bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic characterization of a Puerto Rican Alzheimer disease cohort implicates convergent immune‐related pathways
Authors: Griswold Anthony J. , Gardner Olivia K. , Rajabli Farid , Hamilton‐Nelson Kara L. , Adams Larry D. , Rodriguez Vanessa C. , Mena Pedro Ramon , Whitehead Patrice L. , Hofmann Natalia K. , Garcia‐Serje Catherine , Silva‐Vergara Concepcion , Feliciano Nereida I. , Feliciano‐Astacio Briseida E. , Acosta Heriberto , Haines Jonathan L. , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W. , Pericak‐Vance Margaret A.
Published: December 2020

Background

Genetic risk factors for Alzheimer disease (AD) demonstrate distinct effects across diverse ancestral populations. The ancestral heterogeneity (admixture) of Caribbean Hispanics from Puerto Rico (PR), makes studies of the PR population important in the discovery of ancestry‐specific factors in AD. To expand ongoing genomic investigations of AD in PR individuals, it is necessary to characterize functional downstream effects by studying gene expression and regulation. Here we characterized the differences in gene expression, splicing, and RNA editing of the protein coding transcriptome from peripheral blood in PR individuals. to identify case vs control differential expression, splicing, and RNA editing in this diverse population.

Method

Poly‐A selected RNA was from peripheral whole blood of 76 PR individuals over the age of 65 (39 AD, 37 cognitively normal controls) was sequenced and analyzed with a standard bioinformatics pipeline. Differential expression between PR cases and controls was calculated using DESeq2, alternative splicing using LeafCutter software, and RNA editing with REDITools and linear models. All analyses were adjusted for sex, age, and sequencing coverage. For each analysis, pathway enrichment analysis of Gene Ontology Biological Processes and KEGG gene sets were used to identify underlying biological pathways.

Result

A total of 761 genes (518 up‐regulated, 243 down‐regulated) were differentially expressed between PR AD and controls (adjusted p ≤ 0.05). At the transcript level, 561 genes had a significant (FDR ≤ 0.05) differential splicing event. We also identified 35,246 total RNA editing sites. While there was no significant difference globally, 422 sites in 159 genes showed nominally significant editing difference (p ≤ 0.05). These genes, isoforms, and RNA editing sites overlap little with previous investigations of the transcriptomes of Non‐Hispanic Whites and African‐American AD with only a few genes in common. However, pathway enrichment across all three PR transcriptomic analyses consistently reveals differences in both the adaptive and innate immune response pathways, consistent with other ancestries.

Conclusion

Transcriptomic analyses of diverse populations in AD, shows stark divergence at the single gene level. However, the convergence on immune molecular pathways suggest shared underlying disease etiology and the possibility of broad therapeutic options.
Blood–brain barrier permeability measured by contrast‐enhanced MRI in early Alzheimer’s disease
Authors: Preis Lukas , Cetindag Arda Can , Villringer Kersten , Fiebach Jochen B. , Peters Oliver
Published: December 2020

Background

The importance of vascular integrity in the context of neurodegeneration and specifically Alzheimer’s disease (AD) is increasingly recognized. It has been shown that Blood‐brain barrier (BBB) breakdown in the hippocampus correlates with functional impairment independent of AD pathology. The aim of this study is to investigate BBB permeability in early stages of the AD continuum including subjective cognitive decline (SCD).

Method

Study participants were characterized according to the appropriate research criteria and categorized as normal controls (NC), individuals with SCD and mild cognitive impairment due to AD (MCI‐AD). Besides a clinical and neuropsychological assessment, the participants underwent structural magnet resonance imaging (MRI), ApoE genotyping and lumbar puncture. AD pathology was examined in accordance to the ATN‐system. Dynamic contrast‐enhanced (DCE) MRI T1 mapping and Patlak analysis using Rocketship software were employed to assess BBB permeability changes.

Result

Seventy‐one participants were included (NC = 18, SCD = 36, MCI‐AD = 17). The average age of the cohort was 75 years and the sample consisted of 41% females. The median MMSE scores were 30 for NC and SCD and 27 for the MCI‐AD group. Amyloid pathology, measured in the CSF, was detected in 11% of the NC group (n = 2), 58 % of SCD (n = 21) and 29% of MCI/AD (n = 5). Bilateral BBB dysfunction was identified in 44% of NC (n = 8), in 31% of SCD (n = 11) and 24% of MCI‐AD (n = 4), additionally unilateral BBB dysfunction has been identified in 22% of NC (n = 4), 25% of SCD (n = 9) and 41% of MCI‐AD (n = 7).

Conclusion

By using DCE MRI T1 mapping a surprisingly high proportion of increased BBB permeability in the hippocampus can be detected across all groups. Detailed analyzes will reveal the impact of BBB permeability on cognitive function in SCD.
Do repeated ambulatory cognitive assessments enhance the relation between objective and subjective cognition in non‐demented community dwelling older adults? Results from the Einstein Aging Study
Authors: Rabin Laura , Mogle Jacqueline , Katz Mindy J. , Sliwinski Martin J.
Published: December 2020

Background

Although subjective cognitive concerns are common in older adults and may portend progression to Alzheimer’s disease, the cross‐sectional relationship between subjective and objective cognition is inconsistent. Many studies report statistically significant, though weak, relations between self‐reported cognition and neuropsychological test scores among cognitively normal (CN) older adults and those with mild cognitive impairment (MCI). Others have failed to find an association or have found stronger associations between subjective cognition and psychosocial variables. We applied a novel approach to investigate the subjective‐objective cognition relation, using both conventional measures and daily assessments in ethnically/racially diverse older adults.

