bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebrovascular accumulation of amyloid‐forming amylin secreted from the pancreas induces brain hypoxia
Authors: Verma Nirmal , Ly Han , Despa Florin
Published: December 2022

Background

Islet amyloid polypeptide (amylin) is a β‐cell hormone co‐secreted with insulin. Histological analyses of human brains identified amylin deposits co‐localized with parenchymal and vascular β‐amyloid in humans with vascular cognitive impairment and Alzheimer’s dementia. Because circulating amyloid‐forming amylin triggers systemic hypoxia signaling, we sought to determine the relationship between circulating amylin levels and brain hypoxia markers in a transgenic rat model of amylin‐mediated neurological deficits.

Method

To assess amylin‐related brain hypoxia signaling, we performed a 16‐month longitudinal study in which rats that express amyloid‐forming human amylin in pancreatic β‐cells (HIP rats) were compared to wild type (WT) littermates that express non‐amyloidogenic rodent amylin (n=10 rats/group).

Result

Blood amylin levels measured by ELISA were ∼2‐fold higher in 16‐month old HIP rats compared to WT littermates (P<0.01). The Thiovlavin T (Th T) fluorescence signal intensity in blood lysates from HIP rats increased compared to that in WT littermates indicating the presence of amyloid‐forming in the circulation in HIP rats (P<0.01). This was associated with higher amylin concentration in brain microvessel lysates (P<0.05) and amylin immunoreactivity signal intensity in brain sections. Plasma erythropoietin, a marker of systemic hypoxia was higher in HIP rats than in WT littermates (P<0.05), which correlated with brain accumulation of HIF‐2α (P<0.05) and HIF‐1α (P=0.07), and with altered mitochondrial DNA in brain tissue (P<0.05).

Conclusion

Increased circulating levels of amyloid‐forming amylin promotes cerebrovascular amylin deposition leading to brain hypoxic‐ischemic injury. Future studies need to address functional effects of amylin‐induced brain hypoxia signaling in the brain.
Social isolation and cognitive function in middle aged and older adults in the Wisconsin Alzheimer’s Disease Research Center: Implications for the pandemic
Authors: Fischer Barbara L. , Van Hulle Carol A. , Umucu Emre , Wyman Mary F. , Chin Nathaniel A. , Johnson Sterling C. , Asthana Sanjay , Gleason Carey E. , Zuelsdorff Megan
Published: December 2022

Background

Social isolation and loneliness contribute to cognitive decline, and social isolation represents a key modifiable risk factor for dementia. Substantial interruptions in social engagement due to the COVID‐19 pandemic have heightened awareness of this issue, but common later‐life events may also reduce social connectedness. The neurocognitive impacts of such disruptions are unclear. Using the validated NIH Emotion Toolbox, we examined perceived social support and changes in perceived support as predictors of cognitive function in a sample of middle aged and older adults.

Method

672 participants from the Wisconsin Alzheimer’s Disease Research Center (ADRC) completed cognitive tests and Emotion Toolbox questionnaires at 2+ visits between 2017 and 2021 (mean interim = 1.7 years). Predictors comprised t‐scores on three perceived social support scales: Emotional Support, Instrumental Support, and Loneliness. Cross‐sectional analyses examined associations between social support and cognitive outcomes including memory (RAVLT Immediate and Delayed Recall) and processing speed/executive function (Trails A&B times). Using median t scores from the first and last available visit to categorize social support as high or low (for Loneliness, low loneliness was categorized as “high” social support), support over time was classified as stable‐high, stable‐low, or “change” (high‐low or low‐high). Mixed‐effects regression models examined the demographic‐adjusted predictor‐outcome relationships between social support and cognition across visits.

Result

In this ADRC sample (mean age 65.2, SD = 9.2; Table 1), all three social support scores associated cross‐sectionally (Table 2) with Trails A and B performance. Relative to stable‐high participants, those reporting either stable‐low or declines from high to low social support exhibited poorer performance on measures of processing speed/executive function. Conversely, participants in the low‐high group performed comparably on cognitive tests to those in the stable‐high group (Table 3; Figure 1).

Conclusion

Social support associated with processing speed/executive function in this sample. Participants who reported a change in social support performed comparably to those with either stable high or stable low support, suggesting that processing speed/executive function associated with social support may be modifiable in the shorter term. These findings underscore the cognitive cost of social isolation and highlight the substantial benefits of maintaining ‐ and improving ‐ social connections among middle aged and older adults.
Single amino acid change in the receptor binding domain of mouse APOE results in altered protein dynamics and worsened AD‐related cognitive impairment
Authors: Kaczorowski Catherine C. , Singh Surjeet , Kaur Harpreet , Hadad Niran , Telpoukhovskaia Maria , Zhang Jigang , Philip Vivek M. , O'Connell Kristen MS , Levine Zachary , Dunn Amy R
Published: December 2022

Background

APOE genotype is the strongest genetic modifier of late‐onset Alzheimer’s disease (AD) in humans. In genetically diverse mice, natural variation in the Apoe locus predicts AD‐related cognitive decline, with C57BL/6J (B6) mice harboring a protective variant compared to DBA/2J (D2) (Neuner 2019, Neuron). The mechanisms by which protective and detrimental Apoe/APOE variants affect cognitive decline in AD are not fully understood yet, but likely could provide an opportunity for personalized treatment and prevention strategies.

