bluuebunny/crossref_metadata_2025 huggingface dataset:
Amyloid‐β activates NLRP3 inflammasomes by affecting microglial immunometabolism through the Syk‐AMPK pathway
Authors: Jung Eun Sun , Suh Kyujin , Han Jihui , Kim Heyyoung , Kang Hyung‐Sik , Choi Won‐Seok , Mook‐Jung Inhee
Published: December 2022

Background

Neuroinflammation is considered one of major factors in the pathogenesis of Alzheimer’s disease (AD). In particular, inflammasome activation, including NLRP3 inflammasome in microglia, is regarded as fundamental for the pro‐inflammatory response of immune cells (Hanslik & Ulland, 2020). Aβ functions to primarily activate microglia in AD and reports have been made that Aβ can activate NLRP3 inflammasome(Halle et al., 2008). However, the precise molecular mechanism through which the NLRP3 inflammasome is associated with AD pathologies remains unclear.

Method

Primary microglia were treated with LPS and Aβ, and the induced signaling pathway were examined by RT‐PCR, western blot and immunostaining. Effect of flufenamic acid (FA) were examined and various inhibitors of Syk, AMPK and NLRP3 were used for the verification of the hypothesis. AD mouse model expressing Aβ and tau pathology were intraperitoneally treated with FA. After behavior tests, their brains were obtained for western blot and immunostaining.

Result

Aβ activates the NLRP3 inflammasome in microglia by activating Syk and inhibiting AMPK. Deactivated AMPK induces metabolic dysregulation, mitochondrial fragmentation and reactive oxygen species formation, leading to the activation of the NLRP3 inflammasome. In addition, flufenamic acid (FA), a member of non‐steroid anti‐inflammatory drugs, was found to effectively inhibit activation of the microglial NLRP3 inflammasome by regulating Syk and AMPK. Importantly, FA has marked therapeutic effects on major AD pathologies including amyloid plaque formation, tau phosphorylation, gliosis and memory dysfunction in vivo in microglia‐dependent way.

Conclusion

The molecular mechanism of microglial NLRP3 inflammasome activation by Aβ was demonstrated to be Syk‐AMPK pathway. Also, FA can be repurposed for inhibiting microglial activation of the NLRP3 inflammasome, which is a potential treatment for AD.

*References

Hanslik, K. L., & Ulland, T. K. (2020). The Role of Microglia and the Nlrp3 Inflammasome in Alzheimer’s Disease. Frontiers in Neurology, 11.

Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, K. J., & Golenbock, D. T. (2008). The NALP3 inflammasome is involved in the innate immune response to amyloid‐β. Nature immunology, 9(8), 857.
Findings from a National Consensus Conference: Interdisciplinary Action Steps to Enhance Support for Dementia Family Caregivers
Authors: Brody Lilla A , Falzarano Francesca , Riffin Catherine
Published: December 2022

Background

In 2021, loved ones of individuals with Alzheimer’s disease and related dementias (ADRD) provided an estimated $271 billion worth of unpaid care (Alzheimer’s Association, 2022). While there is mounting consensus for the need to support caregivers, interdisciplinary collaborations are necessary to facilitate the translation of evidence‐based programs into real‐world solutions (Gitlin et al., 2015).

Methods

With funding from the National Institute on Aging, Weill Cornell Medicine hosted “The 2021 Conference on Engaging Family and Other Unpaid Caregivers of People with Dementia in Healthcare Delivery.” The hybrid (virtual/in‐person) event convened interdisciplinary experts from across the nation to establish a policy‐ and practice‐ aligned research agenda aimed at advancing the science of ADRD caregiving. These experts consisted of caregivers of people with ADRD, healthcare providers, researchers, health plan providers, and non‐profit organizations. The conference involved expert panels on caregiving‐related topics (e.g., public policies, intervention research), small group breakout sessions to identify major recommendations, and prioritization of the recommendations through voting.

Results

The resulting recommendations centered on five topic areas: caregiver identification and assessment, caregiver training, provider training, provider reimbursement, and technology. Two cross‐cutting themes—the need for implementation science and leveraging frameworks of intersectionality— permeated throughout all recommendations. The committee recommended actionable next steps to address the need for training and support across the care continuum, acknowledging that a one‐size‐fits‐all approach is inadequate in addressing the needs of a group as diverse as ADRD caregivers (Alzheimer’s Association, 2022). The group advocated for the development of training programs tailored to the care recipient’s disease stage and caregiver’s preferences.

Conclusion

The Alzheimer’s Association and similar organizations are uniquely positioned to support work in the area of caregiver training. These organizations could collaborate with researchers to develop or expand opportunities to aid ADRD caregivers in medical treatment protocols, financial planning, and end‐of‐life preparation. Medical practices could then implement referral protocols connecting ADRD caregivers with local Alzheimer’s Association Chapters, providing much‐needed support. Bridging the gap between training and support could lead to positive outcomes for caregivers, their care recipients, and society at large (Nichols et al., 2017; Rowe et al., 2016; Guterman et al., 2019).
Mid‐to‐Late Life Healthy Lifestyle Modifies Genetic Risk for Longitudinal Cognitive Aging among Asymptomatic Individuals from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Xu Yuexuan , Koscik Rebecca Langhough , Jonaitis Erin M. , Lu Qiongshi , Johnson Sterling C. , Engelman Corinne D.
Published: December 2022

Background

Genetic and lifestyle factors contribute to an individual’s risk for developing Alzheimer’s disease (AD). A better understanding of interactions between these factors may help design targeted interventions. In this study, we investigated whether number of long‐term healthy lifestyles modified the effect of genetic predisposition to AD on cognitive decline during the preclinical stage of AD.

