Journal of Alzheimer's Disease - Volume 99, issue 2

Authors: Bulycheva, Irina | Watanabe, Yumi | Kitamura, Kaori | Kabasawa, Keiko | Saito, Toshiko | Takahashi, Akemi | Kobayashi, Ryosaku | Oshiki, Rieko | Takachi, Ribeka | Tsugane, Shoichiro | Yamazaki, Osamu | Watanabe, Kei | Nakamura, Kazutoshi

Article Type: Research Article

Abstract: Background: Sleep is a potentially modifiable factor associated with dementia, including Alzheimer’s disease, but current evidence supporting this is insufficient. Objective: This study aimed to determine whether sleep duration and bedtime patterns are associated with the risk of dementia among middle-aged and older people. Methods: This cohort study had an eight-year follow-up period. Participants were 13,601 community-dwelling people aged 40–74 years living in Murakami (Niigata, Japan). Data were collected using a self-administered questionnaire. Predictors were self-reported sleep duration and bedtime, and the outcome was newly-diagnosed dementia determined using the long-term care insurance database. Covariates were demographic …characteristics, body mass index, smoking, alcohol consumption, total physical activity, insomnia symptoms, disease history, and either bedtime or sleep duration. Cox proportional hazard models were used to calculate hazard ratios (HRs). Results: The mean age of participants at baseline was 59.2 years. Over a mean follow-up period of 8.0 years, 319 cases of dementia were observed. A long self-reported sleep duration relative to the reference sleep duration (7 hours) was associated with increased dementia risk, with the “8 hours” group (adjusted HR = 1.30, 95% CI:0.99–1.73) and “≥9 hours” group (adjusted HR = 1.46, 95% CI:1.00–2.15) having an increased risk (marginally significant) relative to the reference group. Early bedtime was associated with increased dementia risk (adjusted p for trend = 0.0010), with the “21 : 00 or earlier” group (adjusted HR = 1.61, 95% CI:1.14–2.28) having an increased risk relative to the reference (“23 : 00”). Conclusions: A long self-reported sleep duration and early bedtime are both associated with increased dementia risk in middle-aged and older people Show more

Keywords: Alzheimer’s disease, bedtime, cohort study, dementia, sleep duration

DOI: 10.3233/JAD-231104

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 535-547, 2024

Authors: Asada, Takashi | Tanaka, Mieko | Araki, Wataru | Jon Lebowitz, Adam | Kakuma, Tatsuyuki

Article Type: Research Article

Abstract: Background: Interventions to prevent or attenuate cognitive decline and dementia in older adults are becoming increasingly important. Recently, cognitive training exercise can be via computer or mobile technology for independent or home use. Recent meta-analysis has reported that Computerized Cognitive Training (CCT) is effective at enhancing cognitive function in healthy older and Alzheimer’s disease adults, although little is known about individual characteristics of each computerized program. Objective: We developed a new CCT named Brain Training Based on Everyday Living (BTEL) to enhance cognitive capacity for Instrumental Activities of Daily Living (IADL). We aim to evaluate the efficacy of …the BTEL among cognitively healthy old individuals and to explore its concurrent validity and construct concept. Methods: We conducted a double-blind study where 106 individuals aged 65 years and older (intervened = 53, control = 53) worked on the active and placebo tasks three times a week over three months (clinical trial: UMIN000048730). The main results were examined using ANCOVA and calculating correlation coefficients. Results: We found no effect on total score of the three tests; however, there was significant effect for the BTEL on: recognition in MMSE, and immediate recall in HDSR. The tasks are associated with prefrontal cortex. In addition, correlations indicated that each BTEL domain had some validity as a cognitive assessment tool. Different from previous CCT, we determined the neuropsychological characteristics of specific cognitive tasks of the BTEL to a certain degree. Conclusions: We found modest efficacy of the BTEL in cognitively healthy old individuals and confirmed its concurrent validity and the conceptual construct. Show more

Keywords: Activities of daily living, Alzheimer’s disease, brain training, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-231165

