bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships between polymorphisms in keratin genes and Alzheimer’s disease phenotypes.
Authors: Wong Yuen Yan , Xiong Lisa Y. , Mori‐Fegan Daniel K , Noor Shiropa , Chenoweth Meghan J. , Mirza Saira S. , Masellis Mario , Black Sandra E. , Swardfager Walter ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Keratins are genetically polymorphic and are the largest subset of intermediate filaments. Keratins are also implicated in signaling pathways, inflammation, and disease states. Keratin 9 (KRT9) protein has been identified to have high diagnostic accuracy for Alzheimer’s disease (AD) (PMID:22045497); it was detected in cerebrospinal fluid (CSF) of AD patients but not healthy controls (PMID:24959311). Plasma keratin 9 concentrations also positively correlated with AD‐associated proteins (e.g., apolipoprotein E and tau) in AD patients (PMID:26973255). Post‐translational modification of keratin 83 (KRT83) protein has been associated with serum asymmetric dimethylarginine levels (PMID:34181092), a vascular risk factor implicated in AD. However, our understanding of the role of genetic variation in AD risk is incomplete. Here, we investigate associations between single nucleotide polymorphisms (SNPs) in KRT9, KRT83, and KRT2 (Keratin 2, couples with keratin 9) and AD biomarker phenotypes.

Method

Individuals with mild cognitive impairment (MCI) or AD, and clinically normal controls were selected among ADNI participants. Participants underwent genome‐wide genotyping. Keratin gene variants were identified from the genome‐wide data using dbSNP variant IDs and genotypes were coded additively. Linkage‐disequilibrium‐based clumping on minor allele frequency (MAF) was applied to prioritize more common SNPs. CSF‐Aβ42, ‐tau, and phosphorylated‐tau (p‐tau) levels were quantified via Roche Elecsys immunoassays. Brain‐Aβ deposition was evaluated via normalized PET‐18F‐AV‐45 cortical summary measures (SUVR). White matter hyperintensities (WMH) were obtained from MRI 3D‐T1 and FLAIR sequences via an automated atlas‐based segmentation pipeline. Linear regression models controlling for age, sex, Mini‐Mental State Exam, APOE‐ε4 status, and head size were used to assess association and interaction effects between SNPs and the AD phenotypes in R.

Result

Among included participants (n = 907, 73±7.2 years, 44% female), SNPs in KRT2 (e.g. 3’UTR‐variant rs117041267‐G/A; MAF = 1.4%) and KRT83 (e.g. upstream‐variant KRT83‐rs17119838‐C/T; MAF = 15.6%) were associated with higher CSF‐Aβ42 concentrations (F(2,905) = 4.26,p = 0.014; and F(2,905) = 6.61,p = 0.0014, respectively). Upstream‐variant KRT83‐rs182354391‐C/G (MAF = 1%) showed an association with lower CSF‐tau (F(1,904) = 5.44,p = 0.020). Multiple KRT9 and KRT2 SNPs also showed association with WMH, while KRT2 and KRT83 intron variants showed associations with PET‐Aβ.

Conclusion

These candidate gene analyses suggest involvement of multiple keratin family genes in AD, as indicated by differences in amyloid and tau biomarkers, and white matter disease.
Self‐ and interviewer‐reported cognitive problems in relation to subsequent cognitive decline and dementia: results from two prospective studies
Authors: Huang Yuhui , Chen Hui , Pang Ting , Lv Xiaozhen , Gao Mengyan , Rong Shuang , Xu Xin , Yuan Changzheng
Published: December 2023

Background

Little is known regarding the overall association of self‐reported cognitive problems (SCP) and interviewer‐reported cognitive problems (ICP) with age‐related cognitive decline in later life.

Method

We included 10976 Chinese (age: 57.7 ± 8.7) and 40499 European (age: 64.6 ± 9.4) adults without dementia at baseline from CHARLS and SHARE, respectively. Self‐rated current memory (5‐point scale) and interviewer‐rated frequencies of asking for clarification (6‐point scale) were used to define SCP and ICP (dichotomized). Outcomes included objective cognitive test scores (z‐transformed) and incident dementia. We performed generalized estimating equation models to evaluate mean differences in objective cognitive decline (z‐score) across groups. Logistic regression and cox proportional hazards models were used to estimate relative risk of dementia.

Result

During an average of 5.4 and 5.7 years of follow‐up, rates of cognitive decline were ‐0.039 (‐0.044, ‐0.034) z‐score/year for Chinese and ‐0.027 (‐0.029, ‐0.025) z‐score/year for Europeans. Compared to those without SCP and ICP, participants with coexistence of SCP and ICP were associated with faster cognitive decline (βCHARLS: ‐0.051 [‐0.080, ‐0.021]; βSHARE: ‐0.024 [‐0.043, ‐0.004]; Pooled β: ‐0.035 [‐0.061, ‐0.009] z‐score per year). In addition, individuals with both SCP and ICP had higher risk of developing dementia (ORCHARLS: 1.77 [1.42, 2.20]; HRSHARE: 2.94 [2.42, 3.59]; Pooled relative risk: 2.29 [1.38, 3.77]).

Conclusion

Combination of SCP and ICP could be utilized as strong early indicators to identify individuals at high risk of cognitive decline and dementia.
Validation of a Computable Phenotype for Successful Cognitive Aging
Authors: Smith Glenn E. , Miller Amber H. , Marra David E , Wu Yonghui , Bian Jiang , Maraganore Demetrius M , Anton Stephen
Published: December 2023

Background

Studying successful cognitive aging presents an opportunity to identify factors that may mitigate risk for Alzheimer’s disease and related disorders to inform public health initiatives, community interventions, and policy. Yet, identifying these cohorts is challenging, especially at advanced ages. Commutable phenotype algorithms using electronic health records may serve as an aid to identify cohorts of advanced age adults with intact cognitive function. The purpose of this study was to 1) establish, 2) apply, and 3) validate a machine learning‐based computing algorithm for recruitment of successful aging individuals for clinical cohort study.