Methods

We evaluated longitudinal associations of cognitive aging with a healthy lifestyle composite score, which included physical activity, diet, smoking, cognitive activity, and alcohol consumption, and the interaction of the healthy lifestyle composite score with APOE ε4 carrier status and a non‐APOE polygenic risk score (PRS) in a sample of 848 individuals from the Wisconsin Registry for Alzheimer’s Prevention (Table 1). The primary outcome was a multi‐domain cognitive composite (PACC3); secondary outcomes were immediate/delayed memory and executive function composites. We fitted all analyses using a linear mixed effects model and adjusted for within‐individual and within‐family correlation.

Results

Favorable lifestyles can marginally modify the age dependent influence of APOE on PACC3 (p = 0.1) and executive function (p = 0.14), and significantly mitigate the adverse effect of APOE ε4 on delayed recall as people aging (p < 0.01, Figure 1). However, we observed no statistically significant interactions between non‐APOE PRS, combined lifestyle factors, and age for all the assessed cognitive outcomes (Figure 2). When we further stratify the sample by the APOE ε4 carrier status, we found the interaction between non‐APOE PRS, age, and healthy lifestyle is statistically significant for PACC3 (p = 0.02) and delayed recall (p < 0.01) and marginally significant for immediate learning (p = 0.06) among APOE ε4 carriers (Figure 3). Among APOE ε4 noncarriers, combined lifestyle factors can only modify the age‐dependent adverse genetic influence of non‐APOE PRS on PACC3 (p = 0.01), but the protective effect is more evident at a younger age (Figure 4). These results are robust to multiple sensitivity analyses.

Conclusion

A favorable lifestyle can mitigate the genetic risk caused by both APOE ε4 and non‐APOE PRS, but the protective effect against non‐APOE PRS is more evident among APOE ε4 carriers.
COVID‐19 related life changes for family caregivers of persons with Lewy body disease
Authors: Stacy Kelly E , Miller Elaine , Shatz Rhonna , Bakas Tamilyn
Published: December 2022

Background

Coronavirus disease 2019 (COVID‐19) affected individuals’ physical and mental health. Protective measures such as closures, social‐distancing, masking, and isolation resulted in increased feelings of loneliness and isolation. This study aimed to investigate life changes associated with COVID‐19 for family caregivers of persons with Lewy body disease (LBD).

Method

Data were analyzed from an existing LBD caregiver needs and concerns study that took place between January 2021 and February 2021. A mixed methods approach was used to describe how 20 caregivers’ lives changed as a result of the COVID‐19 pandemic. Items from the Bakas Caregiving Outcomes Scale (BCOS) were adapted for COVID‐19 and rated on a response scale ranging from 1 = changed for the worst to 7 = changed for the best, with 4 = did not change. Qualitative data were collected as participants expanded upon their responses to the scale items

Result

Caregivers experienced both positive and negative life changes as a result of COVID‐19. On average, positive changes included increased use of the internet to order items (Mean = 4.35), videoconferencing to connect with others (Mean = 4.55), and improved financial well‐being (Mean = 4.35). Negative changes included reduced social (Mean = 1.7) and family (Mean = 2.05) activities and decreased ability to cope with stress (Mean = 2.60). Most responses ranged from 1 to 4, with some items having wider ranges from 1 to 7 showing that individual caregivers were impacted differently by the COVID‐19 pandemic. Qualitative comments were consistent with quantitative responses. Some caregivers expressed concerns that limited family and social contact contributed to a more rapid decline in the person with LBD. Caregiver health and well‐being were negatively affected as well, with caregivers noting decreased level of energy and worsened physical health.

Conclusion

Family caregivers of persons with LBD experienced both positive and negative life changes as a result of COVID‐19. Responses indicated that caregivers were affected in a variety of ways and an individualized approach is recommended in dealing with caregiver life changes resulting from the COVID‐19 pandemic.
Serotonin Reuptake Inhibitors are Associated with Less Amyloid‐β Burden Spatial Extent in Military Veterans with only PTSD, but not with TBI or Comorbid PTSD/TBI: Preliminary PET Findings from ADNI‐DOD Project
Authors: Chen Kewei , Goradia Dhruman D. , Chen Yinghua , Luo Ji , Devadas Vivek , Jagust William J. , Mackin R Scott , Su Yi , Landau Susan M. , Weiner Michael W. , Reiman Eric M.
Published: December 2022

Background

Some but not all studies suggested an association of serotonin reuptake inhibitors (SRIs) with a reduction in “magnitude” of amyloid‐β (Aβ) plaque burden. Using PET images from ADNI‐DOD and a voxel‐based Majority Count Algorithm (MCA), we demonstrated that cognitively unimpaired veterans with post‐traumatic stress disorder (PTSD) had significantly more cerebral voxels with lower rather than higher florbetapir standard uptake value ratios (voxel‐based P<0.05), reflecting Aβ burden reduction in “spatial extent” [Chen, AAIC 2018]). We postulated that this finding might relate their SRI use. Here, we investigate the impact of SRI use on the spatial extent of Aβ burden among ADNI‐DOD veterans with PTSD, comorbid PTSD and traumatic brain injury (TBI), and TBI.

Methods

Statistical Brain Mapping (SPM12) adjusted for age, MMSE, education and APOE4 allele, a voxel‐based P<0.05 threshold, and MCA which is free of multi‐comparisons (Stern, NEJM, 2019) were used to compare the greater versus lower number of cerebral voxels with higher Aβ burden in SRI non‐users versus users in 6 groups: 1) PTSD (n=76), 2) PTSD or TBI (n=115), 3) comorbid PTSD/TBI or TBI (n=126), 4) PTSD, PTSD/TBI or TBI (n=202), 5) PTSD/TBI (n=87) and 6) TBI (n=39).

