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

Authors: Fortel, Igor | Zhan, Liang | Ajilore, Olusola | Wu, Yichao | Mackin, Scott | Leow, Alex

Article Type: Research Article

Abstract: Background: Sex differences impact Alzheimer’s disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology. Objective: Examine how AD risk factors (age, APOE ɛ 4, amyloid-β) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures. Methods: Individuals from the OASIS-3 cohort (age 42–95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231). Results: In absence of AD risk factors (APOE ɛ 4/Aβ+), whole-brain EIB decreases with age more …significantly in males than females (p  = 0.021, β= –0.007). Regression modeling including APOE ɛ 4 allele carriers (Aβ–) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p  = 0.013, β= 0.014), persisting with inclusion of Aβ+ individuals (p  = 0.012, β= 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the Trail Making Test (p  < 0.05). Conclusions: Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE ɛ 4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE ɛ 4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population. Show more

Keywords: Alzheimer’s disease, amyloid-β , apolipoprotein E, brain dynamics, hyperexcitation, excitation-inhibition balance

DOI: 10.3233/JAD-230035

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1449-1467, 2023

Authors: Sato, Shuichi | Imaeda, Takao | Mugikura, Shunji | Mori, Naoko | Takanashi, Masaki | Hayakawa, Kazumi | Saito, Tomo | Taira, Makiko | Narita, Akira | Kogure, Mana | Chiba, Ippei | Hatanaka, Rieko | Nakaya, Kumi | Kanno, Ikumi | Ishiwata, Ryosuke | Nakamura, Tomohiro | Motoike, Ikuko N. | Nakaya, Naoki | Koshiba, Seizo | Kinoshita, Kengo | Kuriyama, Shinichi | Ogishima, Soichi | Nagami, Fuji | Fuse, Nobuo | Hozawa, Atsushi

Article Type: Research Article

Abstract: Background: Olfactory function decline has recently been reported to be associated with a risk of cognitive impairment. Few population-based studies have included younger adults when examining the association between olfactory test data with multiple odor intensities and suspected cognitive impairment. Objective: We investigated the association between high-resolution olfactory test data with fewer odors and suspected cognitive impairments. We also examined the differences between older and younger adults in this association. Methods: The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered to 1,450 participants, with three odor-intensity-level olfactometry using six different odors. Logistic regressions to …discriminate suspected cognitive impairment were conducted to examine the association, adjusted for age, sex, education duration, and smoking history. Data were collected from the Program by Tohoku University Tohoku Medical Megabank Organization, with an additional olfactory test conducted between 2019 and 2021. Results: We generally observed that the lower the limit of distinguishable odor intensity was, the higher the MoCA-J score was. The combination of spearmint and stuffy socks contributed most to the distinction between suspected and unsuspected cognitive impairment. Furthermore, the association was significant in women aged 60–74 years (adjusted odds ratio 0.881, 95% confidence interval [0.790, 0.983], p  = 0.024). Conclusions: The results indicate an association between the limit of distinguishable odor intensity and cognitive function. The olfactory test with multiple odor intensity levels using fewer odors may be applicable for the early detection of mild cognitive impairment, especially in older women aged 60–74 years. Show more

Keywords: Alzheimer’s disease, cross-sectional studies, dementia tests, logistic models, mental status, odds ratio, olfactory disorders, risk, smell

DOI: 10.3233/JAD-230318

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1469-1480, 2023

Authors: Du, Yuanyuan | Chen, Xi | Zhang, Bin | Jin, Xing | Wan, Zemin | Zhan, Min | Yan, Jun | Zhang, Pengwei | Ke, Peifeng | Huang, Xianzhang | Han, Liqiao | Zhang, Qiaoxuan

Article Type: Research Article

Abstract: Background: The underlying pathogenic genes and effective therapeutic agents of Alzheimer’s disease (AD) are still elusive. Meanwhile, abnormal copper metabolism is observed in AD brains of both human and mouse models. Objective: To investigate copper metabolism-related gene biomarkers for AD diagnosis and therapy. Methods: The AD datasets and copper metabolism-related genes (CMGs) were downloaded from GEO and GeneCards database, respectively. Differentially expressed CMGs (DE-CMGs) performed through Limma, functional enrichment analysis and the protein-protein interaction were used to identify candidate key genes by using CytoHubba. And these candidate key genes were utilized to construct a prediction model …by logistic regression analysis for AD early diagnosis. Furthermore, ROC analysis was conducted to identify a single gene with AUC values greater than 0.7 by GSE5281. Finally, the single gene biomarker was validated by quantitative real-time polymerase chain reaction (qRT-PCR) in AD clinical samples. Additionally, immune cell infiltration in AD samples and potential therapeutic drugs targeting the identified biomarkers were further explored. Results: A polygenic prediction model for AD based on copper metabolism was established by the top 10 genes, which demonstrated good diagnostic performance (AUC values). COX11, LDHA, ATOX1, SCO1, and SOD1 were identified as blood biomarkers for AD early diagnosis. 20 agents targeting biomarkers were retrieved from DrugBank database, some of which have been proven effective for the treatment of AD. Conclusions: The five blood biomarkers and copper metabolism-associated model can differentiate AD patients from non-demented individuals and aid in the development of new therapeutic strategies. Show more