Method

We identified EHR‐available variables representing successful aging among individuals 85 years and older (85+) by interviewing a panel comprised of 10 aging experts. Based on the identified variables, we developed a rule‐based computable phenotype algorithm composed of 17 inclusion or exclusion criteria. We applied the computable phenotype algorithm to screen all living persons age 85+ at UF Health and identified those meeting successful aging criteria and endeavored to directly evaluate them.

There were 52,841 living 85+ individuals identified at UF Health. Of these 24,024 were identified as successful aged by the computable phenotype algorithm. This sample frame was 58% female, 59% White, and 69% non‐Hispanic. A priori permission to be contacted for research had been obtained on 11,898 of these persons, of whom 470 responded to study announcements and 333 consented to evaluation.

The main outcomes measures were individuals identified by the computational algorithm subsequently being validated by virtue of having a modified Telephone Interview for Cognitive Status score >27 and Geriatric Depression Scale <6.

Results

Forty‐five percent of all living persons 85+ in the UF Health EHR database were identified by the computable phenotype as successfully aged. Approximately 4% of these persons responded to study announcements and 333 were consented. Of these 333, 218 (65%) were ‘validated’ as meeting successful cognitive aging criteria via direct evaluation (See Figure).

Conclusions

The study validated a computable phenotype algorithm for recruitment of individuals for a successful aging study using large‐scale EHRs. Our study provides proof‐of‐concept of using big data and informatics as aids for recruitment of individuals for prospective cohort studies.
Predictive ability of the IQCODE items for detection of cognitive decline and dementia in aging adults with Down syndrome
Authors: Mattar Guilherme Prado , Gonçalves Aline Souza , da Silva Maria de Fátima Rebouças , Leduc Vinicius Ribeiro , Ribeiro Octávio Gonçalves , Martinez Luana Dongue , de Oliveira Alexandra Martini , Sant´Ana Livea Carla Fidalgo , Fonseca Luciana Mascarenhas , Forlenza Orestes Vicente
Published: December 2023

Background

There is evidence of a genetic association between Down Syndrome (DS) and early progression of Alzheimer’s disease (AD). Few brief instruments have been validated for the screening of dementia in this population. Previously, we showed that the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) may be useful for cognitive screening in adults with DS1. Nonetheless, the adaptation of certain items to account for the presence of intellectual deficiency may increase diagnostic accuracy. The aim of the present study is to evaluate the predictive ability of IQCODE items for adults with DS.

Method

Univariate and multivariate logistic regressions were used to assess the effects of the 26 IQCODE items on the diagnosis of cognitive decline (prodromal dementia or dementia versus stable cognition) according to the Cambridge Examination for Mental Disorders of Older People with DS and Others with Intellectual Disabilities, CAMDEX‐DS. The study comprised 92 participants with DS aged ≥35 years. The accuracy of the final multivariate model was evaluated using receiver operator characteristics (ROC) curve.

Result

Associations were found between all IQCODE items and diagnosis, except for two items (handling money for shopping and financial matters). Multivariate logistic regression using the CAMDEX‐DS diagnosis as dependent and the items of IQCODE as predictors, showed that four items remained in the model (remembering: members of family and friends, day and month, things they learned when they were younger, and adjusting to change in routine). Participants who presented more difficult with these items were, respectively, 84.1, 86.1, 10.1 and 23.6 times more likely to have a diagnosis of prodromal dementia or dementia. Using the estimated probability of these 4 items, we found an area under the ROC curve of 0.961.

Conclusion

The IQCODE items showed good ability to discriminate subjects with cognitive decline as indicated by the CAMDEX‐DS. The use of 4 of the IQCODE items proved to suffice to discriminate between diagnostic groups. We will next perform an adaptation and validation study to warrant the “IQCODE‐DS” as a reliable, brief test for the cognitive screening in this population.
The diagnostic performance of plasma amyloid β, total tau and neurofilament light chain levels in mild cognitive impairment and Alzheimer’s disease dementia: the Health & Aging Brain among Latino Elders study
Authors: Wang Shanshan , Hall James , Petersen Melissa , O'Bryant Sid E. , Nandy Rajesh
Published: December 2023

Background

The current diagnostic criteria for Alzheimer’s disease (AD) rely on neuroimaging and cerebrospinal fluid, which are expensive and invasive. Plasma‐based ATN biomarkers, including amyloid β40 (Aβ40), amyloid β42 (Aβ42), total tau, and neurofilament light chain (NfL), are more accessible and cost‐effective. However, the diagnostic performance of plasma‐based ATN biomarkers remains to be determined. This study aims to assess the diagnostic performances of plasma‐based ATN biomarkers for AD dementia and mild cognitive impairment (MCI), and assess whether the diagnostic performances are different between Mexican Americans and non‐Hispanic Whites.

Method

We used data from the Health & Aging Brain among Latino Elders (HABLE) study. A total of 1616 participants (1260 cognitively normal, 247 MCI, and 109 AD dementia) were included in the analyses. Diagnoses of AD dementia and MCI were adjudicated by consensus review. Plasma was analyzed using the single molecule array (Simoa) assays. The overall diagnostic performances of plasma‐based ATN biomarkers were assessed by the area under the curve (AUC) analyses. The DeLong test was used to compare the AUCs.

