bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparative study of Amyloid positive and negative individuals with “Alzheimer Syndrome”
Authors: Lahiri Durjoy , Roncero Carlos Tyler , Lima Bruna Seixas , Verhoeff Nicolaas Paul L.G. , Freedman Morris , Al‐Shamaa Sarmad , Chertkow Howard
Published: December 2023

Background

Outside academic centres, the diagnosis of probable Alzheimer’s Disease remains a clinical diagnosis supported by basic blood work and structural brain imaging. It has already been documented, approximately 1/3rd of individuals meeting clinical criteria for probable AD, do not show underlying amyloidopathy on PET or cerebrospinal fluid. Thus, the clinical “Alzheimer Syndrome” encompasses individuals with abnormal amyloid (Amyloid positive: A+), as well as “amyloid negative” individuals lacking amyloidopathy. Finding ways to distinguish these subgroups clinically will become increasingly important as anti‐amyloid therapies become more available. It is not yet clear if these two groups have any clinical or imaging features that might distinguish them. Our objective was to find out if there are any clinical or imaging pointers towards amyloid biomarker status.

Methods

A retrospective chart review of 23 patients screened for anti‐amyloid clinical trials was performed, of whom 13 were (A+) and 10 were (A‐). The following information was collected from the chart review‐ demography, medical history, clinical presentation, course of disease and rate of progression, neuropsychological test scores, blood work, brain scans, and any other relevant investigations. Relevant data were subjected to appropriate statistical analysis.

Results

This is an ongoing study and the results are derived from interim analysis. Comparison of the (A+) and (A‐) groups revealed no statistically significant difference in terms of age, sex, amnestic presentation and cognitive decline rate. We did not find evidence (in this small group) that (A‐) subjects had a greater vascular load ‐ no difference in Hachinski score or Fazekas score. The only statistically significant difference between the groups was found in their NPI scores, with the A+ group showing a higher score (2.92 versus 0.80, p = 0.008).

Conclusion

Amyloid positive individuals are more likely to have neuropsychiatric manifestations during the course of their cognitive decline than their Amyloid negative counterpart. Work is ongoing to delineate biological and biomarker differences that account for the cortical dementia (Alzheimer Syndrome) in Amyloid negative subjects. Delineating differences in clinical presentation may prove useful in specifying which of these individuals are actually Amyloid positive. Confirmation in a larger group of subjects will be necessary.
Mitochondria in Memory Retrieval in Wild‐Type Mice and in the Impairment of Memory Retrieval in Amyloid Precursor Protein Transgenic Mice
Authors: Beglopoulos Vassilios
Published: December 2023

Background

Treatment of Alzheimer’s disease (AD) would benefit from earlier diagnosis and a better understanding of the biochemical and cellular events underlying memory loss. This study, which follows our previous work identifying early deficits in long‐term memory retrieval and memory‐associated glucose uptake in amyloid precursor protein transgenic (APPtg) mice, aims to a) test our hypothesis of stimulus‐dependent synaptic mitochondrial activity as a mechanism underlying memory retrieval, and b) investigate any mitochondrial abnormalities possibly associated with the impairment of memory retrieval in APPtg mice (and possibly in presymptomatic AD).

Method

The J20 APPtg mouse line has been used. Two genotypes (APPtg and wild‐type) and two behavioral groups have been analysed, a) a group subject to criterion‐based watermaze training, sacrificed 20 sec following a probe trial seven days after learning the task (the memory retrieval group), and b) a group with no behavioral training (the basal levels group). Synaptosome forebrain samples (enriched in synapses) from 16 mice (four mice from each of the genotype/behavioral combinations) have been subjected to proteomics, Western blot and electron microscopy analyses. Oxygen consumption and enzymatic activity assay analyses are ongoing.

Result

Our previous behavioral result of significantly impaired 7‐day memory retrieval has been reproduced. Our proteomics analysis has suggested higher synaptic levels of mitochondrial proteins during memory retrieval, compared to basal levels in wild‐type mice, a phenotype also present but less evident in APPtg mice. Western analysis has indicated lower synaptic levels of proteins involved in mitochondrial fusion and fission during memory retrieval, compared to basal levels. No difference was identified by electron microscopy in a) numbers of synaptic mitochondria or b) synaptic mitochondrial area. Our oxygen consumption and enzymatic activity assay results are planned to be collected on time for this presentation.

Conclusion

Our data provide evidence supporting our hypothesis of mitochondrial involvement a) in memory retrieval and b) in the impairment of memory retrieval in APPtg mice and possibly in early AD. They also provide some clues on the exact mitochondrial mechanisms, which is the focus of our current research.
Novel metabolic biomarkers for diagnosis of Alzheimer’s disease
Authors: Zhao Yingxin , Villasante‐Tezanos Alejandro , Miranda Ernesto , Pappolla Miguel A , Fang Xiang
Published: December 2023

Background

The need for biomarkers for the etiological identification of dementia syndromes can not be overemphasized. Blood metabolites are attractive targets for identifying biomarkers with predictive values for AD diagnosis and progression. This study aims to identify novel AD blood metabolic biomarkers and develop a high‐sensitivity and specificity blood‐based test for AD.

