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

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