bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilingualism and APOE4 alelle as a risk‐protective factor in dementia among Peruvian Andean aging population
Authors: Soto‐Añari Marcio F. , Rivera‐Fernandez Claudia , Ramos‐Vargas Luis , Custodio Nilton , Montesinos Rosa , Chambergo‐Michilot Diego , Ore‐Gomez Maria Fernanda , Carreño‐Galvez Jose , Reyes‐Dumeyer Dolly , Tosto Giuseppe
Published: December 2023

Background

Bilingualism has been considered as a protective factor against dementia. But the evidence in Native American populations is spare and to our knowledge, there are no studies analyzing risk factors, as the APOE4 genotype and environmental protective factors as the bilingualism and education. Our objective was to analyze the risk/protective association between bilingualism and APOE4 status (carrier/non‐Carrier) on Alzheimer Dementia Related Disorders (ADRD). In addition, we analyzed the impact of the bilingual/monolingual condition on cognition.

Method

We used the data of the ongoing study “Genetics of Alzheimer’s disease in Peruvian Populations study” (GAPP). 275 older adults (mean age = 71.57, SD = 8.3) were recruited from 3 Peruvian cities: Lima, Arequipa and Puno. These last located in the southern of Peru where Quechua and Aymara ethnics are the most important population. Bilingual condition was evaluated as a dichotomous condition (yes/no). A clinical and neuropsychological protocol was applied which included brief cognitive test, functional status measures and clinical dementia scales (CDR). Cognitive measures included attention, memory, abstract reasoning, language and visuoconstruction. Genotyping was conducted on The Infinium Global Screening Array‐24 BeadChip, which combines multi‐ethnic genome‐wide content. Binary logistic regression was performed taking the CDR 1 score as the dependent variable and gender, education, being bilingual/monolingual, and APOE4 Carrier/non‐Carrier status as predictors. Finally, we use mean comparison test in cognition measures according the bilingual/monolingual condition.

Result

We observed that bilingualism (OR = 0.23, p<.001), APOE non‐carrier status (OR = 0.26, p<.001) and more years of schooling (OR = 0.92, p<.01) are associated with a lower risk of dementia. We also see that bilinguals have better scores than monolinguals in orientation tasks (t = 2.65, p<.01), memory total recall (t = 2.02, p<.05), semantic fluency‐animals (t = 2.71, p<. 01) and visuoconstructional abilities (t = 6.62, p<.001). Likewise, only in perception recognition tasks, monolinguals scored higher than bilinguals (t = 3.17, p<.01).

Conclusion

Environmental factors seem to have a significant protective effect along with biological known risk factor in dementia and have a significant effect on cognition.
Mediterranean Diet Foods are Associated with Plasma Biomarkers of Alzheimer’s Disease and Related Dementias
Authors: Dempsey Desarae A , Deardorff Rachael , Apostolova Liana G. , Brosch Jared R. , Clark David G. , Farlow Martin R. , Mathew Sunu , Unverzagt Fredrick , Dage Jeff L. , Russ Kristen A. , Blennow Kaj , Zetterberg Henrik , Gao Sujuan , Clark Daniel , Saykin Andrew J. , Risacher Shannon L
Published: December 2023

Background

The Mediterranean diet (MeDi) has been reported as preventative against cognitive decline and AD (Berti et al. 2018, Neurology) and associated with decreased brain atrophy (Staubo et al. 2016, Alz&Dem). Here, we examined associations between specific foods in the MeDi and plasma biomarkers of ADRD in the Indiana ADRC (IADRC) sample.

Method

Plasma ptau181 and neurofilament light (NfL) from 177 individuals (57 CN/53 SCD/40 MCI/27 AD), and amyloid beta (Aβ) 42 and 40, total tau, and glial fibrillary acidic protein 2 (GFAP) from 161 individuals (49 CN/51 SCD/35 MCI/26 AD) were generated using SIMOA assays at IU or Gothenburg, Sweden. Participants completed a self‐report diet questionnaire at the IADRC, which was coded into high, medium, or low intake groups for each food. We performed linear regressions to test the association of the food groups and total MeDi score to ADRD plasma biomarkers, covaried for age, sex, diagnosis, and SIMOA batch.

Result

Higher intake of red meat (p = 0.014), grains (p = 0.029), and beans (p = 0.009) significantly correlated with higher plasma NfL. Fast food also followed this trend (p = 0.053). Higher intake of olive oil showed a trend toward lower pTau181 (p = 0.055). Higher intake of grains was associated with higher Aβ42 (p = 0.038), while higher intake of sweets was associated with lower levels of Aβ40 (p = 0.016). There were no significant associations with specific foods and the Aβ42/40 ratio after covarying.

Conclusion

As expected, olive oil was associated with decreased pTau181, while higher intake of red meat and fast foods were associated with increased levels of NfL. Contrary to the MeDi hypothesis, beans and grains contributed to higher NfL. While grains and sweets influenced individual levels of Aβ42 and Aβ40 respectively, these individual levels are less understood than the ratio and require further investigation. Previous studies have shown correlation of high carbohydrate and sugar intake with smaller entorhinal cortex thickness, and legumes with larger cortical thickness. A limitation is that specific types of beans and grains consumed were not collected. Further studies will investigate diagnostic group, ethnoracial, socioeconomic, and BMI effects, as well as the role of the gut microbiome.
Association of urine dicarboxylic acid levels with intracranial volume–normalized brain regions and with white matter hypo‐intensities
Authors: Fonteh Alfred N. , Maldonado Salvador , Buennagel David P , Aguda Shelly , Butler Ryan , Kang Jimmy , Macias thomas , Sin Caleb , Spezzaferri Mitchell , Rising Shant , Nolty Anne , Chui Helena C , Minazad Yafa , Kloner Robert A , Arakaki Xianghong
Published: December 2023

Background

Non‐invasive molecules related to AD imaging biomarkers can reveal disease mechanisms and may help in the mass screening of an aging population. Our study aims to determine if urine dicarboxylic acids (DCA) that changed in AD are coupled with brain volume changes.