Results

SRI non‐users had a significantly larger number of cerebral voxels with higher Aβ burden than users in the first four groups: 1) 28,539 in non‐users versus 70 in users (voxel count ratio VCR=551) in PTSD; 2) 3,573 versus 21 (VCR=170) in PTSD or TBI; 3) 22,927 versus 1,162 (VCR=20) in comorbid PTSD/TBI or TBI; and 4) 7,569 versus 1,481 (VCR=5) in PTSD, comorbid PTSD/TBI or TBI, MCA p<0.001 for all 4 groups. In contrast, 5) SRI non‐users and users did not differ in the number of cerebral voxels with higher Aβ burden in PTSD/TBI (3,209 versus 4,027, VCR=1, MCA p=0.68); and 6) non‐users had a significantly smaller number of cerebral voxels than users with higher Aβ burden in TBI (60 versus 11,715 VCR=0.005, MCA p<0.001).

Conclusion

This study showed SRIs’ association with spatially less extensive Aβ burden in PTSD, more extensive Aβ burden in TBI, and intermediate/opposing effects in other combinations. Finding conformation and mechanism clarification are needed.
Calcineurin activation and scaffolding in Aß‐induced synaptic dysfunction
Authors: Prikhodko Olga , Sanderson Jennifer L , Freund Ronald K , Sullivan Emily , Kennedy Matthew J , Dell'Acqua Mark L
Published: December 2022

Background

Calcineurin (CaN) is a protein phosphatase that is essential for synaptic long‐term depression (LTD) through its regulation of AMPA‐type glutamate receptors (AMPAR). AMPAR regulation by CaN is critically mediated by the postsynaptic scaffold protein A‐kinase anchoring protein 150 (AKAP150), which localizes a pool of CaN to the postsynaptic membrane. Our lab has generated knockin mice carrying a mutant version of AKAP150 lacking its CaN‐binding site, the PxIxIT motif; AKAP150ΔPIX (PIX). LTD does not occur in these mice, underscoring the importance of the synaptic pool of CaN for normal synaptic function and plasticity. Pharmacological inhibition of calcineurin prevents diverse manifestations of Aβ‐mediated synaptotoxicity, including long‐term potentiation (LTP) blockade, synapse loss, and impaired learning and memory in AD mouse models. However, the importance of synaptically‐localized calcineurin in Aβ synaptotoxicity is unknown.

Method

To test our novel hypothesis that Aβ synaptotoxicity requires spatial positioning of CaN at the synapse via AKAP150 anchoring, we used our innovative AKAP150ΔPIX (PIX) knock‐in mouse model. Primary hippocampal neuronal cultures and acute hippocampal slices from WT and PIX mice were treated with various doses of Aβ oligomers and assayed for Aβ’s effect on dendritic spine density, quantal calcium transients through NMDA receptors (both in culture), and LTP through extracellular field recordings (in slices). Additionally, utilizing the 5xFAD AD mouse model, we generated PIX/5xFAD mice to test long‐term behavioral (via radial arm water maze and contextual fear conditioning tasks) and electrophysiological effects (through field recordings) of the PIX mutation on the 5xFAD phenotype in 6‐month‐old animals.

Result

The PIX mutation protects against acute Aβ‐mediated synaptic loss, decreased Ca2+ entry through NMDA receptors, and LTP deficits. Long‐term, the PIX mutation rescues contextual fear conditioning memory, but not radial arm water maze performance or chronic LTP deficits of 5xFAD mice.

Conclusion

Synaptically‐localized calcineurin is necessary for early Aβ‐mediated synaptic deficits. Long‐term Aβ exposure engages mechanisms beyond its AKAP‐anchored calcineurin pathway.
The Alzheimer’s Disease‐Health Indices (AD‐HI): Development of Two Novel Outcome Measures for Use in Clinical Trials
Authors: Seabury Jamison , Arky Abigail , Ayles Megan , Dilek Nuran , Hance Margaret , Rosero Spencer , Santos Elizabeth , Weinstein Jennifer , Varma Anika , Heatwole Chad
Published: December 2022

Background

In preparation for upcoming clinical trials, there is a clear need for improved clinical trial infrastructure to facilitate therapeutic assessment in Alzheimer’s disease, (AD), mild cognitive impairment (MCI), and related dementias. This research describes the development of a patient‐reported outcome measure, the Alzheimer’s Disease‐Health Index (AD‐HI), and a caregiver‐reported outcome measure, the Alzheimer’s Disease Caregiver‐Health Index (ADCR‐HI). These novel outcome measures were developed using large scale input from patients and caregivers and were designed in accordance with U.S. Food and Drug Administration (FDA) guidelines for use in drug labeling claims.

Method

We first conducted semi‐structured qualitative interviews with individuals with AD, MCI, or dementia and their caregivers to identify potential symptoms of importance to these disease populations. We subsequently performed a cross‐sectional study involving individuals with AD, MCI, or dementia and caregivers to determine the prevalence and relative importance of symptoms identified during preliminary qualitative interviews. Using this data, we developed two outcome measures known as the AD‐HI and the ADCR‐HI. Symptom questions and subscales were selected for the instruments based on their prevalence and importance to the patient populations, their generalizability, and ability to respond to therapeutic intervention. Factor analysis was used to group symptom questions into distinct symptomatic themes of patient health.