Method

In the discovery phase, the serum metabolome of AD patients (n = 10) and age, sex‐matched healthy controls (n = 10) were analyzed with a mass spectrometry (MS)‐based approach. Supervised machine learning was used to identify the biomarker candidates and develop a computational model for AD diagnosis. Finally, the computational model and biomarker candidates were verified with a second AD cohort in the verification phase, where the serum metabolome of AD patients (n = 27) and age, sex‐matched healthy controls (n = 30) were analyzed.

Result

In this discovery study, 7075 metabolic features were quantified. Among them, the abundance of 750 unique features significantly differed between AD and Controls (t‐test p‐value <0.05). Support vector machine (SVM) with radial basis function (RBF) kernel was used for features optimization and identified a panel of 14 metabolic features which predicted AD with 0.0% classification error rate (4‐fold cross‐validation). In the verification study, 10595 metabolic features were quantified. Among them, 908 unique features significantly differed between AD and Controls (t‐test with Permutation q‐value <0.05). Then, the computational model and biomarker panel identified in the discovery phase were tested with the verification dataset and confirmed that they could predict AD with high accuracy (0.0% classification error rate, 4‐fold cross‐validation).

Conclusion

This study comprehensively profiled the AD serum metabolome and identified a panel of metabolic biomarkers and a computational model for AD diagnosis, which will serve as a foundation for a high‐performance, blood‐based test for clinical AD screening and diagnosis.
Ethical social media use for dementia prevention research: Perspectives of research professionals and community members
Authors: Hrincu Viorica , Zaleski Grayden , Robillard Julie M.
Published: December 2023

Background

Ethical social media use underpins effective online engagement for dementia prevention research. Current social media guidelines are broad and lack empirical justification reflecting the values and priorities of the dementia community. By engaging professional and community experts, we seek to identify the ethical parameters of using social media for dementia prevention research.

Method

We conducted semi‐structured, qualitative interviews with professional experts working in dementia research (n = 15; e.g., researchers, coordinators) and experts by experience (n = 14; e.g., persons with lived experience). Experts were from Canada, the USA, the UK, and South America. Discussions were analyzed using thematic qualitative analysis methods.

Result

Professional experts revealed a dearth of ethical guidelines when using social media for research engagement, relying on informal sources of guidance to supplement ethics board approval. Areas identified as needing more attention included privacy concerns, handling instances of misinformation and self‐disclosure, the constraints of prescribed language, and moderating public reactions to posts.

Experts by experience appreciated the educational benefits of social media for learning about healthy aging. They valued accessible resources but expressed uncertainty on distinguishing between facts and misinformation. Factors enhancing trust of social media content included transparent presentation, traceable sources, relationship‐building, and partnering with community organizations. Having a family history of dementia was a key motivator for engaging on social media. The negative consequences of diminished online privacy, such as stigma or being targeted for predatory practices, were a major ethical concern.

Both groups discussed factors that dampen social media’s theoretical reach to diverse publics, such as existing inequalities permeating digital access (i.e., age, socioeconomic, literacy, English fluency, urban/rural) and past violations undermining trust. Nevertheless, participants cited social media’s wide reach as a societal benefit to improve research participation and awareness of dementia prevention. They acknowledged that younger aging populations have more digital fluency and may benefit more from social media research engagement.

Conclusion

Research professionals and community members identified ethical and contextual factors surrounding the use of social media for dementia prevention, and a need for more guidance. The next project phase will use these data to inform the creation of consensus‐based guidelines for brain health research.
Biomarker ratios: does it matter if the biomarker is designated as the numerator or the denominator?
Authors: Ma Yue , Yang Kao Lee , Bendlin Barbara B
Published: December 2023

Background

Ratios of two variables are commonly used in research, such as biomarker ratios, body mass index (BMI), and waist‐to‐hip ratio. Although there are conventions about which variable serves as the numerator and which serves as the denominator in a ratio, these conventions are not always followed. Furthermore, new biomarkers may not have established conventions, leading to difficulties in comparing findings from studies that calculate ratios reciprocally. Taking the logarithm of a ratio equals to the difference between the logarithms of the numerator versus the denominator, transforming it into a linear function of the two terms, and thus may provide a linkage between analyses that employ reciprocal ratios.

Method

For linear and logistic regressions, we mathematically derived the relations in parameter estimates and test statistics between models with log transformed reciprocal ratios in the predictor and/or outcome. Two real data examples (n = 305; National Alzheimer’s Coordinating Center) were analyzed, including linear regressions of CSF P‐tau/Aβ1‐42 ratio on BMI, and logistic regressions of cognitive impairment on P‐tau/Aβ1‐42.

Result

Under log transformation, taking the reciprocal of the predictor flips the sign of the regression coefficient and the test statistic for the predictor only. Whereas, taking the reciprocal of the outcome flips the sign of the coefficient and the test for all variables, including the intercept, the predictor, and all other covariates. In both situations, the magnitudes of coefficients and tests, standard errors, and p‐values all remain the same. For logistic regressions, when the sign of a coefficient is flipped, the corresponding odds ratio becomes reciprocal. In any case, the estimated relationship between the predictor and the outcome is essentially unchanged.

