleles of PICALM rs3851179. These findings firstly revealed the gene-gene interactive effects of PICALM with APOE ɛ4 in pre-dementia stage. Show more

Keywords: Alzheimer’s disease, amyloid, APOE ɛ4, cognition, interaction, memory, PICALM , tau protein

DOI: 10.3233/JAD-230516

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1651-1661, 2023

Authors: Robinson, Morgan J. | Newbury, Sean | Singh, Kartar | Leonenko, Zoya | Beazely, Michael A.

Article Type: Research Article

Abstract: Background: There is a lack of understanding in the molecular and cellular mechanisms of Alzheimer’s disease that has hindered progress on therapeutic development. The focus has been on targeting toxic amyloid-β (Aβ) pathology, but these therapeutics have generally failed in clinical trials. Aβ is an aggregation-prone protein that has been shown to disrupt cell membrane structure in molecular biophysics studies and interfere with membrane receptor signaling in cell and animal studies. Whether the lipid membrane or specific receptors are the primary target of attack has not been determined. Objective: This work elucidates some of the interplay …between membrane cholesterol and Aβ42 on HT22 neuronal cell viability, morphology, and platelet-derived growth factor (PDGF) signaling pathways. Methods: The effects of cholesterol depletion by methyl-β-cyclodextrin followed by treatment with Aβ and/or PDGF-AA were assessed by MTT cell viability assays, western blot, optical and AFM microscopy. Results: Cell viability studies show that cholesterol depletion was mildly protective against Aβ toxicity. Together cholesterol reduction and Aβ42 treatment compounded the disruption of the PDGFα receptor activation. Phase contrast optical microscopy and live cell atomic force microscopy imaging revealed that cytotoxic levels of Aβ42 caused morphological changes including cell membrane damage, cytoskeletal disruption, and impaired cell adhesion; cell damage was ameliorated by cellular cholesterol depletion. Conclusions: Cholesterol depletion impacted the effects of Aβ42 on HT22 cell viability, morphology, and receptor tyrosine kinase signaling. Show more

Keywords: Alzheimer’s disease, amyloid-β, atomic force microscopy, cholesterol, HT22 cells, platelet-derived growth factor, receptor tyrosine kinase

DOI: 10.3233/JAD-230753

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1663-1683, 2023

Authors: Meléndez, Juan C. | Satorres, Encarnación | Pitarque, Alfonso | Escudero, Joaquin | Delhom, Iraida | Navarro-Prados, Ana-Belén

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) stands as the prevailing type of dementia, marked by gradual memory loss and cognitive decline. Transcranial direct current stimulation (tDCS) is a non-invasive method used to regulate cortical brain function and has been explored as a potential treatment for cognitive impairment. Objective: This study aimed to compare the effects of daily home-based active or sham tDCS on cognitive function in patients with early-stage AD and its follow-up after one month. Methods: The study involved a randomized, blinded, and controlled-placebo design, with 18 participants enrolled. The primary outcome measures were general cognitive function, …immediate, and delayed recall, and executive function. Participants included in the study were randomly assigned to the anodal and sham tDCS groups. Participants were assessed before and after the intervention and one month after the end of treatment. The home-based intervention was applied for 5 consecutive days, daily. Results: The results showed a significant interaction between the active and sham groups; in particular, improvements in MMSE scores, immediate memory and delayed recall were observed at one-month follow-up in the active group. Conclusions: The positive effects of tDCS on cognitive function in AD patients observed suggest that tDCS may induce long-term neuroplastic changes, leading to sustained improvements in cognitive abilities. Show more

Keywords: Alzheimer’s disease, delayed memory, short-term memory, transcranial direct current stimulation, working memory

DOI: 10.3233/JAD-230826

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1685-1693, 2023

Authors: Giunti, Elisa | Collu, Roberto | Daley, Sarah | Querfurth, Henry | Morin, Peter | Killick, Richard | Melamed, Rachel D. | Xia, Weiming

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most predominant form of dementia. Rho-associated coiled coil kinase (ROCK) inhibitor, fasudil, is one of the candidate drugs against the AD progression. Objective: We aimed to investigate possible changes of AD associated markers in three-dimensional neuro-spheroids (3D neuro-spheroids) generated from induced pluripotent stem cells derived from AD patients or healthy control subjects (HC) and to determine the impact of pharmacological intervention with the ROCK inhibitor fasudil. Methods: We treated 3D neuro-spheroids with fasudil and tested the possible effect on AD markers by ELISA, transcriptomic and proteomic analyses. Results: …Transcriptomic analysis revealed a reduction in the expression of AKT serine/threonine-protein kinase 1 (AKT1) in AD neuro-spheroids, compared to HC. This decrease was reverted in the presence of fasudil. Proteomic analysis showed up- and down-regulation of proteins related to AKT pathway in fasudil-treated neuro-spheroids. We found an evident increase of phosphorylated tau at four different residues (pTau181, 202, 231, and 396) in AD compared to HC-derived neuro-spheroids. This was accompanied by a decrease of secreted clusterin (clu) and an increase of intracellular clu levels in AD patient-derived neuro-spheroids. Increases of phosphorylated tau in AD patient-derived neuro-spheroids were suppressed in the presence of fasudil. Conclusions: Fasudil modulates clu protein levels and enhances AKT1 that results in the suppression of AD associated tau phosphorylation. Show more