Result

Fifteen individuals with AD, MCI, or dementia and 15 caregivers provided 2,263 quotes regarding the symptomatic burden of AD, MCI, or dementia. One‐hundred and four patients and 329 caregivers participated in a cross‐sectional study to determine the prevalence and relative importance of the most relevant symptoms identified through interviews. The AD‐HI and the ADCR‐HI were developed based on this data and simultaneously measure overall patient disease burden and disease burden in 9 disease specific areas.

Conclusion

The AD‐HI provides researchers and clinicians with a valid mechanism to measure disease burden during therapeutic trials involving individuals with AD, MCI, or dementia. Similarly, the ADCR‐HI provides a viable option when a patient can no longer complete a patient‐reported outcome measure on their own behalf. Ongoing steps will further optimize the usability and reliability of these instruments in preparation for upcoming clinical trials.
A Comparison of MMSE and MoCA for Following Cognitive Performance with a Longitudinal Cohort Study
Authors: Li Daniel , Li Wei
Published: December 2022

Background

Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are two commonly used cognitive screening and diagnostic tools.

Method

At baseline, participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were divided into four groups based on their cognitive diagnoses: healthy control (HC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimer’s Disease (AD). MMSE or MoCA scores were compared among the four groups using one‐way analysis of variance (ANOVA) model with post‐hoc Bonferroni correction. For those participants who had both MMSE and MoCA assessments done, a Pearson correlation analysis was performed between the two assessments for each visit.

Result

The MMSE scores were significantly different among the four groups at baseline, which was true for each of the three annual follow‐up visits. By contrast, the MoCA scores were not significantly different between HC and EMCI groups at either baseline or any of the follow‐up visits. For participants with a diagnosis of LMCI, the cognitive performance deteriorated in a linear manner 12 months after the baseline, which was independent of MMSE or MoCA. At last, the MMSE scores were moderately related to MoCA scores, which got stronger along with the time of follow‐up.

Conclusion

MMSE and MoCA are comparable as cognitive assessment tools to monitor cognitive changes. In addition, the measurements of MMSE and MoCA are moderately correlated for the follow‐up visits.
Metabolite QTL analysis of ROSMAP and ADNI prioritized sequencing data identifies C14:2 genetic locus on Chr 2
Authors: TumSuden Sophia L , Lee Brian N , Bao Jingxuan , Kim Jaesik , Ning Xia , Kim Dokyoon , Shen Li
Published: December 2022

Background

Peripheral metabolic disturbance is a known component of Alzheimer’s Disease (AD), however predictive genetic markers, as well as the associated pathways, remain to be determined. Two AD studies, ROSMAP and ADNI, have generated Whole Genome Sequencing (WGS) and ante‐mortem serum metabolic biomarker samples. A previous study utilizing ROSMAP data has identified the metabolite tetradecadienylcarnitine, C14:2, as protective against incident AD in both brain and serum data (Brain and blood metabolome for Alzheimer’s dementia: Findings from a targeted metabolomics analysis; Huo et. al).

Method

After standard QC procedure, WGS data from ROSMAP participants was prioritized to include only variants within +/‐ 1000 bp of 584 AD prioritized genes identified on the AD Knowledge Portal’s Agora Platform (https://agora.adknowledgeportal.org/genes/(genes‐router:genes‐list)), resulting in a subset of 401,415 variants. A metabolite quantitative trait locus (mQTL) study was performed (N = 67) investigating associations between these variants of interest and the C14:2 metabolite measurements collected from the ROSMAP cohort by Biocrates p180 flow injection analysis. A subsequent single‐variant targeted mQTL analysis (N = 464) utilizing ADNI‐GO/2 WGS and C14:2 metabolic data (Biocrates p180 flow injection analysis) was performed. Age, gender and education were used as covariates in both analyses.

Result: A novel locus, rs147667251, showed significance to the C14

:2 metabolic biomarker in both ROSMAP and ADNI serum mQTL analyses. In ROSMAP data, rs147667251 was identified as most significant to the C14:2 biomarker with a p‐value of 5.507e‐10 (threshold = 1.2e‐7). In a single test mQTL of ADNI C14:2 data, the rs147667251 locus had a significant p‐value of 0.02415 (threshold = 0.05). The locus lies on chromosome two and is an intron variant of the DPP10 gene. The DPP10 gene encodes a type II membrane protein and is known to have altered transcript and protein expression linked to AD.

Conclusion

In this AD prioritized mQTL study, a single genetic locus, rs147667251, within the AD nominated gene DPP10 has been identified as associated with serum levels of C14:2. DPP10 is known to be dysregulated in AD and a previous study has identified the C14:2 metabolite as protective against AD, warranting further investigation into the regulatory impact of rs147667251 on DPP10 expression and the C14:2 metabolic pathway.
Association between Lifespan Exercise Habits and Cognitive Function in Older Age: the Bunkyo Health Study
Authors: Shi Huicong , Tabata Hiroki , Otsuka Hikaru , Someya Yuki , Kaga Hideyoshi , Naito Hitoshi , Abulaiti Abudurezake , Umemura Futaba , Kiya Mai , Ito Naoaki , Tajima Tsubasa , Yoshizawa Yasuyo , Kakehi Saori , Kawamori Ryuzo , Tamura Yoshifumi
Published: December 2022

Background

Preventing or delaying the onset of mild cognitive impairment (MCI) is a crucial strategy for maintaining an independent life in old age (Rodakowski J et al., 2014). Exercise habits for ∼ ten years in the 50s or older were associated with preserving cognitive function (Rovio, S., et al., 2005; J Krell‐Roesch, et al., 2021). However, it is still unclear whether continuous exercise habits throughout the 50s to late life are required to prevent MCI. This study aimed to investigate the association between continuity of exercise habits from the 50s to late life and MCI in older age.