Method

Participants (n=229, mean age=76.97, 65% female, 50% White) completed in‐person neuropsychological tests and a paper‐and‐pencil questionnaire of change in cognitive functioning over 5 years. Additionally, for 14 days, they completed daily cognitive tasks and self‐reported their experience of cognitive difficulties via smartphones. Participants were classified as MCI (n=62) or CN (n=167) using Jak/Bondi criteria. We used correlational analyses (controlling for depression) to compare subjective/objective data stratified by cognitive status and logistic regression to examine associations with diagnosis.

Result

In MCI, there were statistically significant moderate associations (r=.34 to .38; p<.01) between daily diary self‐reported cognition (retrospective and prospective memory) and ambulatory assessments of processing speed and spatial memory, respectively (performance averaged over multiple trials, across days); there was no relationship with traditional neuropsychological tests. In CN, there were statistically significant, weak‐moderate associations between self‐report of decline in various cognitive domains and traditional tests of episodic memory and language (r=‐.22 to ‐.29; p<.01). Self‐reported cognition on daily diary but not questionnaire items was associated with group membership, controlling for age, education, sex, and general cognition (p<.05).

Conclusion

For individuals with MCI, daily reports of cognitive difficulties were moderately aligned with performance on objective ambulatory cognitive assessments. By contrast, in those with intact cognition, there was modest correspondence between single‐occasion retrospective reporting of cognition and traditional neuropsychological tests. Notably, only daily subjective report items predicted MCI status at baseline. Results have implications for enhancing the accuracy of assessments, particularly for those with MCI, through the inclusion of daily measurements to capture features of cognition that may otherwise be missed.
Associations of brain connectivity with disease progression and cognitive dysfunction in autosomal‐dominant Alzheimer disease depend on imaging modality
Authors: Dicks Ellen , Vermunt Lisa , Tijms Betty M. , van Der Flier Wiesje , Barkhof Frederik , Tanenbaum Aaron , Strain Jeremy F. , Morris John C. , Bateman Randall J. , Benzinger Tammie L.S. , Gordon Brian A. ,   the Dominantly Inherited Alzheimer Network
Published: December 2020

Background

In the early stages of Alzheimer disease (AD) brain connectivity becomes disrupted. Brain connectivity can be measured based on resting‐state fMRI, DTI and structural MRI (i.e., grey matter (GM) covariance). It currently remains unclear, whether the timepoint of brain connectivity disruptions and associations with cognitive dysfunction depend on the imaging modality used. Here, we investigated for each modality in autosomal‐dominant AD, at which time to estimated symptom onset (EYO) mutation carriers (MC) and non‐carriers (NC) start to diverge and their association with cognition.

Method

From the Dominantly Inherited Alzheimer Network (DIAN) we included all individuals who had one resting‐state fMRI (n=205), DTI (n=68) and/or structural MRI scan (n=434) available. Preprocessing and analysis are described in Fig.1. We calculated the network measures clustering, path length and their normalized versions (i.e., gamma and lambda). For each modality we used Bayesian mixed effects models with EYO as predictor to determine the first timepoint in the disease process, at which MC and NC start to diverge. We additionally assessed in MC the relationship between network measures and cognitive function (MMSE and logical memory, delayed recall), correcting for age.

Result

Across the EYO, GM‐based network measures showed divergences between MC and NC starting ‐8.1 years before symptom onset, followed by fMRI‐based network measures 0.7 years after symptom onset (Fig.2). For DTI, we found no significant differences, but MC showed slightly decreased clustering values around ‐10 years before symptom onset compared to NC. Both GM‐ and DTI‐based network measures showed associations with the MMSE, with the strongest effects for lower MMSE with lower gamma (standardized β±SE(DTI)=0.44±0.04; standardized β±SE(GM)=0.59±0.06; all p<0.001). GM‐ and fMRI‐based network measures were associated with logical memory performance, with the strongest effects for worse performance with lower lambda in fMRI‐based networks (standardized β±SE=0.16±0.07; p<0.05) and lower gamma for GM‐based networks (standardized β±SE=0.49±0.06; p<0.001).

Conclusion

GM‐based network measures showed the earliest differences between mutation carriers and non‐carriers, followed by fMRI. GM‐based network measures were associated with MMSE and logical memory, DTI with MMSE and fMRI with logical memory. This suggests that different modalities may capture specific processes in AD. Grant: P50AG005681.
Development and piloting of a novel 15‐minute cognitive telephone (FACT) screen to diagnose mild cognitive impairment and dementia
Authors: Ellajosyula Ratnavalli , Narayanan Jwala , Ramanan Siddharth , Dev Nidhi
Published: December 2020

Background

It is crucial to follow up patients with mild cognitive impairment (MCI) and dementia. For persons unable to visit hospital for follow‐up, we designed a brief telephone‐screen, the fifteen‐minute assessment of cognition over the telephone (FACT). This was piloted for its ability to diagnose and differentiate patients with MCI and Alzheimer’s disease (AD).

Method

The FACT consists of 27 items categorized under attention and orientation, memory, language, and executive functions domains. Patients with MCI (n=40), AD (n=40) and healthy age and education matched volunteers (n=23) were administered the FACT a week after presentation and neuropsychological testing at the clinic. Performance on the Addenbrookes Cognitive Examination (ACE III) was used as a gold standard.