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 549-558, 2024

Authors: Scharf, Annelie | Kleinke, Fabian | Michalowsky, Bernhard | Rädke, Anika | Pfitzner, Stefanie | Mühlichen, Franka | Buchholz, Maresa | van den Berg, Neeltje | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: The healthcare needs of People living with Dementia (PlwD) (such as Alzheimer’s disease) are often unmet. Information about the needs of community-dwelling PlwD and their association with sociodemographic and clinical characteristics is needed to fill the knowledge gap regarding factors influencing unmet needs among PlwD and to conduct a comprehensive needs assessment to develop tailored interventions. Objective: To describe sociodemographic and clinical characteristics of the InDePendent study population with particular reference to determinants of unmet needs. Methods: We analyzed baseline data of the multi-centre cluster-randomized controlled trial (InDePendent) using descriptive statistics to describe patients’ sociodemographic …and clinical characteristics and Poisson regression models to predict unmet needs, separated by sex. Data were collected personally via face-to-face interviews. Results: Most of the n  = 417 participating PlwD were mild to moderately cognitively impaired, were not depressed, had an average of 10.8 diagnoses, took 6.7 medications, and had, on average, 2.4 unmet needs (62% of PlwD had at least one unmet need) measured by the Camberwell Assessment of Need for the Elderly (CANE). Low social support, a high body-mass-index, a lower education, functional impairment, and worse health status were associated with more unmet needs, regardless of sex. In women, higher unmet needs were associated with more depressive symptoms, a poor financial situation, living alone and not being recently treated by a general practitioner. In males, unmet needs increased with the number of medications taken. Conclusions: PlwD had a broad array of unmet healthcare needs, indicating primary healthcare provision improvement potentials. The results underscore the significance of early assessment of patient’s clinical characteristics and unmet needs as a basis for individualized gender-sensible intervention strategies.∥ClinicalTrials.gov Identifier: NCT04741932, Registered on February 5, 2021 Show more

Keywords: KeywordsAlzheimer’s disease, Camberwell Assessment of Need for the Elderly (CANE), dementia, elderly population, health services research, needs assessment, people with dementia, primary care, randomized controlled trial

DOI: 10.3233/JAD-231173

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 559-575, 2024

Authors: Li, Yaoru | Yang, Ziying | Zhang, Yanxin | Liu, Fang | Xu, Jing | Meng, Yaping | Xing, Gebeili | Ruan, Xuqin | Sun, Jun | Zhang, Nan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or …likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO , and DCTN1 , were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, frontotemporal lobar degeneration, variant, whole-exome sequencing

DOI: 10.3233/JAD-231361

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 577-593, 2024

Authors: García-Carlos, Carlos Antonio | Basurto-Islas, Gustavo | Perry, George | Mondragón-Rodríguez, Siddhartha

Article Type: Research Article

Abstract: Background: Cognitive deficits observed in Alzheimer’s disease (AD) patients have been correlated with altered hippocampal activity. Although the mechanism remains under extensive study, neurofibrillary tangles and amyloid plaques have been proposed as responsible for brain activity alterations. Aiming to unveil the mechanism, researchers have developed several transgenic models of AD. Nevertheless, the variability in hippocampal oscillatory alterations found in different genetic backgrounds and ages remains unclear. Objective: To assess the oscillatory alterations in relation to animal developmental age and protein inclusion, amyloid-β (Aβ) load, and abnormally phosphorylated tau (pTau), we reviewed and analyzed the published data on peak …power, frequency, and quantification of theta-gamma cross-frequency coupling (modulation index values). Methods: To ensure that the search was as current as possible, a systematic review was conducted to locate and abstract all studies published from January 2000 to February 2023 that involved in vivo hippocampal local field potential recording in transgenic mouse models of AD. Results: The presence of Aβ was associated with electrophysiological alterations that are mainly reflected in power increases, frequency decreases, and lower modulation index values. Concomitantly, pTau accumulation was associated with electrophysiological alterations that are mainly reflected in power decreases, frequency decreases, and no significant alterations in modulation index values. Conclusions: In this study, we showed that electrophysiological parameters are altered from prodromal stages to the late stages of pathology. Thus, we found that Aβ deposition is associated with brain network hyperexcitability, whereas pTau deposition mainly leads to brain network hypoexcitability in transgenic models Show more

Keywords: Alzheimer’s disease, amyloid-β, cross-frequency coupling, hippocampus, network hyperexcitability, network hypoexcitability, oscillatory activity, phospho-tau

DOI: 10.3233/JAD-231365

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 595-607, 2024

Authors: Horvath, Alexandra | Quinlan, Patrick | Eckerström, Carl | Åberg, N. David | Wallin, Anders | Svensson, Johan

