bluuebunny/crossref_metadata_2025 huggingface dataset:
APOE‐e4 Status Moderates Associations between Executive Function and Air Pollution Exposure in Older Men
Authors: Franz Carol E , Elman Jeremy A. , Fennema‐Notestine Christine , Whitsell Nathan , Wu Tsung‐Chin , Tu Xin M , Qin Yongmei Amy , Kremen William S.
Published: December 2022

Background

Air pollution, which includes exposure to tiny particulate matter (PM2.5) and Nitrogen Dioxide (NO2) is a notable public health hazard. Exposure has adverse effects on multiple health outcomes as well as with increased risk of developing cognitive impairment and Alzheimer’s disease and related dementias. Although the primary cognitive focus in Alzheimer’s disease is memory, there is growing recognition of the importance of early executive function (EF) deficits as a risk indicator. In addition, there is some evidence of genetic susceptibility to pollution‐related cognitive decline. Few studies have strong measures of air pollution, EF, as well as APOE genotyping. We recently showed that APOE genotype was associated with significant decline in EF from middle to early old age among individuals who were cognitively unimpaired at baseline (Gustavson et al, 2022). Here we tested the hypothesis that the impact of air pollution on executive functions would be greater in APOE‐ε4+ carriers compared with APOE‐ε4‐ individuals.

Method

We examined associations between exposure in midlife and EF from midlife to early old age in ∼800 men from the Vietnam Era Twin Study of Aging. Measures included average PM2.5 and NO2 exposure in the three years prior to the time 1 (mean age 56; range 51‐61) assessment, and an executive function factor score at time 1 and time 2 (mean age 68; range 65‐72). GEE analyses adjusted for multiple health and lifestyle covariates, as well as the random effect of family.

Result

Cognitive performance declined over time from age 56 to age 68 (F = 439.38, p<0.0001). There were no main effects of air pollution on EF. Overall APOE‐ε4+ carriers had higher EF performance than non‐carriers (F = 5.43, p = 0.02). In addition, we found a significant PM2.5‐by‐APOE genotype interaction (F = 8.80, p = 0.003). Increased exposure to PM2.5 in midlife was related to lower executive function in APOE‐ε4 carriers, but not non‐carriers. The interaction with NO2 did not reach significance (F = 2.83, p = 0.09).

Conclusion

These results indicate that midlife PM2.5 exposure in men is associated with poorer frontal‐executive function, and APOEε4 carriers are more susceptible to the deleterious effects of PM2.5.
APOE genotype and blood pressure influence global and regional cerebral blood flow in older adults post‐high lipid feeding
Authors: Ashford Nathaniel K , Farris Kristen M , Levendovszky Swati Rane , Hanson Angela J
Published: December 2022

Background

Both hypertension and the E4 allele of the APOE gene are known risk factors for Alzheimer’s disease (AD). We investigated the influence of these factors on global cerebral blood flow (CBF) and four prespecified areas (angular gyrus, hippocampus, posterior cingulate, temporal lobe) using arterial spin labeling (ASL) MRI both in fasting state and after ingestion of a high fat drink.

Method

After fasting, 29 older adults (age 66.8 ± 4.1) underwent baseline and 1, 2, 3‐hour ASL MRI after ingestion of 1/2 cup heavy cream with comparable total and saturated fat to a high fat breakfast. We used pCASL MRI with background suppression to measure CBF in ml/100g/min. Imaging parameters were in accordance with the recommendations of ISMRM: label duration = 1.8 s, postlabeling delay = 2 s, labeling offset = 25‐30 mm, slices = 20, resolution = 3.5×3.5×5 mm3, SENSE‐factor = 2, TR/TE= 5000/18 ms. Finally, we acquired a reference scan (M0, 1 minute) identical to above scan but with TR = 10,000 ms and no labeling or background suppression. Statistical analyses included repeated measures ANOVA as well as cross‐sectional multiple regressions with robust estimators adjusting for age, E4 status, BMI, heart rate, systolic and diastolic blood pressure (DBP).

Result

Global CBF decreased at 1‐, 2‐, and 3‐hours post‐lipid drink, compared to time 0 (RM ANOVA F=5.57, p=0.002). These findings were recapitulated in the posterior cingulate (F=3, p=0.036) and hippocampus (F=3.3, p= 0.025); this difference was not seen in the temporal lobe or angular gyrus. E4 genotype was significantly associated with lower global CBF at hour 2 and in three areas examined (Table). Additionally, higher DBP was associated with lower CBF globally and in all four areas (Table).