Result

FACT correlated well with ACE III, the Pearson correlation coefficient was 0.82 (p = 0.00). The subcomponents of both tests also showed moderate to high correlations. The area under the ROC curve for FACT discriminating MCI from AD was 0.92 and MCI from healthy volunteers was 0.83.

Conclusion

The novel telephone interview screen (FACT) was comparable to the ACE III in diagnosing and differentiating patients with MCI from AD. A mobile telephone usage is almost universal across India including poor, illiterate and rural population. Thus the use of FACT as a screening tool may be extended to population surveys, which are crucial in tackling dementia, a major health challenge in India.
Mitochondria‐targeted therapeutics restore cognitive function and halt progression of neuropathology in symptomatic AD mice
Authors: Stojakovic Andrea , Trushin Sergey , Chang Su‐Youne , Li Xing , Khalili Layla , Lee Michael K. , Trushina Eugenia
Published: December 2020

Background

We have previously demonstrated that partial reduction of mitochondrial complex I (MCI) activity using small molecules is efficacious in decreasing levels of amyloid beta (Aβ), phosphorylated Tau, augmenting mitochondrial bioenergetics, promoting resistance to oxidative stress and restoring mitochondrial axonal trafficking, levels of BDNF and synaptic proteins in pre‐symptomatic APP/PS1 mice. In parallel, these mice demonstrated an improved cognitive and behavioral phenotype compared to their untreated littermates.

Method

In the current study, we tested whether treatment with MCI inhibitors could halt the disease progression when treatment was administered to symptomatic APP/PS1 mice.

Result

Treatment improved glucose tolerance, prevented body weight loss, and ameliorated systemic inflammation. Treatment improved glucose uptake in the brain measured using FDG‐PET imaging. Electrophysiological recording in hippocampus indicated that synaptic activity and LTP were restored in treated APP/PS1 mice. Data gathered using 3D electron microscopy reconstruction of dendrites in CA1 region of hippocampus showed that treatment increased the population of mature dendritic spines in APP/PS1 mice, which correlates with restored synaptic activity and improved glucose uptake and utilization in the brain. Immunohistochemical analysis showed that treated APP/PS1 mice had reduced brain level of Aβ plaques, markers of inflammation and reduced degeneration of TH+ neurons in locus coeruleus. The RNA‐seq gene function enrichment analysis showed that pathways down‐regulated by treatment with MCI inhibitors in APP/PS1 mice included the ones involved in oxidative stress and immune system response. Moreover, RNA‐seq data analysis depicted a cluster of genes involved in dendritic morphology, axonal guidance and neuronal development, which expression were reverted by treatment in APP/PS1 mice to the level observed in NTG mice. Western blot analysis in cortico‐hippocampal brain region of APP/PS1 mice confirmed that treatment increased signaling molecules involved in IGF‐1/insulin pathway, mitochondrial biogenesis, oxidative stress protection, autophagy and synaptic function.

Conclusion

Overall, our data suggest that long‐term treatment with MCI inhibitors is safe and efficacious in restoring cognitive function and preventing degeneration in symptomatic APP/PS1 mice. Therefore, partial MCI inhibitors represent a promising therapeutic approach to ameliorate AD and promote healthy aging.
Functional analysis of candidate genes identified through whole genome sequencing in Caribbean Hispanic families for late‐onset Alzheimer disease
Authors: Wang Liyong , Cukier Holly N. , Rajabli Farid , Hofmann Natalia K. , Adams Larry D. , Rodriguez Vanessa C. , Mena Pedro Ramon , Garcia‐Serje Catherine , Silva Concepcion , Feliciano Nereida I. , Feliciano‐Astacio Briseida E. , Acosta Heriberto , Vance Jeffery M. , Beecham Gary W. , Pericak‐Vance Margaret A.
Published: December 2020

Background

To identify LOAD risk genes in Puerto Ricans (PR), a population underrepresented in genetic studies, linkage analysis of whole genome sequencing (WGS) in 23 multiplex PR families identified a peak on chromosome 9p21 (MLOD = 3.9). The 1‐LOD unit down region spans from 31∼38Mb; identity‐by‐descent (IBD) sharing region spans from 23‐39 Mb. Two genes in the linkage region, UNC13B, located in the center of the linkage peak (35.1∼35.4 Mb), and ELAVL2 (23.7∼23.8 Mb), at the edge of the IBD sharing region, are of interest. Both genes have multiple rare variants with low minor allele frequencies (MAF) and high CADD scores that segregate with LOAD in the families. UNC13B encodes a protein involved in Ca2+ release at the synapse, and calcium dysfunction has been associated with LOAD. ELAVL2 encodes a neural‐specific protein involved in RNA processing.

Method

Recombinant plasmids for testing overexpression (UNC13B) and promoter activity (ELAVL2) were made by site‐directed mutagenesis and transfected into the neuronal SH‐SY5Y.

Result

Two UNC13B missense variants, rs35199210 (Asp238Glu, CADD = 22, MAF = 0.5%) or rs41276043 (Phe1096Leu, CADD = 26.5, MAF = 0.5%) have been cloned into overexpression vectors and are currently being evaluated for their effect on Ca2+ release rates. One promoter variant rs542037226 (CADD = 16.6, MAF = 0.03%) in the ELAVL2 demonstrated strong activity (∼200x higher than the empty vector), and the rare allele showed reduced activity compared to the reference allele (10% reduction, p = 0.03).