Article Type: Research Article

Abstract: Background: Insulin-like growth factor-I (IGF-I) regulates myelin, but little is known whether IGF-I associates with white matter functions in subjective and objective mild cognitive impairment (SCI/MCI) or Alzheimer’s disease (AD). Objective: To explore whether serum IGF-I is associated with magnetic resonance imaging – estimated brain white matter volumes or cognitive functions. Methods: In a prospective study of SCI/MCI (n  = 106) and AD (n  = 59), we evaluated the volumes of the total white matter, corpus callosum (CC), and white matter hyperintensities (WMHs) as well as Mini-Mental State Examination (MMSE), Trail Making Test A and B (TMT-A/B), and …Stroop tests I–III at baseline, and after 2 years. Results: IGF-I was comparable in SCI/MCI and AD (113 versus 118 ng/mL, p  = 0.44). In SCI/MCI patients, the correlations between higher baseline IGF-I and greater baseline and 2-year volumes of the total white matter and total CC lost statistical significance after adjustment for intracranial volume and other covariates. However, after adjustment for covariates, higher baseline IGF-I correlated with better baseline scores of MMSE and Stroop test II in SCI/MCI and with better baseline results of TMT-B and Stroop test I in AD. IGF-I did not correlate with WMH volumes or changes in any of the variables. Conclusions: Both in SCI/MCI and AD, higher IGF-I was associated with better attention/executive functions at baseline after adjustment for covariates. Furthermore, the baseline associations between IGF-I and neuropsychological test results in AD may argue against significant IGF-I resistance in the AD brain. Show more

Keywords: Alzheimer’s disease, attention, corpus callosum, executive function, insulin-like growth factor-I, magnetic resonance imaging, mild cognitive impairment, speed, subjective mild cognitive impairment, white matter hyperintensities

DOI: 10.3233/JAD-231026

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 609-622, 2024

Authors: Memon, Ashar | Moore, Jasmine A. | Kang, Chris | Ismail, Zahinoor | Forkert , Nils D.

Article Type: Research Article

Abstract: Background: While various biomarkers of Alzheimer’s disease (AD) have been associated with general cognitive function, their association to visual-perceptive function across the AD spectrum warrant more attention due to its significant impact on quality of life. Thus, this study explores how AD biomarkers are associated with decline in this cognitive domain. Objective: To explore associations between various fluid and imaging biomarkers and visual-based cognitive assessments in participants across the AD spectrum. Methods: Data from participants (N  = 1,460) in the Alzheimer’s Disease Neuroimaging Initiative were analyzed, including fluid and imaging biomarkers. Along with the Mini-Mental State Examination …(MMSE), three specific visual-based cognitive tests were investigated: Trail Making Test (TMT) A and TMT B, and the Boston Naming Test (BNT). Locally estimated scatterplot smoothing curves and Pearson correlation coefficients were used to examine associations. Results: MMSE showed the strongest correlations with most biomarkers, followed by TMT-B. The p-tau181/Aβ1–42 ratio, along with the volume of the hippocampus and entorhinal cortex, had the strongest associations among the biomarkers. Conclusions: Several biomarkers are associated with visual processing across the disease spectrum, emphasizing their potential in assessing disease severity and contributing to progression models of visual function and cognition. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, MRI, neuroimaging, visual processing

DOI: 10.3233/JAD-231084

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 623-637, 2024

Authors: Giraldo-Berrio, Daniela | Jimenez-Del-Rio, Marlene | Velez-Pardo, Carlos

Article Type: Research Article

Abstract: Background: Familial Alzheimer’s disease (FAD) presenilin 1 E280A (PSEN 1 E280A) is characterized by functional impairment and the death of cholinergic neurons as a consequence of amyloid-β (Aβ) accumulation and abnormal phosphorylation of the tau protein. Currently, there are no available therapies that can cure FAD. Therefore, new therapies are urgently needed for treating this disease. Objective: To assess the effect of sildenafil (SIL) on cholinergic-like neurons (ChLNs) harboring the PSEN 1 E280A mutation. Methods: Wild-type (WT) and PSEN 1 E280A ChLNs were cultured in the presence of SIL (25μ M) for 24 h. Afterward, proteinopathy, cell …signaling, and apoptosis markers were evaluated via flow cytometry and fluorescence microscopy. Results: We found that SIL was innocuous toward WT PSEN 1 ChLNs but reduced the accumulation of intracellular Aβ fragments by 87%, decreased the non-physiological phosphorylation of the protein tau at residue Ser202 /Thr205 by 35%, reduced the phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63 /Ser73 by 63%, decreased oxidized DJ-1 at Cys106 -SO3 by 32%, and downregulated transcription factor TP53 (tumor protein p53), BH-3-only protein PUMA (p53 upregulated modulator of apoptosis), and cleaved caspase 3 (CC3) expression by 20%, 32%, and 22%, respectively, compared with untreated mutant ChLNs. Interestingly, SIL also ameliorated the dysregulation of acetylcholine-induced calcium ion (Ca2+ ) influx in PSEN 1 E280A ChLNs. Conclusions: Although SIL showed no antioxidant capacity in the oxygen radical absorbance capacity and ferric ion reducing antioxidant power assays, it might function as an anti-amyloid and antiapoptotic agent and functional neuronal enhancer in PSEN 1 E280A ChLNs. Therefore, the SIL has therapeutic potential for treating FAD. Show more