Method

Study participants (> 65 years) were recruited in an ongoing HMRI Brain aging study, and MRI data were acquired and analyzed using NeuroQuant. The data were normalized to the intracranial volume (icv). DCAs were quantified using gas chromatography/mass spectrometry. We compared DCA and icv‐normalized brain region volumes in two ways: first, we used descriptive statistics to obtain the median (Q2) for short‐chain DCAs (C4+C5), medium‐chain DCAs (C7+C8+C9) and the ratio of short to medium chain DCAs ((C4+C5)/(C7+C8+C9)). Brain regions were then sorted to correspond to less than (Q2). Differences were determined using two‐sample t‐tests and Wilcoxon rank‐sum tests with adjustment for multiple comparisons using FDR. Secondly, icv‐normalized brain regions and T1 hypo‐intensity were compared with DCA levels using a two‐tailed student’s t‐test.

Result

There was no significant difference in the DCA levels of participants with low (icvQ2) (Fig.1A). In contrast, C4+C5 levels were higher, while C7+C8+C9 were lower in participants with higher whole brain volumes (WBV) (Fig. 1B). In addition, hippocampal volumes were greater when participants had a higher urine C4+C5 and lower C7+C8+C9. We identified 19 other icv‐normalized brain regions that were bigger when urine C4+C5 levels were high. In addition, participants with higher white matter hypo‐intensities had lower urine C4+C5 and a higher C7+C8+C9 DCA levels (Table 1).

Conclusion

These data suggest that urine lipid composition is linked to icv‐normalized brain volumes. Higher mitochondrial‐associated lipids reflected larger brain volumes, while oxidized lipids indicated lower brain volumes. Thus, urine lipid levels can be used as surrogate biomarkers in clinical trials targeting brain volume changes. We will use a bigger sample size normalized for ApoE genotype, age, and sex to further examine lipids and brain volumes in participants with different cognitive states.
Recruitment and Retention of Underrepresented Minorities in Interventional Alzheimer’s Disease Clinical Trials
Authors: Soto Elizabeth , Anziska Yaacov
Published: December 2023

Background

Alzheimer’s disease is a progressive neurodegenerative disorder that affects thinking, and behavior and is the most common cause of dementia. In Alzheimer’s disease (AD) clinical trials, there is a severe lack of underrepresented and marginalized populations. Despite overwhelming evidence that these groups are more likely to develop AD, various recruitment barriers impair them from being accepted into current AD clinical studies, which threatens these findings' overall generalizability and scientific impact. As a result, there is less understanding of overall needs, no mechanism for identifying and comparing disease variations, and a limited range of available interventions. In this study, we aim to analyze the recruitment, reporting, and retention strategies of Hispanic/Latinx and Black individuals in AD Clinical Trials for the last 35 years to create a novel model system to increase the diversity and inclusion of minoritized groups in Alzheimer’s Clinical Trials.

Method

We extracted the data from the clinicaltrials.gov database and applied the inclusion criteria: Year: 1999‐Present, Population: Older Adults (65>), Alzheimer’s Diagnosed, and Healthy. Intervention: Pharmaceutical/drug. Funding: NIH, Industry. Status: Completed. For our outcome variables, we included the following: Reported and non‐reported recruitment demographic, the inclusion of white, Hispanic/Latin, Black/African American, Asian, and Unknown. For our analyses, we performed a Linear regression on cohort demographic makeup in five‐year intervals, reported vs. non‐reported demographic, and the percentage of ethnicity recruited.

Result

Our search yielded n = 117 clinical trials. 28% of NIH‐sponsored drug‐based clinical trials have reported cohort demographic makeup. 61% of Industry‐sponsored drug‐based reported cohort demographic make‐up.

Conclusion

We found that despite the increasing research focusing on the importance of the inclusion of underrepresented individuals in clinical trials. The number of underrepresented minorities in AD clinical trials continues to be significantly and alarmingly low, hindering the scientific process of developing therapeutic methods for Alzheimer’s Disease. Moreover, several laws and policies have been released to enforce the reporting of ethnicity/race of clinical trials cohort have not been adequately enforced and followed, raising concerns for policy efficacy.
Potentially Cognitive Stimulating Activities and cognitive performance in middle‐age and older adults
Authors: de Araujo Camila Farias , Ferri Cleusa P , Bertola Laiss
Published: December 2023

Background

Low education attainment is rampant in low‐ and middle‐income countries (LMICs). Considering that education is a protective factor against dementia, engagement in activities promoting learning might be an alternative to the impact of classical schooling. Therefore, we aim to verify if potentially cognitive stimulating activities (PCSAs) could be an alternative to enhance and maintain cognitive performance in middle‐aged and older adults with diverse educational attainment.

Method

We analyzed baseline data from 7,568 participants of the Brazilian Longitudinal Study of Aging (ELSI‐Brazil). We evaluated engagement in PCSAs through questions about currently attending the Open University for older adults program or attending free courses (foreign language, data processing or computer sciences, sewing/tailoring, cooking, or arts). A global cognition regression‐based norms z‐score was computed using episodic memory and fluency tests scores. We performed three linear regression models to verify the association between engagement in PCSAs with cognition. The first unadjusted model with only the PCSAs as a predictor of cognitive performance. The second model was adjusted for sociodemographic characteristics (age, sex/gender, education, and race), and the third model was additionally adjusted for variables related to memory self‐ratings (current performance and perceived decline for the past two years), general health perception, depressive symptoms, and chronic diseases.