Conclusion

A model including log transformed ratio variables can be easily converted to the model with reciprocal ratios by flipping the signs of regression coefficients, allowing the comparison of findings from studies using reciprocal ratios. However, reciprocal and log transformations introduce difficulties in result interpretation. More meaningful interpretations could be achieved by converting ratio variables back to their original untransformed scales, plotting predicted outcome values against the predictor, and reporting predicted values at clinical cutoffs or key statistical points capturing the data distribution.
Safe, Social, and Engaged: Clinician perspectives on good institution‐free days for people with dementia
Authors: Auriemma Catherine L , Silvestri Jasmine , Butt Maayra , McMillan Julia , Turner Dania , Klaiman Tamar , Harkins Kristin , Karlawish Jason , Halpern Scott D
Published: December 2023

Background

Composite measures of survival and residence, such as institution‐free days (IFDs), encompass many patient and family priorities and are readily measured using payer claims or electronic health record data. However, knowledge gaps limit their application to studies of people with dementia (PWD). First, PWD, family care partners, and clinician perspectives on survival‐residence composite outcomes are unknown. Second, approaches to measuring IFDs consider all institution days equally poor and all home days equally well, which may be inconsistent with stakeholder assessments.

Method

We conducted a qualitative study to explore stakeholders’ perspectives on what makes a “good day” for a PWD. This included semi‐structured interviews with clinicians who provide care to PWD. Clinicians were also asked for their opinions regarding the use of survival‐residence composite outcomes in dementia research. Interviews were audio‐recorded and professionally transcribed. De‐identified transcripts were reviewed by the research team independently and during weekly consensus meetings to identify relevant themes.

Result

Thematic saturation was reached after 24 interviews. Nearly half of clinicians also had personal experience as a care partner of a PWD. Participant characteristics are summarized in Table 1. Salient themes were identified and grouped into 2 major categories: (1) attributes of quality of days for PWD, and (2) impressions of survival‐residence composite outcomes (Table 2). Key attributes of quality of days were safety, socialization and engagement, and neuropsychiatric distress. These qualities were more important in defining “home” than type of residence (Figure). Clinicians appreciated that a survival‐residence composite outcome, such as IFDs, could capture the important aspects of “aging in place” and avoiding burdensome hospitalizations. They also noted a desire for such a measure to capture the quality of those days. Concerns were raised over how differential access to home‐based services due to socioeconomic factors would influence patient accrual of IFDs and whether such a measure might also increase existing stigma around institutions.

Conclusion

Future work will integrate these findings with the perspectives of PWD and their family care partners as well as further explore the relative values of these attributes of a survival‐residence composite outcome for studies of patients with ADRD.
Association between physical function and neuroimaging measures in a 2‐year multidomain lifestyle randomized controlled trial
Authors: Stephen Ruth , Kulmala Jenni , Antikainen Riitta , Kemppainen Nina , Lehtisalo Jenni , Mangialasche Francesca , Ngandu Tiia , Rinne Juha O. , Soininen Hilkka , Strandberg Timo , Kivipelto Miia , Solomon Alina , Hall Anette
Published: December 2023

Background

This exploratory study investigated associations between physical function and neuroimaging biomarkers: brain magnetic resonance imaging (MRI) and Pittsburgh compound B‐positron emission tomography (PiB‐PET) measures during the 2‐year Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER).

Method

FINGER targeted 60–77‐year‐old general population at‐risk and without dementia or substantial cognitive impairment. Measures of physical function (activities of daily living (ADL), hand grip strength, physical performance, Fried’s frailty phenotype index and self‐rated health) from baseline and 2‐year visits were used. Baseline neuroimaging measures, MRI (hippocampus, total gray matter volumes, Alzheimer’s disease (AD) signature cortical thickness) were available for 115‐132 participants and PiB‐PET (composite score) for 44‐48 participants. Linear and logistic regressions were used to test the cross‐sectional associations and the impact of baseline imaging measures on changes in physical function. Models were adjusted for site, sex and education.

Result

Cross‐sectionally, higher ADL were associated with higher hippocampus volume (β = 0.18 p = 0.048), total gray matter volume (β = 0.15 p = 0.005) and AD signature cortical thickness (β = 0.25 p = 0.006) while stronger hand grip and was associated with higher total gray matter volume (β = 0.20 p = 0.041) significantly. Baseline imaging measures were associated with changes in physical function: higher baseline hippocampus volume was associated with maintenance/improvement in the ADL (OR = 0.56 p = 0.039) while lower hippocampus at baseline predicted poorer physical performance over time (OR = 1.66 p = 0.036).

Conclusion

Higher brain integrity is associated with better physical function while lower baseline brain integrity predicts poorer physical function over time.
Transcriptomic profiling of prefrontal cortex reveals shared mechanisms underlying Alzheimer’s and Parkinson’s Diseases
Authors: Bendl Jaroslav , Hoffman Gabriel E , Lee Donghoon , M Prashant N , Bennett David A. A , Davis David A. , Scott William K. , Berretta Sabina , Haroutunian Vahram , Fullard John F , Roussos Panos
Published: December 2023

Background

Alzheimer’s disease (AD) and Parkinson’s disease (PD) have overlapping characteristics in terms of symptoms and brain pathology. Understanding the similarities in these diseases could lead to more effective treatments. While there is only limited evidence for genetic overlap between the two, enrichment of heritability in genetic regions that are related to microglia has been found in both diseases. However, most of the transcriptomics studies published on AD and PD employed postmortem brains, which obscures the identification of alteration of gene expression within individual cell types.

