Journal of Alzheimer's Disease - Volume 90, issue 3

Authors: Walter, Sarah | Kim, Anne B. | Flores, Melissa | Ziolkowski, Jaimie | Shaffer, Elizabeth | Aggarwal, Neelum T.

Article Type: Research Article

Abstract: Background: Study participants, patients, and care partners are key stakeholders in research and have asked for greater inclusion in the dissemination of scientific learning. However, the participation of general audiences in scientific conferences dedicated to Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) is not widely supported or studied. Objective: Our objectives were to evaluate the interest, level of engagement, and impact of including general audiences in a virtual dementia conference. Methods: A diverse group of lay participants, identified via community-based health advocacy groups and research centers, were invited to attend the 2021 Alzheimer’s Association International …Conference (AAIC), with optional small-group discussions. Participants received complimentary access to all scientific sessions and were supported via navigation tips, recommended sessions, and a glossary of frequently used terms and acronyms. Results: Lay participants demonstrated a high level of engagement, even among those that were research-naïve, attending virtual sessions for an average of 11.7 hours across the five days and recommending a variety of sessions to each other on topics extending from prevention of dementia to new therapies and care. Most participants said they would attend the conference again and rated the quality of interaction as high, while requesting more opportunities to engage directly with researchers. Conclusion: General audiences, in particular research participants, are advocating for greater participation in scientific conferences. This program can serve as a model to accomplish inclusion; thereby acknowledging their invaluable contribution to science. Show more

Keywords: Dementia, patient activation, patient inclusion, patients and conferences, research participants

DOI: 10.3233/JAD-215681

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1001-1009, 2022

Authors: Arias, Jalayne J. | Lin, Grace A. | Tyler, Ana M. | Douglas, Michael P. | Phillips, Kathryn A.

Article Type: Research Article

Abstract: Background: Research advancements in Alzheimer’s disease (AD) raise opportunities for genetic testing to improve diagnostic and risk assessment. Despite emerging developments, it is unclear how geriatricians perceive the potential clinical and personal utility of genetic testing for their patients. Geriatricians’ perspectives are essential to understanding potential ethical, policy, and clinical challenges. Objective: In this paper, we report on geriatricians’ perspectives on the utility of genetic testing for AD. Methods: Semi-structured interviews with California geriatricians within different practices settings to collect and characterize their perspectives on genetic testing for AD. We used an adapted grounded theory approach …to analyze recorded and transcribed interviews. Results: We identified geriatricians’ (n  = 10) perspectives on the clinical and personal utility of testing, alongside their views on clinical care approaches for older adults. Geriatricians perceived minimal clinical utility of genetic testing for AD, though that may change with the availability of disease-modifying therapies. Yet, they recognized the potential personal utility of testing (e.g., assisting with future financial planning). Finally, geriatricians expressed concerns regarding patients’ anxiety from learning about genetic status, particularly through direct-to-consumer (DTC) testing. Conclusion: Our data highlight that the decision to order genetic testing requires clinical and ethical considerations, including balancing limited clinical utility with the potential personal utility. Although DTC testing is available, geriatricians perceive that they have an important role in managing the decision to test and interpreting the results. Further research is needed to inform policy and ethical guidelines to support geriatricians’ critical role to counsel patients considering clinical and DTC genetic testing. Show more

Keywords: Alzheimer’s disease, APOE, direct-to-consumer testing, genetic testing

DOI: 10.3233/JAD-220674

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1011-1019, 2022

Authors: Largent, Emily A. | Bhardwaj, Twisha | Clapp, Justin T. | Sykes, Olivia Saúl | Harkins, Kristin | Grill, Joshua D.

Article Type: Research Article

Abstract: Background: Participants in Alzheimer’s disease (AD) prevention studies are generally required to enroll with a study partner; this requirement constitutes a barrier to enrollment for some otherwise interested individuals. Analysis of dyads enrolled in actual AD trials suggests that the study partner requirement shapes the population under study. Objective: To understand if individuals can identify someone to serve as their study partner and whether they would be willing to ask that individual. Methods: We conducted semi-structured interviews with cognitively unimpaired, English-speaking older adults who had previously expressed interest in AD research by signing up for a …research registry. We also interviewed their likely study partners. Audio-recorded interviews were transcribed and coded in an iterative, team-based process guided by a content analysis approach. Results: We interviewed 60 potential research participants and 17 likely study partners. Most potential participants identified one or two individuals they would be willing to ask to serve as their study partner. Interviewees saw value in the study partner role but also understood it to entail burdens that could make participation as a study partner difficult. The role was seen as relatively more burdensome for individuals still in the workforce or with family responsibilities. Calls from the researcher to discuss the importance of the role and the possibility of virtual visits were identified as potential strategies for increasing study partner availability. Conclusion: Efforts to increase recruitment, particularly representative recruitment, of participants for AD prevention studies should reduce barriers to participation by thoughtfully designing the study partner role. Show more

Keywords: Alzheimer’s disease, ethics, registries, research, research design

DOI: 10.3233/JAD-220061

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1021-1033, 2022

Authors: Mozersky, Jessica | Roberts, J. Scott | Rumbaugh, Malia | Chhatwal, Jasmeer | Wijsman, Ellen | Galasko, Douglas | Blacker, Deborah