Conclusion

Two potential new LOAD genes with rare variants have been identified within the linkage 9p21 linkage peak. Using segregation and in‐silico analysis we have prioritized rare variants in each gene for testing. Successful demonstration of functional changes in the ELAVL2 variants provide support for this approach. Evaluation of UNC13B variants are underway. Those variants with functional effects will be further evaluated in our inducible pluripotent stem cell models.
Blood‐cell‐based biomarker detection of Alzheimer’s disease
Authors: Cliff Richard O
Published: December 2020

Background

There is an urgent need for early screening diagnostics for Alzheimer’s disease (AD), cases continue to increase without effective diagnosis and treatment solutions. There is no test to diagnose AD at its earliest stages in healthy asymptomatic individuals to determine disease status. Fluid biomarkers, particularly blood‐based, could have the capacity to be widely implemented as diagnostic screens and to rule‐in/rule‐out further invasive and expensive testing. Amyloid‐beta (Aβ) oligomers continue to be a compelling target for therapeutics and diagnostics, are present in blood and are bound by blood cells. Given the accumulated evidence that Aβ oligomers are present in blood; we are developing a novel early detection blood cell‐based biomarker test using proprietary peptide ligands before any signs of AD in healthy asymptomatic individuals, much like a cholesterol blood test for cardiovascular disease.

Method

Our technology, Pronucleon™ peptides, involves custom‐synthesized peptides that mimic the misfolding region of proteins such as Aβ. We’ve established specific, sensitive and selective detection of Aβ oligomers with our peptides using spectroscopic techniques. For this study we measured the binding capacity index (BCI) of blood cells using the following assay: diluted whole blood was incubated with or without our proprietary stabilized Aβ oligomer; fluorescently‐labeled Pronucleon™ peptide was then incubated with the blood samples followed by flow cytometric analysis. We compared the fluorescence intensity of each sample, one with and one without the stabilized Aβ oligomer. The assay was performed on 60 clinical samples (n=20 for each Control, MCI and AD) followed by statistical analysis to confirm any differences within and between the patient groups.

Result

Pronucleon™ peptides displayed specificity and sensitivity for Aβ oligomers; peptides also showed increased binding to AD blood cells as compared to normal; our cell‐based flow cytometry assay exhibited differentiation in BCI scoring between healthy and AD samples.

Conclusion

These results set the stage for further development of an exciting innovative approach toward a screening tool for diagnosing Alzheimer’s disease, allowing the primary care setting in the medical community, the AD therapeutic community and the public an opportunity to address early detection of this disease before its symptoms appear.
A novel gut microbiome therapeutic derived from dietary polyphenols attenuates neuroinflammation in vivo in a model of c9orf72 mediated frontotemporal dementia
Authors: Trageser Kyle J. , Smith Chad , Estill Molly , Sebastian Maria , Pasinetti Giulio Maria
Published: December 2020

Background

Frontotemporal dementia (FTD) is a neurodegenerative disorder with various genetic etiologies, the most prevalent of which include G4C2 expansions in the c9orf72 gene. Expansions produce dipeptide repeat proteins (DPR), forming aggregates with deleterious impacts on cellular processes and correlating with neuroinflammation. Glycine‐Arginine (GR) aggregates are the only significantly correlated DPR found in clinically relevant neuroanatomical regions of the brain. Our current study investigates the contribution of innate immunity to FTD pathogenesis and the attenuation of neuropathologies with the brain bioavailable microbiome‐derived metabolite, 3‐hydroxybenzoic acid (3‐HBA).

Method

Mice were transfected via intracerebroventricular injection with AAV9‐GFP(GR)100 or AAV9‐GFP and treated starting on Day 28 with either PBS vehicle or 50 mg kg‐1 of 3‐HBA. At 14 weeks mice were sacrificed and frontal cortex (FC), somatosensory cortex (CTX), and hippocampal (HP) tissue was dissected and prepared for RNA sequencing. Differentially expressed genes (DEGs) were identified using DESeq2 and pathway alterations were detected using Ingenuity Pathway Analysis. ELISA for IL‐1β was conducted on FC, CTX, and HP tissue. To determine the ability of 3‐HBA to reduce secretion of IL‐1β, primary microglia pretreated with 3‐HBA were stimulated with LPS+ATP and IL‐1β concentration was analyzed by ELISA.

Result

DEGs associated with FTD pathology, protein expression levels of the pro‐inflammatory cytokine IL‐1β, and subsequent amelioration via treatment with 3‐HBA were demonstrated to be a result of contributions from the innate immune system and inflammasome activation in microglia. Inflammatory pathways differentially enriched among treatment groups include TREM1 Signaling, the complement system, and NFκB signaling. GR‐100 Vehicle treated animals exhibited elevated IL‐β in cortical tissue. 3‐HBA was efficacious in vivo in rescuing IL‐1β levels in GR‐100 HBA treated mice to levels of GFP animals. Primary microglia pretreated with 3‐HBA and stimulated with LPS+ATP significantly reduced IL‐1β release, signifying the efficacy of 3‐HBA in attenuating innate immune reactivity.