Method

We included 1585 participants (669 males and 916 females) aged 65 to 84 years old living in an urban area (Bunkyo Health Study). MCI was defined as the Japanese version of The Montreal Cognitive Assessment score of 22 points or less. Participants were divided into three groups based on continuity of exercise habits in each decade of the 50s to current age: never having exercise habits in their 50s to current [Never group, reference], having exercise habits in one or several of ages from 50s to current [Intermittent group], and having continuous exercise habits in all of ages [Continuous group]. The odds ratio (ORs) for the prevalence of MCI were obtained using logistic regression models while adjusting for potential confounders including age, years of education, body fat percentage, smoking history, alcohol intake, and cognition‐related diseases (hypertension, diabetes mellitus, dyslipidemia, cerebrovascular disease).

Result

Compared with the Never group, none of the ORs for MCI were statistically significant in men (Intermittent group: ORs: 0.60, 95%CI: 0.36 – 1.02; Continuous group: ORs: 0.99, 95%CI: 0.61 – 1.63; P for trend: P = 0.93). In contrast, the ORs for MCI were significantly lower in the Continuous group in women (Intermittent group: ORs: 0.74, 95%CI: 0.47 – 1.17; Continuous group: ORs: 0.50, 95%CI: 0.29‐0.87; P for trend: P = 0.01).

Conclusion

More sustained exercise participation from the 50s to late life was associated with a lower prevalence of MCI in women but not in men.
What are the most important prognosticators of Alzheimer's disease progression? – Answers from machine learning
Authors: Chong Yao Feng , Chen Zijiao , Wu Yilei , Kok Bing Cai , Yeo Thomas , Zhou Juan Helen
Published: December 2022

Background

Numerous variables that influence the risk of decline in Alzheimer’s disease (AD) have been identified. Previous studies have only examined a relatively small number of these variables. To our knowledge, no study has compared all variables in a large dataset to determine which are the most important.

We hypothesised that the most important variables are neuropsychological assessment (NPA) scores and neuroimaging findings; moreover, the prognostic value of all variables will vary with disease stage: normal control (NC), mild cognitive impairment (MCI) or dementia. Secondly, we hypothesised that non‐NPA variables, such as imaging, cerebrospinal fluid (CSF) and genetics, will add prognostic value to that provided by NPA variables alone.

Method

We analysed all relevant variables in the Alzheimer’s Disease Neuroimaging Initiative database – the largest open‐access dataset of subjects with or at risk of AD. With machine learning, we identified those variables which are the strongest predictors of the annual rate of change in up to the first 10 years of Alzheimer’s Disease Assessment Scale – Cognitive Subscale, 13‐item version (ADAS‐Cog13) and Clinical Dementia Rating, Sum of Boxes (CDR‐SB) scores. We repeated this analysis for each disease stage subgroup. Secondly, we compared models that only used NPA‐related variables (NPA‐only) with those that used up to 2 non‐NPA modalities (NPA‐plus) and contrasted the findings between the same subgroups.

Result

Across all subjects, the strongest predictors of the rate of change of both ADAS‐Cog13 and CDR‐SB scores are CSF total tau and amyloid levels, fluorodeoxyglucose (FDG) positron emission tomography (PET) findings, and certain NPA measures. At the NC and MCI stages, CSF and imaging variables are strong predictors, but only NPA variables remained useful at the dementia stage. Secondly, NPA‐plus models consistently outperformed NPA‐only models. The non‐NPA modalities which added the most predictive power varied based on a subject’s disease stage in a manner similar to the previous findings.

Conclusion

We identified a multi‐modal set of variables that have the strongest impact on predicting decline during different stages of AD. Our findings are clinically relevant as they recommend the investigations that are of most prognostic yield for clinicians to undertake at each stage of AD progression.
Does Caregiver Education Level Influence Confidence in Care Budgeting and Planning for Persons Living with Alzheimer’s Disease or Related Dementias?
Authors: Fields Beth E , Boutilier Justin J , Jolliff Anna , Elliott Christian , Zuraw Matthew , Werner Nicole
Published: December 2022

Background

The nearly 11 million unpaid caregivers (‘family members or friends’) who provide care to the 6.5 million people living with Alzheimer’s disease and related dementias (ADRD) in the United States are frequently tasked with substantial and overwhelming care budgeting and planning. Yet, many of these caregivers encounter individual‐level barriers that make it difficult to carry out care budgeting and planning tasks. An individual‐level factor that is not well understood is the education level of ADRD caregivers.

Objective

This ongoing study is investigating the role of caregiver education level in predicting confidence in ADRD care budgeting and planning.

Methods

Caregivers of people living with ADRD residing in the United States completed the Caregiving Financial and Legal Planning Survey in 2022. Secondary analyses of cross‐sectional data are currently underway. A total of 238 caregivers self‐reported their confidence in care budgeting and planning, which was assessed by the following question “How confident are you in knowing about care budgeting and planning (1 = not at all confident, 5 = extremely confident). Those responding ‘4’ or greater were designated as high confidence. Descriptive statistics were used to examine demographic characteristics of caregivers. Logistic regression analyses will be used to determine the relationship between caregiver education level and confidence in care budgeting and planning while controlling for demographic characteristics.

Preliminary Results

The average caregiver was 52 years old (range 36‐67), female (78%), white (82%), and had a bachelor’s or equivalent level of education (34%). Thirty‐five percent of the caregivers (83) reported high confidence. Logistic regression analyses are in progress.