Article Type: Review Article

Abstract: In this article we address how the recent, and anticipated upcoming, FDA approvals of novel anti-amyloid medications to treat individuals with mild Alzheimer’s disease (AD) dementia could impact disclosure of biomarker results among asymptomatic research participants. Currently, research is typically the context where an asymptomatic individual may have the option to learn their amyloid biomarker status. Asymptomatic research participants who learn their amyloid status may have questions regarding the meaning of this result and the implications for accessing a potential intervention. After outlining our rationale, we provide examples of how current educational materials used in research convey messages regarding amyloid …positivity and the availability of treatments, or lack thereof. We suggest language to improve messaging, as well as strengths of current materials, in addressing these issues for research participants. Although novel medications are currently only approved for use among symptomatic individuals, their availability may have implications for disclosure among asymptomatic research participants with evidence of amyloid deposition, who may be especially interested in information on these interventions for potential prevention, or future treatment, of mild cognitive impairment or dementia due to AD. Show more

Keywords: Alzheimer’s disease, amyloid, asymptomatic disclosure, biomarkers, dementia, new medications, research ethics

DOI: 10.3233/JAD-220113

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1035-1043, 2022

Authors: Valverde, Audrey | Mitrofanis, John

Article Type: Review Article

Abstract: Although the cause(s) of Alzheimer’s disease in the majority of cases remains elusive, it has long been associated with hypertension. In animal models of the disease, hypertension has been shown to exacerbate Alzheimer-like pathology and behavior, while in humans, hypertension during mid-life increases the risk of developing the disease later in life. Unfortunately, once individuals are diagnosed with the disease, there are few therapeutic options available. There is neither an effective symptomatic treatment, one that treats the debilitating cognitive and memory deficits, nor, more importantly, a neuroprotective treatment, one that stops the relentless progression of the pathology. Further, there is …no specific preventative treatment that offsets the onset of the disease. A key factor or clue in this quest for an effective preventative and therapeutic treatment may lie in the contribution of hypertension to the disease. In this review, we explore the idea that photobiomodulation, the application of specific wavelengths of light onto body tissues, can reduce the neuropathology and behavioral deficits in Alzheimer’s disease by controlling hypertension. We suggest that treatment with photobiomodulation can be an effective preventative and therapeutic option for this neurodegenerative disease. Show more

Keywords: Cell death, infrared, mitochondria, non-pharmacological, red, vascular pathology

DOI: 10.3233/JAD-220632

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1045-1055, 2022

Authors: Huang, Yiyao | Driedonks, Tom A.P. | Cheng, Lesley | Rajapaksha, Harinda | Routenberg, David A. | Nagaraj, Rajini | Redding, Javier | Arab, Tanina | Powell, Bonita H. | Pletniková, Olga | Troncoso, Juan C. | Zheng, Lei | Hill, Andrew F. | Mahairaki, Vasiliki | Witwer, Kenneth W.

Article Type: Research Article

Abstract: Background: Brain tissue-derived extracellular vesicles (bdEVs) play neurodegenerative and protective roles, including in Alzheimer’s disease (AD). Extracellular vesicles (EVs) may also leave the brain to betray the state of the CNS in the periphery. Only a few studies have profiled the proteome of bdEVs and source brain tissue. Additionally, studies focusing on bdEV cell type-specific surface markers are rare. Objective: We aimed to reveal the pathological mechanisms inside the brain by profiling the tissue and bdEV proteomes in AD patients. In addition, to indicate targets for capturing and molecular profiling of bdEVs in the periphery, CNS cell-specific markers …were profiled on the intact bdEV surface. Methods: bdEVs were separated and followed by EV counting and sizing. Brain tissue and bdEVs from age-matched AD patients and controls were then proteomically profiled. Total tau (t-tau), phosphorylated tau (p-tau), and antioxidant peroxiredoxins (PRDX) 1 and 6 were measured by immunoassay in an independent bdEV separation. Neuron, microglia, astrocyte, and endothelia markers were detected on intact EVs by multiplexed ELISA. Results: Overall, concentration of recovered bdEVs was not affected by AD. Proteome differences between AD and control were more pronounced for bdEVs than for brain tissue. Levels of t-tau, p-tau, PRDX1, and PRDX6 were significantly elevated in AD bdEVs compared with controls. Release of certain cell-specific bdEV markers was increased in AD. Conclusion: Several bdEV proteins are involved in AD mechanisms and may be used for disease monitoring. The identified CNS cell markers may be useful tools for peripheral bdEV capture. Show more

Keywords: Alzheimer’s disease, brain, cell of origin markers, central nervous system, ectosomes, exosomes, extracellular vesicles, microvesicles, proteomics

DOI: 10.3233/JAD-220322

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1057-1072, 2022

Authors: Frenzel, Stefan | Bis, Joshua C. | Gudmundsson, Elias F. | O’Donnell, Adrienne | Simino, Jeannette | Yaqub, Amber | Bartz, Traci M. | Brusselle, Guy G. O. | Bülow, Robin | DeCarli, Charles S. | Ewert, Ralf | Gharib, Sina A. | Ghosh, Saptaparni | Gireud-Goss, Monica | Gottesman, Rebecca F. | Ikram, M. Arfan | Knopman, David S. | Launer, Lenore J. | London, Stephanie J. | Longstreth, W.T. | Lopez, Oscar L. | Melo van Lent, Debora | O’Connor, George | Satizabal, Claudia L. | Shrestha, Srishti | Sigurdsson, Sigurdur | Stubbe, Beate | Talluri, Rajesh | Vasan, Ramachandran S. | Vernooij, Meike W. | Völzke, Henry | Wiggins, Kerri L. | Yu, Bing | Beiser, Alexa S. | Gudnason, Vilmundur | Mosley, Thomas | Psaty, Bruce M. | Wolters, Frank J. | Grabe, Hans J. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. Objective: To study the cross-sectional associations of pulmonary function with structural brain variables. Methods: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter …volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. Results: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. Conclusion: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden. Show more

Keywords: Dementia, epidemiology, magnetic resonance imaging, respiratory function tests