Conclusion

Pathways and genes associated with the innate immune system show enrichment in a model of FTD and are rescued by administration of 3‐HBA. Overexpression of IL‐1β in the cortex of GR‐100 Vehicle animals is attenuated by the administration of 3‐HBA. Our data implicates a gut‐brain axis mechanism of treatment for key FTD associated neuropathologies.
Top‐line data from a phase 1b biomarker‐directed, proof of biology study in Alzheimer's patients treated with XPRO1595, a second‐generation treatment for immune dysfunction
Authors: Tesi Raymond , Barnum Christopher , Tansey Malu Gamez
Published: December 2020

Background

Tumor Necrosis Factor (TNF) is the master regulator of chronic inflammation and immune dysfunction, which play a critical role in Alzheimer's Disease (AD). The current TNF inhibitors are contraindicated for neurologic disease due to complications (i.e., cause demyelination). XPro1595 is a second‐generation inhibitor designed to overcome the limitations of the current generation of TNF inhibitors to treat neurologic disease. We have received the Part the Cloud to RESCUE Award from the Alzheimer’s Association to conduct a biomarker directed, proof of biology, Phase 1b study.

Method

18 patients with a diagnosis of Alzheimer’s disease and biomarkers of inflammation in the blood were eligible to participated in a 12‐week, dose escalation study to establish safety and proof of concept that XPro1595 can reduce inflammation within the CNS.

Result

This presentation will focus on the challenges and lessons of using inflammatory biomarkers for patient enrollment in AD studies along with the safety data and available efficacy data.

Conclusion

Clinical data will be presented.
Subjective cognitive decline predicts progression to dementia in a multiracial community sample
Authors: Chapman Silvia , Rentería Miguel Arce , Avila Justina F. , Joyce Jillian L. , Manly Jennifer J. , Brickman Adam M. , Cosentino Stephanie
Published: December 2020

Background

Subjective Cognitive Decline (SCD) is the perception of cognitive decline before such decline is evident on standard neuropsychological testing. SCD is believed to precede the Mild Cognitive Impairment stage of Alzheimer’s disease (AD) when objective cognitive deficits first become evident and has potential as an early marker of AD. However, studies examining SCD have largely focused on non‐Hispanic White populations, limiting its applicability to Blacks and Hispanics, who are known to be at increased risk of developing AD. This study examines the predictive utility of SCD for conversion to dementia in a racially and ethnically diverse sample.

Method

Participants were a total of 5,379 older adults enrolled in a longitudinal, population‐based study of aging. Participants were non‐demented at baseline and were 26% non‐Hispanic White, 31% Black and 44% Hispanic (67% female; age=75±6yrs). SCD was assessed with a questionnaire assessing complaints of memory difficulties. Follow ups of approximately 18‐month intervals assessed for dementia at each visit based on comprehensive assessment of everyday function and cognition. Multi‐group Cox regression models tested main effects of baseline SCD on progression to dementia, and jointly modeled death during follow up as a function of race/ethnicity. Models were adjusted for age, depressive symptoms, sex, years of education, medical comorbidity burden, and enrollment cohort.

Result

SCD significantly predicted conversion to dementia in all groups (Non‐Hispanic White HR=1.65 [1.04, 2.61]; Blacks HR=1.62 [1.17, 2.24] and Hispanics (HR=1.74 [1.40, 2.17]). Although multi‐group modeling revealed no significant interactions between SCD and race (p> .05), when depressive symptoms were entered as a covariate in each model SCD significantly predicted conversion to dementia in Blacks (HR=1.77 [1.10, 2.84]) and Hispanics (HR=1.84 [1.36, 2.48]) only.

Conclusion

SCD predicted conversion to dementia across all racial/ethnic groups. However, when adjusting for depressive symptoms, the predictive utility of SCD remained only among Blacks and Hispanics. This pattern of findings highlights the utility of SCD as a marker of future conversion to dementia in diverse groups, while underscoring the complex association between SCD and depression. Future work should tease apart the basis of the unique pathways between depression and SCD as a function of race/ethnicity.
Mapping Alzheimer disease–associated regions in the African American population
Authors: Whitehead Patrice L. , Rajabli Farid , Hamilton‐Nelson Kara L. , Kunkle Brian W. , Reitz Christiane , Naj Adam C. , Bush William S. , Farrer Lindsay A. , Schellenberg Gerard D. , Mayeux Richard , Martin Eden R. , Byrd Goldie S. , Haines Jonathan L. , Beecham Gary W. , Pericak‐Vance Margaret A. ,   Alzheimer’s Disease Genetics Consortium (ADGC) and Collaboration on Alzheimer’s Disease Research (CADRE)
Published: December 2020

Background

Genetic studies in Alzheimer disease (AD) are underrepresented in African‐descent populations. The African American (AA),population, with the admixed genetic ancestry (African and European) and high African ancestral background (∼80%), provides a unique opportunity to discover African ancestry‐specific genetic factors in AD. Admixture mapping (AM) is a powerful approach for genetic mapping of complex disease in admixed populations. AM uses local ancestry estimates to identify the genetic regions of specific ancestral origins (African, and European) that are associated with AD. These regions are likely to contain risk or protective genes for AD, and identifying these regions will inform sequence analysis in these and additional datasets.

Methods

Analyses included 9050 individuals from 16 ADSP and ADGC cohorts We estimated and inferred global ancestry using the GENESIS software that provides robust inference of genetic ancestry in the presence of known and/or cryptic relatedness. To infer local ancestry the target AA dataset was combined with appropriate reference population samples from HGDP reference panel. Local ancestry was estimated using SHAPEIT followed by RFMix. We performed AM using the GENESIS software separately on 16 different cohorts. To meta‐analyse the admixture mapping results we developed in‐house scripts to align the ancestral blocks across cohorts. We used the METAL software for meta‐analysis and STEAM software to estimate the significance threshold.