Result

Plasma NfL had better differentiation performances than plasma Aβ42/Aβ40 ratio, total tau and the combination of plasma ATN biomarkers. When age and sex were combined to the diagnostic model, the AUCs did not change significantly. The performances of plasma ATN biomarkers were not significantly different between Mexican Americans and non‐Hispanic Whites (P values>0.05). However, when age and sex were incorporated to the diagnostic model, the performances to distinguish AD dementia and MCI vs. CN, AD dementia vs. MCI, and MCI vs. CN were significantly different between Mexican Americans and non‐Hispanic Whites (P values<0.05).

Conclusion

The current study provided more evidence on the potential capacity of plasma‐based ATN biomarkers for diagnosing AD among Mexican Americans and non‐Hispanic Whites. Overall, the diagnostic capacities of plasma ATN biomarkers were not ideal. More research is needed to explore the utilization of plasma ATN biomarkers.
Importance of functional outcome measures when evaluating the efficacy of tau immunotherapies
Authors: Ji Changyi , Lin Yan , Sigurdsson Einar M.
Published: December 2023

Background

Tau immunotherapies are promising approaches to treat Alzheimer’s disease and other tauopathies. Using in vivo two‐photon calcium imaging, we have observed altered neuronal calcium activity in behaving JNPL3 tauopathy mice at both early and advanced stage of tauopathy. We have also shown that two mouse monoclonal antibodies, targeting phosphorylated tau‐Ser396/Ser404, partially restored these neuronal deficits (Wu Q et al Neurobiol Dis 2021, Ji C et al Alzheimers Dement AAIC 2022). Recently, we reported that novel single domain antibodies (sdAbs) and their divalent derivatives conjugated to Fc fragment showed varied efficacy to reduce tau pathology in culture, and to clear tau in brain interstitial fluid by in vivo microdialysis. Whether these sdAbs restore tauopathy‐induced neuronal deficits warrants further evaluation.

Method

Somatic calcium activity in the motor cortex of homozygous 6‐month‐old JNPL3 mice was imaged by two‐photon microscopy when animals were either quiet or running. Two doses (100 µg each) of a tau IgG1‐(sdAb)2 or a control IgG1 were administered intravenously four days apart after the first imaging session. Somatic calcium activity was assessed again four days later, and compared to profile before treatment. Tau pathology was then analyzed in the mouse brain lysates by immunoblotting.

Result

Abnormal cortical calcium activity was observed in resting and running JNPL3 mice at 6 months of age. Acute treatment with the tau IgG1‐(sdAb)2 did not normalize the frequency, amplitude or total activity of calcium transients in motor cortical neurons. Littermate mice treated with control IgG1 showed worsening of the tauopathy‐induced calcium dysfunction in the resting condition, and no improvement in the running condition. Interestingly, tau IgG1‐(sdAb)2 treatment decreased soluble phosphorylated tau in the treated mice, although it did not improve neuronal function. Additional analyses are ongoing, including of antibody target engagement.

Conclusion

These findings confirmed neuronal calcium dysregulation in young JNPL3 mice. The failure of this particular acute tau antibody treatment to restore neuronal function is in contrast to our prior findings on two other tau antibodies targeting a different epitope, although all reduced soluble phospho‐tau. Therefore, these results highlight the importance of including a functional readout during preclinical development of tau antibodies.
Specific damages to olfactory‐related structures and their relation to episodic memory in Individuals at Risk of Alzheimer’s Disease.
Authors: Jobin Benoît , Frasnelli Johannes , Boller Benjamin ,   CIMAQ group
Published: December 2023

Background

One of the major challenges in the diagnosis of Alzheimer’s disease (AD) is to increase the specificity of the early diagnosis. While episodic memory impairment is a sensitive marker of AD, other markers are needed to improve diagnostic specificity. A promising biomarker might be a cerebral atrophy of the central olfactory processing areas in the early stages of the disease since an impairment of olfactory identification is present at early clinical stages of AD. Our goal was to evaluate whether reduced grey matter volume (GMV) in the central olfactory processing regions could be observed in early and preclinical stages of AD. We also aimed to verify if GMV of central olfactory processing regions is associated with episodic memory performance.

Method

166 participants from the Consortium for the Early Identification of Alzheimer’s Disease‐Quebec (CIMA‐Q) (92 with subjective cognitive decline ‐ SCD, 40 with mild cognitive impairment ‐ MCI and 34 cognitively healthy controls) were included. We performed regions of interest (ROI) analysis using a mask of the regions that are activated during olfactory stimulation. We also extracted GMV outside ROIs, representing non‐olfactory areas of these regions, i.e., regions which do not respond to olfactory stimulation. Verbal episodic memory was assessed using a free word recall task from Memoria Word Recall test.

Result

Compared to controls (p = .019) and participants with SCD (p = .003), participants with MCI exhibited a smaller total GMV of central olfactory processing regions, with a significant interaction effect between region and group (p = .004). Specifically, the piriform cortex, amygdala, entorhinal cortex, and left hippocampus were significantly smaller in individuals with MCI (p≤.05, corrected). In contrast, when comparing GMV outside ROIs between the three groups, there was no such interaction between region and group (p = .428). Additionally, GMV in the olfactory areas of the piriform cortex, amygdala, and left hippocampal gyrus was correlated with episodic memory performance, while GMV in the non‐olfactory areas of the left hippocampus and left parahippocampal gyrus was correlated with episodic memory performance (p≤.05, corrected).