Keywords: Alzheimer’s disease, fasudil, induced pluripotent stem cells, ROCK

DOI: 10.3233/JAD-230551

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1695-1709, 2023

Authors: Ding, Pingjian | Gurney, Mark | Perry, George | Xu, Rong

Article Type: Research Article

Abstract: Background: Epidemiological studies showed that COVID-19 increases risk of Alzheimer’s disease (AD). However, it remains unknown if there is a potential genetic predispositional effect. Objective: To examine potential effects of genetic susceptibility of COVID-19 on the risk and progression of AD, we performed a non-overlapping 2-sample Mendelian randomization (MR) study using summary statistics from genome-wide association studies (GWAS). Methods: Two-sample Mendelian randomization (MR) analysis of over 2.6 million subjects was used to examine whether genetic susceptibility of COVID-19 is not associated with the risk of AD, cortical amyloid burden, hippocampal volume, or AD progression score. Additionally, …a validation analysis was performed on a combined sample size of 536,190 participants. Results: We show that the AD risk was not associated with genetic susceptibility of COVID-19 risk (OR = 0.98, 95% CI 0.81–1.19) and COVID-19 severity (COVID-19 hospitalization: OR = 0.98, 95% CI 0.9–1.07, and critical COVID-19: OR = 0.98, 95% CI 0.92–1.03). Genetic predisposition to COVID-19 is not associated with AD progression as measured by hippocampal volume, cortical amyloid beta load, and AD progression score. These findings were replicated in a set of 536,190 participants. Consistent results were obtained across models based on different GWAS summary statistics, MR estimators and COVID-19 definitions. Conclusions: Our findings indicated that the genetic susceptibility of COVID-19 is not associated with the risk and progression of AD. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease progression score, cortical amyloid beta load, COVID-19, hippocampal volume, 2-sample Mendelian randomization analysis

DOI: 10.3233/JAD-230632

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1711-1720, 2023

Authors: Zhang, Xinghao | Wu, Pengfei | Zhao, Yue

Article Type: Article Commentary

Abstract: The potential link between COVID-19 and Alzheimer’s disease (AD) has been an intriguing topic in the global pandemic. Whether the susceptibility and severity of COVID-19 affects the onset and progression of AD is of great concern. Clinical studies suggested an increased risk of AD occurrence or cognitive deficit after COVID-19. Basic research found that severe COVID-19 induced changes resembling AD. Evidence synthesis should always take into account diverse study designs, both traditional and novel. The recent study by Ding et al. aimed to investigate the association of COVID-19 with AD using a non-overlapping two-sample Mendelian randomization analysis.

Keywords: Alzheimer’s disease, causal inference, COVID-19, genome-wide association study, Mendelian randomization

DOI: 10.3233/JAD-231151

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1721-1722, 2023

Authors: Lewis, John E. | Reginald McDaniel, H. | Woolger, Judi M. | Khan, Sher Ali

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a leading killer of Americans, imparting a tremendous societal toll. Relationships between immune function and inflammation with cognition are well-established in AD, but the Th1/Th2 ratio of immune function is unknown. Describing the Th1/Th2 ratio and its relationship with cognition may shed light on the disease’s clinical context. How the Th1/Th2 ratio responds to dietary supplementation is another unknown question in this population. Objective: The objectives of the study were to: 1) characterize the Th1/Th2 ratio according to IL-2/IL-10, IFN-γ/IL-10, IL-2/IL-4, IFN-γ/IL-4, IL-2/TNF-α, and IFN-γ/TNF-α in subjects with moderate-to-severe AD and in comparison …to healthy adults; 2) investigate the effect of an aloe polymannose multinutrient complex (APMC) dietary supplement on the Th1/Th2 ratios over 12 months; and 3) compare the changes in the Th1/Th2 ratios with the changes in cognition from baseline to 12 months. Methods: Subjects consumed 2.5 g of the APMC four times per day for 12 months, and they were assessed on cognition and cytokines at baseline and 12 months. Results: The Th1/Th2 ratios in AD patients were significantly higher than the healthy controls, and five of the six ratios decreased from baseline to 12 months follow-up (other than IL-2/TNF-α). Several significant relationships were noted between the changes in Th1/Th2 ratios with cognitive assessments. Conclusions: Our results showed an overall rebalancing of the Th1/Th2 ratio in response to APMC, these changes were related to improved cognition in subjects with moderate-to-severe AD, and the APMC supplement was safely tolerated. Show more