Result

Participants had a mean age of 61.5 (±8.98) years, a mean of 6.3 (±4.73) years of schooling, 53.5% of females and 54.9% of Black/Brown (Table 1). Engagement in PCSAs was a predictor of better cognitive performance in model 1 (β = 0.10, CI 95% 0.01;0.18), model 2 (β = 0.10, CI 95% 0.02;0.19) and model 3 (β = 0.10, CI 95% 0.03;0.21) (Table 2).

Conclusion

Our results suggest that better global cognition might be associated with some socially common and cheaper activities. Despite the study limitations, in a scenario where structured continuing education might not be readily available, these results indicate that PCSAs should be a target of future studies as a potential source of cognitive reserve.
Associations of APOE4 and Alzheimer’s disease biomarkers with cortical reinstatement and episodic memory in clinically unimpaired older adults
Authors: Trelle Alexandra N , Wilson Edward N. , Romero America , Kasireddy Nandita , Deutsch Gayle K. , Sha Sharon , Greicius Michael D , Andreasson Katrin I. , Carr Valerie A , Kerchner Geoffrey A. , Mormino Elizabeth C. , Wagner Anthony D
Published: December 2023

Background

Cortical reinstatement is a key neural correlate of episodic remembering across the lifespan and explains significant variability in memory performance among older adults. We assessed whether Alzheimer’s disease (AD) risk factors – cerebrospinal fluid (CSF) Aβ42/Aβ40, CSF pTau181, plasma pTau181, and APOE genotype – impact cortical reinstatement in clinically unimpaired older adults.

Method

Participants were 150 clinically unimpaired older adults enrolled in the Stanford Aging and Memory Study (SAMS). APOE genotype was determined from whole‐genome sequencing and participants were classified as ε4 carriers (N = 38) or non‐carriers (N = 112). CSF Aβ42/Aβ40 and pTau181 and plasma pTau181 were quantified using the automated Lumipulse G system. Cortical reinstatement was quantified during successful retrieval of word‐picture associations using fMRI multivoxel pattern analysis (MVPA) in five regions of interest, including parahippocampal gyrus (PHG), ventral temporal cortex (VTC), middle temporal gyrus (MTG), angular gyrus (ANG), and posterior medial cortex (PMC). Regression analyses examined cross‐sectional relationships between regional cortical reinstatement and a) APOE genotype (N = 150), b) CSF Aβ42/Aβ40 and pTau181 (N = 113), and (c) plasma pTau181 (N = 140), as well as associations of these variables with associative memory discrimination (d’). All models included age, sex, and regional MVPA classifier accuracy during memory encoding.

Result

APOE ε4 genotype was negatively associated with reinstatement strength in VTC (β = ‐0.54, p < .005), MTG (β = ‐0.32, p < .05), and ANG (β = ‐0.32, p < .05) and CSF Aβ42/Aβ40 burden was linked to weaker reinstatement in ANG (β = 0.16, p < .05). In VTC, the effect of APOE ε4 on reinstatement remained significant after controlling for CSF Aβ42/Aβ40 (β = ‐0.47, p < .05); a similar pattern was observed in MTG and ANG. Although CSF pTau181 was unrelated to reinstatement strength, both pTau181 and cortical reinstatement explained unique variance in memory performance (pTau181: β = ‐0.26, p < .005, reinstVTC: β = 0.39, p < .001). Analogous findings were observed with plasma pTau181.

Conclusion

These results suggest that APOE ε4 impacts cortical reinstatement, and that this effect may be independent of amyloid burden. These effects of APOE ε4 may be distinct from tau‐mediated effects on episodic memory in human aging.
Preliminary analysis of verbal and nonverbal indicators of episodes of lucidity in advanced AD/ADRD
Authors: Dillon Kayla , Fehland Jess , Botsch Meghan , Coulson Alison , Benson Clark , Block Laura M , Gilmore‐Bykovskyi Andrea L
Published: December 2023

Background

Alzheimer’s disease and related dementias (ADRD) are progressive neurodegenerative diseases believed to cause irreversible cognitive and functional losses. Episodes of lucidity (ELs) are described broadly as spontaneous and unexpected return of abilities believed to have been lost in individuals living with advanced ADRD.1 These events have been qualitatively identified by caregivers and healthcare staff but have yet to be quantitatively described.1 This study aimed to measure potential quantitative verbal/nonverbal indicators of ELs in individuals living with advanced ADRD.

Method

Five participants living with advanced ADRD in a regional hospice unit were enrolled, from which 281 hours of audiovisual data were collected. A behavioral coding scheme captured potential verbal/nonverbal indicators that may characterize lucid events. Indicators were coded (timed‐events) independently by two coders using Observer XT. Descriptive statistics for verbal/nonverbal indicators of ELs included: indicator frequency, rate, duration, and proportion. Additionally, we compared descriptive statistics for verbal/nonverbal indicators in high‐likelihood ELs identified by the research team, caregivers, or hospice staff to verbal/nonverbal indicators in the participant’s baseline typical behavior with similar stimuli.

Result

Ten potential ELs were identified by the research team, with three of these episodes endorsed by caregivers and hospice staff. For endorsed ELs, the average proportion and duration of all coded indicators was greater than that of their respective comparators, except for three nonverbal indicators (shakes head, manipulates object, directed attention). The average rate and frequency of all coded indicators was greater than that of their respective comparators, except for two nonverbal indicators (shakes head, directed attention).