Method

Here we used single‐nucleus transcriptomics to examine over eight million nuclei generated from prefrontal cortex samples of over a thousand postmortem donors with AD, PD, both diseases and controls. Then, we built gene regulatory networks (GRNs) to detect the shared gene expression alterations in all major cell types and detected key drivers within each module.

Result

Examining multiple levels of transcriptomic organization, such as gene expression and GRNs for both protein‐coding and noncoding genes, provided a comprehensive understanding of the molecular pathology of AD and PD. Our analysis revealed cell‐specific modules linked to shared and distinct mechanisms of both diseases. Network‐derived signatures showed cell‐type specificity, implicating regulatory regions within AD and PD genetic risk loci that participate in a variety of biological pathways as well as changes in TF regulation.

Conclusion

The integration of transcriptomic and genetic data from AD and PD provides a quantitative, genome‐wide resource for mechanistic insight and potential therapeutic development.

Funding: U01NS125580, R01AG067025, AARF‐21‐722200
The genetic architecture of Lewy body dementia
Authors: Scholz Sonja W
Published: December 2023

Background

Lewy body dementia (LBD) is a clinically heterogeneous neurodegenerative disease with a poorly defined genetic architecture.

Method

To study the genetic risk factors associated with LBD, we performed genome‐sequencing in 2,591 European‐ancestry cases and 4,027 controls and undertook comprehensive genomic evaluations.

Result

We discovered disease‐associated common and rare variants, defined pathways, and examined genotype‐pathology associations. Further, we leveraged our data to demonstrate that the genetic architecture of LBD partially intersects with Parkinson’s disease, frontotemporal dementia, and Alzheimer’s disease.

Conclusion

We present an update on the current understanding of the genetic risk factors in LBD. The genome data from this initiative have been made publicly available to the research community to accelerate the pace of discovery in LBD research. Increasing the cohort size and in‐depth phenotype collection is needed to define the missing heritability of this complex neurodegenerative disease.

References:

Chia R. et al., Nature Genetics (2021)

Kaivola K. et al., Brain (2022)

Reho P. et al., Movement Disorders (2022)
Neuropsychological change in Mild Cognitive Impairment using estimated standardized regression‐based formulas
Authors: Guevara Jasmin E , Kurniadi Natalie , Duff Kevin
Published: December 2023

Background

Neuropsychological change in Mild Cognitive Impairment (MCI) can be tracked with repeated assessments to determine if an individual remains stable or progresses to dementia. However, few studies have quantified these cognitive changes over time, especially using standardized regression‐based (SRB) change formulae.

Method

Participants included 283 MCI patients from a cognitive disorders clinic who were assessed twice with a comprehensive neuropsychological battery across approximately one‐ and one‐half years. SRB z‐scores were calculated for each of 17 test scores this battery for each participant. Change on these 17 z‐scores were examined for the entire sample, as well as between two subgroups: those who remained MCI on follow‐up (i.e., MCI‐Stable) and those who progressed to dementia (i.e., MCI‐Decline).

Result

For the entire MCI sample, significant declines were observed on all 17 z‐scores (p<0.001), with the largest declines occurring on memory tests. When the two subgroups were compared, significant differences were observed between these two groups across nearly all cognitive domains, with the largest differences being on tests of attention and processing speed. For these group differences, those in the MCI‐Decline group showed the most decline compared to the MCI‐Stable participants. However, notable cognitive decline was also observed in the MCI‐Stable group.

Conclusion

This study highlights the degree of cognitive decline that occurs in MCI across time, even among those who remain “stable” on follow‐up. It also highlights the value of the SRB method in more accurately capturing and quantifying cognitive decline, which may help identify individuals most vulnerable to MCI progression.
Hyper‐sensitive interferon response in a mouse model of Alzheimer’s disease‐Down syndrome
Authors: Mumford Paige , Farrell Clíona , Banks Gareth , Salih Dervis , Tybulewicz Victor , Fisher Elizabeth , Wiseman Frances K
Published: December 2023

Background

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and leads to an elevated risk of early‐onset Alzheimer’s disease. People with DS have a perturbed immune system including an over‐activated interferon response, which is likely due to four genes encoding interferon receptors being located on Hsa21 (1). How this affects inflammation in the brain is not well understood. In this study, we investigate if an extra copy of these genes is sufficient to elevate the interferon response in the brain of mouse models of DS, using in vivo and ex vivo approaches.

Methods

The Dp1Tyb (MGI:5703798) mouse has three‐copies of ∼148 Hsa21 orthologous genes, while the Dp2Tyb (MGI:5703800) mouse has a sub‐region of ∼32 of those Hsa21 orthologous genes in three‐copies, including the four interferon receptor genes. Organotypic brain slice cultures (OBSCs) were prepared from P7‐P9 pups and treated with interferon‐β (24 hours). Slices were collected for western blotting, qPCR, or immunohistochemistry, and media for CXCL10 ELISA.