Method

Here, we have used CRISPR/Cas9 gene editing to introduce the D2 Apoe variant into the B6 genome. We crossed these heterozygous APOEB6/E163D mice to B6 congenic heterozygous 5XFAD carriers in order to explore the effects of this single variant on AD‐related cognitive function, pathology, cell‐type specific gene dysregulation, and hippocampal and cortical network function. We also performed molecular dynamics modeling to ask how this variant affects APOE protein biophysics.

Result

5XFAD‐APOEB6/E163D mice showed exacerbated cognitive dysfunction compared to 5XFAD‐APOEB6/B6 mice, indicating that the single D2 variant in Apoe significantly contributes to AD‐related cognitive decline. We did not observe differences in amyloid pathology or phosphorylated tau across Apoe genotypes, suggesting that the effect on cognitive function is not mediated by pathological protein aggregation. However, snRNAseq revealed that excitatory neuron gene expression was substantially dysregulated in 5XFAD‐APOEB6/E163D mice compared to other cell types; we then performed in vivo electrophysiology to characterize how this translates to circuit‐level neuronal dysfunction. Finally, computational modeling of protein structure and function showed that the APOEE163D variant results in protein states most closely resembling human APOE4, particularly in the presence of lipids, suggesting that APOEE163D may show impaired lipid binding and transport function.

Conclusion

C57BL/6J mice harbor a protective Apoe variant which confers resiliency to AD‐related cognitive dysfunction. This protection, and–by the same measure–the detrimental effects of the DBA/2J variant of Apoe (APOEE163D), is likely ultimately mediated by altered neuronal gene expression and activity. We are currently exploring the intermediate mechanisms between APOEE163D and neuronal function; altered APOE protein states hint at impairments in lipid binding and transport, which may result in pathological lipid and protein accumulation affecting neuron function.
Neighborhood greenspace as a social determinant of health and how associations with brain health outcomes may differ by race/ethnicity
Authors: Besser Lilah M. , Jimenez Marcia Pescador , Meyer Oanh L. , George Kristen M. , Adkins‐Jackson Paris AJ , Mitsova Diana , Galvin James E
Published: December 2022

Background

Residential greenspaces such a parks and other areas of natural vegetation are social determinants of health that have been associated with brain health outcomes including Alzheimer’s disease and related disorders (ADRD). Greenspace access is associated with reduced risk of ADRD‐related comorbidities and increased participation in risk‐reducing behaviors such as physical activity. Therefore, exposure to greenspace may present an ideal opportunity to encourage risk‐reducing behaviors while intervening on the impact of comorbidities on brain health. Although structural determinants of health such as residential segregation and the built environment may influence these outcomes, racial/ethnic minoritized groups are less likely to live in neighborhoods where physical activity is feasible. Additionally, such groups have elevated risk for comorbidities that may increase risk for ADRD. Yet few known studies have investigated greenspace and brain health by racial/ethnic group.

Method

We will include papers previously identified in a published rapid scoping review on greenspace and brain health outcomes (Besser, 2020; n = 22), and will employ the same review methods from that paper to identify additional papers published since February 13, 2020. For each article, we will catalog the racial/ethnic composition of the sample, observed differences between racial/ethnic groups, methods employed, other related findings, as well as guiding theories, conceptual frameworks, and causal mechanisms.

Result

We will: 1) examine the extent to which the current literature investigates racial/ethnic differences in greenspace and brain health associations; 2) cover the potential mechanisms relating greenspace to brain health and how these mechanisms may differentially impact individuals based on race/ethnicity; and 3) discuss the methodological issues surrounding the study of racial/ethnic disparities in greenspace‐brain health associations. Lastly, we will describe greenspace characteristics for select existing datasets and cohorts by race/ethnicity to provide context for future investigations using these and similar resources.

Conclusion

The goal of this review is to provide a foundation for understanding and a starting point for studies of racial/ethnic differences in greenspace‐brain health associations.
Is childhood or midlife socioeconomic status more predictive of brain health across race/ethnicity?
Authors: Turney Indira C , Avila Justina F , Lao Patrick J. , Igwe Kay C , Rivera Andres M. , Berroa Joncarlos , Brickman Adam M. , Manly Jennifer J
Published: December 2022

Background

Lower lifecourse socioeconomic status (SES) is associated with worse cognition and greater risk for Alzheimer’s disease (AD). Parental level of educational attainment is one indicator of childhood SES, which predicts myriad health outcomes throughout the lifespan. It is unclear whether midlife SES moderates the impact of childhood SES on midlife outcomes, like brain health. Subgroup differences are important for future risk reduction efforts; therefore, we tested whether midlife SES modifies the influence of childhood SES similarly in White, Black, and Latinx middle‐aged adults.

Method

Participants were 569 middle‐aged older adults drawn from the Offspring study of Racial/Ethnic Disparities in AD (adult children of WHICAP participants), who received MRI (mean age = 54.5 (SD = 10.6) years; 46 non‐Latinx White, 131 non‐Latinx Black, 392 Latinx; 66% women). We used general linear models to examine the relationship of childhood SES (e.g., parental education) with MRI markers of cerebrovascular disease (e.g., white matter hyperintensity volume; WMH) and whether MSES (e.g., educational attainment) moderated this relationship, controlling for sex/gender and age.