Conclusion

Our preliminary analyses found that a comparative analysis approach to characterizing ELs provides an opportunity to identify substantial variability of potential ELs from individual baseline. While verbal/nonverbal indicators were generally more frequent/intense during ELs, this was not always true. Given the current lack of a formal definition for ELs, efforts to identify and characterize the content of ELs benefit from triangulation across event indicators with qualitative data collected from informants.

References:

[1] Mashour GA, Frank L, Batthyany A, et al. Paradoxical lucidity: A potential paradigm shift for the neurobiology and treatment of severe dementias. Alzheimers Dement. 2019;15(8):1107‐1114. https://doi.org/10.1016/j.jalz.2019.04.002
The Alzheimer’s Disease Sequencing Project – Follow Up Study (ADSP‐FUS): APOE genotype status and demographic characteristics across datasets
Authors: Mena Pedro R. , Zaman Andrew , Faber Kelley M. , Adams Larry D. , Inciute Jovita D. , Whitehead Patrice , Foroud Tatiana M. , Reyes‐Dumeyer Dolly , Kuzma Amanda B , Nicaretta Heather Issen , Naj Adam C. , Martin Eden R. , Dalgard Clifton L. , Schellenberg Gerald D. , Wang Li‐San , Mayeux Richard , Vardarajan Badri N , Vance Jeffery M. , Cuccaro Michael L. , Kunkle Brian W. , Pericak‐Vance Margaret A.
Published: December 2023

Background

The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP beyond non‐Hispanic Whites of European Ancestry (NHW‐EA) populations. Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to whole genome sequence (WGS) existing ethnically diverse and unique cohorts. The upcoming phase ADSP‐ FUS 2.0: The Diverse Population Initiative, focuses on inclusion of Hispanic/Latino (HL), non‐Hispanic Black with African Ancestry (NHB‐AA), and Asian populations.

Methods

ADSP‐FUS cohorts consist of studies of AD, dementia, and age‐related conditions. Clinical classifications are assigned based on standard criteria from clinical measures and history, as well as additional neuropathologic data. In addition to production of WGS, genome‐wide array and APOE genotyping is acquired or performed for all ADSP‐FUS samples.

Results

The ADSP‐FUS currently consists of 38 cohorts comprised of ∼40,000 individuals, with plan to sequence >100,000 individuals from diverse ancestries. Genotyping, sequencing, and clinical adjudication has been performed on 23,428 participants (cases N = 6,961, median age = 73; controls N = 13,007, median age = 72; ADRD N = 3,460, median age = 77. More participants are female (62.3%) than male and are evenly distributed across cases (61.0%), controls (63.1%), and ADRD (61.8%). As expected, the most prevalent APOE genotype is APOE 3/3 (% by cases/controls for 2/2 = 0.2,0.4; 2/3 = 4.3, 8.2; 2/4 = 2.2, 1.8; 3/3 = 43.8, 64.4; 3/4 = 39.5, 23.0; 4/4 = 10.1, 2.2). These proportions vary greatly between ethnicities, with the highest for APOE 4/4 observed in Asian participants (8.8%) and the lowest in Hispanic participants (2.5%), for example. Mean Braak stage for AD cases is higher (5.1+1.2) than controls (2.6+1.3) and ADRD participants (3.5+1.6).

Conclusion

The results provide an overview of features of ADSP‐FUS cohorts. As the ADSP‐FUS expands in size and diversity, this genomic resource, available via NIAGADS, will be integrated with ADSP programs focused on phenotype harmonization, association analyses, functional genomics, and machine learning. In concert with these programs, the ADSP‐FUS will accelerate the identification and understanding of potential genetic risk and protective variants for AD across all populations with the target of developing new treatments that are globally effective.
SARS‐CoV‐2 infection worsens Vascular Dementia (VaD)‐associated neuropathology in mice
Authors: Gressett Timothy E , Biose Ifechukwude Joachim , Narayanappa Amruta , Ismael Saifudeen , Talkington Grant , Bix Gregory J
Published: December 2023

Background

Vascular Dementia (VaD) is the second leading cause of dementia behind Alzheimer’s disease (AD) and has a profound association with the morbidity and mortality of COVID‐19. Recent evidence demonstrates that preexisting vascular dementia is associated with increased COVID‐19 incidence and worsened outcomes after COVID‐19 infection. Collectively, these observations suggest that vascular pathology in VaD such as blood‐brain barrier (BBB) disruption, directly contributes to this association. Previously we and others have demonstrated that SARS‐CoV‐2 binds to the vascular integrin α5β1 receptor and that inhibition of α5β1 integrin with the clinically‐validated peptide ATN‐161 can improve acute SARS‐CoV‐2 infection and reduce SARS‐CoV‐2‐mediated vascular disruption. Furthermore, we have previously demonstrated that ATN‐161 reduces BBB disruption in models of brain ischemia (stroke) and VaD‐modeled chronic bilateral carotid artery stenosis (BCAS), which models reduced blood flow, BBB disruption, neuroinflammation, white matter damage and cognitive decline in VaD. In the present study, we tested the hypothesis that experimental VaD worsens COVID‐19‐associated neuroinflammation and exacerbates subsequent neurovascular damage, which may be targeted therapeutically by ATN‐161.