Dp2Tyb mice were crossed with AppNL‐G‐F (MGI:5637817) mice to generate four genotypes, to determine if the amyloid‐β interferon response is elevated by the additional copy of the Dp2Tyb region. Mice were tested in the light‐dark box and marble burying test to assay the effect on anxiety. Amyloid accumulation and interferon response in the brain will be determined by immunofluorescence, MSD amyloid‐β assay and qPCR.

Results

Both Dp1Tyb and Dp2Tyb OBSCs had a hypersensitive response to interferon‐β treatment, with higher expression of interferon‐stimulated genes in lysed slices and higher levels of CXCL10 protein secreted into the media.

Conclusion

Both DS preclinical models displayed a hypersensitive interferon response, indicating that interferon hypersensitivity may occur in the brain of individuals with DS and is likely due to having three‐copies of the interferon receptor genes encoded on Hsa21. Amyloid pathology has been shown to induce an interferon response (2,3). How interferon hypersensitivity in individuals with Down syndrome affects the neuroinflammatory response to amyloid pathology is unknown. To investigate this, we have crossed the Dp2Tyb model with the AppNL‐G‐F mouse model of amyloid pathology.

References:

1. https://doi.org/10.7554/eLife.16220

2. https://doi.org/10.1172/JCI133737

3. https://doi.org/10.3389/fncel.2022.949340
Apathy, depression and risk of incident dementia in community‐dwelling older adults
Authors: Harrison Fleur , Mortby Moyra E , Guastella Adam J , Trollor Julian N , Kochan Nicole A. , Sachdev Perminder S. , Brodaty Henry
Published: December 2023

Background

Apathy, which may be a risk or prognostic factor for incident dementia in older adults, has been little investigated in cognitively normal populations and has largely lacked consideration of comorbid depression. Understanding the potential role of apathy in the development of dementia has also been limited by short follow‐up periods, and cohorts with restricted age ranges (below 80 years). Our aim was to investigate whether self‐report apathy predicted incident dementia over 14 years, when adjusting for comorbid depression in a population‐based sample of older adults (aged 70‐90) without dementia at baseline.

Method

The Sydney Memory and Ageing Study included 1,037 community‐dwelling participants at baseline (median age 78 years (range 70‐90); 55% female). Assessments included the self‐report Geriatric Depression Scale, from which apathy (GDS‐3A) and depression (GDS‐12D) subscores were obtained. Incident dementia was diagnosed by expert panel clinical consensus at biennial assessments for up to 14 years. Cox survival analyses examined risk conferred by apathy and depression for incident dementia separately, and then included both in the same model as concurrent predictors. Analyses were initially unadjusted. The fully adjusted model controlled for baseline age, sex, education, non‐English speaking background, global cognition (MMSE), APOE4 status and health conditions.

Result

Of the 858 participants with follow‐up data, 271 developed dementia (31.6%), over an average 9 years follow‐up. Self‐report apathy and depression separately predicted higher risk for dementia in the unadjusted models (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.05, 2.00; HR 1.47, 95% CI 1.06, 2.04, respectively). When including both apathy and depression concurrently in the model, apathy remained a significant risk factor, but depression did not. In the fully adjusted model, apathy no longer significantly predicted incident dementia. Post‐hoc analyses using split‐half groups by age showed the effect was attenuated only for younger participants (below 78 years).

Conclusion

Apathy was associated with increased risk of incident dementia, independently of depression, over 14 years in a community‐dwelling population‐based cohort of older adults. This novel evidence of long‐term risk addresses prior limitations in the literature and implicates apathy as a prognostic marker for dementia, particularly with increasing age.
A Collaborative Care Coordination Model: Reaching older adults living alone with cognitive impairment.
Authors: Manning Carol A , Reilly Shannon , Fields Samantha , Boyd Elizabeth
Published: December 2023

Background

The number of persons aged 65+ with Alzheimer’s Disease who live alone in Virginia was estimated at 42,000 in 2018. This population commonly has need for therapeutic, social, and other services, however, therapists and social and other service providers commonly lack knowledge of how to reach this population. We sought to identify people with dementia who live alone in Virginia, and to provide services that would be beneficial for psychological health.

Method

We conducted multifaceted outreach and delivered two programs for people with dementia living alone, (1) individualized care coordination provided by a Dementia Care Manager that focuses on behavioral symptom management training and education, (n = 51) and (2) the Effective Strategies Program (ESP) which includes education and support in memory, practical strategies, exercise, diet, home, and safety (n = 11). We assessed outcomes on depression using the Center for Epidemiologic Studies Depression Scale‐Revised and on behavioral symptoms using the Revised Memory and Behavior Problem Checklist & Neuropsychiatric Inventory‐Questionnaire in the Care Coordination participants.

Result

At 12‐month follow‐up in the Care Coordination Program, depression significantly decreased and behavioral symptoms were significantly lower. Almost all (94%) of the participants reported overall the program in which they participated was beneficial.