Conclusion

Results may suggest that caregivers with higher education levels feel more confident in care budgeting and planning. Practitioners and researchers may need to evaluate ways to improve training resources on how to budget and plan for ADRD care. A better understanding of factors that contribute to care budgeting and planning may inform tailored caregiving interventions and future social support policies.
Measuring Associations Between Physical Activity, Cognitive Ability, and AD‐Vulnerable Brain Networks in Periadolescent Children
Authors: Heller Abi , Phipps Connor J , Ramirez Meghan K , Sexton Jennifer N , Behm Lillian , Zatkalik Abigail L , Nickolas Kristen , Maerlender Arthur C. , Phatak Vaishali S , Cramer Justin A. , Blair James , Murman Daniel L , Warren David E
Published: December 2022

Background

As our population ages, and Alzheimer’s Disease (AD) and related pathologies become more prevalent, the need for preventative interventions continues to increase. Physical activity has been investigated as a mechanism to improve memory and other cognitive processes in both healthy and pathological aging. In adults, there is evidence that exercise increases hippocampal volume and strengthens connectivity within functional brain networks such as the Default Mode Network (DMN), Frontoparietal Network (FPN), and Dorsal Attention Network (DAN). These networks support cognitive functions such as spatial working memory (SWM) which involves maintenance and manipulation of visuospatial information; notably, SWM declines as AD progresses. Underlying connectivity in functional brain networks and SWM ability are both influenced by exercise in adults. However, this effect has not been replicated in younger cohorts. The effects of exercise on brain structure and function during periadolsecence, a neurodevelopmental period characterized by expansive changes to functional networks that support cognition, remains unclear. The current study tested associations between resting‐state functional connectivity (rs‐FC) in brain networks, SWM ability, and self‐reported physical activity in a group of periadolescents.

Method

Typically‐developing periadolescent children aged 8 – 13 years (N = 60) completed the Cambridge Neuropsychological Test Automated Battery (CANTAB) SWM task, a self‐report physical activity questionnaire, and underwent an MRI of the brain to assess rs‐FC of several functional networks. MRI data were processed using the Human Connectome Project processing pipelines and AFNI software.

Result

Analysis of covariance between rs‐FC of the DMN and physical activity suggested greater within‐network connectivity was associated with more minutes of exercise. A similar pattern of within‐network connectivity in the DMN was also observed in association with SWM performance. The DAN and DMN demonstrated greater between‐network connectivity associated with increased physical activity. The FPN displayed a pattern of greater within‐network connectivity associated with SWM performance.

Conclusion

Characterizing the influence of physical activity on development of brain networks that support memory may provide key insights on preserving those networks. Understanding these developmental trajectories, and ways to potentially enhance them, could be important for developing interventions to promote brain health by reducing the risk of neurological disease, including late‐life disorders such as AD.
Linking molecular abnormalities to balance deficits using a zebrafish model for tauopathies
Authors: Zhu Yunlu , Leary Paige , Bai Qing , Burton Edward A , Schoppik David
Published: December 2022

Background

The ability to maintain balance is an evolutionarily‐conserved behavior that is frequently disrupted found in patients with neurodegenerative diseases. One of the most prominent balance disorders is found in patients with progressive supranuclear palsy (PSP), a primary tauopathy pathologically characterized by tau over‐representation in the brainstem vestibulospinal (VS) nucleus, where they frequently exhibit accidental‐backward falls starting from the early stage of the disease. Although pathological features of PSP correlate well with its clinical phenotype, how tau aggregation affects neuronal and circuit functions, which eventually leads to behavioral deficits, remains unclear.

Method

To dissect disease mechanisms across molecular, cellular, circuitry, and behavioral levels, we generated tau fish by expressing human 0N/4R‐Tau in zebrafish VS nucleus. Tau expression and phosphorylation were validated using immunohistochemistry staining with PHF‐1 antibody. To examine the effect of tau on balance behavior, we measured postural control of free‐swimming tau fish and compared to that of tau‐negative siblings. Moreover, we tested response of VS neurons to nose‐down and nose‐up tilt stimulus using 2‐photon calcium imaging.

Result

Ttau‐expressing zebrafish exhibit impaired balance control while maintaining normal locomotor ability. Interestingly, we did not observe any neuronal death in the VS nucleus. Functional imaging of the VS nucleus shows impaired directional tuning in tau‐expressing neurons in response to tilt stimulus. We also found ectopic accumulation of acidic organelles in the cell bodies of tau‐positive neurons, suggesting abnormal lysosomal function.

Conclusion

Our results demonstrate how molecular abnormalities disrupt specific behavior in tauopathies before neurodegeneration appeared.
Facilitators and Barriers of Social Participation of Older Adults: Systematic Review of Qualitative Studies
Authors: Lee Hamin , Park Hae Yean , Lim Young Myoung , Park Sun Ha , Kim Mi Kyeong
Published: December 2022

Background

As the population of older adults is increasing, the number of older adults exposed to vulnerability of social isolation is also growing. It has been reported that maintaining regular level of social participation in old age is closely related to health, well‐being and cognitive benefits. Previous studies on factors that affect older adults’ social participation have mainly focused on logistical barriers. However logistical barrier alone is not sufficient to understand the factors of older adults’ social participation. The purpose of this study is to systematically examine the facilitators and barriers of older adults’ social participation, and to present basic data that comprehensively consider the individual, environmental and social contexts to promote the older adults’ social participation.