Conclusion

There is a specific neurodegeneration of limbic and medial‐temporal olfactory‐structures in MCI, GMV of these regions being related to cognitive performance.
Structural brain network degeneration associated with agitation in dementia
Authors: Jenkins Lisanne M , Gupta Sonya M , Kouchakidivkolaei Maryam , Sridhar Jaiashre , Rogalski Emily J , Weintraub Sandra , Popuri Karteek , Rosen Howard J. , Wang Lei
Published: December 2023

Background

Agitation is a behavioral syndrome involving increased motor activity, restlessness, aggressiveness and emotional distress. Its has a 30% prevalence across multiple types of dementia and is associated with negative outcomes, including reduced quality of life, caregiver distress, and mortality. Pharmacological treatment risks serious side effects, including mortality. Understanding brain network topology could provide insights into novel treatment methods.

Method

Participants comprised 600 subjects from 3 existing databases: the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD) and the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University.

Participants were clinically diagnosed with either behavioral variant frontotemporal dementia (bvFTD), mild cognitive impairment (MCI), dementia of the Alzeheimer type (DAT) or cognitively normal (CN). The Neuropsychiatric Inventory Questionnaire (NPI‐Q) caregiver rating was used to determine whether individuals were agitated or not.

Morphometric similarity networks (MSNs) were generated from Freesurfer statistics calculated from T1‐weighted MRIs. 7 surface‐based cortical metrics (e.g. gray matter volume, surface area) were calculated for each of 360 parcels. Pairwise inter‐parcel Pearson correlations of feature vectors were calculated to produce a morphometric similarity matrix for each individual. We calculated sub‐matrices for salience (SN) cognitive control (CCN) and default mode networks (DMN). Brain Connectivity Toolbox calculated transitivity and global efficiency of each network. Metrics were calculated at different thresholds to ensure the results were not threshold‐dependent.

We calculated 2 (Agitation present/absent) x 4 (Diagnosis) repeated measures ANCOVAS for transitivity and global efficiency for each network. Covariates were age, sex, race, database, education, ICV, CDR‐SB and days MRI‐NPI‐Q.

Result

For the SN, people with Agitation had significantly lower global efficiency than people without Agitation (Figure 1). There were no significant effects of diagnosis or interaction.

For the CCN, people with agitation had significantly lower transitivity than people without Agitation (Figure 2). There were no significant effect of diagnosis or interaction.

Conclusion

Across different forms of dementia, Agitation is associated with reduced integration (global efficiency) of the salience network, and reduced segregation (transitivity) of the cognitive control network. Interventions that alter these topological network features may be effective in reducing agitation in dementia, regardless of clinical diagnosis.
Genetic associations with mixed neuropathologies in the aging brainGenetic associations with mixed neuropathologies in the aging brain
Authors: Katsumata Yuriko , Fardo David W. , Abner Erin L , Nelson Peter T
Published: December 2023

Background

““Mixed” neuropathologies (NPs) are common in aged brains. Classic Alzheimer’s disease neuropathologic change (ADNC) proteinopathies are amyloid‐β plaques and tau neurofibrillary tangles (NFTs). In addition, α‐synuclein and TDP‐43 are also key proteinaceous disease markers, and cerebrovascular diseases (CVDs) often coexist. Although the scientific problems regarding mixed NPs are increasingly recognized, genetic associations with mixed NPs have not been well‐investigated. In this study, we applied item response theory (IRT) to optimize the clustering and combination of mixed NPs and examined the genetic associations.

Method

NP data were drawn from the National Alzheimer’s Coordinating Center (NACC) NP v10‐11 forms through the March 2022 data freeze, including Thal phase ratings (A score); Braak NFT stage (B score); CERAD neuritic plaque scores (C score); Lewy bodies (LBs); TDP‐43; hippocampal sclerosis (HS); cerebral amyloid angiopathy (CAA); infarct and lacunes; microinfarcts; atherosclerosis of the circle of Willis; and brain arteriolosclerosis. We determined dominant pathology patterns in 1,228 participants who had no missing data using a multidimensional graded response model within the IRT framework. The NACC NP data were linked to the U.S. Alzheimer’s Disease Research Centers genetic data provided by the Alzheimer’s Disease genetic Consortium.

Result

From the leave one out cross validation simulation, the model fitness tests showed that the 4‐factor model had fewer differences from the data than the other models. As shown in Figure, the predominant NPs were TDP‐43 and HS for factor 1 (F1), CVDs other than CAA for factor 2 (F2), A, B, and C scores and CAA for factor 3 (F3), and LBs for factor 4 (F4). The TMEM106B locus was genome‐wide significant with F1 (TDP‐43/HS) and the APOE locus was genome‐wide significant with F3 (ADNC/CAA) after adjusted for age at death, sex, and other factor scores. The SDK1 and FMNL2 loci were not genome‐wide significant, but had noteworthy associations with F2 (CVDs).

Conclusion

Our new approach to create mixed NP scores could detect the TMEM106B and APOE loci as TDP‐43/HS related and ADNC related regions, respectively. Although previous studies reported SDK1 as an ADNC related gene, we showed that the gene may be associated with CVDs.
An Investigational RNAi Therapeutic for Tau Lowering
Authors: Farley Jonathan , Haines Jeffery D , Gannon Sean , Nguyen Tuyen , Abbott Stephen , Darcy Justin , Tymon Roxanne , Cha Diana , Schlegel Mark , Castoreno Adam , Bisbe Anna , Zlatev Ivan , Rollins Jeff , Bostwick Bret , Avbersek Andreja , Macdonald Lynn , Gao Min , Anderson Matthew , Brown Kirk
Published: December 2023

Background

The hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a class of progressive neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer’s Disease (AD). There is a high unmet medical need for new approaches to target Tau in these numerous tauopathies. While anti‐Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs.