Conclusion

Despite numerous challenges with reaching this population, gaining trust, and maintaining contact, it is possible to reach and provide beneficial services for people with dementia who live alone. Successes partnering with pre‐existing resources and recommendations for sustainability are highlighted.
Providers’ perceptions of the role played by living alone in providing services to diverse patients with cognitive impairment in the US
Authors: Portacolone Elena
Published: December 2023

Background

The potential moderating role of living alone in either facilitating or hampering access to services to older adults with cognitive impairment is largely unknown. Given the estimated 4.3 million older adults from diverse racial/ethnic backgrounds who are living alone with cognitive impairment in the United States, it is critical to understand directly from providers of healthcare and social services whether living alone creates barriers to supportive services for racially/ethnically diverse patients with cognitive impairment. The objective of this study was to identify the potential moderating role of living alone in the use of healthcare and social services for patients with cognitive impairment by eliciting providers’ perceptions of caring for diverse patients with cognitive impairment living alone, in comparison to counterparts living with others.

Method

This qualitative study used semi‐structured interviews conducted between March 2021 and June 2022 with purposively sampled providers of services to diverse patients with cognitive impairment in Michigan, California, and Texas. An inductive content analysis was used to analyze the data.

Result

The majority of the 76 interviewed providers belonged to communities of color and cared for racially/ethnically diverse patients with cognitive impairment. Providers included physicians, nurses, social workers, home care aides, for a total of 20 professions. Providers elucidated specific factors that made serving people living alone with cognitive impairment (PLACI) more challenging, as well as specific factors that increased their concerns when serving PLACI, including a crisis‐dominated healthcare system. Providers also elucidated reasons for systematic unmet needs of PLACI for essential healthcare and social services, such as policies limiting access to home‐care aides.

Conclusion

The vast majority of providers underscored the critical, yet understudied, role of living alone in moderating access to essential healthcare and social services among patients with cognitive impairment. Findings suggest that living arrangement are a social determinant to health among patients with cognitive impairment because patients with cognitive impairment who live alone are more likely to experience gaps in services because they are more challenging to serve than counterparts living with others and the healthcare system is not designed to address these challenges.
Testing a Faith‐based Model to Increase Alzheimer’s Disease Knowledge, Detection and Management in a Rural, Racially/Ethnically Diverse Farmworker Community
Authors: Wiese Lisa Ann Kirk , Lingler Jennifer H , Williams Ishan Canty , Schoenberg Nancy E , Williams Christine Lynn , Holt Janet , Galvin James E
Published: December 2023

Background

Rural and racially/ethnically diverse residents face multiple disparities that may increase Alzheimer’s disease and related disorder (ADRD) risk, including less formal education, less access to health care information, delayed disease detection, and challenges with management (Liu et al., 2022). Health‐promoting behaviors may reduce ADRD risk in the presence of these and other factors, e.g., environmental exposures (Peritogiannis et al., 2022; Livingston et al., 2020). We hypothesized that providing ADRD‐related education would increase disease knowledge, cognitive screening behaviors, dementia detection, and diagnosis rates in multiculturally diverse field workers in the Lake Okeechobee region of South Florida.

Method

Schoenberg’s (2009) Faith Moves Mountains framework guided this CBPR descriptive, quasi‐experimental study of 241 primarily African American and Afro‐Caribbeans ≥ age 50. Local church congregants were engaged as health educators and research assistants in recruiting, enrolling, surveying, and screening participants. The Basic Knowledge of Alzheimer’s Disease survey (Wiese et al., 2020) and brief Montreal Cognitive Assessment (MiniMoca) (Nasreddine, 2019) were administered at baseline and one year later. Persons scoring below the MiniMoca score cutoff of 12 were referred to providers for further assessment and potential diagnosis/treatment.

Result

Positive screen rates were 45.6% at Time 1 and 51.2% at Time 2. Lower pretest BKAD scores [β = ‐0.14, t = ‐3.02, p = .002] and lower years of education [β = ‐0.07, t = ‐1.81, p = .04] were associated with higher referrals. Longer duration of rural residence [β = 0.02, t = 3.09, p = .001], and ethnicity predicted referrals: African American [β = 0.62, t = 3.48, p<.001] or Afro Caribbean [β = 1.04, t = 1.81, p = .04]. Self‐report by participants on follow‐up by the health educators revealed new ADRD diagnoses primarily among African American (47.2%), Afro‐Caribbean (36.1%), White (13.9%) rural residents; Hispanics comprised 2.8%. Rates of new treatments by ethnicity were similar (Table 1).

Conclusion

Extending Schoenberg’s successful “Faith Moves Mountains” approach beyond the Appalachian setting and chronic illnesses of cancer (2009), smoking cessation (2016), and diabetes (2017) was effective for increasing ADRD knowledge, detection, and management in a unique non‐White rural community. A larger, randomized controlled trial is needed to test if ADRD education among varied faith‐based settings increases health‐seeking behaviors among rural residents experiencing health inequities due to social and medical determinants of health.
Rural childhood residence, college education, and late‐life brain health
Authors: Peterson Rachel , George Kristen M , Maillard Pauline , Gilsanz Paola , Soh Yenee , Lor Yi , Corrada María M. M. , Decarli Charles , Barnes Lisa L. , Whitmer Rachel A.
Published: December 2023

Background

Rural communities tend to have higher prevalence of dementia risk factors including cardiovascular diseases and low education. Childhood rural residence has also been associated with worse late life cognition.1 It is unknown if these associations extend to neuroimaging markers of late life brain health.