Results

We estimated significant threshold for admixture mapping analysis in AA dataset as 7.3e‐5 using analytic approximation approach from the STEAM package. The most significant region from the meta‐analysis was found on chromosome 4p16.3 (p‐value = 1.4e‐4) failed to reach genome‐wide significance. However, n two individual cohorts ADC8 (sample size = 850) and ADGC‐CHOP (sample size = 2,869) two regions showed genome‐wide significant association with disease on chromosome 18q21.33 (p‐value = 1.2e‐6) and chromosome 19p13.3 (p‐value<2.1e‐5), respectively.

Conclusion

Our results confirm association of AD with the known ABCA7 genetic region on chromosome 19p13.3 through AM and suggest a genetic region for AD in AA population on 18q21.33; however, findings were not consistent across cohorts. We are in the process of analyzing data from additional AA cohorts to increase the power and allow us to dissect heterogeneity of AD in AA population.
Distinct contributions of longitudinal tau and amyloid to decline in various cognitive domains in preclinical AD
Authors: Farrell Michelle E. , Papp Kathryn V. , Jacobs Heidi I.L. , Buckley Rachel F. , Properzi Michael J. , Schultz Aaron P. , Hanseeuw Bernard , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A.
Published: December 2020

Background

We sought to assess the preclinical contributions of longitudinal Aβ and tau accumulation at different baseline Aβ levels to decline across multiple cognitive domains.

Method

124 clinically normal older adults from the Harvard Aging Brain Study with longitudinal Aβ (PIB), tau (FTP) and cognition (PACC) were included (median follow‐up=8.0±1.0 years). The following linear mixed models examined neocortical PIB and inferior temporal (IT) FTP change effects on PACC and its component tasks and included age, sex, APOE and education as covariates: 1) Time*PIB level t0*PIB change t0‐3 on cognition t0‐8, with post‐hoc regional analyses. 2) Time*PIB level t3*FTP change t3‐8 on cognition t3‐8, because FTP was introduced at t3. Mediation analyses assessed whether the effect of PIB change t0‐3 on subsequent cognitive decline t3‐8 was mediated by IT‐FTP at t3.

Result

Increasing PIB change‐t0‐3 was associated with declining cognition‐t0‐8 across all tasks at higher PIB‐t0 levels (Figure 1). The Digit Symbol Substitution Test (DSST) also declined with increasing PIB change at low PIB‐t0 levels (β=‐1.99, p=.002). FTP change‐t3‐5 was associated with declines at high PIB‐t3 levels for all PACC components except DSST (Figure 2). Only free recall (Free and Cued Selective Reminding Test; FCsrt‐FR) exhibited FTP change‐related decline in low PIB adults (β=‐1.70, p=.02). Mediation analyses demonstrated that FTP‐t3 mediated the effect of PIB change t0‐3 on cognitive decline t3‐8 for all PACC components except DSST, which remained associated only with PIB change (Figure 3). Regional analyses revealed different patterns of increasing PIB change associated with FCsrt‐FR and DSST decline (Figure 4).

Conclusion

Two different patterns of cognitive decline were observed: 1) A tau‐mediated pattern of steeper decline across multiple domains in individuals with high Aβ. Free recall declined starting at low Aβ levels, in association with tau and accumulating Aβ in regions important for memory retrieval. 2) A decline on the DSST associated with accumulating Aβ, but not IT tau, even in those with low Aβ. DSST involves processing speed and executive function. The broader pattern of Aβ accumulation was associated with DSST decline suggests it may reflect a general cognitive slowing in response to Aβ‐mediated changes in synaptic transmission.
Sex differences in cortical microstructural changes in asymptomatic individuals at risk for Alzheimer’s disease
Authors: Chance Steven A , Torso Mario , Chiesa Patrizia Andrea , Lemercier Pablo , Vergallo Andrea , Lista Simone , Potier Marie‐Claude , Dubois Bruno , Hampel Harald ,   the INSIGHT‐preAD Study group
Published: December 2020

Background

The preclinical phase of Alzheimer’s disease (AD) is characterized by cortical microstructural changes before the appearance of clinical symptoms. Previous studies have shown that women can present significantly faster age‐related decline than men [Filon et al., 2016; Barnes et al., 2005; Ferretti et al., 2018]. The aim of the present study was to investigate the impact of sex in whole brain cortical changes in an asymptomatic population at risk for AD.

Method

A total of 167 subjects (68 males and 99 females) recruited in the Investigation of Alzheimer’s Predictors in Subjective Memory Complainers (INSIGHT‐preAD) study, were included in the present work. The T1 structural and diffusion tensor imaging (DTI) scans acquired at baseline and after 24 months, were analysed to calculate 3 novel cortical diffusion measures (AngleR, PerpPD and ParlPD) [McKavanagh et al., 2019] and the mean diffusivity (MD). An independent sample t‐test was used to assess group differences in demographic, clinical and MRI volumetric values. A linear regression analysis was performed to investigate the role of sex, age and APOE genotype on baseline cortical values. The repeated measures ANOVA was used to assess cortical diffusion differences at baseline and follow‐up.