Keywords: Agents, Alzheimer’s disease, biomarkers, copper metabolism, polygenic prediction model

DOI: 10.3233/JAD-230565

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1481-1496, 2023

Authors: Salzman, Talia | Tobón, Diana P. | Perreault, Hannah | Farhat, Farah | Fraser, Sarah

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) refers to individuals who report persistent cognitive deficits but perform normally on neuropsychological tests. Performance may be facilitated by increased prefrontal cortex activation, known as neural compensation, and could be used to differentiate between older adults with and without SCD. Objective: This cross-sectional pilot study measured changes in the hemodynamic response (ΔHbO2) using functional near-infrared spectroscopy (fNIRS) as well as cognitive and motor performance during fine and gross motor dual-tasks in older adults with and without SCD. Methods: Twenty older adults over 60 years old with (n  = 10) and without (n … = 10) SCD were recruited. Two experiments were conducted using 1) gross motor walking and 2) fine motor finger tapping tasks that were paired with an n-back working memory task. Participants also completed neuropsychological assessments and questionnaires on everyday functioning. Results: Repeated measures ANOVAs demonstrated slower response times during dual-task gait compared to the single task (p  = 0.032) and in the non-SCD group, slower gait speed was also observed in the dual compared to single task (p  = 0.044). Response times during dual-task finger tapping were slower than the single task (p  = 0.049) and greater ΔHbO2 was observed overall in the SCD compared to non-SCD group (p  = 0.002). Conclusions: Examining neural and performance outcomes revealed differences between SCD and non-SCD groups and single and dual-tasks. Greater brain activation during dual-task finger tapping may reflect neural compensation, which should be examined in a larger sample and longitudinally to better characterize SCD. Show more

Keywords: Alzheimer’s disease, cognitive aging, cognitive dysfunction, dual-task, gait, near-infrared spectroscopy, prefrontal cortex, subjective cognitive decline

DOI: 10.3233/JAD-230469

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1497-1508, 2023

Authors: Wang, Shanshan | Liu, Suzhi | Ke, Shaofa | Zhou, Wenjun | Pan, Tengwei

Article Type: Research Article

Abstract: Background: Elevated tau phosphorylation has been linked to the Apolipoprotein E (APOE ) ɛ 4 allele, which is considered one of the most significant genes related to Alzheimer’s disease (AD). However, it is uncertain whether the impact of increased plasma tau phosphorylated at threonine 181 (p-tau181) on memory and executive function decline would be greater among APOE ɛ 4 carriers. Objective: To investigate the effects of plasma p-tau181 and APOE ɛ 4 on memory and executive function. Methods: The longitudinal analysis included 608 older adults without dementia (aged 72±7 years; 47% female; follow-up period …of 1.59±1.47 years) from the ADNI dataset, including 180 individuals with normal cognition and 429 individuals with mild cognitive impairment. Linear mixed-effects models were utilized to assess the contributions of APOE ɛ 4 status and plasma p-tau181 to longitudinal changes in memory composite score and executive function composite score. Results: At baseline, the APOE ɛ 4+/Tau+ group exhibited poorer performance in memory composite score and executive function composite score, and an elevated load of cerebrospinal fluid Aβ and tau pathologies. To further understand longitudinal changes, we compared groups directly based on plasma p-tau181 and APOE ɛ 4 status (four groups: APOE ɛ 4–/Tau–, APOE ɛ 4–/Tau+, APOE ɛ 4+/Tau–, APOE ɛ 4+/Tau+). Both the memory composite score and executive function composite score showed a significantly greater decline in the APOE ɛ 4+/Tau+ group than in all other groups. Conclusions: Our findings indicate that there is an interaction between plasma p-tau181 levels and APOE ɛ 4 status, which contributes to the longitudinal changes of memory and executive function in older adults without dementia. Show more