Keywords: Alzheimer’s disease, amyloid-β , apoptosis, caspase 3, DJ-1, hydrogen peroxide, sildenafil

DOI: 10.3233/JAD-231169

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 639-656, 2024

Authors: Liu, Jiaqi | Sun, Sirui | Chen, Yongjie

Article Type: Research Article

Abstract: Background: Numerous studies have investigated the correlation between malondialdehyde (MDA) and cognitive decline. However, limited research has explored the interplay between superoxide dismutase (SOD), C-reactive protein (CRP), and MDA. Objective: This study aims to scrutinize the association between MDA and cognitive function in older adults, while also elucidating the roles of SOD and CRP within this relationship. Methods: Utilizing data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) spanning 2008–2009, 2011–2012, and 2014, this study included 2,696 eligible subjects. Cognitive function was evaluated using the Chinese version of the Mini-Mental State Examination (MMSE). Linear mixed-effects models …were employed to examine the links between MDA, SOD, CRP, and their interactions with cognitive function. Results: Elevated serum levels of MDA and CRP, as well as decreased serum SOD levels, were related to decreased cognitive function (β= –0.220 and –0.346, 95% CI: –0.399, –0.041 and –0.526, –0.167 for MDA and CRP; β= 0.384, 95% CI: 0.204, 0.564 for SOD). Notably, a significant interaction between MDA and SOD was detected (p  = 0.001). An increase per standard deviation in serum MDA levels was significantly associated with a 0.347-point lower MMSE score only in participants with normal cognitive function and high SOD levels (β= –0.347, 95% CI: –0.497, –0.197; p  < 0.001). Conclusions: Elevated serum MDA levels in the normal population with high SOD levels suggested diminished cognitive performance. Combining MDA with SOD could be pivotal in identifying older adults at risk of cognitive decline in clinical settings. Show more

Keywords: Alzheimer’s disease, cognitive decline, C-reactive protein malondialdehyde, mini-mental state examination score, superoxide dismutase

DOI: 10.3233/JAD-231278

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 657-665, 2024

Authors: Chu, Yili | Xie, Qihui | Meng, Rongrong | Leng, Bing | Cao, Zhenxiang

Article Type: Research Article

Abstract: Background: With the increasing popularity of the internet, a growing number of patients and their companions are actively seeking health-related information online. Objective: The aim of this study was to assess the quality and readability of online information about Alzheimer’s disease (AD) in China. Methods: A total of 263 qualified AD-related web pages from different businesses, governments, and hospitals were obtained. The quality of the web pages was assessed using the DISCERN tool, and the readability of the web pages was assessed using a readability measurement website suitable for the Chinese language. The differences in readability …and quality between different types of web pages were investigated, and the correlation between quality and readability was analyzed. Results: The mean overall DISCERN score was 40.93±7.5. The government group scored significantly higher than the commercial and hospital groups. The mean readability score was 12.74±1.27, and the commercial group had the lowest readability score. There was a positive correlation between DISCERN scores and readability scores. Conclusions: This study presents an evaluation of the quality and readability of health information pertaining to AD in China. The findings indicate that there is a need to enhance the quality and readability of web pages about AD in China. Recommendations for improvement are proposed in light of these findings. Show more

Keywords: Alzheimer’s disease, internet, quality evaluation, readability evaluation

DOI: 10.3233/JAD-231339

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 667-678, 2024

Authors: Duran, Tugce | Gaussoin, Sarah A. | Latham, Lauren A. | Rundle, Melissa M. | Espeland, Mark A. | Williams, Benjamin J. | Hughes, Timothy M. | Craft, Suzanne | Sachs, Bonnie C. | Bateman, James R. | Lockhart, Samuel N.