Result

Men compared with women showed higher angle between the principal diffusion direction and the radial minicolumn direction across the cortex at the baseline (p=0.001). No demographic, clinical nor brain volumetric differences between men and women were detected. The linear regression analysis revealed that only sex explains differences in AngleR values (p=0.001). The repeated measures ANOVA showed a significant effect of time (p=<0.001) and a significant interaction between time and sex (p=0.013), with a higher progression rate in women compare to men.

Conclusion

These findings indicate that sex has a significant effect on cortical changes and in their progression rate. The DTI measures could have a central role in enabling individual’s specific characterization and may be informative for the development and assessment of potential drug targets that are specific for each subgroup.
Creating technology for and with people with MCI and dementia in the workplace
Authors: Shastri Karan , Dove Erica , Marashi Sheida , Boger Jennifer , Astell Arlene J
Published: December 2020

Background

The potential of technology to assist people who are diagnosed with MCI or early dementia (EOD) whilst still working is under‐explored.

Method

Semi‐structured interviews and participatory design sessions were held with people working with MCI/EOD and family care partners aged between 45‐65 years to identify their technology preferences, challenges they faced, redesigning their workspace and future solutions. Sessions were video and audio recorded for analysis of the problems with NVivo 12 and to elicit design considerations.

Results

Five themes emerged from the interviews and participatory sessions: 1. Challenges at work, 2. Accommodations at work, 3. Diversity of supportive technologies, 4. Pressure points and strategies, and 5. Potential ideas and design cues.

Conclusion

People working with MCI/EOD currently appropriate technology to support them, have clear ideas of the challenges they face and design suggestions for future technological supports. These should be viewed within the ecosystem surrounding individuals working with MCI/EOD, particularly workplace legislation and stimulus for employers to meet their needs.
Agora: An open platform for exploration of Alzheimer’s disease evidence
Authors: Greenwood Anna K. , Gockley Jake , Daily Kenneth , Aluthgamage Duminda , Leanza Zoë , Sieberts Solveig K. , Woo Kara H. , Simon Stockard , Gendel Alina , Thyer Tess , Do Khai , Doerr Megan , Peters Mette A. , Omberg Larsson , Logsdon Benjamin A. , Mangravite Lara M.
Published: December 2020

Background

New therapies for treating Alzheimer’s Disease (AD) are urgently needed. Discovery‐based research approaches have identified a host of promising new AD targets across a spectrum of therapeutic hypotheses. However, progress to validate selected targets and develop new experimental reagents and therapeutics requires efforts beyond the focus of any single research group. We have built the Agora site as an open repository that publicly shares information about new AD targets to facilitate target evaluation by the broader AD research community.

Method

Agora aggregates information and experimental resources in support of nascent AD targets. We are expanding Agora to catalog evidence and experimental reagents being generated by the Open Drug Discovery Center for AD (Open‐AD).

Result

Agora is available at https://agora.ampadportal.org. Agora presents a list of nominated targets stemming from the Accelerating Medicines Partnership in AD (AMP‐AD) consortium and the broader AD research community. Agora also hosts interactive visualizations designed to support non‐bioinformaticians in the evaluation of data from RNAseq, proteomic, and metabolomic studies. Updates to Agora in support of the new Open‐AD center include 1) presentation of individual scorecards for nominated targets based on multiple lines of evidence and 2) a new exploration framework in which targets are mapped onto therapeutic hypotheses.

Conclusion

Agora is a platform to enable the AD research community to unite around promising target hypotheses.
Illiteracy and risk of mild cognitive impairment among Mexican older adults: Data from the Mexican Health and Aging Study (MHAS)
Authors: Rentería Miguel Arce , Vonk Jet M.J. , Arango Silvia Mejia , Obregon Alejandra Michaels , Samper‐Ternent Rafael , Wong Rebeca , Barral Sandra , Tosto Giuseppe , Manly Jennifer J
Published: December 2020

Background

Mild cognitive impairment (MCI) is a diagnostic entity associated with increased risk of incident dementia. Prior epidemiological studies have associated illiteracy and low to no formal education with increased prevalence of MCI and dementia. A recent study using a robust neuropsychological approach with the harmonized cognitive assessment ancillary study (Mex‐Cog) of the Mexican Health and Aging Study (MHAS) found that low education as well as older age, depression, diabetes, and rurality were independently associated with MCI among older adults. Rates of illiteracy are relatively high among older adults in Mexico, due to limited access to formal education, but some people attained literacy despite not attending school. To assess the unique contribution of literacy to MCI independent of educational achievement in a Mexican population, we evaluated literate and illiterate older adults with no formal schooling.

Method

Analyses included a sample of literate and illiterate non‐demented adults over the age of 55 living in both urban and rural areas of Mexico who reported that they never attended school (N = 231). MCI diagnosis was assigned based on a comprehensive cognitive assessment for domains of memory, executive functioning, language, and visuospatial ability. Cognitive impairment was defined using a robust norms approach and a 1.5‐SD cut‐off per cognitive domain correcting for age, years of education, and sex. Multinomial logistic regressions evaluated the association of self‐reported literacy, age, and sex with risk of MCI. We then evaluated whether the relationship between literacy and MCI remained after controlling for sociodemographic and health factors.

Result

Illiteracy was associated with increased risk of MCI (OR=6.05 [3.33, 11.34]) compared to literate participants. The relationship between literacy and risk of MCI persisted after taking into account depression, rurality, hypertension, and diabetes.