DOI: 10.3233/JAD-220667

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1073-1083, 2022

Authors: Shikimoto, Ryo | Nozaki, Shoko | Sawada, Norie | Shimizu, Yoko | Svensson, Thomas | Nakagawa, Atsuo | Mimura, Masaru | Tsugane, Shoichiro

Article Type: Research Article

Abstract: Background: The relationship between coping in mid- to late life and cognitive functions remains unclear. Objective: To investigate the relationship between habitual coping behaviors of a large Japanese population in their mid- to late-lives and their risk of cognitive decline 15 years later. Methods: Overall 1,299 participants were assessed for coping behaviors (in 2000) and cognition (2014–2015). We used the Stress and Coping Inventory to assess the frequency of six coping behaviors (i.e., consulting, planning, positive reappraisal, avoidance, fantasizing, and self-blame). Logistic regression analyses were conducted to examine odds ratios (ORs) for the diagnosis of mild …cognitive impairment (MCI), MCI subtypes (single- and multiple-domain MCI), and dementia for coping behaviors. Results: Among the eligible 1,015 participants (72.6 [SD = 5.5] years old in 2014–2015), the numbers for cognitively normal, single-domain MCI, multiple-domain MCI, and dementia were 650 (64.0%), 116 (11.4%), 213 (21.0%), and 36 (3.5%), respectively. Among the six coping behaviors, avoidant coping was significantly associated with noticeable cognitive decline (multiple-domain MCI and dementia). This association remained significant after adjusting for sex, age, education, diagnosis of current major depressive disorder, past history of ischemic heart disease, diabetes, regular alcohol consumption, and smoking (OR = 2.52, 95% CI = 1.23 to 5.15). No significant association with other coping behaviors was found. Conclusion: Avoidant coping in mid- and late life is associated with cognitive decline among older people. Show more

Keywords: Avoidance behavior, cognitive decline, cognitive dysfunction, coping behavior, coping strategy, dementia, mild cognitive impairment, mild cognitive impairment subtype, multiple-domain MCI, psychological adaptation

DOI: 10.3233/JAD-215712

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1085-1101, 2022

Authors: Bittar, Alice | Al-Lahham, Rabab | Bhatt, Nemil | Moore, Kenya | Montalbano, Mauro | Jerez, Cynthia | Fung, Leiana | McAllen, Salome | Ellsworth, Anna | Kayed, Rakez

Article Type: Research Article

Abstract: Background: Tau oligomers are one of the most toxic species, displaying prion-like strains which have different conformations resulting in different tauopathies. Passive immunotherapy targeting different tau species is a promising therapeutic approach. Age is one of the greatest risk factors; however, most immunotherapy studies are done in young to middle-aged mice tauopathy models, which is not representative of the many clinical trials done with older humans with established tauopathies. Objective: We utilized two different clones of tau oligomer monoclonal antibodies (TOMAs) in aged Htau and JNPL3 mouse models to investigate the potential of passive immunotherapy. Methods: …Aged mice received a single intravenous injection of 120 μg/animal of either TOMA1, TOMA3 clones or a non-specific IgG. Their cognitive functions were assessed one-week post-injection using Y-maze and novel object recognition tests. Brain tissues were analyzed using biochemical and immunological assays. Results: TOMA 1 and 3 rescues cognitive phenotypes in aged animals in a mouse model-specific manner, indicative by a reduction in tau oligomers levels. The TOMAs were shown to have strong reactivity with different tau oligomeric species in the different mouse models in vitro and ex vivo . Conclusion: This is the first study testing tau passive immunotherapy in aged animals and supports our previous reports on of the role of oligomeric tau in disease progression further validating the potential of TOMAs to rescue the late-stage disease pathology and phenotype. Moreover, this study suggests that multiple tau oligomeric strains exist in aged animals; therefore, it is of great importance to further characterize these strains. Show more

Keywords: Aged mouse models, brain-derived tau oligomers, tau immunotherapy, tau oligomers, tau oligomers strains, tauopathies, TOMA clones

DOI: 10.3233/JAD-220518

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1103-1122, 2022

Authors: Li, Tao-Ran | Lyu, Di-Yang | Liu, Feng-Qi

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is considered a biomarker of microglial activation. The relationships between CSF sTREM2 levels and Alzheimer’s disease (AD) CSF core biomarkers, cognitive status, and neurodegeneration remain unclear. Objective: To assess the association between CSF sTREM2 levels and AD progression and other AD hallmarks. Methods: Using the Alzheimer’s Disease Neuroimaging Initiative database, we investigated 1,035 participants, including 310 cognitively normal controls, 527 patients with mild cognitive impairment, and 198 patients with dementia. They were grouped according to CSF pathology (A/T profile) severity. CSF sTREM2 levels …were compared between the groups, and linear regression analysis was performed to evaluate the factors affecting sTREM2 levels. The predictive effectiveness of sTREM2 levels was tested, and the correlation with other indicators was explored. The increase rate was assessed using linear mixed-effects models. Results: Higher CSF sTREM2 levels were associated with older age as well as higher CSF p-tau or t-tau and amyloid-β levels (all p  < 0.001), but not with cognitive status. sTREM2 levels were not correlated with the baseline or longitudinal scale and neuroimaging result changes, and could not predict clinical conversion, but were correlated with multiple non-amyloid-β and non-tau CSF cytokines related to inflammation and neurodegeneration (p  < 0.0001). The increased sTREM2 expression rate did not change among groups. Conclusion: CSF sTREM2 levels were jointly determined by age, amyloid-β, and tau pathologies, leading to complex AD cognitive continuum changes. Although sTREM2 levels could not predict cognitive deterioration and neurodegeneration, they could reflect the microglial state as a non-specific biomarker. Show more