Keywords: Alzheimer’s disease, APOE ɛ4, executive function, memory, older adults without dementia, p-tau181

DOI: 10.3233/JAD-230437

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1509-1518, 2023

Authors: Hasan, Gulam Mustafa | Shamsi, Anas | Sohal, Sukhwinder Singh | Alam, Manzar | Hassan, Md. Imtaiyaz

Article Type: Research Article

Abstract: Background: Tyrosine-protein kinase receptor Ret (RET), a proto-oncogene, is considered as an attractive drug target for cancer and neurodegenerative diseases, including Alzheimer’s disease (AD). Objective: We aimed to identify potential inhibitors of RET kinase among natural compounds present in the ZINC database. Methods: A multistep structure-based virtual screening approach was used to identify potential RET kinase inhibitors based on their binding affinities, docking scores, and interactions with the biologically important residues of RET kinase. To further validate the potential of these compounds as therapeutic leads, molecular dynamics (MD) simulations for 100 ns were carried out and subsequently …evaluated the stability, conformational changes, and interaction mechanism of RET in-complex with the elucidated compounds. Results: Two natural compounds, ZINC02092851 and ZINC02726682, demonstrated high affinity, specificity for the ATP-binding pocket of RET and drug-likeness properties. The MD simulation outputs indicated that the binding of both compounds stabilizes the RET structure and leads to fewer conformational changes. Conclusions: The findings suggest that ZINC02092851 and ZINC02726682 may be potential inhibitors for RET, offering valuable leads for drug development against RET-associated diseases. Our study provides a promising avenue for developing new therapeutic strategies against complex diseases, including AD. Identifying natural compounds with high affinity and specificity for RET provides a valuable starting point for developing novel drugs that could help combat these debilitating diseases. Show more

Keywords: Alzheimer’s disease, computer-aided drug design, molecular dynamics simulations, natural compounds, proto-oncogene tyrosine-protein kinase receptor Ret, virtual screening

DOI: 10.3233/JAD-230698

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1519-1533, 2023

Authors: Nakamura, Yu | Narita, Kohei | Kim, Rei | Nishiyama, Kenichi | Kikuchi, Takashi | Ishikawa, Ichiro | Aoki, Hiroshi

Article Type: Research Article

Abstract: Background: Oral formulations are not suitable for demented patients with dysphagia, those refuse to take tablets, or those with drug compliance problem. However, only oral formulations of donepezil hydrochloride are approved for the treatment of severe Alzheimer’s disease in Japan. Objective: To evaluate the safety, tolerability, and efficacy of long-term application of a 55.0 mg transdermal donepezil patch switched from a 10 mg oral donepezil hydrochloride tablet, for the treatment of patients with severe Alzheimer’s disease. Methods: A 52-week, multicenter, open-label, uncontrolled (phase III) study (jRCT2080224612) was conducted in Japan between April 2019 and August 2021. A 10 mg …donepezil hydrochloride tablet was administered once a day for four weeks; a 55.0 mg donepezil patch was then applied once a day for 52 weeks in patients with severe Alzheimer’s disease. Results: Of 64 patients received the patch, 45 completed the 52-week period. The overall discontinuation rate was 29.7% (19/64). Among the 19 patients discontinued, six patients 9.4% (6/64) discontinued due to adverse events. The incidence of adverse events at application sites was 67.2% (43/64), including application site erythema 29.7% (19/64), application site pruritus 25.0% (16/64), and contact dermatitis 20.3% (13/64). Adverse events were mild and did not increase with time, demonstrating a favorable safety profile. Cognitive function, measured using the Mini-Mental State Examination, was maintained for up to 24 weeks. Conclusions: Adverse events were considered manageable in a clinical setting. The long-term application of a 55.0 mg donepezil patch once a day was feasible treatment in patients with severe Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, dementia donepezil, donepezil patch, long-term