Method

Through PubMed, Embase, Cochrane, data from 2012 to 2022 was collected. The main keyword search terms were ‘elderly’, ‘older adults’, social participation’, ‘engagement’, ‘motiv*’, ‘barrier’, ‘facilitat*’. 7 articles that satisfy the inclusion criteria were selected for analysis.

Result

In the results, the activities the older adults are participating were related to religious activities, volunteering, socilaizing, leisure and ICT. The factors promoting and hindering social pariticpation of the older adults were analyzed. The analyzed factors were assorted into ‘personal/ internal factors’, ‘environmental facotrs’, ‘social network factors’. Facilitators included the desire for belongness, the desire to give back to society, interest, and interaction with a special person. Barriers included environmental accessibility, uniteresting activities, fear, lack of ability to maintain social relationships, and economic difficulties. Factors that either facilitated or hindered social participation included socioeconomic status, infrastructure accessibility, presense of supporters, religion and ethnicity. The results of this study emphasize that not only logistical factors, but also motivation, desire, social context of older adults’ can promote or inhibit their social participation.

Conclusion

As ageing population increases, the number of older adults who are vulnerable to social isolation is also increasing. To prevent this, a broad understanding of what promotes and inhibits the participation of the older adults is needed. In this study, facilitators and barriers of older adults social participation were comprehensively identified.
Bioequivalence and safety comparison of once‐weekly donepezil transdermal system with oral donepezil: results of a phase 1 pharmacokinetic study in healthy volunteers
Authors: Tariot Pierre N. , Braeckman Rene , Oh Charles
Published: December 2022

Background

Oral donepezil, a reversible acetylcholinesterase inhibitor, is a widely prescribed treatment for dementia of the Alzheimer type. Dose escalation of oral donepezil can result in gastrointestinal distress, leading to treatment discontinuation, which emphasizes the need for a transdermal system (TDS). Donepezil TDS (Adlarity®) was recently approved for the treatment of mild, moderate, and severe dementia of the Alzheimer’s type.

Methods

An open‐label, randomized, crossover, 3‐period trial (NCT04617782) with healthy volunteers (aged 18‐55 years) was conducted to assess bioequivalence of once‐weekly 10‐mg/d and 5‐mg/d donepezil TDS with once‐daily 10‐mg oral donepezil. All participants received 5‐mg/d donepezil TDS during the 5‐week Period 1, followed by 10‐mg/d TDS or 10‐mg/d oral donepezil in the 5‐week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state in Week 5 of each treatment. Safety and tolerability were also evaluated.

Results

Of 60 participants enrolled, all received 5‐mg/d TDS, 55 received 10‐mg/d TDS, and 56 received oral donepezil. At steady state, adjusted geometric mean ratio (GMR; % [90% CI]) of TDS to oral donepezil for maximum plasma concentration and area under the plasma concentration versus time curve (0‐168 h) were 88.7 (81.7‐96.2) and 108.6 (100.5‐117.4) for 10‐mg/d and 86.1 (79.8‐92.9) and 105.3 (97.6‐113.6) for 5‐mg/d TDS (dose normalized). The 90% CIs for the GMRs were generally within the accepted 80%–125% range for establishing bioequivalence. Adverse events (AEs) were reported in 80% of participants—53.3% for the 5‐mg/d TDS, 54.5% for the 10‐mg/d TDS, and 57.1% for oral donepezil. Except for abdominal pain (5.5% vs 1.8%), fewer gastrointestinal AEs were reported with 10‐mg/d TDS than oral donepezil (constipation, 5.5% vs 17.9%; nausea 1.8% vs 30.4%; diarrhea 3.6% vs 12.5%), respectively. There were also fewer AEs of dizziness (3.6% vs 19.6%) and no incidence of somnolence (0 vs 10.7%) reported with TDS. No serious AEs, AEs leading to treatment discontinuation, or deaths were reported.

Conclusion

Both donepezil TDS strengths were bioequivalent to oral donepezil on a milligram‐per‐day basis. The safety profile of donepezil TDS supports its use in treating dementia of the Alzheimer type.
Common vaccines and the risk of dementia: a population‐based study
Authors: Douros Antonios , Ante Zharmaine , Suissa Samy , Brassard Paul
Published: December 2022

Background

The growing evidence for an infectious etiology of dementia supports the investigation of immunization as a preventative intervention. Prior observational studies suggesting that common vaccines are associated with an up to 60% decreased risk of dementia had several methodological limitations. Thus, to provide evidence for this question, we assessed in a large population whether common vaccines are associated with a decreased risk of dementia.

Method

We conducted a population‐based cohort study with a nested case‐control analysis using the Gold and Aurum datasets from the United Kingdom’s Clinical Practice Research Datalink (CPRD). The study cohort included all dementia‐free individuals aged ≥50 years enrolled in the CPRD between January 1988 and December 2018, and followed until March 2021. Each case of dementia identified during follow‐up was matched on sex, age, cohort entry date, duration of follow‐up, and CPRD dataset with up to four controls randomly selected via risk‐set sampling. Conditional logistic regression yielded confounder‐adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of dementia associated with exposure to common vaccines (influenza, pneumonia, shingles, tetanus, diphtheria or pertussis) >2 years before the index date compared to no exposure to these vaccines during the study period. In sensitivity analyses, we applied a longer lag period (10 years) and used active comparators (participation in screening programs for breast and prostate cancer) to account for detection bias.