Keywords: Alzheimer’s disease, biomarker, microglial activation, sTREM2, TREM2

DOI: 10.3233/JAD-220598

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1123-1138, 2022

Authors: Chu, Min | Liu, Li | Nan, Haitian | Jiang, Deming | Wang, Yihao | Rosa-Neto, Pedro | Piao, Yueshan | Wu, Liyong

Article Type: Research Article

Abstract: Background: In most cases, the onset of frontotemporal dementia (FTD) occurs between the ages of 45 and 65 years. However, some patients experience an extremely early disease onset. Objective: To investigate the clinical, genetic, and pathological features of extremely early-onset FTD. Methods: We conducted a comprehensive clinical, genetic, and neuropathological analysis of a 25-year-old patient experiencing the onset of behavioral variant frontotemporal dementia (bvFTD). In addition, we conducted a literature review and summarized the clinical, genetic, and pathological features of patients with FTD with onset age≤25 years. Results: The patient was diagnosed with bvFTD; …however, there was no family history of FTD, no positive genetic test results and no deposition of TDP43, tau, ubiquitin, and synuclein in the brain. Literature screening identified 18 patients with onset age ≤25 years with FTD. The youngest patient was 14 years of age. Most patients (8/14) had a positive family history. The most common clinical phenotype was the behavioral variant (12/14). Genetic results were reported for 11 patients; the most common pathogenic gene was MAPT (10/12), with four cases of G389 R, two cases of P301 S, one case of G335 S, one case of G335A, one case of G335 V, and one case of L315 R. Pathological results were reported for 13 patients; the most common pathological subtype was tau (8/13). Conclusion: FTD can start at an extremely early age. The most common phenotype of extremely early onset FTD was the behavioral variant, the most common pathogenic gene was MAPT, and the most common neuropathological type was tau. Show more

Keywords: Early onset, frontotemporal lobe degeneration, genetics, pathology

DOI: 10.3233/JAD-220679

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1139-1151, 2022

Authors: Wu, Shijing | Hu, Li | Lin, Jiajing | Li, Kanglan | Ye, Shicai | Zhu, Shaoping | Liu, Zhou

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) is important in the etiology of Alzheimer’s disease (AD). Removal of Aβ from the brain is a major strategy for the prevention and treatment of AD. Objective: To clarify whether Aβ42 can be cleared by intestinal excretion and whether the gut microbiota (GM) can affect the excretory clearance of Aβ42 in the peripheral blood and intestines. Methods: Male 8-month-old C57BL6 mice were maintained on either normal chow or received broad-spectrum antibiotics in their drinking water for one week. Sterile saline, fluorescein isothiocyanate (FITC), or FITC-Aβ42 (fluorescein isothiocyanate-labeled amyloid-β42 peptides) …was injected 1 h before sampling. Related changes of Aβ42 before and after injection were evaluated. Results: FITC-Aβ42 was injected into mice through the tail vein and could later be detected in feces. Furthermore, the fecal concentrations of FITC-Aβ42 were higher in mice that had been fed antibiotics to alter their GM than in normal mice. However, the FITC-Aβ42 concentrations in blood showed the opposite pattern. Conclusion: Aβ42 can be excreted into the intestinal lumen and is regulated by the GM. Show more

Keywords: Alzheimer’s disease, amyloid-β , antibiotics, excretion of Aβ , gut microbiota

DOI: 10.3233/JAD-220705

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1153-1162, 2022

Authors: Tian, Yizhu | Li, Deyu | Wang, Daifa | Zhu, Ting | Xia, Meiyun | Jiang, Wenyu

Article Type: Research Article

Abstract: Background: The brain activation patterns of mild cognitive impairment (MCI) are still unclear and they involve multiple brain regions. Most previous studies have focused on abnormal activation in the frontal and temporal lobes, with few investigating the entire brain. Objective: To identify and compare the changes in cerebral hemodynamics and abnormal activation patterns in the entire brain of MCI patients and healthy older adults. Methods: Patients with MCI (n  = 22) and healthy controls (HC, n  = 34) matched by age, education levels, sex, and mental state were enrolled. They performed the same letter and category verbal fluency …test (VFT) tasks while their behavioral performance and global cerebral hemodynamics were analyzed. Results: The performance during the category VFT task was significantly better than that during the letter VFT task across all participants (HC: correct: p  < 0.001; intrusions: p  < 0.001; MCI: correct: p  < 0.001; intrusions: p  < 0.001). The number of correct words during the letter and category VFT tasks was significantly higher in the HC group than in the MCI group (p  < 0.001). The deoxygenated-hemoglobin (HbR) concentrations in the left parietal lobule (p  = 0.022) and left inferior parietal lobule (p  = 0.034) were significantly different during the category VFT task. Conclusion: The differences between HC and MCI groups were greater in the category task. The HbR concentration was more sensitive for the category VFT task and concentration changes in the left parietal lobule and left inferior parietal lobule may be useful for clinical screening and application; thus, they deserve more attention. Show more

Keywords: Deoxyhemoglobin, functional near-infrared imaging, hemoglobin oxygenation, mild cognitive impairment, verbal fluency