Method

10‐week‐old wild‐type (WT) BALB/c male mice were infected with 2×105 PFU mouse‐adapted (MA10) SARS‐CoV‐2 or mock infection 1‐week after BCAS surgery to model the effects of preexisting VaD in mice and subsequent SARS‐CoV‐2 infection. Body weight was monitored daily. The brain was isolated 3‐days post‐infection (dpi) and analyzed for immunohistochemical and mRNA expression of selected markers of neuroinflammation and immune response.

Result

BCAS+SARS‐CoV‐2 infected mice exhibited a significant reduction in body weight at 3 dpi compared with the BCAS+mock infected group. Immunohistochemical analysis demonstrated a significant increase in α5 integrin signal in the cortex. SARS‐CoV‐2 infection after BCAS worsened brain and vascular inflammation and glial activation, indicated by increased Iba‐1 (microglia) and GFAP (astrocyte) immunofluorescence and brain (proinflammatory) IL‐1β cytokine transcript levels. Lastly, SARS‐CoV‐2 infection worsens white matter (myelin) integrity as measured by myelin basic protein (MBP) immunofluorescence.

Conclusion

SARS‐CoV‐2 aggravated VaD‐associated morbidity indicated by elevated white matter damage, glial activation, and neuroinflammation along with increased integrin α5 expression. Integrin α5β1 could, therefore, be a therapeutic target for improving both acute SARS‐CoV‐2 infection, and VaD post‐COVID morbidity and cognitive decline.
Network Understanding of Genetic Interplay Between Alzheimer’s Disease Endophenotypes
Authors: Keegan Stephen , Cary Gregory A. , Wiley Jesse C , Gockley Jake , Leal Karina , Butler Robert R. , Greenwood Anna K , Carter Gregory W ,   The Emory‐Sage‐SGC TREAT‐AD Center
Published: December 2023

Background

Alzheimer’s disease (AD) therapeutics have largely been unsuccessful in alleviating disease burden in those afflicted by the disease. The TREAT‐AD Consortium is an international group of academic researchers dedicated to identifying novel molecular targets for AD from underexplored areas of disease linked pathology.

Method

We generate 19 disease biology specific networks, Biological Domains (biodomain), from pathway reconstructions based on interactions from pathway databases. The networks are composed of gene lists which represent Gene Ontology terms (GO Terms) that best describe AD endophenotypes. We interrogate these networks to identify plausibly causal genes using a weighted Key Driver Analysis (KDA). The networks are also used as priors for training Graph Neural Networks (GNN) on transcriptomic data.

Result

Because a biodomain network object has genes and GO Terms that are annotated to other biodomains, we inferred inter‐biodomain relationships. Analysis of the directed biodomain network provided predictions of the ordering of processes that contribute to AD progression. Molecular targets inferred to be causal across multiple biodomains provide druggable targets that are upstream of AD‐correlated processes. For example, we found gene expression changes in the lipid metabolism biodomain that are driven by genes annotated to autophagy and immune response.

Conclusion

Alzheimer’s Disease biology can be subdivided into networks which represent processes that are notable to AD patients. Genes from these networks will be prioritized to identify candidate therapeutic targets that are well situated to affect the network biology. TREAT‐AD investigators will validate these targets in cell models and generate experimental resources to support further target development.
Development of system for assessing neurologic impact of long COVID‐19 and post‐COVID‐19 vaccination symptoms
Authors: Ruchisrisarod Chanida
Published: December 2023

Background

The coronavirus disease (COVID‐19) pandemic has had a global impact on health. Some patients experience persistent symptoms even after the infection has cleared. The virus affects the body’s inflammation system, potentially leading to brain and organ damage. This study aims to develop a tool to assess the impact of COVID‐19 infection and vaccination, as well as the inflammatory response in patients with Long COVID and those who reported symptoms after receiving various COVID‐19 vaccines.

Method

Patients who report prolonged symptoms after contracting COVID‐19 or significant symptoms after receiving various types of vaccines will be assessed, including serological testing to detect antibodies against the virus, cytokine profiling, biomarkers for neurodegenerative diseases (plasma levels of amyloid beta, glial fibrillary acidic protein and neurofilament light hain) and clinical symptoms. The study will investigate the association of evidence of ongoing active brain injury, biomarkers, elevations of pro‐inflammatory cytokines, and the presence of autoantibodies to various antigens.

Result

The study comprised 85 participants, including 50 with long COVID‐19, 30 of whom presented with neurological symptoms and 20 with non‐neurological symptoms, and 35 who reported post‐vaccination symptoms, 11 of whom had neurological symptoms and 24 had non‐neurological symptoms. Participants underwent the proposed assessment system, with 33 having completed their first follow‐up evaluation, and 3 having completed their second evaluation.

Conclusion

We present our initial findings from our proposed assessment system for evaluating the impact of long COVID‐19 and post‐vaccination symptoms. The results of this study aim to provide insight into the lasting effects of COVID‐19 and the potential impact of COVID‐19 vaccinations on patients. The full results of this study will be reported in due course.
COGNITIVE IMPAIRMENT AFTER THE DIAGNOSIS OF LATE‐ONSET EPILEPSY ‐ A SYSTEMATIC REVIEW
Authors: Chamoun Joelle , De Almeida Ribeiro Margaux , Contenseaux Coralie , Mockler David , Moroni Christine , Chen Yaohua Sophie
Published: December 2023

Background

The management of late‐onset epilepsy in older people (LOE) is often suboptimal despites its high incidence. The impact of LOE is not only epileptic, it also leads to multiple consequences, such as cognitive decline, and other geriatric syndromes. Cognitive decline, as one of the major consequences of LOE, causes in turn deterioration in quality of life and loss of autonomy. However, the effect of de novo LOE on cognitive decline without dementia in older people remains poorly understood. Similarly, very few studies have analysed the risk factors associated with cognitive decline. Therefore, we conducted a systematic review to describe the long‐term effect on cognition of LOE on older people, including the incidence of cognitive decline after the diagnosis of LOE and the associated risk factors.

