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