DOI: 10.3233/JAD-220691

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1163-1175, 2022

Authors: Fukuda, Haruhisa | Maeda, Megumi | Murata, Fumiko | Murata, Yutaka

Article Type: Research Article

Abstract: Background: Donepezil is frequently used to treat Alzheimer’s disease (AD) symptoms but is associated with early discontinuation. Determining the persistence rates of anti-dementia drug use after donepezil initiation may inform the development and improvement of treatment strategies, but there is little evidence from Japan. Objective: To determine anti-dementia drug persistence following donepezil initiation among AD patients in Japan using insurance claims data. Methods: Insurance claims data for AD patients with newly prescribed donepezil were obtained from 17 municipalities between April 2014 and October 2021. Anti-dementia drug persistence was defined as a gap of ≤60 days between …the last donepezil prescription and a subsequent prescription of donepezil, another cholinesterase inhibitor, or memantine. Cox proportional hazards models were used to analyze the association between care needs levels and discontinuation. Results: We analyzed 20,474 AD patients (mean age±standard deviation: 82.2±6.3 years, women: 65.7%). The persistence rates were 89.1% at 30 days, 79.4% at 90 days, 72.6% at 180 days, 64.5% at 360 days, and 58.3% at 540 days after initiation. Among the care needs levels, the hazard ratio (95% confidence interval) for discontinuation was 1.01 (0.94–1.07) for patients with support needs, 1.12 (1.06–1.18) for patients with low long-term care needs, and 1.31 (1.21–1.40) for patients with moderate-to-high long-term care needs relative to independent patients. Conclusion: Japanese AD patients demonstrated low anti-dementia drug persistence rates that were similar to those of other countries. Higher long-term care needs were associated with discontinuation. Further measures are needed to improve drug persistence in AD patients. Show more

Keywords: Alzheimer’s disease, claims database, dementia, donepezil, persistence

DOI: 10.3233/JAD-220200

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1177-1186, 2022

Authors: Beam, Christopher R. | Luczak, Susan E. | Panizzon, Matthew S. | Reynolds, Chandra A. | Christensen, Kaare | Dahl Aslan, Anna K. | Elman, Jeremy A. | Franz, Carol E. | Kremen, William S. | Lee, Teresa | Nygaard, Marianne | Sachdev, Perminder S. | Whitfield, Keith E. | Pedersen, Nancy L. | Gatz, Margaret

Article Type: Research Article

Abstract: Background: Epidemiological research on dementia is hampered by differences across studies in how dementia is classified, especially where clinical diagnoses of dementia may not be available. Objective: We apply structural equation modeling to estimate dementia likelihood across heterogeneous samples within a multi-study consortium and use the twin design of the sample to validate the results. Methods: Using 10 twin studies, we implement a latent variable approach that aligns different tests available in each study to assess cognitive, memory, and functional ability. The model separates general cognitive ability from components indicative of dementia. We examine the validity …of this continuous latent dementia index (LDI). We then identify cut-off points along the LDI distributions in each study and align them across studies to distinguish individuals with and without probable dementia. Finally, we validate the LDI by determining its heritability and estimating genetic and environmental correlations between the LDI and clinically diagnosed dementia where available. Results: Results indicate that coordinated estimation of LDI across 10 studies has validity against clinically diagnosed dementia. The LDI can be fit to heterogeneous sets of memory, other cognitive, and functional ability variables to extract a score reflective of likelihood of dementia that can be interpreted similarly across studies despite diverse study designs and sampling characteristics. Finally, the same genetic sources of variance strongly contribute to both the LDI and clinical diagnosis. Conclusion: This latent dementia indicator approach may serve as a model for other research consortia confronted with similar data integration challenges. Show more

Keywords: Dementia, genetic correlation, harmonization, latent index, quality of life, twin study

DOI: 10.3233/JAD-220472

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1187-1201, 2022

Authors: Chen, Ting-Hsiang | Yeh, Yi-Chun | Huang, Mei-Feng | Chen, Hui-Mei | Lee, Jia-In | Chen, Cheng-Sheng

Article Type: Research Article

Abstract: Background: The Mild Behavioral Impairment Checklist (MBI-C) has been developed to assess mild behavioral impairment (MBI). However, no study has validated the use of MBI-C using a promising translation method in Taiwan. Thus, consistency and discrepancy between informant-rated and self-rated scores have not been extensively researched. Objective: This study validated and compared the informant- and self-rated versions of the MBI-C among community-dwelling people in Taiwan. Method: We recruited 202 pairs of individuals without dementia aged ≥50 years and their cohabitating informants. The participants completed the MBI-C (MBI-C-self), and the informants completed the MBI-C (MBI-C-informant) and the …Neuropsychiatric Inventory Questionnaire (NPI-Q) independently. Internal consistency, inter-rater reliability, and convergent validity were examined. Results: Both MBI-C-self and MBI-C-informant exhibited satisfactory Cronbach’s α values (0.92 and 0.88, respectively). The MBI-C-informant total scorewas correlated with the NPI-Q total score (r = 0.83, p < 0.001). Inter-rater reliability between the two versions, as represented by the inter-rater correlation coefficient, was 0.57 (p < 0.001). The prevalence of MBI based on the MBI-C-informant scores was 1.5% higher than that based on the MBI-C-self scores according to the suggested cut-off score of 8.5. The affective dysregulation domain score of MBI-C-informant was significantly lower than that of MBI-C-self. Conclusion: MBI-C-informant exhibited both high reliability and validity. Discrepancies between MBI-C-informant and MBI-C-self related to the detection rates and affective dysregulation domain scores were noted. The level of consistency and discrepancy between these two versions provide implications for the use of MBI-C in clinical practice and future research. Show more

Keywords: Mild behavioral impairment, Mild Behavioral Impairment Checklist, prodromal, validation

DOI: 10.3233/JAD-220006

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1203-1213, 2022

Authors: Guo, Yumiao | Kang, Meimei | Hui, Xinjie | Fan, Xiaojun | Zhang, Lianguo | Wang, Yejun | Wang, Rong | Nie, Xiuhong