Conclusion

CBF decreased in response to lipid ingestion, both globally and in regions known to be important in AD, and this was exaggerated in individuals with the E4+ genotype and with elevated DBP. Further examination of E4 and blood pressure interactions are ongoing, as well as how these findings relate to cognitive performance.
3D chromatin structure in human macrophages and iPSC‐derived microglia identifies putative Alzheimer’s Disease risk genes
Authors: Bond Marielle L , Quiroga Ivana Yoseli , Sahasrabudhe Isha R , Won Hyejung , Phanstiel Douglas H
Published: December 2022

Background

Alzheimer’s disease (AD) genome‐wide association studies (GWAS) identified 75 disease‐associated loci. The vast majority of risk variants are located in non‐coding genomic regions, suggesting a regulatory function (i.e. enhancer activity). Enhancers can regulate distal genes via DNA loops, bringing elements millions of base pairs away into close physical proximity in three‐dimensional (3D) space. Mapping 3D chromatin contact frequencies using Hi‐C can reveal enhancer‐promoter connections and assign disease‐associated variants to putative causal genes. Because enhancer and 3D chromatin structures are cell‐type specific, it is critical to map these features in the relevant cell type and biological context. Genetic risk factors for AD are located within microglia and macrophages chromatin‐accessible regions. The aim of this work was to map 3D chromatin structures in human microglia and macrophages and intersect them with AD GWAS to identify novel genes regulated by non‐coding AD risk variants.

Method

We performed deeply sequenced Hi‐C, RNA‐seq, ATAC‐seq, and Cut&Run targeting histone H3K27 acetylation to map regulatory networks in THP‐1 macrophages and human iPSC‐derived microglia‐like cells (IMGLs). Next, we performed differential analysis to identify cell‐type specific differences in 3D chromatin structure, enhancer activity, and gene expression. Finally, we intersected these regulatory networks with AD GWAS to identify variants that may disrupt these networks and reveal novel AD risk genes for further study.

Result

We identified 19,608 chromatin loops, 766 of which were specific to either cell type. These loops connected 14,413 enhancers (8,023 of which were cell‐type specific) to 7,548 genes (2,280 of which differed between cell types). Cell‐type specific regulatory features correlated with cell‐type specific gene expression. For example, a microglia‐specific loop connected a distal regulatory loci to the promoter of PER1, which was also upregulated in microglia and has a known role in circadian rhythm regulation, underscoring microglia’s known circadian‐regulated behavior.

Conclusion

We identified cell‐type specific regulatory networks in human macrophages and microglia. While these networks exhibited similarities, we identified thousands of enhancer‐promoter connections that differed. Intersecting with AD GWAS enables us to identify cell‐type specific genes regulated by non‐coding AD risk variants and reveal novel regulatory connections that would be otherwise unknown.
The influence of Apolipoprotein E ε4 carrier status on posterior cingulate cortex thickness and learning
Authors: Slutsky‐Ganesh Alexis B , Park Kyoung Shin , Anderson Travis , Hugenschmidt Christina E , DuBois Samantha L , Vance Jarod C , Ueno Aiko , O'Brokta Megan M , Kibildis Samuel , Holder Hadassah , Labban Jeffrey D , Wideman Laurie , Etnier Jennifer L
Published: December 2022

Background

Thinning of the posterior cingulate cortex (PCC) is implicated in Alzheimer’s disease (AD). Though some evidence suggests ApolipoproteinE (APOE) ε4 carriers (ε4+) have thinner PCCs than non‐carriers (ε4‐), the evidence is conflicting and lacks association with learning outcomes relevant to AD.

Method

A subset from an ongoing clinical trial (NIH/NIA: R01AG058919) was used for analyses and included 26 ε4+ (73% female, Agemean=55.81±5.53) and 42 ε4‐ (88% female, Agemean= 57.54±5.10), who were all cognitively normal, sedentary, and had a family history of AD. Genetic sampling was completed via passive drool. Structural MRI was completed to assess PCC cortical thickness, and the Rey Auditory Verbal Learning Task (AVLT) was used to assess learning. Brain segmentation was completed with Freesurfer’s automated pipeline, and left and right PCC cortical thickness was extracted for analysis. A learning over trials (LOT) composite score from the AVLT was calculated to represent learning. An analysis of covariance was completed to assess the effect of carrier status on left/right PCC thickness, controlling for age and sex. Linear regressions were completed to assess main effects and interaction of carrier status and left/right PCC thickness in predicting LOT when controlling for age and sex.

Result

ε4+ had less cortical thickness in the left PCC (F(1,64)=5.07, p=.03), but not the right PCC (p=.33), relative to ε4‐. Carrier status predicted LOT (Left: F(1,62)=10.37, p<.01; Right: F(1,62)=10.66, p<.01), however this was superseded by significant interactions between carrier status and PCC thickness predicting LOT (Left: F(1,62)=10.72, p<.01; Right: F(1, 62)=11.10, p<.01), with post‐hoc analyses demonstrating PCC thickness predicts LOT for ε4+ (Left:β=‐21.07, p=.04; Right:β=‐24.33, p<.01), but not ε4‐ (p’s>.09).

Conclusion

In cognitively normal sedentary adults with a family history of AD, carrying the APOE ε4 allele was associated with a thinner left PCC. Further, thinner bilateral PCCs in ε4+ were associated with greater learning during the AVLT task. This suggests that ε4+ may have compensatory neural pathways to account for losses in the PCC, which temporarily bolster learning to delay the onset of AD. However, additional research is needed to continue understanding the neural mechanisms affected by carrying the APOE ε4 allele.
Investigating the associations between regional tau burden measured using [F18]‐MK6240 positron emission tomography, clinical and cognitive outcomes
Authors: Quenon Lisa , Gérard Thomas , Malotaux Vincent , Dricot Laurence , Lhommel Renaud , Colmant Lise , Ivanoiu Adrian , Hanseeuw Bernard J
Published: December 2022

Background

The recent development of positron emission tomography (PET) radiotracers for tau aggregates allows visualizing tau pathology in vivo. The aim of this study was to investigate the associations between regional tau‐PET binding, measured using [18F]‐MK6240, a promising second‐generation tau‐PET tracer, and clinical and cognitive outcomes.