Result

White participants were more likely to have higher childhood SES (F(2,568) = 199.3, p<.001) and MSES (F(2,568) = 36.1, p<.001), followed by Black, then Latinx participants. In the full sample, childhood SES was not associated with WMH volume. Race/ethnicity stratified models revealed that greater childhood SES was associated with lower WMH volume, but only in White participants (B = ‐0.60, CI = ‐0.109,‐0.010). Midlife SES was not associated with WMH volume in the full sample or within each race/ethnicity group. Among White participants, midlife SES did not modify the effect of childhood SES on WMH volume. Midlife SES was unrelated to WMH volume in Black and Latinx participants.

Conclusion

We found that childhood SES predicts brain health in middle aged White people. We found racial and ethnic subgroup differences in the relationship of socioeconomic indicators to brain health. However, future studies aim to further understand mechanisms of brain health disparities by considering other SES indicators than parental and offspring education, larger subgroup sample sizes, absolute versus relative SES mobility, other lived experiences, and cognitive outcomes.
Metabolomics Technologies for Defining Diet Influences on Brain Metabolome and in Alzheimer’s Disease
Authors: Dorrestein Pieter
Published: December 2022

Background

Diet and our gut microbiota influence brain function. This is also true in Alzheimer’s disease. Technologies are emerging to inventory the complexity of the gut microbiome produced chemicals and also the complexity of chemicals released in the body from types of food we ingest. Many of these chemicals can cross blood brain barrier and can impact brain function.

Method

In this presentation, we will describe new technologies that enable us to understand the true diversity and complexities of the small molecules that can be detected using an MS/MS‐based untargeted metabolomics platform. Strategies, such as MASST, FoodMASST, and reference data‐driven metabolomics that enable an empirical readout of diet effects on metabolic profiles of AD patients will be discussed (Figure 1a).

Result

These new computational strategies provide a direct roadmap to relate diet, and diet ingredients, to clinical phenotypes such as empirical readout of variability of diet composition (Figure 1b), and how machine learning strategies, such as regression analysis, are employed to understand how the diet readouts relate to microbiome composition, cognition, and memory function from analysis of Alzheimer’s cohorts (Figure 1c). We will describe the influences of diet on brain metabolome in AD patients and links to imaging changes.

Conclusion

We have developed a new metabolomics approach that can provide an empirical, and even retrospective, diet readout form clinical samples of AD patients. We illustrate how diet components relate to clinical symptoms in AD.
Deficiency of NMDA receptor subunit GluN3A as a pathogenic factor for endogenous amyloid deposition and sporadic Alzheimer’s disease
Authors: Yu Shan P , Zhong Weiwei , Berglund Ken , Gu Xiaohuan , Jiang Michael Q , Wei Ling
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative disease, evolving amyloidosis and tau protein hyperphosphorylation, synapse dysfunction, neuron degeneration and cognitive deficits. Investigations based on the Aβ/tau hypothesis have been performed in transgenic animal models expression familial/mutated AD genes. However, treatments based on this hypothesis have not provided effective clinical therapies. Hyperactivity of the glutamatergic NMDA receptor (NMDAR) is a common pathophysiology of AD and has been viewed as a consequence of Aβ pathology. Among NMDAR subunits, GluN3A is a unique inhibitory subunit that suppresses NMDA currents and Ca2+ influx. Recent evidence from rodent and human studies shows that GluN3A is widely expressed and plays important functional roles in neonatal and adult brains. Ca2+ overload is a trigger of excitotoxicity, while GluN3A plays a regulatory role of Ca2+ homeostasis. The role of GluN3A regulation in AD is unknown.

Method

GluN3A knockout mice, gene modifications, immunohistochemistry, Western blotting, MEA recordings, Ca2+ imaging, pathological examinations, functional and behavioral tests.

Result

Chronic neuronal hyperactivity and Ca2+ dysregulation caused by GluN3A deficiency lead to slowly advanced “neurodegenerative excitotoxicity”, dementia and AD pathology in an age‐dependent manner. Ca2+ imaging and MultiElectrode Array recordings in GluN3A KO brain slices revealed moderate but sustained elevation of cytosolic Ca2+ levels, neuronal hyperactivity, and impaired synaptic plasticity compared to age matched controls. Aging GluN3A KO mice showed increased Ca2+‐dependent signals, chronic inflammation, neuronal loss and disease symptoms including early onset of olfactory dysfunction followed by cognitive deficits. β‐Amyloid deposition and tau protein hyperphosphorylation were identified as a late pathology in the cortex and hippocampus. Expression of GluN3A in the GluN3A KO brain prevented AD progression. Early treatment at the pre‐clinical stage using the NMDAR antagonist memantine prevented symptoms in GluN3A KO mice. Western blot analysis of AD patient’s brains showed lower levels of GluN3A in the cortex compared to normal aging subjects.

Conclusion

Our results identified a novel amyloid‐independent mechanism that the deficiency of GluN3A alone causes a slight lifelong Ca2+ dyshomeostasis, leading to AD pathophysiology and amyloid pathology. The long‐term GluN3A modulation of NMDARs signifies new therapeutic targets and possible preventive interventions for a sporadic type of AD.
Reduction and Prevention of Agitation in Patients with Neurocognitive Disorders: An International Psychogeriatric Association Consensus Algorithm
Authors: Cummings Jeffrey ,   IPA agitation algorithm work group
Published: December 2022

Background

The International Psychogeriatric Association (IPA) extends its commitment to serving those with psychiatric and behavioral manifestation in the presence of cognitive impairment and dementia with this introduction of an agitation reduction and prevention algorithm that builds on the definition of agitation developed by IPA.