Method

According to PRISMA 2020 guidelines, we searched 5 electronic databases (“EMBASE”, “Medline”, “CINAHL”, “PsycINFO”, “Web of Science”) for articles published until 27th Oct 2022. The criteria selected were patients “60 years old and older” with “late onset epilepsy” diagnosis and “cognitive decline” or “cognitive impairment”, whom do not have known brain tumor or a posttraumatic etiology. Four researchers independently screened studies based on the title and abstract, then by full text. Data extraction was done through “Covidence” platform with each study being processed by two reviewers and conflicts were solved by a third reviewer.

Result

We selected 26 out of 326 initially retrieved publications based on full text review. Most of the studies conducted so far however did not take into consideration or did not control for the baseline cognitive status of their patients before or at the onset of epilepsy and therefore could not objectively determine the real burden of late onset epilepsy on cognitive impairment in this population.

Conclusion

Data in favour of a causal relationship between late onset epilepsy and cognitive decline in elderly with no known baseline cognitive impairment is still precarious. More studies should be conducted with more specific assessment tools that could permit us to have a better estimate of the burden of LOE on cognition such for example imaging and neuropsychological assessment before and after the incidence of epilepsy.
Transcriptomic similarities in vulnerable and resilient brain regions of Parkinson’s disease and Alzheimer’s disease
Authors: Siebert Marina , Carello‐Collar Giovanna , Bastiani Marco Antônio De , Zimmer Eduardo R
Published: December 2023

Background

Parkinson’s disease (PD) and Alzheimer’s disease (AD) share multiple pathophysiological features but affect different brain regions. While the hippocampus is highly vulnerable in AD, the loss of dopaminergic neurons in the substantia nigra (SN) is a hallmark of PD. By contrast, other brain regions, such as the cerebellum, seem resilient to neurodegenerative processes in both diseases. However, the biological mechanisms driving brain regional vulnerability and resilience to neurodegeneration in PD and AD remain elusive. Here, we aimed to analyze the transcriptomic profiles of PD and AD in vulnerable (VR) and resilient (RR) brain regions.

Method

PD and AD datasets were obtained from the Gene Expression Omnibus public data repository (PD: GSE28894, GSE20186, GSE20314, GSE42966, GSE49036, GSE54282, GSE20164, GSE20163, and GSE8397; AD: GSE118553, GSE44768, GSE036980, GSE084422, GSE1297, GSE29378, and GSE48350). Hippocampal, SN, and cerebellar differential expression analysis was performed to identify differentially expressed genes (DEGs) for each disease versus age‐matched controls. Functional enrichment analysis (FEA) was accomplished to identify similar signatures in VR and RR in PD and AD. Analyses were performed using the R (adj p‐value <0.05).

Result

607 DEGs overlapped in the VR of PD and AD, while 1780 DEGs in the RR. FEA revealed 114 gene ontology (GO) terms shared between the VR and 276 GO terms overlapping between PD and AD RR. The GO terms were assembled in clusters of biological processes (Table 1). Cluster observation suggests that both VR and RR share similar enriched processes, such as “cellular respiration”, “regulation of neuron death”, “catabolic pathways”, “response to injury and DNA damage”, and “exocytosis and neurotransmitter secretion”. By contrast, “regulation of cell growth”, “response to steroid hormones”, and “regulation of nervous system development” were unique for the RR, while “membrane lipid metabolic process” and “regulation of cell communication” clusters were found only in the VR.

Conclusion

Our results highlight a transcriptomic landscape shared by PD and AD in both VR and RR. Looking at the similarities between brain regions vulnerable and resilient in different neurodegenerative diseases may contribute to the understanding of their pathogenesis and clinical course, as well as guide the development of therapeutic strategies.
Plasma biomarkers of tau for the differentiation between slow and fast tau‐PET accumulators
Authors: Tissot Cécile , Therriault Joseph , Rahmouni Nesrine , Servaes Stijn , Macedo Arthur C. , Wang Yi‐Ting , Stevenson Jenna , Snellman Anniina , Rodriguez Juan Lantero , Stevenson Alyssa , Arias Jaime Fernandez , Lussier Firoza Z , Chamoun Mira , Mathotaarachchi Sulantha , Bezgin Gleb , Kunach Peter , Triana‐Baltzer Gallen , Gauthier Serge , Karikari Thomas K , Kolb Hartmuth C. , Benedet Andrea Lessa , Blennow Kaj , Zetterberg Henrik , Pascoal Tharick Ali , Ashton Nicholas J. , Rosa‐Neto Pedro
Published: December 2023

Background

Plasma markers of tau are currently being studied as proxies of cerebral neurofibrillary tangle (NFT) accumulation. Phosphorylated tau (pTau) and N‐terminal tau fragment (NTA) assays are associated with present and future tau‐PET load. Our aim was to investigate whether plasma markers could predict whether someone will be a slow or fast accumulator.

Method

We assessed 143 individuals [72 CU, 54 MCI, 17 AD] from the TRIAD cohort, with two available [18F]MK6240 tau‐PET scans and calculated the relative change (Δ[18F]MK6240) between baseline and follow‐up [mean follow‐up time: 2.1 ± 0.7 years]. We used tertiles to divide individuals as slow, medium and fast accumulators. Additionally, we measured baseline plasma pTau181, pTau217, pTau231 and NTA concentrations. We computed the effect size (Cohen’s d) and area under the curve (AUC) for each plasma marker for Δ[18F]MK6240 between slow and fast accumulators. Δ[18F]MK6240 was calculated in Braak stages I/II, III/IV and V/VI.