Article Type: Research Article

Abstract: Background: The preclinical Alzheimer’s cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline. At the outset of the COVID-19 pandemic, cognitive testing was increasingly performed remotely by telephone or video administration. It is desirable to have a harmonized composite measurement derived from both in-person and remote assessments for identifying cognitive changes and to examine its relationship with common neuroimaging biomarkers. Objective: We defined a telehealth compatible PACC (tPACC) and examined its relationship with neuroimaging biomarkers related to neurodegeneration, brain function and perfusion, white matter integrity, and amyloid-β. Methods: We examined 648 participants’ …neuroimaging and in-person and remote cognitive testing data from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core cohort (observational study) to calculate a modified PACC (PACC5-RAVLT) score and tPACC scores (in-person and remote). We performed Spearman/intraclass correlation coefficient (ICC) analyses for reliability of tPACC scores and linear regression models to evaluate associations between tPACC and neuroimaging. Bland-Altman plots for agreement were constructed across cognitively normal and impaired (mild cognitive impairment and dementia) participants. Results: There was a significant positive relationship between tPACCin - person and PACC5-RAVLT (Overall group: r2  = 0.94, N  = 648), and tPACCin - person and tPACCremote (validation subgroup: ICC = 0.82, n  = 53). Overall, tPACC showed significant associations with brain thickness/volume, gray matter perfusion, white matter free water, and amyloid-β deposition. Conclusions: There is a good agreement between tPACCand PACC5-RAVLTfor cognitively normal and impaired individuals. The tPACC is associated with common neuroimaging markers of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-beta, cognitive composite, cognitive decline, MRI, PET, reliability, telehealth testing

DOI: 10.3233/JAD-231435

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 679-691, 2024

Authors: Elghanam, Yomna | Purja, Sujata | Kim, Eun Young

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease that imposes economic and societal burden. Biomarkers have played a crucial role in the recent approval of aducanumab and lecanemab as disease-modifying therapies which marked a significant milestone for the treatment of AD. The inclusion of biomarkers in AD trials facilitates precise diagnosis, monitors safety, demonstrates target engagement, and supports disease modification. Objective: This study analyzed the utilization state and trends of biomarkers as endpoints in AD trials. Methods: In this retrospective study, trials were collected by searching clinicaltrials.gov using the term “Alzheimer”. Primary and secondary outcomes were …analyzed separately for each phase. Results: Among the 1,048 analyzed trials, 313 (29.87%) adopted biomarkers as primary endpoints and 364 (34.73%) as secondary endpoints, mainly in phases 1 and 2. The top three biomarkers adopted as primary endpoints in phases 1, 2, and 3 were amyloid-PET, tau-PET, and MRI. The top three biomarkers adopted as secondary endpoints, in phase 1, were cerebrospinal fluid (CSF) amyloid-β (Aβ), blood Aβ and amyloid-PET; in phase 2, they were MRI, CSF Aβ, and CSF phospho-tau; and in phase 3, they were amyloid PET, MRI, and blood Aβ. There was a statistically significant increase in the adoption of biomarkers as primary endpoints in phase 2 trials (p  = 0.001) and secondary endpoints in phase 3 trials (p  = 0.001). Conclusions: The growing recognition of the importance of biomarkers in AD trial’ design and drug development is evident by the significant steady increase in biomarkers’ utilization in phases 2 and 3. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, clinical trials, drug development, endpoint, tau

DOI: 10.3233/JAD-240008

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 693-703, 2024

Authors: Um, Yoo Hyun | Wang, Sheng-Min | Kang, Dong Woo | Kim, Sunghwan | Lee, Chang Uk | Kim, Donghyeon | Choe, Yeong Sim | Kim, Regina E.Y. | Lee, Soyoung | Lee, Min-Kyung | Lim, Hyun Kook