Method

This presentation describes a review of literature, treatment guidelines, to recommend an algorithm for care and a reiterative integration of expert opinion within the context of an IPA Agitation Work group, a panel of international experts on agitation. The outcome is an integration of available information into a comprehensive algorithm.

Result

The IPA Agitation Work Group recommends the Investigate, Plan, and Assess (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and implementation with an emphasis on shared decision‐making; the success of the plan in assessed and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Nonpharmacologic interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal agitation, mild‐moderate agitation or agitation with prominent mood features, moderate‐severe agitation, and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a different venues is considered (home, nursing home, emergency depa

The IPA definition of agitation is operationalized into an agitation management algorithm emphasizing the integration of non‐pharmacologic and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision‐making. rtment, hospice), with adjustments to the therapeutic approach.

Conclusion

The IPA definition of agitation is operationalized into an agitation management algorithm emphasizing the integration of non‐pharmacologic and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision‐making.
Raindrop animation: Visualizing change in longitudinal biomarker data
Authors: Saef Benjamin A. , Henson Rachel L. , Volluz Katherine , Yarasheski Kevin E. , West Tim , Kirmess Kris , Meyer Matthew R. , Gordon Brian A. , Benzinger Tammie L.S. , Morris John C. , Fagan Anne M. , Schindler Suzanne E.
Published: December 2022

Background

The Knight ADRC has collected fluid biomarker data from some participants over more than >15 years, affording a unique opportunity to explore trends in the progression of Alzheimer disease biomarkers. Evaluation of intra‐individual change provides a uniquely powerful approach to understanding the development of Alzheimer disease pathophysiology, notably non‐linear changes in biomarkers. To facilitate understanding of longitudinal analyses, an approach was developed to visualize longitudinal change in biomarkers.

Method

Samples from ADRC participants enrolled in studies of memory and aging were analyzed for CSF Aβ40, Aβ42, total tau, and phospho‐tau181 using the fully automated LUMIPULSE assay platform (Fujirebio). Plasma Aβ40 and Aβ42 were measured via a high‐precision immunoprecipitation‐mass spectrometry assay (C2N Diagnostics). Brain amyloid burden was measured within two years of fluid collection via amyloid PET. Biomarker values between measurements were estimated by linear regression. A Shiny application was written in R to visualize estimated longitudinal biomarker values on a granular time scale.

Result

The R Shiny and ggplot2 packages were used to create interactive animated plots of biomarker changes over time. This application utilizes CSF, plasma, and amyloid PET data to display within‐participant longitudinal change of the selected biomarkers as a function of other baseline biomarker measurements. The estimated biomarker value at a timepoint after the baseline is shown as a larger point, and the estimated values from the previous year are shown as smaller points, giving the visual appearance of one raindrop for each individual. The interface allows for users to select the biomarkers represented on each axis, color coding by longitudinal or baseline biomarker values, and biomarker cut‐offs. The user can animate the customized graph to show changes over >15 years of accumulated longitudinal data.

Conclusion

Our web‐based application allows for visualization of biomarker changes over time. This tool allows for comparison of CSF, plasma, and imaging markers in an interactive format, facilitating the creation of novel hypotheses by observation of longitudinal trends.
Insomnia symptoms and markers of preclinical Alzheimer’s disease in the community
Authors: Nicolazzo Jessica , Cavuoto Marina G. , Gibson Madeline , Rowsthorn Ella , Buckley Rachel F. , Yassi Nawaf , Yiallourou Stephanie , Brodtmann Amy , Hamilton Garun S , Naughton Matthew T , Lim Yen Ying , Pase Matthew P
Published: December 2022

Background

Amyloid production increases during wakefulness before being cleared during sleep. Insomnia is one of the commonest sleep disorders, yet its relationship to core markers of preclinical Alzheimer’s disease remains unknown. We investigated the cross‐sectional relationship between insomnia symptom severity, APOE e4 carriage, and cerebrospinal spinal fluid (CSF) concentrations of Alzheimer’s disease biomarkers in a non‐demented community‐sample aged 43‐67 years.

Method

66 participants from the Healthy Brain Project Biomarker Sub‐study (age = 58±6 years; MMSE = 29±7; 68% women) completed a lumbar puncture, two weeks of actigraphy to measure sleep and wake patterns, and the Insomnia Severity Index (ISI) to measure insomnia symptom severity over the past two weeks. The ISI was split into two groups (normal vs. high [>7]) based on established cut‐off values (42% of the sample were high). Two core insomnia features were captured: Difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (high wake after sleep onset (WASO) duration and number of awakenings), with each variable classified as the top 25th percentile versus the remainder of the sample. Analysis of covariance was used to compare CSF amyloid‐beta 42 (Aβ42), phosphorylated tau 181 (p‐tau181), total‐tau, and neurofilament light chain protein (NfL) across each of the sleep groups, adjusting for age and sex.