Article Type: Research Article

Abstract: Background: Obstructive sleep apnea (OSA) is a multi-component disorder, which has many comorbidities, including cognitive impairment. Although its potential risk factors were unknown, they could affect the patient’s quality of life and long-term prognosis. Objective: The purpose of this study was to investigate the application of urinary Alzheimer’s disease-associated neurofilament protein (AD7c-NTP) levels in the assessment of cognitive impairment in OSA patients, and to analyze the predictive value of potential high-risk factors on cognitive impairment in OSA patients. Methods: 138 young and middle-aged adults were recruited and underwent overnight polysomnographic recording, Montreal Cognitive Assessment (MoCA), and …urinary AD7c-NTP test. AD7c-NTP and other factors were further applied as biomarkers to develop a cognition risk prediction model. Results: Compared with the control, OSA patients showed significantly lower MoCA scores and higher urinary AD7c-NTP concentrations, while the severe OSA group appeared more significant. The urinary AD7c-NTP level of the OSA cognitive impairment group was higher than that of the non-cognitive impairment group. The results of regression analysis showed that urinary AD7c-NTP level was an independent predictor of cognitive impairment in OSA patients. Based on urinary AD7c-NTP levels and other selected factors, a multimodal prediction model for assessing the risk of cognitive impairment in OSA patients was initially established. Conclusion: The increased urinary AD7c-NTP level could be used as a relevant peripheral biomarker of cognitive impairment in OSA patients. A model using urinary AD7c-NTP combined with other factors was developed and could accurately assess the cognition risk of OSA patients. Show more

Keywords: Alzheimer’s disease-associated neurofilament protein (AD7c-NTP), mild cognitive impairment, obstructive sleep apnea, risk prediction model, PredCI_OSA

DOI: 10.3233/JAD-220451

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1215-1231, 2022

Authors: Weller, Andrew E. | Ferraro, Thomas N. | Doyle, Glenn A. | Reiner, Benjamin C. | Crist, Richard C. | Berrettini, Wade H.

Article Type: Research Article

Abstract: Background: 5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer’s disease (AD)-related pathology. Objective: To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice. Methods: Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models. We analyzed cell type-specific DEGs further using Ingenuity Pathway Analysis (IPA). …Results: We identified several DEGs in both neuronal and glial cell subtypes in comparisons of wild type (WT) versus 5XFAD and WT versus T2KO mice, including Ttr , Fth1 , Pcsk1n , Malat1 , Rpl37 , Rtn1 , Sepw1 , Uba52 , Mbp , Arl6ip5 , Gm26917 , Vwa1 , and Pgrmc1 . We also observed DTU in common between the two comparisons in neuronal and glial subtypes, specifically in the genes Prnp , Rbm4b , Pnisr , Opcml , Cpne7 , Adgrb1 , Gabarapl2 , Ubb , Ndfip1 , Car11 , and Stmn4. IPA identified three statistically significant canonical pathways that appeared in multiple cell types and that overlapped between 5XFAD and T2KO comparisons to WT, including ‘FXR/RXR Activation’, ‘LXR/RXR Activation’, and ‘Acute Phase Response Signaling’. Conclusion: DEG, DTU, and IPA findings, derived from two different mouse models of AD, highlight the importance of energy imbalance and inflammatory processes in specific hippocampal cell types, including subtypes of neurons and glial cells, in the development of AD-related pathology. Additional studies are needed to further characterize these findings. Show more

Keywords: Alzheimer’s disease, animal disease models, gene expression profiling, knockout mice, mice, polyadenylation, RNA-seq

DOI: 10.3233/JAD-220391

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1233-1247, 2022

Authors: Wu, Xin-Rui | Wu, Kai-Min | Deng, Yue-Ting | Huang, Shu-Yi | Yang, Liu | Dong, Qiang | Feng, Jian-Feng | Cheng, Wei | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Previous studies have reported inconsistent associations between chronic kidney disease (CKD) and dementia. Objective: To evaluate whether CKD is a risk factor for dementia and compare the performance of different measures of calculating estimated glomerular filtration rate (eGFR). Methods: 275,167 participants from UK Biobank were included and eGFR at baseline was calculated using serum creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C equations (eGFRcr-cys). Restricted cubic splines and Cox regression models were performed to assess the relationship of eGFR with all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD). Results: We observed a …U-shaped relationship between each eGFR and risk of all-cause dementia and VaD, with eGFRcys and eGFRcr-cys showing a closer linkage (peGFRcys <0.0001, peGFRcrhboxcys <0.0001 and peGFRcr  = 0.0001). Lower and supranormal eGFR were related to increased risk of all-cause dementia. Compared to the reference category of 90–104 ml/min/1.73 m2 , adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause dementia for eGFRcr-cys 30–59, <30, and ≥105 ml/min/1.73 m2 were 1.26 (95% CI [1.05–1.50], p  = 0.012), 2.62 (95% CI [1.54–4.47], p  < 0.001), and 1.41 (95% CI [1.17–1.70], p  < 0.001). No statistically significant association was observed between eGFR with risk of AD. Conclusion: This prospective study identified impaired kidney function as a critical risk factor for dementia and noted the application of cystatin C strengthened the relationship between CKD and dementia, underlining the significant value of preserving kidney function to reduce the risk of dementia and considering cystatin C measurement as part of clinical practice. Show more

Keywords: Creatinine, cystatin C, dementia, glomerular filtration rate, kidney function

DOI: 10.3233/JAD-220609

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1249-1261, 2022

Authors: Gan, Jinghuan | Chen, Zhichao | Shi, Zhihong | Li, Xudong | Liu, Shuai | Liu, Yiming | Zhu, Hongcan | Shen, Lu | Zhang, Guili | You, Yong | Guo, Qihao | Zhang, Nan | Lv, Yang | Gang, Baozhi | Yuan, Junliang | Ji, Yong