Method

125 participants were recruited between June 2019 and April 2022 at the Memory Clinic of Saint‐Luc University Hospital. Each participant underwent [F18]‐MK6240 tau‐PET, MRI, cognitive assessment, and either lumbar punction or [F18]‐Flutemetamol amyloid‐PET. A visual read of tau‐PET images was performed according to the Braak stage classification. Tau‐PET imaging data were also quantitatively processed using PMOD‐Neuro tools and Freesurfer. Cognition was assessed using four composite scores evaluating memory, language, executive and visuospatial functions.

Result

Braak 0 visual reads included 12 cognitively unimpaired, 7 SCI, 5 MCI due to AD (MCI AD), and 7 non‐AD patients (Fig.1). The number of MCI AD cases ranged from Braak 0 to Braak 5 categories, while the number of patients with AD dementia ranged from Braak 4 to Braak 6. Only 3 non‐AD cases had positive scans (1 APP Aβ‐, 1 FTLD, 1 PART). On average, in Braak 0‐2 cases, all cognitive composite scores were in the normal range (Fig.2). In Braak 3‐4 cases, only episodic memory was impaired, while in Braak 5‐6 cases all cognitive domains were impaired.

Conclusion

Visual Braak staging of [F18]‐MK6240 PET images matches clinical diagnosis of MCI, AD dementia and non‐AD dementia. Moreover, cases with neocortical temporal uptake (Braak 3‐4) accordingly presented isolated episodic memory, while cases with extensive neocortical uptake (Braak 5‐6) were impaired in almost all cognitive domains. Correlational analyses are currently ongoing to test whether the associations between regional tau burden and cognitive scores map onto established brain‐behavior relationships.
The Digital Maze Test (dMaze) Reveals Subtle Decision‐Making Difficulties in MCI: Hurrying to Keep Up?
Authors: Penney Dana L , Davis Randall
Published: December 2022

Background

Traditional Maze tests are time‐consuming and insensitive to early AD cognitive changes. We combine behavior capture using a digitizing pen with novel test design to produce person‐centric/relative metrics that disembed cognitive from motor speeds. This enables comparison of complex decision‐making behavior across difficulty levels within a single test. We compare traditional measures with our person‐centric/relative measures.

Method

Participants were healthy (HC = 22), Mild Cognitive Impairment (MCI = 37), Alzheimer’s (AD = 39), and Parkinson’s (PD = 43) volunteers (N = 141). Diagnosis was determined by consensus using standard of care data (neuropsychological/neurological evaluations, MRI and DAT scans). Participant groups differed in age: HC (52.27) younger than PD (64.07), MCI (75.05) and AD (75.38) oldest. Groups differed in the expected direction for DCTclock and MoCA scores.

The dMaze test contains a path‐following condition without choice points, followed by a choice (CH) condition with identical solution paths/motor demands. CH contains simple and complex choices. Relative measures use the participant’s overall speed to normalize within‐test speed deviations. We examined: Total Time (TTime) to completion, Max motor speed (MaxSpd) and Median speed (MedSpd), Choice point Average Speed (AveSpd) and Relative Average Speed (rAveSpd).

Result

TTime in seconds differentiated (p = .001) AD (141.24) from HC (52.98) and PD (77.35), not MCI (103.16). MaxSpd was slowest (p = .004) for HC (59.82mm/sec) compared to all clinical groups (MCI = 76.71mm/sec, PD = 77.11, AD = 85.52). Groups did not differ for MedSpd or choice point AveSpd. Simple choice point rAveSpd differentiated only AD (p = .001) from HC, PD & MCI. Complex choice point rAveSpd differentiated HC from MCI (p = .05) and AD (p = .001). HC and PD did not differ, suggesting simple motor speed did not account for ink speed differences.

Conclusion

Fast completion time despite slow maximum speed and relative average speed across choice points suggests HC use a modulated approach balancing speed and task difficulty. MCI faster relative maximum speed (hurrying) with completion time similar to HC, suggests a less well‐modulated approach. Relative speed differences for more complex choices may be sensitive to preclinical cognitive change even when total completion time is not. The ability to precisely measure and parse person‐centric motor and cognitive test behaviors provides opportunity to improve preclinical detection, disease monitoring and treatment efficacy.
Projection in Proxy Assessments of Everyday Preferences for Persons with Cognitive Impairment
Authors: Wilkins James M. , Locascio Joseph J , Gomez‐Isla Teresa , Hyman Bradley T. , Blacker Deborah , Forester Brent P. , Okereke Olivia I
Published: December 2022

Background

A source of bias in surrogate decision‐making has been articulated alternatively as the false consensus effect, assumed similarity, and attributive/social projection by which proxies overestimate the degree that their values and preferences are shared by others, resulting in a projection of their own beliefs onto others in the process of surrogate decision‐making. The aims of this study are to assess for projection of proxies’ preferences onto surrogate assessments of everyday preferences for persons with cognitive impairment (CI) and to address cognitive and neuropsychiatric symptom burden as predictors of projection.