Keywords: Aloe, Alzheimer’s disease, cognition, cytokines, dietary supplements, immunology, polysaccharides

DOI: 10.3233/JAD-230659

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1723-1737, 2023

Authors: Gao, Yuan | Duan, Xiaocui | Li, Wanlin | Zhang, Xiaoyu | Xian, Xiaohui | Zhu, Yuan | Wang, Hualong

Article Type: Research Article

Abstract: Background: Recent studies have identified a relationship between elevated homocysteine levels and hypertension (HTN) with Alzheimer’s disease (AD), but its pathogenesis remains unclear. Objective: To evaluate elevated homocysteine levels and HTN as risk factors for cognitive impairment (CI) and determine their relationship with white matter hyperintensity (WMH) volume. Methods: A total of 521 subjects were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and divided into two groups according to the diagnostic criteria of the ADNI database. The CI group included 370 subjects, consisting of 122 with AD and 248 with mild CI, while the …cognitively normal (CN) group contained 151 subjects. The history of HTN, homocysteine levels, WMH volume and Mini-Mental State Examination (MMSE) scores were analyzed. Results: The study found that patients with CI had higher homocysteine levels than those with CN. Additionally, WMH volume was significantly correlated with homocysteine levels in CI patients, and MMSE scores decreased as WMH volume increased. Further analysis revealed that CI patients with HTN had significantly higher homocysteine levels than those without HTN. Furthermore, the correlation between WMH volume and homocysteine levels was significant only in CI patients with HTN and not in those without HTN. In CN patients, there was no correlation between WMH volume and homocysteine levels in either the HTN or non-HTN groups, and no difference was observed in homocysteine levels. Conclusions: It is indicated that elevated homocysteine levels in conjunction with HTN are associated with the increased volume of WMHs and CI. Show more

Keywords: Alzheimer’s disease, homocysteine, hypertension, white matter hyperintensities

DOI: 10.3233/JAD-230687

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1739-1746, 2023

Authors: Sluggett, Janet K. | Air, Tracy | Cations, Monica | Caughey, Gillian E. | Lang, Catherine E. | Ward, Stephanie A. | Ahern, Susannah | Lin, Xiaoping | Wallis, Kasey | Crotty, Maria | Inacio, Maria C.

Article Type: Research Article

Abstract: Background: There is a need for clinical quality indicators (CQIs) that can be applied to dementia quality registries to monitor care outcomes for people with Alzheimer’s disease and other forms of dementia. Objective: To develop tertiary and primary care-based dementia CQIs for application to clinical registries for individuals with dementia accessing aged care services and determine 1) annual trends in CQI incidence between 2011–2012 and 2015–2016, 2) associated factors, and 3) geographic and facility variation in CQI incidence. Methods: This retrospective repeated cross-sectional study included non-Indigenous individuals aged 65–105 years who lived with dementia between July …2008-June 2016, were assessed for government-funded aged care services, and resided in New South Wales or Victoria (n  = 180,675). Poisson or negative binomial regression models estimated trends in annual CQI incidence and associated factors. Funnel plots examined CQI variation. Results: Between 2011–2012 and 2015–2016, CQI incidence increased for falls (11.0% to 13.9%, adjusted incidence rate ratio (aIRR) 1.05 (95% CI 1.01–1.06)) and delirium (4.7% to 6.7%, aIRR 1.09 (95% CI 1.07–1.10)), decreased for unplanned hospitalizations (28.7% to 27.9%, aIRR 0.99 (95% CI 0.98–0.99)) and remained steady for fracture (6.2% to 6.5%, aIRR 1.01 (95% CI 0.99–1.01)) and pressure injuries (0.5% to 0.4%, aIRR 0.99 (95% CI 0.96–1.02)). Being male, older, having more comorbidities and living in a major city were associated with higher CQI incidence. Considerable geographical and facility variation was observed for unplanned hospitalizations and delirium CQIs. Conclusions: The CQI results highlighted considerable morbidity. The CQIs tested should be considered for application in clinical quality registries to monitor dementia care quality. Show more

Keywords: Accidental falls, Alzheimer’s disease, bone fractures, delirium, dementia, home care services, hospitalization, long-term care, nursing homes, pressure ulcer

DOI: 10.3233/JAD-230730

Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1747-1758, 2023