Method

KHANDLE and STAR are harmonized cohorts of racially/ethnically diverse long‐term Kaiser Permanente Northern California members. Regional brain volumes and white matter integrity were measured among a 25% random sample using 3T MRI. Stabilized inverse probability weights were estimated to account for imaging selection based on study, race/ethnicity, baseline age, sex/gender, and geographic region of birth. Rural residence was self‐reported using birth address or imputed from addresses at age 5 (n = 8) or age 10 (n = 1) when missing. MRI measures, except free water fraction and fractional anisotropy, were normalized on intracranial volume. All MRI measures were z standardized. Weighted general linear models tested associations between childhood rurality and MRI measures among those ages 65+. Exploratory models stratified analyses by college degree attainment.

Result

Compared to the overall cohort, the imaging sample was slightly younger, had slightly higher educational attainment and was comprised of more males. Imaging participants with a rural childhood were about 1 year older (mean = 76, SD 6.0) and had about ½ year less education (mean = 14.5, SD = 2.4) than the imaging sample overall (Table 1). In weighted linear models (Table 2), childhood rurality was associated with smaller occipital cortex volumes (β = ‐0.25 95% CI = ‐0.50, ‐0.004). In models stratified by education, we observed a non‐significant trend of worse brain health among participants who were college‐educated with rural childhoods (vs. college educated without rural childhoods), that was not present among those without a college degree (Table 3).

Conclusion

We observed limited effect of childhood rurality on MRI markers of brain health. Although under‐powered, our analyses suggest that among college educated older adults rural childhoods (vs. non‐rural) may have a negative impact on brain health.

Reference:

1. Peterson, et. al., (In press: 2023). Rural residence across the lifecourse and late‐life cognitive decline in KHANDLE: A causal inference study. Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring. https://doi.org/10.1002/dad2.12399
APOE4 Carrier Status Modifies Alzheimer’s Disease Plasma Biomarker Concentrations in Healthy Adults Over 85 Years Old
Authors: Cooper Jennifer G , Ghodsi Mohammad , Stukas Sophie K , Leach Stephen , Brooks‐Wilson Angela , Wellington Cheryl L
Published: December 2023

Background

Many blood‐based biomarkers have been thoroughly investigated in the context of Alzheimer’s disease (AD) and other dementias. However, few studies have examined these biomarkers in healthy seniors in the absence of dementia or other age associated morbidities. Investigating biomarkers in a healthy geriatric population allows for the identification of novel biological associations that might otherwise be masked by presence of disease. This study will investigate the effect of APOE genotype on plasma biomarkers of AD to determine whether carrying the APOE4 allele, which increases risk of AD, modifies biomarker concentrations in healthy seniors. Plasma biomarkers analyzed include: amyloid beta 42/40 (Aβ42/40), phosphorylated tau‐181 (p‐tau‐181), neurofilament light (NF‐L), and glial fibrillary acidic protein (GFAP).

Methods

370 plasma specimens from the Super Seniors study, which enrolled participants ≥85 years old who have never been diagnosed dementia, cancer, diabetes, cardiovascular or major pulmonary disease; were used. Biomarkers were analysed on the Quanterix Simoa HD‐X analyzer using commercial Neurology 4‐plex E and p‐tau‐181 assays. Group comparisons were performed using a Mann‐Whitney test for continuous variables and a Fisher’s exact test for categorical variables. The association between APOE genotype and biomarker concentration was analyzed using multivariable linear regression.

Results

80 (22%) participants were APOE4 carriers (E3E4 N = 71, E4E4 N = 3, E2E4 N = 6) and 290 (73%) were non‐carriers (E2E2 N = 3, E2E3 N = 58, E3E3 N = 229). No significant differences were found between APOE4 carriers and non‐carriers in age (p = 0.3215), sex (p>0.9999), or mini mental state exam scores (p = 0.1327). In APOE4 carriers, Aβ42/40 is lower (0.0596 vs 0.0618 pg/ml, p = 0.0462), and p‐tau‐181 (3.24 vs 2.78 pg/ml, p = 0.0069) and GFAP (196 vs 172 pg/ml, p = 0.0474) are higher than in non‐APOE4 carriers. NF‐L had no significant difference between carrier status (p = 0.1188). After adjusting for age and sex, p‐tau‐181 remains significantly associated with APOE4 carrier status (β = 0.066, p = 0.0112), while Aβ42/40 and GFAP no longer have significant associations.