DOI: 10.3233/JAD-230386

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1535-1543, 2023

Authors: Ziyad, Shabana R. | Altulyan, May | Alharbi, Meshal

Article Type: Research Article

Abstract: Background: In the digital era monitoring the patient’s health status is more effective and consistent with smart healthcare systems. Smart health care facilitates secure and reliable maintenance of patient data. Sensors, machine learning algorithms, Internet of things, and wireless technology has led to the development of Artificial Intelligence-driven Internet of Things models. Objective: This research study proposes an Artificial Intelligence driven Internet of Things model to monitor Alzheimer’s disease patient condition. The proposed Smart health care system to monitor and alert caregivers of Alzheimer’s disease patients includes different modules to monitor the health parameters of the patients. This …study implements the detection of fall episodes using an artificial intelligence model in Python. Methods: The fall detection model is implemented with data acquired from the IMU open dataset. The ensemble machine learning algorithm AdaBoost performs classification of the fall episode and daily life activity using the feature set of each data sample. The common machine learning classification algorithms are compared for their performance on the IMU fall dataset. Results: AdaBoost ensemble classifier exhibits high performance compared to the other machine learning algorithms. The AdaBoost classifier shows 100% accuracy for the IMU dataset. This high accuracy is achieved as multiple weak learners in the ensemble model classify the data samples in the test data accurately. Conclusions: This study proposes a smart healthcare system for monitoring Alzheimer’s disease patients. The proposed model can alert the caregiver in case of fall detection via mobile applications installed in smart devices. Show more

Keywords: Alzheimer’s disease, artificial intelligence system, Internet of Things, sensors, smart health care

DOI: 10.3233/JAD-230402

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1545-1557, 2023

Authors: Fukuda, Haruhisa | Kanzaki, Hiroshi | Murata, Fumiko | Maeda, Megumi | Ikeda, Manabu

Article Type: Research Article

Abstract: Background: Accurate epidemiological data on mild cognitive impairment (MCI) and Alzheimer’s disease (AD) can inform the development of prevention and control measures, but there is a lack of such data in Japan. Objective: To investigate the disease burden and progression in patients with new-onset MCI or AD in Japan. Methods: Using claims data, this multi-region cohort study was conducted on new-onset MCI and AD patients in 17 municipalities from 2014 to 2021. To characterize the patients, we investigated their age, comorbidities, and long-term care (LTC) needs levels at disease onset according to region type (urban, suburban, …or rural). Disease burden was examined using health care expenditures and LTC expenditures, which were estimated for 1, 2, and 3 years after disease onset. Kaplan-Meier curves were plotted for AD progression in new-onset MCI patients and death in new-onset AD patients. Results: We analyzed 3,391 MCI patients and 58,922 AD patients. In MCI and AD patients, health care expenditures were high in the first year ($13,035 and $15,858, respectively), but had declined by the third year ($8,278 and $10,414, respectively). In contrast, LTC expenditures (daily living support) steadily increased over the 3-year period (MCI patients: $1,767 to $3,712, AD patients: $6,932 to $9,484). In the third year after disease onset, 30.9% of MCI patients developed AD and 23.3% of AD patients had died. Conclusions: This provides an important first look at the disease burden and progression of MCI and AD in Japan, which are high-priority diseases for a rapidly aging population. Show more

Keywords: Alzheimer’s disease, disease progression, mild cognitive impairment, real-world data

DOI: 10.3233/JAD-230471

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1559-1572, 2023

Authors: Davidson, Skylar | Allenback, Gayle | Decourt, Boris | Sabbagh, Marwan N.

Article Type: Research Article

Abstract: Background: Although insulin dysregulation and resistance likely participate in Alzheimer’s disease (AD) etiologies, little is known about the correlation between type 2 diabetes mellitus (T2DM) and the progression of cognitive decline in patients with AD. Objective: To determine whether AD patients with T2DM experience more rapid cognitive decline than those without T2DM. Methods: All cognitive performance data and the presence or absence of T2DM comorbidity in patients with AD were derived from the US National Alzheimer’s Coordinating Center’s (NACC) Uniform Data Set (UDS). A search of the UDS identified 3,055 participants with AD who had more …than one epoch completed. The data set culled clinically diagnosed AD dementia patients who were assessed for diabetes type identified during at least 1 visit. These patients were divided into 2 groups based on whether they had a diagnosis of T2DM. The data from these groups were then analyzed for differences in cognitive decline based on neuropsychological test battery scores and a Clinician Dementia Rating using a general linear model. Results: Comparisons of the mean scores for 16 selected tests from the neuropsychological test battery showed no significant differences in baseline scores and scores at subsequent visits between the T2DM and nondiabetic groups. Conclusions: The results revealed no differences in cognitive decline metrics over the course of 5 visits in either study group. These data indicate that the presence of T2DM does not increase the rate of cognitive decline in AD. This finding contradicts expected disease burden and will need to be explored further. Show more

Keywords: Alzheimer’s disease, cognitive progression, National Alzheimer’s Coordinating Center, neuropsychological test battery, type 2 diabetes mellitus, Uniform Data Set

DOI: 10.3233/JAD-230489

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1573-1584, 2023