Method

The sample included 116 dyads of persons with CI (Clinical Dementia Rating Scale score ≥ 0.5) and their care partners. The Preferences for Everyday Living Inventory (PELI) was used to assess importance of preferences among persons with CI. Care partners completed two separate PELI assessments: one from the perspective of the persons with CI (i.e., acting as a surrogate decision‐maker) and one from their own perspective. To assess for projection of care partners’ preferences onto surrogate assessments of preferences for persons with CI, two‐step regression with multivariable‐adjusted general linear models was used.

Result

Significant projection effects were noted within the PELI domains of autonomous choice, personal growth, and keeping a routine (p < 0.0005). More significant cognitive impairment was associated with increased projection effects within the PELI domains of autonomous choice and personal growth (p < 0.01)

Conclusion

The results of this study suggest that projection effects of care partners own preferences may be a significant source of bias in everyday proxy decision‐making for persons with CI, particularly for those with more significant CI.
Concordance of CSF biomarkers with amyloid PET at baseline in EMERGE/ENGAGE, phase 3 studies of aducanumab in patients with early Alzheimer’s disease
Authors: Rubel Carrie E. , Nisenbaum Laura , Chen Tianle , Dent Gersham , Fraser Kyle , Graham Danielle , Harrison Katie , He Ping , Racine Annie M , Rajagovindan Raj , Beaver John , Haeberlein Samantha Budd
Published: December 2022

Background

Recent technical performance improvements with the introduction of fully automated platforms have made cerebrospinal fluid (CSF) biomarkers attractive alternatives to positron emission tomography (PET) for brain amyloid pathology confirmation in the diagnosis of Alzheimer’s disease. Growing the body of evidence demonstrating high agreement between CSF biomarkers and amyloid PET across multiple automated platforms is critical to ensuring widespread access to and adoption of CSF biomarkers. Adding to previous data generated with Lumipulse® CSF immunoassays, this study assessed CSF biomarkers on the Elecsys® platform as valid alternatives to PET for amyloid confirmation by conducting a concordance analysis using data from EMERGE and ENGAGE, including performance evaluation of the Elecsys® Gen2 recommended cutoff.

Methods

EMERGE and ENGAGE were randomized, double‐blind, placebo‐controlled, global Phase 3 studies of aducanumab. Participants were 50‐85 years old and met clinical criteria for mild cognitive impairment due to AD or mild AD dementia. All enrolled participants had amyloid pathology detected by amyloid PET (visual read) during screening. Positive percent agreement (sensitivity), negative percent agreement (specificity), and overall percent agreement (OPA) were determined (with amyloid PET visual read as reference standard) for the following CSF biomarkers (and applicable ratios) using the Elecsys® immunoassay: using an internal cutoff value maximizing the Youden J index for Abeta40, Abeta42, phosphorylated tau (ptau181), tau; Abeta40/Abeta42, ptau181/Abeta42, tau/Abeta42; and for the ptau181/Abeta42 ratio using the Elecsys® Gen2 cutoff.

Results

N=349 participants (n=309 PET positive; n=40 PET negative) provided CSF at screening and were included in the analysis. Using internal cutoff values, tau, ptau181 and Abeta42 demonstrated OPA of 69%, 83% and 89% respectively, and CSF biomarker ratios showed increased diagnostic accuracy (OPA ≥95% for all ratios assessed). The Elecsys® Gen2 cutoff demonstrated excellent sensitivity(93%), specificity(82%), and OPA(92%).

Conclusions

These analyses demonstrate robust concordance between CSF biomarkers and amyloid PET visual read in EMERGE/ENGAGE and align with results generated previously. This supports the interchangeability of these biomarker methods for determination of amyloid positivity and applicability of the Elecsys® recommended cutoff in similar patient populations, with significant potential to improve accessibility of this critical biomarker for AD diagnosis in clinical trials and clinical practice.
Plasma Aβ42/40 and PET amyloid associations among late‐middle‐aged African Americans: Preliminary results from the AA‐FAIM study
Authors: Koscik Rebecca Langhough , Betthauser Tobey J , Van Hulle Carol A. , Zuelsdorff Megan , Salazar Hector , Carter Fabu P , Norris Nia , Green‐Harris Gina , Fischer Barbara L. , Chin Nathaniel A. , Gooding Diane C. , Cody Karly Alex , Meyer Matthew R. , Holubasch Mary S. , Kirmess Kristopher M. , Verghese Philip B. , West Tim , Venkatesh Venky , Yarasheski Kevin E. , Christian Bradley T , Johnson Sterling C. , Gleason Carey E.
Published: December 2022

Background

Alzheimer’s disease (AD) models of disease progression have been built largely on non‐Hispanic White samples. Availability of AD blood‐based biomarkers may improve screening for AD risk and facilitate greater diversity in research studies; little is known about these biomarkers within African Americans (AA). Here, we characterized associations between plasma Ab42/40 and Positron Emission Tomography (PET) amyloid measures in an AA sample.