Result

We first observed that the highest effect size for Δ[18F]MK6240 in Braak I/II was depicted by pTau231. For Δ[18F]MK6240 in Braak III/IV and Braak V/VI, pTau217 presented the highest effect size (Figure 1). Moreover, AUC values were the highest, and highly similar, in ΔBraak I/II for pTau181, pTau217 and pTau231. For ΔBraak III/IV, pTau181 and pTau217 presented the highest values. Finally, AUC for ΔBraak V/VI, pTau231 and NTA had the highest values, which were also similar (Figure 2).

Conclusion

Plasma pTau biomarkers (181, 217 and 231) are great predictors of fast accumulation in early to middle Braak regions. For late Braak regions, fast accumulation was best predicted by pTau217 and NTA. Plasma markers are able to determine whether someone will be a fast accumulator in a stage‐specific manner. The currently available tau biofluid measures could be used in the clinical and clinical trial settings, as these are less invasive and cheaper than CSF or PET assessments. Especially in the recruitment phase, pTau217 could be used for screening individuals that are more likely to accumulate tau fast.
Progressive dysregulation of circular RNAs in the hippocampus of a transgenic mouse model of amyloidosis
Authors: Carvalho Lavínia Perquim , Bastiani Marco Antônio De , Carello‐Collar Giovanna , Limberger Christian , Zimmer Eduardo R
Published: December 2023

Background

Circular RNAs (circRNAs) are a class of RNAs that act as transcriptional regulators. They have a circular structure and are produced from back‐splicing events, which makes them more stable than linear RNAs. In Alzheimer’s disease (AD), the role of circRNAs remains elusive. Here, we aimed to evaluate whether the transcription of circRNAs is altered in the hippocampus, a region highly vulnerable to AD, of a transgenic amyloid mouse model.

Method

We selected hippocampal RNA‐sequencing or microarray datasets of circRNAs of the APPswe/PSEN1dE9, a widely used transgenic amyloid mouse model, from the NCBI databases. CircRNAs were detected with the CIRI2 algorithm by using the gene symbol of the parent transcript and the transcript ID. We identified the differently expressed circRNAs between APPswe/PSEN1dE9 and age‐matched wild‐types using the DESeq2 method (p‐value < 0.01). The packages UpSetR and VennDiagram were used to uncover the circRNAs commonly altered between the studies. All analyses were performed in R.

Result

From 12 databases, three had hippocampal circRNA data of 4, 6, and 8‐month‐old APPswe/PSEN1dE9 mice (GSE166393; GSE158995; and PRJNA712946, n = 3 per group). Amyloid‐beta (Aβ) starts to deposit at six months in the APPswe/PSEN1dE9 hippocampus. The number of dysregulated circRNAs increased with age: 41 (4‐month‐old), 82 (6‐month‐old), and 425 (8‐month‐old) (Figure 1). Interestingly, only one circRNA was shared between the three studies at all time points, originating from the CCDC141 gene. Additionally, 15 circRNAs were shared in at least two ages, such as CD2AP, FMN1, HOMER1, IL1RAP, NDST3, and TET1 (Please, see the full list of intersections in Figure 2). By dividing groups into pre‐plaque (4‐month‐old) and amyloid (6 and 8‐month‐old) phases, we found that four altered circRNAs were shared in both stages, 37 exclusively in pre‐amyloid stage and 490 in amyloid stage (Figure 3).

Conclusion

Our results demonstrate an increasing dysregulation in circRNAs profiles in the hippocampus of the APP/PS1 mice. Considering the role of circRNAs as transcriptional regulators, one could argue that these progressive changes may impact gene expression in AD‐related brain regions.
Association of Chronic Anti‐GERD Medication Usage and Cognitive Decline in a Racially Diverse Elderly Population
Authors: Holland Thomas Monroe , Dhana Klodian , Agarwal Puja , Krueger Kristin R , Desai Pankaja , Liu Xiaoran , Beck Todd , Schneider Julie A , Rajan Kumar B
Published: December 2023

Background

It is understood that early medical intervention of various diseases, like cardiovascular or gastroenterological, is a potential way to mitigate the progression of cognitive decline and dementia. However, some medications’ mechanisms of action (MOA), may alter the metabolism of foods and absorption of nutrients and inhibit neurotransmitters. The long‐term influence of chronic medication use on cognition in a racially‐diverse elderly population is unknown. As such, we aim to investigate how chronic use of specific Anti‐GERD medications (e.g., proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA’s), may be associated with global cognitive decline and cognitive functional domains

Method

Utilizing data collected from a long‐running, community‐based study, the Chicago Health and Aging project (CHAP) which started in 1993, we examined the association of anti‐GERD medication use and cognition in n = 7742, 1268 (16%) PPI users and 939 (12%) H2RA users, aged ≥65 years. This study sample consists of 63% African American (AA) participants and 60% female participants. Recruitment and data collection occurred in triennial cycles. Medication use was assessed through direct observation while neuro‐cognition was evaluated using a battery of 4‐standardized cognitive tests. Using linear mixed effects change‐point models, adjusted for age, sex, education and race, we investigated whether chronic anti‐GERD medication usage is associated with cognitive decline