Conclusions

p‐tau‐181 concentration is associated with APOE4 genotype in healthy seniors, making it an important variable to account for in future analysis.
Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease
Authors: Serrano‐Pozo Alberto , Li Zhaozhi , Woodbury Maya E. , Muñoz‐Castro Clara , Wachter Astrid , Jayakumar Rojashree , Bryant Annie G , Noori Ayush , Welikovitch Lindsay A. , Hu Miwei , Lin Gen , Pastika Timothy , Tamm Joseph A. , Abdourahman Aicha , Kwon Taekyung , Bennett Rachel E , Talanian Robert V. , Biber Knut , Karran Eric H , Hyman Bradley T. , Das Sudeshna
Published: December 2023

Background

Alzheimer’s disease (AD) is defined by widespread accumulation of Ab plaques and phospho‐tau neurofibrillary tangles throughout the brain, with the latter following a stereotypical hierarchical spatiotemporal pattern along neural networks. These AD neuropathological changes are accompanied by a dramatic loss of synapses and neurons as well as prominent morphological and functional changes of astrocytes, collectively termed reactive astrogliosis. Astrocytes also play a critical role in maintaining brain homeostasis. However, their changes along the spatiotemporal progression of AD neuropathology remain largely unknown. To investigate these astrocyte changes, we performed single‐nucleus RNA‐sequencing on 5 brain regions along the stereotypical progression of AD neuropathology from 32 donors representing the entire normal aging‐severe AD spectrum.

Method

Nuclei were isolated from five brain areas of n = 32 donors with increasing AD neuropathology (total n = 160 samples). The five brain areas were chosen based on their hierarchical accumulation of tau pathology: entorhinal cortex (EC)> inferior temporal gyrus (BA20) > dorsolateral prefrontal cortex (BA46) > secondary visual cortex (V2 or BA18/19) > primary visual cortex (V1 or BA17). To enrich in astrocytic nuclei, NEUN+ and OLIG2+ nuclei were separated via FACS, whereas NEUN‐/OLIG2‐ nuclei (including astrocytes) were subjected to snRNA‐seq resulting in a transcriptomic dataset of 629,755 astrocyte nuclei, which were subsequently examined for common and region‐specific AD related changes.

Result

We discovered temporal gene‐expression‐trajectories with gene sets differentially activated at various disease stages. Surprisingly, a gene set enriched in proteostasis (genes encoding heat shock proteins) and energy metabolism (e.g., ATP synthases) was upregulated at late‐stage but unexpectedly returned to baseline levels at end‐stage, suggesting exhaustion of response in “burnt‐out” astrocytes. The spatial gene‐expression‐trajectories revealed that genes related to tripartite synapses (e.g., GLUL, GRIA2, NRXN1, SLC1A2) are dysregulated in parallel to the stereotypical progression of tangle pathology across regions. In addition, we identified substantial astrocyte heterogeneity across brain regions with a continuum from homeostatic to reactive cells through “intermediate” transitional states.

Conclusion

Our astrocyte snRNA‐seq dataset encompassing five regions of control and AD brains revealed distinct spatial and temporal gene trajectories, suggesting complex astrocytic dysfunction with AD progression.
ADNI4’s novel remote screening approach ‐ weighing priorities in participant selection
Authors: Miller Melanie Jayne , Weiner Michael S. W. , Nosheny Rachel L , Albala Bruce , Mindt Monica Rivera , Okonkwo Ozioma , Aisen Paul S. S , Petersen Ron , Shaw Leslie M. , Beckett Laurel , Harvey Danielle J. , Fristed Emil
Published: December 2023

Background

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a longitudinal observational study of individuals across the dementia spectrum that validates biomarkers for clinical trials. The newest phase of the study, ADNI4, aims to substantially increase the inclusion of underrepresented populations to improve generalizability of ADNI results. Novel biomarkers, including a speech‐based cognitive assessment and blood‐based plasma biomarkers, are integrated into the study design as key participant screening measures.

Method

To help achieve recruitment goals, ADNI4 uses a new, multi‐phase approach to remotely enroll and screen participants. A large study cohort (aiming for 20,000+ participants) provide initial screening data via an online study platform including demographics, medical history related to study exclusionary criteria, and results from a speech‐based cognitive memory assessment (Novoic Ltd. Storyteller test) and a measure of subjective cognitive/functional decline (Everyday Cognition (ECog) 12‐item). Based on screening results, a subset of online study participants is referred to a Quest Diagnostics location to provide a blood sample for plasma biomarker analysis (aiming for 4,000+ participants). Finally, select participants are referred to ADNI clinical sites for in‐depth characterization (goal of up to 1,500 in‐clinic participants).

Result

We report ADNI’s initial approach for selecting participants from the online screening cohort to undergo plasma biomarker phenotyping, and subsequent selection to a clinical site. Participants from diverse demographic backgrounds (especially for race, ethnicity, and/or education) and those with a higher estimated likelihood of cognitive impairment are given priority in the referral selection process. Likelihood of cognitive impairment is assessed using results from subjective memory complaint questions, responses to the ECog 12‐item questionnaire, and the Novoic Storyteller results. Individuals with results showing high concordance across these measures are prioritized, as well as those who have subsequent plasma results indicating biomarker positivity.

Conclusion

Weighing the various study requirements and inclusivity goals increases the complexity of participant selection decision making, and is a time‐intensive process. As the ADNI study progresses we aim to automate the participant selection/referral process by developing algorithms that account and encode for changing study prioritizations and dynamics across numerous dimensions. Learnings from ADNI4’s new remote processes will help inform future clinical trial design.