Method

Participants in the African Americans Fighting Alzheimer’s in Mid‐Life (AA‐FAIM) with >=1 PET scan and plasma Ab42/40 assay were included (n=34 participants; n=117 EDTA plasma samples). The ratio Ab42/40 was calculated from plasma Ab40 and Ab42 quantified by C2N Diagnostics (PrecivityAD™). PET 11C‐Pittsburgh compound B (PIB)‐derived amyloid measures included a mean cortical DVR (global PiB DVR), PET_A+ (DVR>1.19) and estimated PET_A+ duration at each plasma sample. In separate models where “time” was age or PET_A+ duration at each plasma sample (outcome=plasma Ab42/40), we used mixed effects models to estimate simple slopes from time*PET_A+ status interactions. Sensitivity, specificity and related statistics were calculated for two plasma_A+ cutoffs (0.0975, West et al., 2021; 0.089, Hu et al., 2022).

Result

Baseline plasma sample and baseline PET scan average(sd) ages were 61(8.6) and 65(9), respectively. Closest plasma Ab42/40 explained 47% of variability in last global PiB DVR (mean(sd)=‐0.85(0.91) years plasma‐to‐PET). Seven(20.6%) participants were PET_A+. In longitudinal analyses, simple age‐slopes for plasma Ab42/40 change were ‐0.00061(0.00024) for PET_A+ and ‐0.00057(0.00018) for PET_A‐ (age*PET_A status interaction NS; model AICc=‐792.6). In a parallel mixed effect model, simple slopes were ‐0.00093(0.00026) for PET_A+ change/year and ‐0.00039(0.00012) for PET_A‐ change/year (interaction p∼0.06; AICc=‐800.6). Figures 1 and 2 depict relationships among plasma and PET amyloid measures. Positive and negative predictive values were 50.0% and 95.5% (0.0975 cut‐off) and 68% and 83% (0.089 cut‐off; see Figure 1 for additional statistics).

Conclusion

Preliminary results from this small African American sample provide encouraging data regarding plasma Ab42/40’s potential to screen for PET A+ in AAs. PET A+ duration explained more variability than age in plasma Ab42/40 trajectories. The on‐going AA‐FAIM study continues the critical effort to increase representation of AA in AD research, ensuring findings are broadly applicable.
Lipophilic Statins in Subjects with early Mild Cognitive Impairment and Low Serum Cholesterol: Association with Long‐Term Cerebral Metabolic and Cognitive Decline in a Prospective Longitudinal Multi‐Center Study
Authors: Padmanabham Prasanna S , Liu Stephen , Silverman Daniel H
Published: December 2022

Background

We recently reported that lipophilic statins, known to penetrate the blood‐brain barrier, were associated with accelerated decline in regional cerebral metabolism in subjects with early Mild Cognitive Impairment (eMCI) who had relatively low serum cholesterol levels (J Nucl Med. 2021;62:Suppl 1). In this study, we expand upon our past results by studying the relationship between metabolic decline in lipophilic statin users and their decline in neuropsychological test scores.

Methods

Subjects with eMCI were drawn from a consecutive series enrolled in the Alzheimer's Disease Neuroimaging Initiative, identifying 70 having serum cholesterol levels below the 206 mg/dl median of non‐statin users and with clear histories of time‐frames of prescriptions and types of statins used – 41 taking lipophilic statins throughout the 2‐year follow‐up period (LS), and 29 demographically similar non‐statin users (nonS). FDG‐PET scans acquired at baseline and 2 years later were compared for each group, and standardized Volume of Interest (sVOI) methods were used to calculate rates of regional metabolic decline. Correlations between changes in regional metabolism and changes in neuropsychological test scores were assessed by linear regression.

Results

The strongest association occurred between declining metabolism in the left parietotemporal cortex (PTC) and declining function, as indexed by the Functional Activities Questionnaire (FAQ), which was highly significant among LS users (p=0.0004), but not among nonS subjects (p=0.56). Decline of left PTC was also a significant correlate of decline in LS memory performance (p= 0.001), but not nonS (p = 0.11). Both the left posterior cingulate and right PTC declines correlated with LS MMSE decline (p = 0.01 for both), while that metabolic decline was again uncorrelated for nonS subjects.

Conclusion

Subjects with eMCI with low serum cholesterol levels , who nevertheless were persistently prescribed lipophilic statins over two years, underwent accelerated metabolic decline in the brain regions most significantly hypometabolic in patients with Alzheimer's disease that was in turn significantly correlated with decline in key measures of both function and cognition, in a manner specific to statin use.
Associations between gut microbial families and brain myelin in a human cohort
Authors: Yang Kao Lee , Heston Margo B. , Kohli Akshay , Kecskemeti Steven R , González Antonio , Knight Rob , Kaddurah‐Daouk Rima , Rey Federico E. , Bendlin Barbara B.
Published: December 2022

Background

We previously reported brain myelin (Dean et al, 2017) and gut microbial composition alterations (Vogt et al, 2017) in Alzheimer’s disease (AD). Prior animal studies suggest that myelin is impacted by experimentally altered gut microbiota (Keogh et al, 2021), suggesting that gut microbiota may be linked to brain myelination. However, little is yet known about the human gut microbiome and myelin alterations in the context of AD. Here, we examined the gut‐brain association in humans using biomarker and neuroimaging data.