Result

Persons with high insomnia symptom severity had higher CSF Aβ42 levels (p=0.033, d=0.58). Difficulty maintaining sleep (both high WASO and number of awakenings) was also associated with higher Aβ42 levels (p=0.023, d=0.77 for WASO; p=0.013, d=0.92 for awakenings), whereas difficulty initiating sleep was not (p= 0.776, d=0.08). The sleep variables were not associated with p‐tau181, total‐tau, or NfL levels (p>0.05). APOE e4 modified the association between WASO and Aβ42. The strength of the relationship between higher WASO (versus normal) and Aβ42 was stronger in e4 carriers, compared to non‐carriers (F(df) = 6.94 (1, 44), p=0.012).

Conclusion

In this relatively young sample, symptoms and features of insomnia were associated with higher CSF Aβ42 levels. These findings may reflect increased amyloid production due to acute sleep disruption. Longitudinal studies are needed to determine whether sustained sleep disruption associates with amyloid accumulation over time.
Rates of cortical thinning in Alzheimer’s disease signature regions: pathological influences and cognitive consequences in members of the 1946 British birth cohort
Authors: Keuss Sarah E , Cash David M , Nicholas Jennifer M , Parker Thomas D , Lane Christopher A , Keshavan Ashvini , Buchanan Sarah M , Wagen Aaron Z , Storey Mathew , Harris Matthew J , Lu Kirsty , James Sarah‐Naomi , Street Rebecca E , Barnes Jo , Malone Ian B , Sudre Carole H , Thomas David L , Dickson John , Murray‐Smith Heidi , Freiberger Tamar , Wong Andrew , Crutch Sebastian J , Richards Marcus , Fox Nick C , Schott Jonathan M , Coath William
Published: December 2022

Background

Consistent patterns of reduced cortical thickness (so‐called signature regions) have been identified in early Alzheimer’s disease (AD), including in the pre‐dementia stages, but studies investigating the pathological underpinnings and cognitive consequences of longitudinal changes in these regions have been limited.

Method

337 cognitively normal participants (mean [SD] age 70.5 [0.6] years) underwent 18F‐florbetapir amyloid‐ß PET, volumetric MRI, and cognitive assessment as part of Insight 46, a sub‐study of the 1946 British birth cohort (Table 1 for characteristics). Baseline and follow‐up T1‐weighted MRI (mean [SD] interval 2.4 [0.2] years) were processed using Freesurfer’s longitudinal stream (v.7.1.0) and cortical thickness was derived in two AD signatures (Table 2 footnote for details). Linear regression was used to test whether rates of change in AD signature cortical thickness were influenced by baseline amyloid‐ß deposition (positive/negative status or continuous SUVR) or white matter hyperintensity volume (WMHV; a marker of presumed cerebrovascular disease), and whether they were related to longitudinal cognitive change as measured using the Preclinical Alzheimer Cognitive Composite (PACC). Covariates included sex, age at baseline scan, childhood cognition, educational attainment, and socioeconomic position. Interaction terms were added to test whether associations with longitudinal cognitive change differed by baseline amyloid‐ß status.

Result

Higher baseline WMHV was associated with faster rates of cortical thinning in AD signature regions, but baseline amyloid‐ß status and SUVR were not (Table 2; Figure 1). There were differential effects of rates of change in AD signature cortical thickness by baseline amyloid‐ß status, whereby greater rates of AD signature cortical thinning predicted faster rates of PACC decline in amyloid‐ß positive participants only (Table 3; Figure 2).

Conclusion

Cortical thinning in AD signature regions may arise via non‐amyloid‐ß pathways in cognitively normal elderly. However, the presence of amyloid‐ß may make individuals more susceptible to the effects of faster rates of cortical thinning in these regions (or vice versa) since these factors interact to influence rates of cognitive decline. These findings provide insight into processes that might underlie progression to dementia in later life and have implications for the utility of AD signature cortical thickness as a biomarker in the preclinical phase of AD.
Single and chronic administration of cellulose ethers rescue memory deficit in a transgenic mouse model of Alzheimer’s disease
Authors: Ali Tahir , Klein Antonia N. , Vu Alex , Doh‐ura Katsumi , Gilch Sabine
Published: December 2022

Background

Alzheimer’s disease (AD) is an incurable neurodegenerative disease and the major cause of dementia. Recent studies including our findings showed that cellulose ethers (CEs) derivative (TC‐5RW) treatment as a single subcutaneous (SC) dose (4g/kg) have therapeutic effects in neurodegenerative diseases via inhibiting the aggregation of misfolded proteins such as prions and amyloid beta (Aβ). CEs are approved by the FDA as safe, inactive ingredients in foods and pharmaceuticals. Therefore, in this study we aimed to test whether single and repeated treatment with the CE TC‐5RW improves cognitive functions in an animal model of AD.

Methods

We used the 5xFAD mouse model, which harbours five familial AD mutations. The 5xFAD mice co‐overexpress human amyloid precursor protein and presenilin‐1, resulting in overproduction of Aβ and memory deficit. At the age of 6 weeks, one group of 5xFAD mice was treated with a single dose of TC‐5RW (4g/kg/SC) while another group of mice was treated weekly with TC‐5RW (4g/kg/SC) until 7 months of age. Two other groups of mice, wild type (WT) of same background and non‐treated 5xFAD mice were included as controls in our experiment. After completion of TC‐5RW treatment, behavioral studies (novel object recognition (NOR), Y‐maze and contextual fear conditioning (CFC) tests) were performed.