Article Type: Research Article

Abstract: Background: Recent interest has surged in the locus coeruleus (LC) for its early involvement in Alzheimer’s disease (AD), notably concerning the apolipoprotein ɛ4 allele (APOE4 ). Objective: This study aimed to discern LC functional connectivity (FC) variations in preclinical AD subjects, dissecting the roles of APOE4 carrier status and amyloid-β (Aβ) deposition. Methods: A cohort of 112 cognitively intact individuals, all Aβ-positive, split into 70 APOE4 noncarriers and 42 carriers, underwent functional MRI scans, neuropsychological assessments, and APOE genotyping. The research utilized seed to voxel analysis for illustrating LC rsFC discrepancies between APOE4 …statuses and employed a general linear model to examine the interactive influence of APOE4 carrier status and Aβ deposition on LC FC values. Results: The investigation revealed no significant differences in sex, age, or SUVR between APOE4 carriers and noncarriers. It found diminished LC FC with the occipital cortex in APOE4 carriers and identified a significant interaction between APOE4 carrier status and temporal lobe SUVR in LC FC with the occipital cortex. This interaction suggested a proportional increase in LC FC for APOE4 carriers. Additional notable interactions were observed affecting LC FC with various brain regions, indicating a proportional decrease in LC FC for APOE4 carriers. Conclusions: These findings confirm that APOE4 carrier status significantly influences LC FC in preclinical AD, showcasing an intricate relationship with regional Aβ deposition. This underscores the critical role of genetic and pathological factors in early AD pathophysiology, offering insights into potential biomarkers for early detection and intervention strategies. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, functional connectivity, locus coeruleus, preclinical

DOI: 10.3233/JAD-240065

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 705-714, 2024

Authors: Xie, Linhui | Raj, Yash | Varathan, Pradeep | He, Bing | Yu, Meichen | Nho, Kwangsik | Salama, Paul | Saykin, Andrew J. | Yan, Jingwen

Article Type: Research Article

Abstract: Background: There are various molecular hypotheses regarding Alzheimer’s disease (AD) like amyloid deposition, tau propagation, neuroinflammation, and synaptic dysfunction. However, detailed molecular mechanism underlying AD remains elusive. In addition, genetic contribution of these molecular hypothesis is not yet established despite the high heritability of AD. Objective: The study aims to enable the discovery of functionally connected multi-omic features through novel integration of multi-omic data and prior functional interactions. Methods: We propose a new deep learning model MoFNet with improved interpretability to investigate the AD molecular mechanism and its upstream genetic contributors. MoFNet integrates multi-omic data with …prior functional interactions between SNPs, genes, and proteins, and for the first time models the dynamic information flow from DNA to RNA and proteins. Results: When evaluated using the ROS/MAP cohort, MoFNet outperformed other competing methods in prediction performance. It identified SNPs, genes, and proteins with significantly more prior functional interactions, resulting in three multi-omic subnetworks. SNP-gene pairs identified by MoFNet were mostly eQTLs specific to frontal cortex tissue where gene/protein data was collected. These molecular subnetworks are enriched in innate immune system, clearance of misfolded proteins, and neurotransmitter release respectively. We validated most findings in an independent dataset. One multi-omic subnetwork consists exclusively of core members of SNARE complex, a key mediator of synaptic vesicle fusion and neurotransmitter transportation. Conclusions: Our results suggest that MoFNet is effective in improving classification accuracy and in identifying multi-omic markers for AD with improved interpretability. Multi-omic subnetworks identified by MoFNet provided insights of AD molecular mechanism with improved details. Show more

Keywords: Alzheimer’s disease, deep learning, multi-omics, neural network, systems biology

DOI: 10.3233/JAD-240098

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 715-727, 2024

Authors: Libard, Sylwia | Hodik, Monika | Cesarini, Kristina Giuliana | Dragomir, Anca | Alafuzoff, Irina

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) is one of the hallmark lesions of Alzheimer’s disease (AD). During the disease process, Aβ undergoes biochemical changes, producing toxic Aβ variants, proposed to be detected within the neurons. Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive impairment, gait, and urinary symptoms in elderly, that can be reversed by a ventriculo-peritoneal shunt. Majority of iNPH subjects display different Aβ variants in their brain biopsies, obtained during shunting. Objective: To study the cellular compartmentalization of different Aβ variants in brain biopsies from iNPH subjects. Methods: We studied the cellular localization of different proteoforms of Aβ …using antibodies towards different amino acid sequences or post-translational modifications of Aβ, including clones 4G8, 6F/3D, unmodified- (7H3D6), pyroglutamylated- (N3pE), phosphorylated-(1E4E11) Aβ and Aβ protein precursor (AβPP), in brain biopsies from 3 iNPH subjects, using immunohistochemistry and light microscopy (LM), light microscopy on semi-thin sections (LMst), and electron microscopy (EM). Results: In LM all Aβ variants were detected. In LMst and EM, the Aβ 4G8, 6F/3D, and the pyroglutamylated Aβ were detected. The AβPP was visualized by all methods. The Aβ labelling was located extracellularly with no specific signal within the intracellular compartment, whereas the AβPP was seen both intra- and extracellularly. Conclusions: The Aβ markers displayed extracellular localization when visualized by three assessment techniques, reflecting the pathological extracellular accumulation of Aβ in the human brain. No intracellular Aβ pathology was seen. AβPP was visualized in intra- and extracellularly, which corresponds to the localization of the protein in the membranes of cells and organelles. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease neuropathological change, amyloid-β, idiopathic normal pressure hydrocephalus