Article Type: Research Article

Abstract: Background: Lewy body dementia is the second most common neurodegenerative dementia, but data concerning the onset age and clinical features in the prodromal stage remain limited in China. Objective: To investigate the associations between onset age and clinical manifestations of cognitive impairment with Lewy bodies in a large-sample cohort. Methods: We included 74 patients with mild cognitive impairment with Lewy bodies (MCI-LB), 533 patients with dementia with Lewy bodies (DLB), 118 patients with Parkinson’s disease with MCI (PD-MCI), and 313 patients with Parkinson’s disease dementia (PDD) in this multicenter cohort from 22 memory …clinics of China from 1 January 2018 to 31 March 2022. The onset age, clinical manifestations, and neuropsychological assessments were recorded and analyzed after reviewing the medical records. Results: The average onset age of memory loss was 68.28 (±7.00) years, and parkinsonism happened 2.00 (±1.24) years later for patients with MCI-LB. The average onset age of parkinsonism was 60.56 (±8.96) years, and the memory loss happened 3.49 (±3.02) years later for patients with PD-MCI. Rapid eye movement sleep behavior disorder and visual hallucinations were frequently reported in MCI-LB, DLB, and PDD, while visual hallucinations were least frequently reported in PD-MCI. Lower scores of MMSE and depression, and higher scores of activities of daily living and delusions, were independently associated with older onset age in DLB. Conclusion: The onset of PD-MCI precedes MCI-LB, and memory loss occurs 3 years after parkinsonism. The onset age is associated with cognition and neuropsychiatric symptoms in process. Show more

Keywords: Age, sep Lewy body, sep mild cognitive impairment, sep multicenter, sep Parkinson’s disease

DOI: 10.3233/JAD-220657

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1263-1275, 2022

Authors: Shen, Jialun | Li, Meng | Long, Cheng | Yang, Li | Jiang, Jinxiang

Article Type: Research Article

Abstract: Background: Olfactory decline is an indicator of early-stage Alzheimer’s disease (AD). Although the anterior piriform cortex (aPC) is an important brain area involved in processing olfactory input, little is known about how its neuronal activity is affected in early-stage AD. Objective: To elucidate whether odor-induced electrophysiological responses are altered in the aPC of 3-5-month-old APP/PS1 mice. Methods: Using head-fixed multi-channel recording techniques in APP/PS1 AD mouse model to uncover potential aberrance of the aPC neuronal firing and local field potential (LFP) in response to vanillin. Results: We show that the firing rate of aPC …neurons evoked by vanillin is significantly reduced in conscious APP/PS1 mice. LFP analysis demonstrates reduced low- and high-gamma (γ low, γ high ) oscillations during both the baseline and odor stimulation periods in APP/PS1 mice. Moreover, according to spike-field coherence (SFC) analysis, APP/PS1 mice show decreased coherence between odor-evoked spikes and γ low rhythms, while the coherence with γ high rhythms and the Δ SFC of the oscillations is unaffected. Furthermore, APP/PS1 mice show reduced phase-locking strength in the baseline period, such that there is no difference between baseline and odor-stimulation conditions. This contrasts markedly with wild type mice, where phase-locking strength decreases on stimulation. Conclusion: The abnormalities in both the neuronal and oscillatory activities of the aPC may serve as electrophysiological indicators of underlying olfactory decline in early AD. Show more

Keywords: Alzheimer’s disease, anterior piriform cortex, APP/PS1, firing rate, head-fixed recording, olfaction, oscillations

DOI: 10.3233/JAD-220694

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1277-1289, 2022

Authors: Ritchie, Marina | Witbracht, Megan | Nuño, Michelle M. | Hoang, Dan | Gillen, Daniel L. | Grill, Joshua D.

Article Type: Research Article

Abstract: Background: Clinical trials now test promising therapies in the preclinical stages of Alzheimer’s disease (AD). Participant willingness to enroll in different types of preclinical AD trials is understudied and whether the FDA approval of aducanumab affected these attitudes is unknown. Objective: To evaluate preferences toward three preclinical AD trial scenarios and whether the FDA approval of aducanumab changed willingness to participate among potential trial participants. Methods: Through an electronic survey, we asked enrollees in a recruitment registry age 50-79 to rate their willingness (using a 6-point Likert scale) to enroll in three hypothetical preclinical AD trial …scenarios: an in-clinic infused monoclonal antibody intervention, a home-infused monoclonal antibody intervention, and an oral BACE inhibitor intervention. We administered the survey before and after the FDA approval of aducanumab. We used a generalized estimating equation model to assess group differences in preference for the trial scenarios. We used a paired t-test to determine if willingness to participate (using total willingness across three scenarios as the outcome) changed after the FDA decision. Results: At baseline, the mean participant willingness was highest in the in-clinic infusion scenario. There was no significant change in willingness to participate, overall, after the FDA decision. Participants who were independently aware of the FDA’s decision (prior to the second survey) demonstrated reduced willingness to participate; participants unaware of the FDA decision demonstrated no change. Conclusion: Willingness to participate in preclinical AD trials may have been negatively affected by the FDA’s decision to approve aducanumab among those aware of the decision. Show more

Keywords: Aducanumab, Alzheimer’s disease, clinical trial, earned media, recruitment, secondary prevention

DOI: 10.3233/JAD-220801

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1291-1300, 2022

Authors: Harrison, Krista L. | Garrett, Sarah B. | Halim, Madina | Bernstein Sideman, Alissa | Allison, Theresa A. | Dohan, Daniel | Naasan, Georges | Miller, Bruce L. | Smith, Alexander K. | Ritchie, Christine S.