Method

Amyloid positive (n=27) and negative (n=91) participants from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention were included based on completion of one MPnRAGE (Kecskemeti et al., 2018) scan and donation of one stool sample. Myelin was assessed using MPnRAGE‐derived quantitative R1 and myelin content in 9 white matter tracts were examined as primary outcomes (Table). Intestinal microbiota composition was characterized using 16S rRNA sequencing of fecal samples. QIIME2 was used to denoise and classify features. Phyloseq was used to filter rare taxa, compute relative abundances, and agglomerate at the family taxonomic rank, resulting in 35 microbial families used as primary predictors. Multiple regression was used to test associations between each microbial family and regional myelin content. Benjamini‐Hochberg false discovery rate (FDR) adjustment was applied post‐regression; results were considered significant at q<.05.

Result

Microbial family Turicibacteraceae was positively associated with myelin indexed by R1 (Figure) in the forceps minor (b=.014, q=.037) and uncinate fasciculus (b=.011, q=.028). Across all white matter tracts, higher age was associated with lower R1. Interestingly, there was a significant Paraprevotellaceae‐by‐amyloid effect in the superior longitudinal fasciculus (b= ‐.017, p =.031) and Clostridiaceae‐by‐amyloid effect in the forceps major (b=.002, p=.037) though neither interaction survived FDR correction.

Conclusion

In both the uncinate fasciculus and forceps minor, higher levels of Turicibacteraceae were associated with greater myelin content. Turicibacteraceae were previously identified as less abundant among individuals with AD; the current study’s microbial associations with large white matter tracts that are altered in AD warrants further study. Future studies will test additional metrics of AD pathology to clarify gut microbe and brain relationships.
Plasma NfL associated neurodegeneration in adults with Down syndrome
Authors: Padilla Concepcion , Bejanin Alexandre , Montal Victor , Pegueroles Jordi , Carmona‐Iragui Maria , Aranha Mateus Rozalem , Vera Elena , Zua Ania , Videla Laura , Altuna Miren , Benejam Bessy , Ribas Laia , Arranz Javier , Fernandez Susana , Iulita Maria Florencia , Barroeta Isabel , Blesa Rafael , Alcolea Daniel , Lleó Alberto , Fortea Juan
Published: December 2022

Background

Down’s syndrome (DS) is a genetic form of Alzheimer´s disease (AD). Plasma NfL is a neurodegeneration biomarker which has shown excellent diagnostic and prognostic performances. However, its association with brain atrophy has not been established.

Methods

Single‐centre cross‐sectional study in adults with DS. Participants had blood drawn and underwent an MRI and were classified into asymptomatic and symptomatic AD patients after a structured neurological and neuropsychological evaluation blind to the biomarker data. Plasma Neurofilament light (NfL) levels were determined with SIMOA and cortical thickness (CTh) with Freesurfer. We assessed the correlation of plasma NfL levels with CTh across the cortical mantel and with the Dickerson´s CTh signature.

Results

We recruited 169 adults with DS (74 females, mean age 42.85 [18.23 – 61.79] years old), of which 114 were asymptomatic (46 females, mean age 38.44 [18.23 – 57.17] years old) and 55 symptomatic (mean age 51.99 [39.40 – 61.79] years old). Plasma NfL levels were associated with cortical atrophy only in the symptomatic AD group in widespread medial and lateral posterior cortical regions (Figure 1). Plasma NfL showed a moderate negative correlation (r= ‐0.54; p<0.01) with Dickerson´s cortical signature (Figure 2).

Conclusions

Plasma NfL levels are a good biomarker to track neurodegeneration in DS associated AD.
Disrupted RNA‐networks in Alzheimer’s disease
Authors: Uneri Ayse , Niere Farr , Deng Zhiyong , McArdle Colin J , Raab‐Graham Kimberly F
Published: December 2022

Background

Synapse loss is well‐documented and underlies cognitive decline in Alzheimer’s disease (AD) and other comorbid neuropsychiatric disorders such as depression. To date, few molecular targets and mechanisms are identified to restore/maintain healthy synapses in AD. AD and depression both have disrupted mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. Since mTORC1 is involved in protein synthesis, disruptions in mTORC1 activity creates an imbalance between mRNA translation and repression at synapses. We have demonstrated that mTORC1 signaling is overactive in the prefrontal cortex (PFC) of AD patients and animal models. RNA binding proteins (RBP) are significant regulators of mRNA translation. A single RBP can bind to multiple mRNAs to either enhance or repress their translation. Dysregulated expression of RBPs can thus lead to imbalanced mRNA translation and protein synthesis.