Result

Our study cohort included 13,383,431 dementia‐free individuals aged ≥50 years, including 212,562 who developed dementia over a mean 10‐year follow‐up (mean age 70 years; 62% female). Exposure to common vaccines was associated with an increased risk of dementia (OR, 1.38; 95% CI, 1.36‐1.40), compared with no exposure, driven mostly by immunization for influenza (OR, 1.39; 95% CI, 1.37‐1.41). Applying a longer lag period (OR, 1.22; 95% CI, 1.20‐1.24) and using active comparators (versus breast cancer screening: OR, 1.34; 95% CI, 1.26‐1.42 / versus prostate cancer screening: OR, 1.22; 95% CI, 1.14‐1.31) slightly attenuated the risk increase.

Conclusion

Our large population‐based study showed no decreased risk of dementia associated with exposure to common vaccines. The observed increase in the risk is likely a result of detection bias.
Investigating the binding of high molecular weight tau to LRP1
Authors: Cooper Joanna M , Lathuiliere Aurelien , Dickson John , Glynn Calina , Fan Zhanyun , Donahue Cameron , Migliorini Mary , Hyman Bradley T. , Strickland Dudley K
Published: December 2022

Background

The spread of neurofibrillary tangle (NFT) pathology across the brain is a hallmark of Alzheimer’s disease (AD) and is thought to be driven by the cell‐to‐cell transport of seed competent tau protein. LRP1 is a receptor for tau that mediates tau uptake, degradation, and seeding of intracellular tau aggregation. We previously found that LRP1 binds recombinantly produced 2N4R tau with high affinity, and that phosphorylation on tau reduces its affinity for LRP1. However, it is unknown if LRP1 interacts with the soluble HMW forms of tau that drive tau seeding, and here we investigate LRP1 binding to HMW phospho‐mimetic tau or HMW tau isolated from AD patient brains.

Method

We recombinantly produced tau containing mutations to mimic phosphorylation patterns of high‐molecular weight (D20Q3) or low molecular weight (D8Q2) tau found in AD brains. Next, we measured their ability to bind purified LRP1 binding via surface plasmon resonance (SPR) and determined the ability of LRP1 expressed in cells to mediate 125I‐labeled tau internalization. We also investigate the binding of HMW pathogenic forms of tau as well as LMW forms of tau isolated by size exclusion chromatography from AD patient brain extracts to LRP1 using a novel SPR capture assay.

Result

We found that D20Q3 and D8Q2 tau bind LRP1 much weaker (Kd = 1249nM & Kd = 388nM, respectively) than unmodified 2N4R tau (Kd = 20nM). 125I‐labeled tau uptake assays indicate reduced uptake for both D20Q3 and D8Q2 tau compared to 2N4R tau. Finally, preliminary results demonstrate that LRP1 is able to bind pathogenic forms of HMW tau isolated from AD patient brains, although there appears to be variability from different patients and LRP1 may bind HMW tau weaker than LMW tau. Studies are underway to determine the affinity of these forms for LRP1.

Conclusion

Our results demonstrate that LRP1 binds pathogenic forms of tau, with significant variation seen between patients. Future studies will investigate if the affinity of these forms correlate with their ability to promote tau seeding.
An oligomer‐directed Aβ antibody decreases synaptotoxic oligomeric Aβ in brain and improves behavioral abnormality in humanized APP knock‐in mice
Authors: Liu Lei , Lawton Trebor L , Liu Wen , Cai Yuqi , Meunier Angela , Lauro Bianca , Jin Shanxue , Selkoe Dennis J
Published: December 2022

Background

There is strong evidence that soluble oligomers of amyloid beta protein (oAβ) help initiate the pathogenic cascade of Alzheimer’s disease (AD), which suggests therapeutic strategies targeting oAβ over monomeric or fibrillar Aβ. A new antibody, 71A1, is 1∼00‐fold more sensitive for oAβ than synthetic monomers. The material that 71A1 specifically immunoprecipitates from AD soluble brain extracts impairs synaptic function as much as does the full extract. In accord, pre‐incubating brain extracts with 71A1 neutralizes its synaptotoxicity. 71A1 has potentially unique activities against disease‐relevant oAβ, making it a novel candidate for treating AD.

Methods

15 mg/kg 71A1 or anti‐KLH (negative control) was administered i.p. to 45 humanized APP knock‐in mice (APPNLGF/NLGF) weekly from 8 to 20 weeks of age. Cognition was assessed by spontaneous alternation (Y‐maze). Brains were harvested at age 21‐wk for biochemical, electrophysiological and immunohistochemical analyses. Diffusible (“soaking”) extracts of the brains were prepared to measure monomeric and oligomeric Aβ using homebrew ultra‐sensitive assays. Aliquots of the same soaking extracts were used to treat wild‐type mouse hippocampal slices and measure long‐term potentiation (LTP) to assess synaptotoxicity in the APPNLGF/NLGF brains post‐treatment.

Results

71A1 recognized oAβ and neutralized its synaptotoxicity in APPNLGF/NLGF mouse brain extracts. 71A1 effectively treated male APPNLGF/NLGF mice, which improved cognition significantly. The antibody reduced brain Aβ (1‐42) and oAβ levels with a trend toward statistical significance. Mouse brains with less oAβ had less synaptotoxicity as assessed by LTP.

Conclusions

These results demonstrate 71A1 is an oligomer‐preferring monoclonal antibody as a therapeutic candidate for AD, decreasing brain oAβ and oAβ‐induced synaptotoxicity. We believe this provides the first proof‐of‐concept mouse trial using an antibody that has been carefully characterized as oAβ‐preferring. We observed 1) a correlation between oAβ concentration and its synaptotoxicity; and 2) that 71A1 ameliorated aspects of cognitive impairment in APPNLGF/NLGF mice by targeting oAβ.