Article Type: Research Article

Abstract: Background: In the United States, dementia specialty centers affiliated with centers of excellence for research hold promise as locations to develop innovative, holistic care in care systems otherwise siloed by discipline or payer. Objective: We conducted foundational research to inform development of patient-and family-centered palliative care interventions for dementia specialty centers. Methods: We interviewed persons living with dementia (PLWD), current, and former care partners (CP) recruited from a specialty dementia clinic and purposively selected for variation across disease syndrome and stage. A framework method of thematic analysis included coding, analytic matrices, and pattern mapping. …Results: 40 participants included 9 PLWD, 16 current CPs, and 15 former CPs of decedents; 48% impacted by Alzheimer’s disease dementia. While help from family, support groups and adult day centers, paid caregiving, and sensitive clinical care were invaluable to PLWD, CPs, or both, these supports were insufficient to navigate the extensive challenges. Disease-oriented sources of distress included symptoms, functional impairment and falls, uncertainty and loss, and inaccessible care. Social and relational challenges included constrained personal and professional opportunities. The obligation and toll of giving or receiving caregiving were challenging. Clinical care challenges for PLWD and/or CPs included care fragmentation, insufficient guidance to inform planning and need for expert interdisciplinary clinical care at home. Conclusion: Findings highlight the breadth and gravity of gaps, which surpass the disciplinary focus of either behavioral neurology or palliative care alone. Results can inform the development of novel interventions to add principles of geriatrics and neuropalliative care to dementia care. Show more

Keywords: Caregivers, dementia, geriatrics, hospice care, neuropalliative care, palliative care, quality of life

DOI: 10.3233/JAD-220536

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1301-1320, 2022

Authors: Fonseka, Lochanie | Wang, David | Ryan, Brigid | Cheung, Gary | Ma’u, Etuini

Article Type: Research Article

Abstract: Background: There is limited epidemiological research on the incidence of young onset dementia (YOD). Estimates of YOD incidence in New Zealand are extrapolated from international studies that do not reflect New Zealand’s population and ethnic diversity. Objective: To determine the incidence of YOD in the geographical area served by the Waikato District Health Board Methods: All new inpatient and outpatient in the age range 30–64 years with a documented diagnosis of dementia at Waikato Hospital between 1 January 2014 –31 December 2016 were identified. Incidence rates were calculated by 5-year age-band, sex, and ethnicity. …Results: 64 incident cases of YOD were included. Incidence rates for all cause YOD were 13.3 (95% CI 10.3–17.0) and 22.7 (95% CI 17.5–29.1) per 100,000 person-years in the age range 30–64 years and 45–64 years respectively. The incidence rate in Māori (20.0, 95% CI 11.4–32.4) was higher compared to non-Māori (12.0, 95% CI 8.9–15.9), but this difference was not statistically significant (p  = 0.09). Conclusion: The incidence of YOD in this study is similar to global estimates. Incidence may be higher in Māori compared to non-Māori, highlighting the need for culturally appropriate approaches to dementia prevention, intervention, and care. Show more

Keywords: Epidemiology, incidence, New Zealand, young onset dementia

DOI: 10.3233/JAD-220802

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1321-1327, 2022

Authors: Shi, Xiaolei | Zhou, Nan | Sun, Bin | Wu, Yongshun | Hu, Yachun | Ning, Yuping

Article Type: Research Article

Abstract: Background: Reduced signal on fluorodeoxyglucose-positron emission tomography (FDG-PET) is a valid proxy for neurodegeneration in Alzheimer’s disease (AD). Perivascular space (PVS) is believed to be associated with AD pathology and cognitive decline. Objective: This study aimed to investigate the associations of PVS with FDG-PET and cognitive performance based on the burden of amyloid pathology. Methods: We used magnetic resonance imaging (MRI) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). MRI-visible PVS in basal ganglia (BG) and centrum semi-oval (CSO) were visually classified as: none/mild, moderate or frequent/severe. The association of PVS with brain FDG-PET was explored …based on the burden of amyloid pathology, where a cerebrospinal fluid (CSF) t-tau/Aβ42 with the ratio≥0.27 was defined as high amyloid pathology. Moreover, the relationships between PVS and cognitive performance variables (ADNI-MEM and ADNI-EF) were studied. Results: For participants with higher tau/Aβ42 ratio, CSO-PVS severity was independently associated with lower FDG-PET. There were significant interaction effects between moderate or frequent/severe CSO-PVS and time on FDG decline in people with high amyloid pathology. The interaction between CSO-PVS and time (follow-up) was consistently associated with ADNI-MEM and ADNI-EF decline in individuals with high amyloid pathology. Conclusion: The study established the differential utility of PVS in BG and CSO for predicting brain metabolism. These findings suggest that CSO-PVS serves as a contributing factor to brain metabolism and cognitive decline associated with amyloid pathology. Show more

Keywords: Amyloid, basal ganglia, centrum semi-oval, metabolism, perivascular space

DOI: 10.3233/JAD-220426

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1329-1337, 2022

Authors: Berger, Miles | Cooter, Mary | Roesler, Alexander S. | Chunga, Stacey | Park, John | Modliszewski, Jennifer L. | VanDusen, Keith W. | Thompson, J. Will | Moseley, Arthur | Devinney, Michael J. | Smani, Shayan | Hall, Ashley | Cai, Victor | Browndyke, Jeffrey N. | Lutz, Michael W. | Corcoran, David L.

Article Type: Correction

DOI: 10.3233/JAD-229018

Citation: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1339-1340, 2022