Method

Computational methods, combined with the literature, have identified putative DJ‐1 mRNA binding proteins. DJ‐1 RNA‐immunoprecipitation were used to verify FMR1 mRNA as a target. A new protein synthesis assay was used to test if DJ‐1 expression affects FMRP expression. Network analyses was performed to identify new targets shared and unique to these two RNA binding proteins.

Result

We recently identified the mTORC1 regulated RBP, DJ‐1 (Park7) as a translational regulator whose expression can impact the expression and/or function of multiple proteins. We have found that Fmr1 mRNA, which is translated to the RBP, fragile X messenger ribonucleoprotein 1 (FMRP), is a target of DJ‐1. We have shown that FMRP functions to suppress the translation of various synaptic mRNAs to maintain proper transsynaptic signaling which is essential in the formation, stability, and remodeling of synapses. Notably, depression is often comorbid with AD. Furthermore, we have demonstrated that FMRP is required for antidepressant efficacy. Herein, we provide data that supports disrupted DJ‐1/FMRP expression at the synapse in preclinical models of AD. Network analysis of how these two RNA binding proteins interact will be discussed and their impact on synapse stability and behaviors in AD.

Conclusion

DJ‐1 and FMRP RNA networks are disrupted in Alzheimer’s disease. Network analyses linking these two proteins may reveal novel targets involved in synapse stability and comorbid neuropsychiatric disorders.
APOE and CLU cooperatively promote amyloid formation
Authors: Ding Zonghui , Haug Katelin , Fryer John D.
Published: December 2022

Background

Apolipoprotein E (APOE) and clusterin (CLU) are critical in the pathogenesis of Alzheimer’s disease (AD). Common coding variants in APOE (e.g. APOE4) impart at least 3‐fold higher risk of developing AD, while common noncoding variants in CLU impart smaller but still highly significant risk for AD. Using genetically engineered mouse models lacking either APOE or CLU, previous studies from our lab and others have shown that both are critical in the formation of amyloid. However, only a single published study has examined the combined effects of APOE and CLU in a mouse model of amyloidosis.

Methods

We generated mice that lacked both murine APOE and CLU (double knockout mice) on the APP/PS1 background of AD amyloidosis. We assessed these mice using histological analysis as well as single‐cell RNAseq profiling from brain tissue.

Results

Compared to APP/PS1 controls, we found that double knockout mice for both APOE and CLU had a striking reduction in the amount of amyloid plaques in the cortex. Moreover, we found that these double‐knockout mice were completely void of amyloid plaques in the hippocampus. Single‐cell RNAseq experiments revealed a strong reduction in the amount of activated microglia in these double knockout mice.

Conclusions

Contrary to a previous study that reported increased amyloid load in APOE‐/‐;CLU‐/‐ double knockout mice, we found a dramatic reduction in amyloid plaques and a concomitant loss of activated microglia when using genetically inbred (C57BL/6J) mouse lines. Further studies are needed to determine whether these effects are cell‐type specific (e.g. astrocyte‐derived APOE and CLU conditional knockouts) or whether these lipoproteins have synergistic roles in tau pathology.
The Association of Religious Attendance and Neuropsychiatric Symptoms, Cognition, and Sleep Disturbances in Dementia
Authors: Britt Katherine Carroll , Richards Kathy C , Kesler Shelli C , Acton Gayle C , Hamilton Jill B , Radhakrishnan Kavita C
Published: December 2022

Background

Neuropsychiatric symptoms (NPS), cognitive decline, and sleep disturbances are commonly found in dementia and are indicators of dementia progression (Alzheimer’s Association, 2021; Santacruz Escudero, et al., 2019; Tsunoda, et al., 2020). Given the growing number of older adults with dementia and absence of a cure, it is increasingly important to identify protective factors that may slow progression of dementia, particularly since up to 40% of risk factors are modifiable (Livingston et al., 2020). A growing body of literature supports religion and spirituality as modifiable risk factors for mental and physical health, yet few studies have been conducted in older adults with dementia (Koenig et al., 2012; VanderWeele et al., 2017).

Method

We analyzed data from the Health and Retirement Study in 2000, 2006, and 2008 and sub‐study, Aging Demographics, and Memory Study in 2001‐2003, 2006‐2007, and 2008‐2009 to examine the association of religious attendance with neuropsychiatric symptoms, cognitive function, and sleep disturbances among older adults in the U.S. (N = 72) age 70 years and older with dementia. A cross‐sectional analysis using Spearman’s partial Rho correlation was utilized to determine associations beyond social interaction.

Result

Aged 73‐100 years, participants had a mean age of 84.23 (5.73) years, mean cognitive function (Clinical Dementia Rating)(Hughes et al., 1982; Morris, 1993) of 1.17(.53), were 35.5% male, and 64.5% female. Significant associations were found for reported religious attendance and caregiver‐reported NPS using the Neuropsychiatric Inventory (Cummings et al., 1994; Kaufer et al., 1998) (rs (97) = ‐ .124, 95% CI [‐.129, ‐.119], p<.0005), cognitive function as measured by CDR, rs (97) = ‐ .018, 95% CI [‐.023, ‐.013], p<.001), and caregiver reported sleep disturbance captured by 3 yes/no items (Jelicic et al., 2002; Moon et al., 2017), rs (97) = ‐ .275, 95% CI [‐.280, ‐.271], p<.0005). Increased religious attendance was associated with lower NPS, better cognitive function, and fewer sleep disturbances beyond adjusting for social interaction.