Conclusion

We found that illiteracy was independently associated with higher risk of prevalent MCI. Our findings suggest that independent of formal education, attainment of literacy has a long‐lasting impact on brain health at older ages. Future studies in low socioeconomic populations should consider functional literacy as a powerful predictor of cognitive function in old age.
Longitudinal online weekly health reports of non‐cognitive symptoms and events can differentiate incident MCI from stable cognitively healthy older adults
Authors: Kaye Jeffrey , Mattek Nora , Beattie Zachary , Sharma Nicole , Riley Thomas , Dodge Hiroko H.
Published: December 2020

Background

Changes in mood, loneliness, pain, and need for assistance may be potential early markers of cognitive decline in older adults. These changes can be subtle, and fluctuating, and thus easily missed during intermittent clinic visits. Continuous long‐term monitoring of these self‐reported internal states and needs, and their relationship to developing cognitive impairment has not been assessed.

Method

Weekly online reports of health‐related activities and mood in relation to MCI were assessed over four years in volunteers participating in the Oregon Life Laboratory, a study using home‐based unobtrusive remote sensing and monitoring of physical, cognitive, behavioral, physiological, and health‐related activities. Participants were older adult computer users living in retirement communities and free‐standing homes.

Result

The analytic sample included 129 cognitively healthy volunteers with a mean monitoring period of 2.9 ± 1.2 years completing 16,738 online surveys. Mean age was 83.5 ±7.8 years, mean education was 15.7 ± 2.7 years, and 76% were female. Twenty‐two participants (17%) developed MCI or dementia while 107 remained cognitively healthy. Results from longitudinal models with dichotomous outcomes including 1) loneliness, 2) low mood, 3) pain intensity and pain interference, and 4) in‐home assistance were run adjusting for covariates. Over time, those destined to develop MCI reported: 1) more loneliness (p=0.049), 2) more low mood (p=0.07), 3) greater pain intensity (p=0.026) and pain interference (p=0.011), and 4) needing more in‐home assistance (p=0.022) than those remaining cognitively healthy. Baseline standard clinical scale scores assessing these symptoms were not clinically concerning nor predictive of MCI. Baseline mean pain intensity scores (range: 0‐9) were 2.2 ± 2.0 among incident MCI and 1.8 ± 2.0 in stable cognitively healthy participants (p=0.23). Geriatric Depression Scale baseline scores were 1.0 ± 1.5 in incident MCI and 1.1 ± 1.7 in stable cognitively healthy participants (p=0.82).

Conclusion

Continuous home‐based online assessment of non‐cognitive aspects of function or internal states (loneliness, mood, pain, needing more assistance) can be sensitive early indicators of changes in brain function leading to cognitive decline. These clinically important measures may reflect both direct as well as indirect relationships to underlying neuropathology.
Single nucleus and bulk homogenate RNA‐sequencing comparison of vascular endothelial growth factor family associations with Alzheimer's disease
Authors: Moore Annah M. , Mahoney Emily R. , Dumitrescu Logan , De Jager Philip L. , Koran Mary Ellen I. , Petyuk Vladislav A. , Robinson Renã A.S. , Ruderfer Douglas M. , Cox Nancy J. , Schneider Julie A. , Bennett David A. , Jefferson Angela L. , Hohman Timothy J.
Published: December 2020

Background

Previous work from our group and others has suggested that the VEGF family of genes and proteins may be involved in the pathophysiology of Alzheimer’s disease (AD) and associated cognitive decline. Using dorsolateral prefrontal cortex (DLPFC) RNA sequencing (RNA‐seq) data (N = 531), we have characterized robust associations between gene expression of four family members (VEGFB, PGF, FLT1 and FLT4) and AD diagnosis, neuropathology, and associated cognitive decline. More specifically, increased brain expression of these genes was associated with worse outcomes. Single nucleus RNA sequencing (snRNA‐seq) of DLPFC became available for a small subset of this cohort (N = 48). We set out to assess associations between gene expression of these family members and cognitive decline using snRNA‐seq and compare to homogenate RNA‐seq findings to better understand the cell specificity of observed effects.

Method

Longitudinal cognitive and snRNA‐seq data from astrocytes, endothelial cells, microglia, oligodendrocytes, oligodendrocyte progenitor cells, pericytes, excitatory and inhibitory neurons were obtained from the Religious Orders Study and Rush Memory and Aging Project cohort studies. Linear regression and mixed‐effects regression were used to assess VEGF gene expression associations with global cognition and cognitive change, respectively. Models covaried for age at death, sex and postmortem interval and were subjected to the Benjamini‐Hochberg procedure to correct for multiple comparisons within cell types.

Result

PGF and FLT4 expression across cell types was too low to be considered in statistical models. FLT1 expression was largely restricted to endothelial cells. while VEGFB expression was highest in neurons and astrocytes. Interestingly, inhibitory neuron VEGFB expression approached a positive association with cross‐sectional cognition (p.fdr = 0.055), in opposition to the direction of our bulk homogenate finding. In contrast, oligodendrocyte VEGFB was negatively associated with cross‐sectional (p.fdr = 0.039) and longitudinal (p.fdr = 0.053) cognition, consistent with our previous findings in bulk.

Conclusion

Single nucleus VEGF expression analyses suggest that homogenate VEGFB associations with AD outcomes are driven by oligodendrocytes. VEGFB is a neuroprotective factor, and the observed upregulation in VEGFB could represent a stress response to AD pathology. The highly restricted expression of FLT1 to endothelial cells suggests that the relationship between FLT1 and cognitive trajectory reflects alterations in endothelial signaling.