Method

Here, using our lipophilic C16‐conjugated siRNA for CNS delivery, we identified potent molecules targeting the MAPT gene in both in vitro and in vivo models.

Results

Our RNAi molecules targeting the MAPT gene durably reduce MAPT mRNA and Tau protein levels in both in vitro and in vivo model systems. Furthermore, in a 16‐week non‐human primate study, we observed robust target engagement resulting in sustained reduction of MAPT transcript and Tau protein in brain tissue and cerebrospinal fluid.

Conclusion

Together, these results suggest that RNAi lowering of Tau could be a novel strategy to address both intra‐ and extra‐cellular accumulation of Tau aggregates, which could have therapeutic advantages for treating tauopathies.
Development of the COMET tool: Caregiver‐reported Outcome Measure for Emergency care Transitions
Authors: Gettel Cameron , Galske James , Uzamere Ivie , Serina Peter , Hernandez‐Bigos Kizzy , Mane Sahil , Chen Kelly , Ottilie‐Kovelman Sierra , Sandoval Jacqueline , Venkatesh Arjun , Cohen Andrew , Monin Joan , Fried Terri , Hwang Ula
Published: December 2023

Background

Despite a recognized need for more robust metrics, caregiver‐reported outcome measures have not been developed for care partners of persons living with cognitive impairment (PLWCI) navigating emergency department (ED)‐to‐community care transitions. Our objective was to develop the Caregiver‐reported Outcome Measure for Emergency care Transitions (COMET) tool through a 5‐phase process.

Methods

The study was conducted in four EDs and included care partners of PLWCI discharged from the ED identified by validated screening tools. In Phase 1, 25 participants completed semi‐structured interviews to identify barriers experienced during ED‐to‐community care transitions. In Phase 2, research team members performed item generation, in which candidate items were developed through findings from Phase 1 qualitative interviews and adaptation of items on existing outcome measures. In Phase 3, we utilized member checking, in which 27 new participants ranked candidate items they felt important for inclusion within the final COMET tool. Phase 4 included 10 cognitive debriefing interviews, in which participants assessed candidate items for comprehensiveness, content validity, and comprehension. In Phase 5, 19 multidisciplinary stakeholders participated in a modified Delphi approach to generate the COMET tool.

Results

Phase 1 identified four major barriers experienced by care partners of PLWCI during ED‐to‐community care transitions: 1) unique care considerations while in the ED setting impact the perceived success of the care transition, 2) poor communication and lack of care partner engagement was a commonplace during the ED discharge process, 3) care partners experienced challenges and additional responsibilities when aiding during acute illness and recovery phases, and 4) navigating the health care system after an ED encounter was perceived as difficult by care partners. Phase 2 generated 50 candidate items grouped into 3 domains: discharge process, care transition, and impact on the caregiver. Phase 3 quantitatively identified high‐ and low‐scoring candidate items for inclusion in the final COMET tool. Phase 4 resulted in revisions to the wording of several candidate items. Phase 5 resulted in the 19‐item COMET tool.

Conclusions

Development of the COMET tool will provide a means for caregiver‐centric outcome assessment of interventions targeting ED‐to‐community care transitions among PLWCI.
Dementia prevention strategies in Low and Middle Income Countries: A systematic review
Authors: Jeraldo Rosario Isabel Espinoza , Chandra Avinash , Anjum Rifah , Bothongo Phazha L K , Waters Sheena , Uchegbu Ijeoma , Byford Michelle , Marshall Charles R , Cooper Claudia
Published: December 2023

Background

Amidst the global efforts to target potentially modifiable dementia risk factors, Low and Middle Income Countries (LMIC) have been described as having considerable potential for prevention. Although there is growing interest in the design, testing and implementation of preventive strategies, most of the existing literature focuses on countries with higher income levels. This systematic review aims to 1) describe the approaches that have been tried in LMIC to prevent dementia in adults over 50 years old at high risk 2) explore the key potential mechanisms and contexts associated with a positive outcome.

Method

We conducted our search on appropriate electronic databases for articles published between January 2010 to January 2023. We included all primary research intervention studies meeting a priori criteria. Our primary outcomes were any change in cognition, and/or dementia diagnosis. Two authors are independently reviewing articles and assessing study quality using the Mixed Methods Appraisal Tool (MMAT). We will narratively synthesise results.

Result

In line with current literature on dementia prevention, and due to both the diversity of populations and the broad range of possible approaches, we expect heterogeneity of studies with mixed results. We also expect multi‐domain interventions to be reported as the most effective.

Conclusion

This project will add to current knowledge on how dementia prevention is being approached in the context of LMIC. Findings will allow us to understand which factors make local interventions work and inform the implementation of preventive strategies for people at high risk of dementia.
Impact of mobile research unit in SKYLINE trial to broaden trial access in traditionally underrepresented communities
Authors: Croney Ruth , Jan Adam Y , Hurley Vicki , Markham‐Coultes Kelly , Smith Jill , Batchuluun Dawn , Jaime Lucia , Fils‐Aime Lucie , Pingshaw Astrid , Ostrowitzki Susanne
Published: December 2023

Background

The SKYLINE prevention trial (NCT05256134) aimed to enroll cognitively unimpaired, elderly, amyloid‐positive adults, which is known to be challenging. Additionally, it is essential to address disparities of access to trials, particularly in underrepresented populations (URPs) where the need to travel to a research site and lack of comfort or distrust of medical providers have been identified as barriers to participation (Alzheimers Dement 2021;17:327‐406). Potential participants in URPs may have limited experience/knowledge of clinical research; therefore, additional community‐based initiatives were launched to improve awareness and education.