Result

Of anti‐GERD medication users, after starting the medication, chronic use of PPI’s was associated with a faster rate of global cognitive decline β = ‐0.028 (p≤0.000), memory score β = ‐0.023 (p≤0.000) and speed score β = ‐0.012 (p≤0.034). H2RA’s were not associated with global cognition or memory score but were suggestive for speed score β = ‐0.011 (p≤0.057). In models stratified by race and separately, sex, after starting, chronic PPI use was associated with faster global cognitive decline in AA β = ‐0.030 (p≤0.000), White β = ‐0.026 (p≤0.001) and female β = ‐0.037 (p≤0.000) but not male individuals. H2RA’s were only associated with faster global cognitive decline in White individuals β = ‐0.025 (p≤0.039)

Conclusion

Chronic use of PPI’s and H2RA’s may be associated with faster rates of global cognitive decline and memory & speed scores in an elderly population. The associative results presented, demonstrate the need for further investigation into how medication usage potentially impacts cognition
Alzheimer’s disease‐associated post‐translational modifications of tau influence tau propagation
Authors: Dickson John R , Fernandes Analiese R , Sobolewski Robert , Fan Zhanyun , Hyman Bradley T.
Published: December 2023

Background

In Alzheimer’s disease (AD), tau accumulates with a stereotyped progressive involvement of brain regions. The cellular mechanism for this is the neuron‐to‐neuron propagation of tau, but the factors that influence tau propagation are not fully understood. We hypothesize that AD‐associated post‐translational modifications (PTMs) of tau reduce its propagation since lysines are critical for LRP1‐mediated tau uptake.

Method

A construct was designed to model tau propagation in Chinese hamster ovary (CHO) cells and allow identification of donor and recipient cells by immunocytochemistry and flow cytometry. In addition to the wildtype (WT) tau sequence, constructs were made with pseudophosphorylation and pseudoacetylation mutations corresponding to the phosphorylations and acetylations found on low molecular weight (LMW) and high molecular weight (HMW) tau species in AD brains. Additionally, individual PTM mimic mutations corresponding to PTMs of the LMW tau species were made. The constructs were transfected into CHO cells and tau propagation was assessed by flow cytometry after 48 hours. Statistical analysis was performed by ANOVA with adjustment for multiple comparisons.

Result

Tau propagation using this cell culture model was demonstrated by immunocytochemistry and flow cytometry. Comparison of the WT, LMW‐mimic (8D2Q mutant), and HMW‐mimic (20D3Q mutant) tau propagation constructs revealed that the 8D2Q and 20D3Q mutants displayed reduced tau propagation compared to WT by 23.7% (p = 0.0186) and 26.5% (p = 0.0087), respectively. Comparing the ten single mutant constructs to WT, T181D and T231D showed increased tau propagation by 20.3% (p = 0.0002) and 15.9% (p = 0.0094), respectively. Compared to WT, T217D, K281Q, K353Q, and S404D showed reduced tau propagation by 17.3% (p = 0.0030), 15.3% (p = 0.0123), 23.7% (p <0.0001), and 16.6% (p = 0.0046), respectively.

Conclusion

The mimics of AD‐associated tau PTMs found on LMW and HMW tau reduce tau propagation, consistent with the initial hypothesis. The impact of individual PTM mimics on tau propagation is variable, but notably both pseudoacetylation mimics reduce propagation, possibly due to lower affinity with LRP1. Understanding how AD‐associated tau PTMs impact tau propagation may suggest novel targets to slow the progression of AD pathology.
Alzheimer’s disease risk genes are differentially expressed upon Lipopolysaccharide stimulation in a myelogenic cell model
Authors: Arnesen Peter Mikael , Wettergreen Marianne , You Panpan , Fladby Tormod
Published: December 2023

Background

Lipopolysaccharides (LPS) is a molecule present in the outer membrane of Gram‐negative bacteria. Previous studies have shown that LPS treatment can lead to upregulated pro‐inflammatory and chemotactic cytokines, or elevate the expression of anti‐inflammatory factors in mouse or cell models. Inflammation is seen around amyloid plaques and around small cerebral vessels with Ab1‐40 deposits in AD brains. Increased levels of LPS have been found in the hippocampus of patients with Alzheimer’s disease, compared to age‐matched controls. Other studies demonstrated that LPS is also present and associated with white matter injury in AD and aging brains. Continued inflammation activates microglia and macrophages, which are ialso localized in perivascular tissue. However, to what extent the increased inflammation influences the expression of AD risk genes in myelogenic cells is not well known. Here we utilized RNA sequencing on THP‐1 derived macrophages using Aβ and LPS as stressors to further elucidate this.

Method

We performed RNA sequencing on THP1‐derived macrophages, with or without Aβ and LPS stimulation. 50 known AD risk genes were cross‐checked against the differentially expressed genes discovered. Furthermore, KEGG pathway analysis was performed on the Aβ versus the LPS and Aβ group.

Result

Out of 50 AD risk genes, we identified a total of 24 genes in the various comparison groups (Figure 1). 14 AD risk genes were discovered in all the groups: TREM2, LILRB2, BIN1, TNIP1, CD2AP, CD33, CASS4, MS4A4A, NCK2, ADAMTS1, SPI1, RIN3, ECHDC3, AGRN (Figure 1 and2). KEGG pathway analysis pointed out TNF signaling pathway, lysosome, endocytosis and ubiquitin mediated proteolysis as enriched for cells stimulated by LPS with Aβ present (Figure 3).

Conclusion

Our study demonstrates that LPS activates inflammatory responses in myelogenic cells that further affects AD risk gene expression. Enriched pathways not only relate to Aβ uptake and clearance, but also reflect AD pathology. LPS and/or LPS induced inflammation may be a significant initiator or progressive contributor to inflammatory degeneration in AD.