DOI: 10.3233/JAD-240167

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 729-737, 2024

Authors: Xu, Jing | Chen, Yao | Shi, Yi | Sun, Anna | Yang, Yuedi | Boustani, Malaz | Su, Jing | Zhang, Pengyue

Article Type: Research Article

Abstract: Background: Early detection of Alzheimer’s disease (AD) is a key component for the success of the recently approved lecanemab and aducanumab. Patients with neuroinflammation-related conditions are associated with a higher risk for developing AD. Objective: Investigate the incidence of AD among patients with neuroinflammation-related conditions including epilepsy, hemorrhage stroke, multiple sclerosis (MS), and traumatic brain injury (TBI). Methods: We used Optum’s de-identified Clinformatics Data Mart Database (CDM). We derived covariate-matched cohorts including patients with neuroinflammation-related conditions and controls without the corresponding condition. The matched cohorts were: 1) patients with epilepsy and controls (N  = 67,825 matched pairs); …2) patients with hemorrhage stroke and controls (N  = 81,510 matched pairs); 3) patients with MS and controls (N  = 9,853 matched pairs); and 4) patients TBI and controls (N  = 104,637 matched pairs). We used the Cox model to investigate the associations between neuroinflammation-related conditions and AD. Results: We identified that epilepsy, hemorrhage stroke, and TBI were associated with increased risks of AD in both males and females (hazard ratios [HRs]≥1.74, p  < 0.001), as well as in gender- and race-conscious subpopulations (HRs≥1.64, p  < 0.001). We identified that MS was associated with increased risks of AD in both males and females (HRs≥1.47, p ≤0.004), while gender- and race-conscious subgroup analysis shown mixed associations. Conclusions: Patients with epilepsy, hemorrhage stroke, MS, and/or TBI are associated with a higher risk of developing AD. More attention on cognitive status should be given to older patients with these conditions. Show more

Keywords: Alzheimer’s disease, epilepsy, hemorrhagic stroke, multiple sclerosis, neuroinflammatory disease, traumatic brain injury

DOI: 10.3233/JAD-231286

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 739-752, 2024

Authors: Georgescu, Michael F. | Beydoun, May A. | Ashe, Jason | Maino Vieytes, Christian A. | Beydoun, Hind A. | Evans, Michele K. | Zonderman, Alan B.

Article Type: Research Article

Abstract: Background: Loneliness, dementia, and mortality are interconnected. Objective: We aimed at understanding mediating pathways and interactions between loneliness and dementia in relation to mortality risk. Methods: The study tested bi-directional relationships between dementia, loneliness, and mortality, by examining both interactions and mediating effects in a large sample of older US adults participating in the nationally representative Health and Retirement Study. Out of≤6,468 older participants selected in 2010, with mean baseline age of 78.3 years and a follow-up time up to the end of 2020, 3,298 died at a rate of 64 per 1,000 person-years (P-Y). Cox …proportional hazards and four-way decomposition models were used. Results: Algorithmically defined dementia status (yes versus no) was consistently linked with a more than two-fold increase in mortality risk. Dementia status and Ln(odds of dementia) were strongly related with mortality risk across tertiles of loneliness score. Loneliness z-score was also linked to an elevated risk of all-cause mortality regardless of age, sex, or race or ethnicity, and its total effect (TE) on mortality was partially mediated by Ln(odds of dementia), z-scored, (≤40% of the TE was a pure indirect effect). Conversely, a small proportion (<5%) of the TE of Ln(odds of dementia), z-scored, on mortality risk was explained by the loneliness z-score. Conclusions: In sum, dementia was positively associated with all-cause mortality risk, in similar fashion across loneliness score tertiles, while loneliness was associated with mortality risk. TE of loneliness on mortality risk was partially mediated by dementia odds in reduced models. Show more