Results

In the NOR and Y‐maze tests, we observed a reduced percentage of recognition index and spontaneous alteration behavior in 5xFAD mice compared to WT mice. The TC‐5RW treatment at single and chronic dosage significantly increased the percentage of recognition index and spontaneous alteration behavior in 5xFAD mice compared to non‐treated 5xFAD mice. Similarly, the CFC test results showed a lower percentage of time freezing in 5xFAD mice compared to WT mice. Interestingly, TC‐5RW at both dosage regimen significantly improved the percentage of time freezing in 5xFAD mice compared to non‐treated 5xFAD mice.

Conclusion

In summary, single and chronic administration of TC‐5RW induce beneficial effects via improving learning and memory functions of 5xFAD mice. These results demonstrate that CE based compounds might be valuable and emerging therapeutics for the prevention and treatment of AD.
Circulating plasminogen activator inhibitor‐1 (PAI‐1) levels in the preclinical stage of Alzheimer’s disease
Authors: Eruysal Emily , Iadecola Costantino , Ishii Makoto
Published: December 2022

Background

Plasminogen activator inhibitor‐1 (PAI‐1), a secreted glycoprotein and member of the serine protease inhibitor family, has been implicated to have a role in Alzheimer’s disease (AD) pathogenesis by regulating amyloid‐beta (Aβ) accumulation (Neurobiol Aging 32:1079,2011; J Alzheimers Dis. 64:447,2018). A recent study found that plasma PAI‐1 was differentially expressed in subjects with Aβ pathology and neurodegeneration (A+TN+) compared to A‐TN‐ subjects, with decreased plasma PAI‐1 levels in clinical AD compared to cognitively normal controls (Alzheimers Dement 17:1452,2021). However, whether circulating PAI‐1 levels are altered during the preclinical stage of AD, where there is Aβ and tau pathology but no significant cognitive impairment, remains unclear.

Method

Cognitively normal (Clinical Dementia Rating of 0) volunteers from the Healthy Aging & Senile Dementia and Adult Children Study (Missouri, USA) with body mass index < 30, fasting plasma and cerebrospinal fluid (CSF) samples were included in this cross‐sectional study. Preclinical AD was defined by previously established CSF criteria (preclinical AD: 29 men, 26 women; control: 35 men, 65 women). Plasma PAI‐1 levels were measured by a commercially available immunoassay (MilliporeSigma) and log transformed.

Result

In men, plasma PAI‐1 levels were significantly lower in preclinical AD compared to control subjects (p=0.029) and were associated with CSF Aβ42 and p‐tau181 levels (CSF Aβ42: age‐adjusted beta coefficient 0.38, p=0.007; CSF p‐tau181: age‐adjusted beta coefficient ‐0.32, p=0.026) but not CSF tau levels (p>0.05). In women, there was no significant difference in plasma PAI‐1 levels between preclinical AD and control subjects (p>0.05).

Conclusion

These studies raise the possibility that, in men, alterations in peripheral PAI‐1 occur during the earliest stages of AD. Studies in larger cohorts will be needed to confirm these observations and to determine their clinical utility and the underlying mechanisms of any sex differences.
Human microRNA‐298 plays a vital role in maintaining APP and tau homeostasis and IL‐induced inflammation: Implication in Alzheimer’s disease.
Authors: Wang Ruizhi , Maloney Bryan , Long Justin M , Sambamurti Kumar , Counts Scott E. , Lahiri Debomoy K
Published: December 2022

Background

Alzheimer’s disease (AD) is marked by neurofibrillary tangles mainly composed of hyperphosphorylated microtubule‐associated protein tau; senile plaques comprising amyloid β (Aβ) peptides; and neuroinflammation. How these pathological changes are regulated remains unclear. Genetic, epigenetic, and environmental factors play important roles in disease progression. MicroRNA (miRNA), a group of small non‐coding RNAs, regulates multiple biological and pathological processes by binding to target mRNAs and altering translation levels. Disrupting this process could contribute to AD pathogenesis. We hypothesize that miR‐298 plays a vital role in maintaining APP and tau homeostasis and IL‐induced inflammation, particularly gliosis.

Method

We performed miR‐298 treatments and blockade by antisense‐miR298 (antagomiRs) in 3’UTR‐reporter clone‐transfected cultures and protein levels from target native mRNAs (Chopra et al‐Mol. Psychiatry‐2021). We transfected human astrocyte cells with miR‐298 mimics or antagomiRs. We analyzed culture media and lysates for protein and mRNA. We performed ELISA and real‐time‐qPCR assays to determine cytokines, APP and tau levels. We analyzed autopsy brain tissues from non‐cognitively impaired (NCI) and AD subjects by measuring levels of miR‐298, target mRNAs and proteins in cortical samples, as we described (Wang et al‐Mol. Psychiatry‐2022).

Result

We identified putative sites for miR‐298 in mRNAs encoding APP, BACE1, MAPT, IL1α, and IL6. Treatment by miR‐298 significantly increased production and secretion of multiple pro‐inflammatory cytokines, specifically IL‐1, IL‐6 and TNF‐α in human astrocyte cultures. Furthermore, treatment by miR‐298 reduced tau, APP and BACE1 protein and mRNA levels in astrocyte cultures. Levels of miR‐298 varied in postmortem human temporal lobe between AD patients and age‐matched NCI controls.