Method

A mobile research unit (THOR) was designed to visit selected communities and provide education on memory loss and initial access to screening for the SKYLINE trial. THOR was designed to optimize participant experience and study visit flow (Figure), and was strategically operationalized in Florida due to the large prevalence of older adults, high proportions of URPs, and concentration of Alzheimer’s research centers. Two multilingual personnel, representative of the targeted populations and with expertise in outreach within URPs, managed the unit. Community‐based settings were targeted, including community centers, churches, retirement communities, restaurants, and doctors’ offices. In addition to SKYLINE prescreening, THOR offered community‐based memory screenings and memory loss education to help build relationships and trust with communities. A survey was used to assess site staff perceptions of the implementation of THOR.

Result

Between July and November 2022, THOR was deployed at 20 community outreach events; 325 participants were prescreened for SKYLINE (Table 1). Race and ethnicity data were provided by 127 participants at 12 events from Global Alzheimer’s Platform (GAP) Foundation‐partnered sites; 64/127 (50.4%) participants were from an URP. Overall, 80% of surveyed site staff agreed/strongly agreed that THOR had a positive impact on relationship‐building and prescreening rates in URPs (Table 2).

Conclusion

THOR was an innovative, strategic way to increase access to SKYLINE by raising awareness of brain health and clinical research in the community. Site survey responses indicated utilization of THOR improved engagement with URPs. Implementation of a mobile research unit with capabilities to perform trial prescreening activities was an effective way to engage potential trial participants including URPs.
Blood‐derived mitochondrial DNA copy number is associated with Alzheimer’s Disease through the regulation of plasma lipid and amino acid metabolism
Authors: Tong Tong , Zhu Congcong , Farrell John , Khurshid Zainab , Martin Eden R. , Pericak‐Vance Margaret A. , Wang Li‐San , Schellenberg Gerald D. , Haines Jonathan L. , Lunetta Kathryn L. , Farrer Lindsay A. , Zhang Xiaoling
Published: December 2023

Background

Blood‐derived mitochondrial DNA copy number (mtDNA‐CN) is the proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA‐CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA‐CN and Alzheimer’s Disease (AD) and the underlying mechanisms of mitochondrial dysfunction in the pathogenesis of AD are still unclear.

Method

To investigate the causal relationship between mtDNA‐CN and AD, we performed two‐sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA‐CN and AD. Further, we estimated mtDNA‐CN using whole‐genome sequence data from blood samples of 1,521 ADNI participants and used a Cox proportional hazard model, adjusted for age, sex, and study phase, to assess the association between mtDNA‐CN and AD risk. The association of AD biomarkers measured in brain and plasma metabolites with mtDNA‐CN was evaluated using linear regression. We conducted causal mediation analysis to test the natural indirect effects of mtDNA‐CN change on AD risk through the significantly associated biomarkers and metabolites.

Result

MR analysis using a profile likelihood approach suggested a causal relationship between decreased blood‐derived mtDNA‐CN and increased risk of AD (OR = 0.71; P = 0.023). Survival analysis showed that decreased mtDNA‐CN was significantly associated with increased risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.0017). We also identified significant associations between mtDNA‐CN and brain glucose metabolism (β = 0.050; P = 0.047) and amyloid‐β (Aβ) (β = 0.069; P = 0.015) and CSF Aβ (β = ‐0.051; P = 0.048). Plasma Aβ was, however, not associated. Several lipid species, amino acids, biogenic amines, and inflammatory proteins in plasma were also significantly associated with mtDNA‐CN. Finally, causal mediation analyses showed that the effect of change in mtDNA‐CN on AD risk is mediated by plasma neurofilament light (β = ‐0.055; P = 0.010), glycine (β = 0.016; P = 0.044), and hexadecenoylcarnitine (β = ‐0.017; P = 0.049).

Conclusion

Our study indicates that mtDNA‐CN measured in blood is predictive of AD risk. Associations of mtDNA‐CN with Aβ in CSF and brain, but not plasma, suggest cross‐tissue regulation of mitochondria. Decreased mtDNA‐CN might increase AD risk through lipid and amino acid metabolism. These results also suggest potential development of mtDNA‐CN as a blood‐based biomarker.
Alzheimer’s disease linked amyloid beta 1‐42 exerts product feedback inhibition on gamma‐secretase impairing downstream signaling cascades
Authors: Zoltowska Katarzyna Marta , Das Utpal , Lismont Sam , Enzlein Thomas , Maesako Masato , Houser Mei CQ , Franco María Luisa , Moreira Diana Gomes , Karachentsev Dmitry , Becker Ann , Hopf Carsten , Vilar Marçal , Berezovska Oksana , Mobley William C , Chávez‐Gutiérrez Lucía
Published: December 2023

Background

Γ‐secretases are proteolytic switches at the membrane regulating multiple signaling cascades. Their dysfunction, resulting in enhanced generation of longer amyloid β (Aβ) peptides from the amyloid precursor protein (APP), leads to neurodegeneration in the context of Alzheimer’s disease (AD), while their inhibition causes neurodegenerative phenotypes in mice and cognitive worsening in AD patients treated with γ‐secretase inhibitors. The accumulation of Aβ in the brain is the earliest pathological hallmark of AD. Based on the proven affinity of Aβ peptides for γ‐secretases, we hypothesized that elevations in Aβ levels would promote an inhibitory‐feedback mechanism on γ‐secretases and impair downstream cell signaling events.