Keywords: Aging, Alzheimer’s disease, cohort studies, dementia, loneliness, mortality

DOI: 10.3233/JAD-231359

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 753-772, 2024

Authors: Wu, Bin | Chen, Mulan | Meng, Ling | Tian, Qiuyun | Dong, Zhifang

Article Type: Research Article

Abstract: Background: The amyloid-β (Aβ) enhances the number and activity of blood monocyte-derived osteoclasts (OCs). Individuals with osteoporosis (OP) face an increased risk of developing dementia or Alzheimer’s disease (AD). Despite this association, the contribution of bone-resorbing OCs to the progression of AD pathology remains unclear. Objective: Our objective was to investigate the potential impacts of OCs on the development of AD pathology. Methods: We conducted targeted analysis of publicly available whole blood transcriptomes from patients with AD to characterize the blood molecular signatures and pathways associated with hyperactive OCs. In addition, we used APP23 transgenic (APP23 …TG) AD mouse model to assess the effects of OCs pharmacological blockade on AD pathology and behavior. Results: Patients with AD exhibited increased osteoclastogenesis signature in their blood cells, which appears to be positively correlated with dysfunction of peripheral clearance of Aβ mediated by immune cells. Long-term anti-resorptive intervention with Alendronate inhibited OC activity in APP23 mice, leading to improvements in peripheral monocyte Aβ-degrading enzyme expression, Aβ-deposition, and memory decline. Conclusions: Our findings suggest that OCs have a disease-promoting role in the development and progression of AD, possibly linked to their modulation of peripheral immunity. These findings guide future research to further elucidate the connection between OP and AD pathogenesis, highlighting the potential benefits of preventing OP in alleviating cognitive burden. Show more

Keywords: Alzheimer’s disease, amyloid-β burden, monocyte, osteoclast, osteoporosis

DOI: 10.3233/JAD-240096

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 773-785, 2024

Authors: Jiang, Xiaqing | Bahorik, Amber L. | Graff-Radford, Neill R. | Yaffe, Kristine

Article Type: Research Article

Abstract: Background: Plasma amyloid-β (Aβ) has emerged as an important tool to detect risks of Alzheimer’s disease and related dementias, although research in diverse populations is lacking. Objective: We compared plasma Aβ42/40 by race with dementia risk over 15 years among Black and White older adults. Methods: In a prospective cohort of 997 dementia-free participants (mean age 74±2.9 years, 55% women, 54% Black), incident dementia was identified based on hospital records, medication, and neurocognitive test over 15 years. Plasma Aβ42/40 was measured at Year 2 and categorized into low, medium, and high tertile. We used …linear regression to estimate mean Aβ42/40 by race and race-stratified Cox proportional hazards models to assess the association between Aβ42/40 tertile and dementia risk. Results: Black participants had a lower age-adjusted mean Aβ 42/40 compared to White participants, primarily among APOE ɛ4 non-carriers (Black: 0.176, White: 0.185, p  = 0.035). Among Black participants, lower Aβ 42/40 was associated with increased dementia risk: 33% in low (hazard ratios [HR] = 1.77, 95% confidence interval 1.09–2.88) and 27% in medium tertile (HR = 1.67, 1.01–2.78) compared with 18% in high Aβ 42/40 tertile; Increased risks were attenuated among White participants: 21% in low (HR = 1.43, 0.81–2.53) and 23% in medium tertile (HR = 1.27, 0.68–2.36) compared with 15% in high Aβ 42/40 tertile. The interaction by race was not statistically significant. Conclusions: Among community-dwelling, non-demented older adults, especially APOE ɛ4 non-carriers, Black individuals had lower plasma Aβ 42/40 and demonstrated a higher dementia risk with low Aβ42/40 compared with White individuals. Show more

Keywords: Amyloid, Alzheimer’s disease, Alzheimer’s disease and related dementias, cohort studies, race

DOI: 10.3233/JAD-240007

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 787-797, 2024

Authors: Ghani, Zartashia | Saha, Sanjib | Jarl, Johan | Andersson, Martin | Sanmartin Berglund, Johan | Anderberg, Peter

Article Type: Correction

DOI: 10.3233/JAD-249009

Citation: Journal of Alzheimer's Disease, vol. 99, no. 2, pp. 799-810, 2024