Conclusion

MiR‐298 induced a variety of pro‐inflammatory cytokines without administration of other challenges. Induction of multiple cytokines may be due to combinations of direct miRNA activity and regulation of upstream signaling pathways. MiR‐298 may play an important biological role in AD by reducing APP, BACE1 and tau expression while increasing the physiologic production of IL cytokines. This apparent paradox is resolved by noting that early‐stage (prodromal) gliosis may contribute to the clearance of toxic aggregates. We plan to test miR‐298 in AD animal models, including human tau‐overexpressing transgenic mice.

We appreciate NIH‐NIA grants: (R01AG051086, R21AG056007, R56AG072810, P01AG014449, P30AG072976).
Classification of amyloid positivity in PET imaging using end‐to‐end deep learning: a multi‐cohort, multi‐tracer analysis
Authors: Fan Shuyang , Ha Sung Min , Chakrabarty Satrajit , Lee John , Flores Shaney , LaMontagne Pamela , Gordon Brian A. , Raji Cyrus A. , Benzinger Tammie L.S. , Morris John C. , Ances Beau M , Marcus Daniel S. , Sotiras Aristeidis
Published: December 2022

Background

Positron emission tomography (PET) imaging with amyloid‐specific tracers is the gold standard for assessing amyloid positivity in vivo. However, visual interpretation of PET images is limited by availability of clinicians and interobserver variability. Classification of amyloid status typically requires calculation of standardized uptake value ratios (SUVRs), Correspondence with neuroanatomy from magnetic resonance imaging, and additional complex, computationally intensive preprocessing steps requiring specialized software. We developed a deep learning model that can automatically classify unprocessed PET images as amyloid positive or negative.

Method

Florbetapir (AV45), florbetaben (FBB), and Pittsburgh compound B (PiB) images from the Alzheimer’s Disease Neuroimaging Association (ADNI), AV45 and PiB images from the Open Access Series of Imaging Studies 3 (OASIS3), and FBB, flutametamol (FMT), and flutafuranol (NAV4694) images from the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) were used (Table 1). Each image was resized to isotropic 2 mm voxels, and voxel intensities between the 5th and 95th percentile were normalized to zero mean and unit variance. We trained and internally validated a convolutional neural network (CNN) on AV45 images from ADNI before testing it on images from an independent cohort and/or acquired with a different tracer.

Result

The model achieved an AUC of 0.98 [0.97, 1.0] on test AV45 images from ADNI and generalized well to AV45 images from OASIS3, achieving an AUC of 0.95 [0.92, 0.97] (Table 2). Critically, the model’s performance remained robust even when evaluating imaging from different tracers, including FBB, FMT, PiB, and NAV4694, scoring an AUC of at least 0.97 on each and demonstrating its ability to learn a tracer‐agnostic pattern of abnormality. Similar conclusions can be drawn from other performance metrics.

Conclusion

We developed a deep learning model that can classify amyloid PET scans with a high degree of accuracy. We demonstrated that the model generalizes well to unseen images acquired from an independent cohort, under a different protocol, and/or with tracers unseen during training. Our model may usefully provide concise metrics for amyloid research as well as support clinical assessment of amyloid‐specific PET when expertise or computational resources are limited.
How Researchers Can Build Research‐Strengthening Partnerships Through Centering the Lived Experiences of Self‐Identified Members of African American/Black Communities
Authors: Aggarwal Neelum T. , Glover Crystal M
Published: December 2022

Background

Persons who self‐identify as Black or African American comprise more than 14% of the population in the United States of America, with Black persons populating the entire globe. Notably, heterogeneity and within‐group diversity exist, especially due to geographic location, migration, and immigration. However, researchers continue to conduct studies that do not adequately represent this critical group of individuals with a higher risk of Alzheimer’s disease and related dementias (ADRD) coupled with salient experiences of negative structural and social determinants of health. ADRD research requires diverse participant perspectives to ensure that research findings – from educational materials to lifestyle interventions and pharmacologic discoveries are safe and relevant to all of us. This presentation will feature a panelist with both lived dementia experience and who identifies as African American/Black. The panelist will provide their perspectives and input to identify and address barriers, and amplify facilitators of ADRD research participation.

Method

Researchers at the Rush Alzheimer’s Disease Center will work with community partners to identify the panelist to share their perspectives regarding such topics as ADRD diagnosis, care, and research participation. The panelist will also share their input on how researchers can build better partnerships within African American/ Black communities and subsequent study participants and partners.

Result

This session will benefit researchers and the field of ADRD by offering the opportunity to hear and understand the lived experiences of a member of the African American/Black community, and discuss strategies to meaningfully engage with demographically diverse communities and their heterogenous members.

Conclusion

The voices of individuals identifying as African American/Black are essential to consider and incorporate throughout the research process ‐ from determining the research purpose and discussing research priorities to study conduct and finding dissemination ‐ and addressing challenges to facilitate demographically diverse participation in ADRD research.
Amyloid‐β plus cholesterol treatment impairs the ability of microglia to efflux excess cholesterol
Authors: Muñoz Oscar M. , Rhodes Christopher H. , Maezawa Izumi , Jin Lee‐Way , Lebrilla Carlito B. , Harvey Danielle J. , Zivkovic Angela M.
Published: December 2022

Background

Microglia, specialized phagocytic cells of the brain, play a critical role in the clearance of amyloid beta (Aβ), which is involved in the pathogenesis of Alzheimer’s disease. The ability of microglia to remove Aβ is influenced by their cellular cholesterol clearance capacity. It is not known to what extent Aβ impairs microglial cholesterol efflux capacity, especially in the context of excess cholesterol.