Method

We conducted rigorous kinetic analyses of γ‐secretase activity in the presence of a series of Aβ and p3 peptides, by quantifying the levels of intracellular domains generated from different γ‐secretase substrates in cell‐free assays. In addition, we determined the effects of these peptides on endogenous γ‐secretase activity in living neurons, using a ratiometric FRET‐based reporter and western blot analysis of the levels of immediate γ‐secretase substrates. Furthermore, we assessed the impact of Aβ and p3 peptides on γ‐secretase‐mediated, p75‐ and TrkA‐dependent downstream signaling via immunostaining for an apoptotic marker: cleaved caspase 3. Finally, we evaluated the impact of Aβ peptides on APP processing in synaptosome fractions derived from mouse brains.

Result

Our analyses showed that human Aβ42 inhibited γ‐secretase activity and accordingly caused accumulation of unprocessed γ‐secretase substrates in neuronal cells, i.e. CTFs of APP, p75 and pan‐cadherin. Remarkably, neither murine Aβ42 nor human p3 (17‐42) peptides exerted the inhibition. In TrkA signaling deficient PC12 cells and basal forebrain cholinergic neurons, Aβ1‐42‐mediated inhibition of γ‐secretase led to the accumulation of unprocessed p75‐CTFs and potentiated p75‐dependent cell death, mimicking the effects of γ‐secretase inhibitors.

Conclusion

We demonstrate that the pathologically relevant human Aβ1‐42 exerts product feedback inhibition on γ‐secretases, leading to dysregulation of downstream cellular signaling. These findings provide a novel conceptual framework for investigations of Aβ toxicity in the context of γ‐secretase‐dependent homeostatic signaling and raise the possibility that Aβ42‐mediated inactivation of these enzymes contributes to AD development.
Investigating the role of mitochondrial calcium uniporter beta in Alzheimer’s disease
Authors: Jadiya Pooja , Tomar Dhanendra , Elrod John W
Published: December 2023

Background

We have recently shown that mitochondrial calcium (mCa2+) overload significantly contributes to the development of Alzheimer’s disease (AD). We found that either genetic inhibition of the neuronal mitochondrial calcium uniporter (MCU, the primary route for mCa2+ influx)1 or enhancement of mitochondrial Na+/Ca2+ exchanger (NCLX, the primary route for mCa2+ efflux)2 in the AD mouse model reduces AD‐associated phenotype and mitochondrial permeability transition pore (MPTP)‐induced cell death. However, blocking either the mCa2+ influx or enhancing mCa2+ efflux can also shut down the bioenergetics. Thus, it is vital to find a regulator of mCa2+ homeostasis that will positively impact Ca2+‐dependent physiological functions.

Methods

To define the new molecular regulatory mechanism to limit mCa2+ overload in AD that will maintain bioenergetics and prevent cell death, we have examined the role of Mitochondrial Calcium Uniporter Beta (MCUB), a paralog of MCU that acts as a negative regulator of mCa2+ uptake3. This study used AD patient samples, mice, and cell lines to examine MCUB expression. A neuroblastoma cell line stably expressing the human Swedish mutant amyloid precursor protein (N2a/APPswe) with adenovirus encoding MCUB was examined for mitochondrial alterations in: Ca2+ handling, ROS generation, permeability transition pore activation, oxidative phosphorylation (OxPHOS) and cell death.

Results

5xFAD mice and human AD brain samples displayed significant reductions in the expression of MCUB. Studies performed in N2a/APPswe neurons discovered that mCa2 handling, redox, and bioenergetics was severely impaired in AD cells. Rescue of MCUB via adenoviral expression enhanced the clearance of pathogenic mCa2+, enhanced OxPHOS, and prevented ROS and cell death.

Conclusions

Our data suggest that MCUB modulation has the therapeutic potential to preserve bioenergetics and limit cell death in AD. This project will further utilize neuronal‐specific knockouts and overexpression of MCUB to increase or decrease mCa2+ uptake, respectively, in 5xFAD mouse models and will explore whether and how MCUB‐mediated changes in uptake are able to preserve metabolism, mCa2+ dynamics, and AD‐phenotype in vivo.
Prevalence of Depressive Symptoms in the Whole Spectrum of Cognitive Aging: Findings from the HELIAD Community Study
Authors: Georgiou Eliza (Eleni‐ Zacharoula) , Politis Antonis , Yannakoulia Mary , Dardiotis Efthimios , Hadjigeorgiou Georgios M. , Kosmidis Mary , Sakka Paraskevi , Economou Polychronis , Scarmeas Nikolaos , Alexopoulos Panagiotis
Published: December 2023

Background

Depressive symptoms embody a risk factor for developing age‐related cognitive impairment, while they belong to the most common non‐cognitive symptoms of dementia. The conundrum of the prevalence of depressive symptoms in older adults in the Mediterranean region, but also worldwide is vividly reflected in reported prevalence rates ranging from 7.7% in a study from Malaysia and Australia to 81.1% in India. The present study aimed to shed light on the prevalence of mild, moderate and severe depressive symptoms in the entire spectrum of cognitive aging based on a cohort of randomly selected older adults from municipal rosters of two locations in Attica and central Greece.

Methods

Based on a thorough neurological and neuropsychological assessment, the diagnoses of mild cognitive impairment, Alzheimer’s dementia (AD) or dementia caused by other diseases (non‐AD) were established in participants of the Hellenic Epidemiological Longitudinal Investigation of Aging and Diet (HELIAD). The presence of depressive symptoms was tapped with the 15‐item Geriatric Depression Scale (GDS). Scores between 0‐4 point to the absence of depression, while scores between 5‐8, 9‐11, 12‐15 are compatible with mild, moderate and severe depressive symptoms, respectively. Statistical analyses were based on Pearson’s Chi‐squared test and pairwise proportions tests.