Method

HMC3 microglia were treated with Aβ‐oligomer (AβO, 2µM), cholesterol loading (20µg), or AβO + cholesterol in combination, and with or without cholesterol acceptor, high‐density lipoprotein (HDL), at 0.1 mg/mL. Pooled HDL from 18 individuals in a 2‐hour postprandial state and a 36‐hour fasted state were compared. The cellular content of unesterified and esterified cholesterol was measured.

Results

The addition of cholesterol, AβO, and cholesterol+AβO increased cellular cholesterol content, which was attenuated by the addition of HDL. Importantly, cells treated with cholesterol plus AβO had the highest overall cholesterol content (27.80+/‐2.85µM), and both fasted (20.67+/‐3.04µM, p≥0.05) and postprandial HDL (21.95+/‐3.84µM, p<0.05) were not able to reduce the cellular cholesterol content as well as in the untreated (fasted: 16.17+/‐2.28µM, p<0.05; postprandial: 18.55+/‐2.01µM, p>0.05), cholesterol only (fasted: 17.72+/‐2.17µM, p<0.05; postprandial: 18.14+/‐3.19µM, p<0.05), or AβO only condition (fasted: 16.80+/‐1.40µM, p<0.05; postprandial: 18.42+/‐2.05µM, p>0.05). Fasted HDL more efficiently removed cellular cholesterol in the untreated and in AβO+cholesterol treated cells. Intriguingly, cellular esterified cholesterol content was significantly lowered with fasted HDL but not postprandial HDL in both AβO alone (fasted: 5.73+/‐2.27 µM, p<0.05; postprandial: 10.32+/‐2.70µM, p>0.05) and AβO + cholesterol (fasted: 2.87+/‐2.13µM, p<0.05; postprandial: 9.03+/‐1.74µM, p>0.05).

Conclusion

These findings suggest that microglia exposed to a double‐hit of AβO and excess cholesterol experience an impaired ability to efflux excess cholesterol. Additionally, HDL from fasted individuals displayed an enhanced capacity to efflux cholesterol, especially in microglia dually encumbered by AβO + cholesterol. Further studies are needed to examine the impact of this diminished cholesterol efflux capacity and cholesterol accumulation on the phagocytic capacity of microglia.
African‐ancestry based polygenic risk scores improve Alzheimer disease risk prediction in individuals of African Ancestry
Authors: Akgun Bilcag , Hamilton‐Nelson Kara L. , Kushch Nicholas A. , Adams Larry D. , Starks Takiyah D. , Martinez Izri , Laux Renee A. , Whitehead Patrice L. , Kunkle Brian W. ,   Alzheimer’s Disease Genetics Consortium (ADGC), Cuccaro Michael L. , Vance Jeffery M. , Reitz Christiane , Byrd Goldie S. , Haines Jonathan L. , Beecham Gary W. , Pericak‐Vance Margaret A. , Rajabli Farid
Published: December 2022

Background

Polygenic risk scores (PRS) may be a useful approach to predict the risk of the complex disease and to be an important clinical tool for early intervention. PRS studies in Alzheimer Disease (AD) have focused on individuals of European Ancestry resulting in a >75% prediction accuracy. PRS generated from genome wide data in one population often provides reduced predictive accuracy in other populations. This is particularly problematic for underserved groups. In this study, we assessed and compared the PRS prediction accuracy of AD in individuals of African Ancestry (AA) using both AA and non‐Hispanic White (NHW) Genome Wide Association (GWAS) studies.

Method

As part of the Research in African American Alzheimer Disease Initiative (REAAADI) and ADGC, two TOPMED imputed AA datasets were generated (REAAADI:AD=234, cognitively unimpaired (CU)=676 and ADC9: AD cases=109, CU=224). We assessed the PRS using the effect sizes from summary statistics from the NHW (Kunkle et al. 2019) and the AA (Kunkle et al. 2021) studies. To model the effect of APOE we excluded APOE region in PRS constructing and included APOE alleles as separate terms in the prediction model. First, we generated PRS scores on the REAAADI dataset, and validated our model in ADC9 dataset. To assess the PRS performance, we employed the logistic regression modeling (covariates‐only (age, sex, and PC1:3),PRS‐only, and full (PRS+APOE+covariates) model) to construct receiver operator (ROC) curves.

Result

European ancestry‐derived PRS has the poor prediction power (AUC=0.53) in the REAAADI dataset whereas the AA‐derived PRS predicts better (AUC= 0.87). Further validation of the AA PRS in ADC9 dataset using covariates‐only, PRS‐only and full modelsvalidated that inclusion of African ancestry derived PRS significantly improves the accuracy of AD prediction in AA individuals (AUCcovariates‐only=0.59; AUCPRS‐only=0.74 and AUCfull=0.81).

Conclusion

Our results showed that AA‐derived PRS significantly improves AD risk prediction in AA individuals over European ancestry‐derived PRS. Our findings demonstrate the importance of increasing the diversity in genetic studies to improve precision medicine approaches. Moreover, the development of more accurate PRS models that can detect the risk of AD in all in all groups paves the way for more accurate prevention, early detection, and intervention of AD.