Results

The prevalence of depressive symptoms in the total sample (n = 1937 participants; mean age 73,84 SD: 5,427, females: 1148) was 19.5% (mild 13.1%, moderate 3.8%, severe 2.5%). The prevalence of depressive symptoms in older adults without cognitive impairment was 18%, in patients with MCI 27%, in AD 25% and in non‐AD 23.5%. The differences in the distribution of depressive symptoms of different severity across the four groups reached statistical significance (chi‐squared = 28.957, df = 9, p‐value<0.001). The prevalence of moderate to severe depressive symptoms reached its maximum in AD (11.3%) and its lowest in people without cognitive impairment (5.4%).

Conclusions

Almost one out of five older adults suffered from depressive symptoms, with the prevalence and severity increasing significantly in cases of cognitively impaired individuals. These observations highlight the urgent need for raising awareness regarding the presence of depressive symptoms in older adults and improving primary, secondary and tertiary preventive strategies.
Evidence of distinct subjective cognitive decline profiles in a community sample
Authors: Jacova Claudia , Splonskowski Moriah , Smith Samantha , Gehling Jacklyn , Dhaliwal Ravneet
Published: December 2023

Background

Subjective Cognitive Decline (SCD) refers to a self‐perceived decline in cognitive ability despite normal performance on objective tests. SCD has been conceptualized as a marker of preclinical Alzheimer’s disease (AD) but research has uncovered considerable heterogeneity in symptoms and outcomes. Therefore, it is likely that SCD encompasses distinct subtypes, similarly to Mild Cognitive Impairment (MCI). Here we sought to identify and characterize subgroups based on patterns of subjective cognitive symptoms.

Methods

Community‐dwelling participants aged ≥50 years (n = 483), located within the United States, were recruited via a crowdsourcing website, and completed a survey consisting of the following: SCD Questionnaire‐MyCog, PROMIS depression scale, and demographic questions. The SCD‐Q includes 24 items assessing self‐perceived recent decline on memory, language, and executive functioning tasks with a yes or no format. Two‐step cluster analysis using AIC was performed on all SCD‐Q items.

Results

The analysis yielded a 3‐cluster solution with fair cohesion and separation (silhouette measure = 0.46). Cluster 1 (No Subjective Decline) included 36% of participants reporting no decline except for sporadic endorsement (≤2%) on a few memory tasks. Cluster 2 (Mild Subjective Decline) consisted of 42% of participants who frequently (≤50%) endorsed decline on select memory and language tasks, and less frequently on executive functioning tasks (≤25%). Cluster 3 (Moderate Subjective Decline) included 22% of participants who almost unanimously (≥80%) reported decline on a wide range of memory and language tasks, and frequently (≥60%) on executive functioning tasks. Clusters differed on total SCD‐Q scores (1<2<3, M = 0.1, 3.5, 13.7), percent below the SCD cutoff of 7/24 (1 and 2<3, 0%, 8.4%, 100%), depression score (1<2<3, M = 10.9, 13.0, 16.7), gender (percent women 1<2 and 3, 58.7%, 71.0%, 704%) and AD family history (percent with history 1<2 and 3, 20%, 29%, 34.9%) but not on age.

Conclusion

We identified three distinct subgroups in our community sample, defined by escalating subjective symptom burden, growing involvement of language and executive functioning domains and increasing prevalence of AD risk factors (female gender/AD family history). All Moderate‐Subjective‐Decline subgroup members but none/very few of the others, scored above the published SCD cut‐off. Longitudinal outcomes are needed to establish subgroup validity.
Interim Analysis Results of Buntanetap in Phase 3 Clinical Studies in Alzheimer’s and Parkinson’s Disease
Authors: Fang Cheng , Gaines Melissa , Damiano Eve , Nagy Anne‐Marie , Ng David , Maccecchini Maria L.
Published: December 2023

Background

Overexpression of neurotoxic proteins drives downstream events that dysregulate axonal transport, lead to inflammation, nerve cell death, and loss of function. By inhibiting the translation of neurotoxic aggregating proteins ‐ amyloid precursor protein, tau, alpha‐synuclein etc., buntanetap restores axonal transport, lowers inflammation, and protects nerve cells from dying. In phase 2a studies, buntanetap showed efficacy in two double‐blind, placebo controlled clinical studies in both AD and PD patients. These encouraging data support our further development of buntanetap into phase 3 as a potential treatment for both AD and PD.

Method

We started two double‐blind, placebo‐controlled phase 3 studies to further test buntanetap’s efficacy and safety in PD and AD patients.

Result

For the PD study, patients are dosed with either 10mg, 20mg buntanetap or placebo QD. A total of 450 early PD patients are being recruited for a 6‐month treatment. Primary endpoint is MDS‐UPDRS 2 and 3. We will present the study design and the data from the interim analysis, when 30% of the patients have been treated for 2 months.

For the AD study, patients are dosed with three doses of buntanetap (placebo, 7.5, 15 and 30 mg QD). A total of 320 mild to moderate AD patients are being recruited for a 3‐month treatment. Primary endpoints are ADAS‐Cog11 and ADCS‐CGIC. We will present the study design and the data from the interim analysis, when 30% of the patients have been treated for 6 weeks.

Conclusion

Our phase2 data support that buntanetap is safe, well‐tolerated, and efficacious in both AD and PD population. The interim analysis will ensure we have the right sample size to test buntanetap’s efficacy in treating AD and PD.