Conclusion

Longitudinal studies and clinical trials in large, diverse samples are warranted to further examine the relationship between religion and spirituality, and dementia progression.
Examining differences across cognitive trajectory profiles in late middle‐aged adults: Results from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Du Lianlian , Hermann Bruce P , Jonaitis Erin M. , Burghy Cory , Cody Karly Alex , Betthauser Tobey J , Larget Bret , Chappell Richard J. , Janelidze Shorena , Hansson Oskar , Johnson Sterling C. , Koscik Rebecca Langhough
Published: December 2022

Background

Cognitive decline in Alzheimer’s disease (AD) and other dementias may accelerate in preclinical phases as brain pathology increases. Here we: 1) developed cognitive trajectory profiles using longitudinally‐based random slope and change point (CP) parameter estimates from a cognitive composite; and 2) examined how AD‐related biomarkers varied across these cognitive profiles.

Method

WRAP participants with > = 3 Preclinical Alzheimer’s Cognitive Composite (PACC3) scores, dementia‐free at baseline, were included (n = 1068). Amyloid measures from positron emission tomography (PET) [C‐11]Pittsburgh Compound B (PiB; n = 361) scans included Global PiB DVR and proportion PiB+ (Global PiB DVR>1.16). Tau measures included PET MK‐6240 regional entorhinal cortex and hippocampal SUVR (n = 321). Neurodegeneration measures included MRI hippocampal volume and global brain atrophy (GBA; n = 581). Plasma measures included pTau217 (n = 166). Posterior median estimate person‐level CPs, slopes pre‐ and post‐CP, and intercepts at CP for PACC3 were extracted from Bayesian random CP mixed models (BRCPMM; age = time scale) and used to characterize cognitive trajectory profiles (K‐means clustering). We compared demographic, last visit cognitive statuses (cognitively unimpaired‐stable (CU‐S), CU‐declining (CU‐D), and MCI/Dementia), amyloid, tau, neurodegenerations and plasma measures across the cognitive trajectory profiles using analysis of variance, chi‐square and Fisher’s exact tests. Significant omnibus tests (p<.05) were followed with pairwise comparisons.

Result

Mean(sd) last cognitive assessment age was 66.6(6.6) years; PiB, MK, MRI scans and plasma occurred within mean(sd) 1.1(2.7), 1.6(1.4), .6(3) and .09(.7) years of cognitive assessment. Cluster analysis identified 3 groups of performance patterns representing highest to lowest risk of cognitive decline (high: n = 77(7.2%); intermediate: n = 446(41.8%); and low: n = 545(51.0%); Figure 1 & 2). The high risk group was older, had more females, APOE e4 carriers, and MCI/Dementia at last visit (Table 1). The high risk group also had worse PiB‐amyloid, MK‐tau, pTau217, and MRI‐neurogeneration levels than the lower risk groups (Table2; Figure 3).

Conclusion

In this initially non‐demented sample, differences between cognitive clusters across multiple biomarkers and AD risk factors indicate that within‐person PACC3 performance patterns are sensitive to preclinical change. Identifying cognitive trajectory profiles may provide an opportunity for early intervention for high‐risk subjects at the right time for treatment and/or enrollment in a clinical trial.
Caregiving Burdens in Aphasic Dementia and the Relationship to Communication Challenges
Authors: Roberts Angela C , Santos Haylie N , Gill Nathan Pruneau , Zhang Hui , Rogalski Emily J.
Published: December 2022

Background

Primary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language are the primary and persistent symptom, and severely limit participation in everyday activities and family conversations. PPA is also associated with high caregiving burden. Few studies have examined the relationship between conversation difficulties and caregiving burdens. We tested the hypothesis that the severity of care partner (CP) perceived conversation difficulties predicts caregiving burdens.

Method

A mediation analysis focusing on the Baron‐Kenny approach was conducted using baseline data from 78 CPs (62% female) enrolled in the Communication BridgeTM‐2 randomized control trial of a speech‐language intervention for mild to moderate PPA. Measures included the Conversation Difficulties subscale of the Perception of Conversation Index‐Dementia Alzheimer’s Type (PCI‐DAT) and the subscales of Montgomery Burden Interview (MBI), namely objective burden subscale (perceived infringement on tangible aspects of life), subjective demand subscale (perception that the dependent person is overly demanding), and subjective stress subscale (perception of emotional impact). Higher ratings indicate higher burden and greater conversation difficulties.

Result

CPs had a mean age of 64.5 years (SD = 10.76), education level of 16.2 years (SD = 2.77), and a relationship duration with the PPA participant of 38.6 years (SD = 15.29). Eighty‐six percent were spouses, 5% were adult children, and 9% were friends or siblings. CPs endorsed a broad range of burden severity with a mean objective burden score of 9.29/30 (Range = 6 to 26; SD = 4.01), subjective demand burden score of 5.81/15 (Range = 5 to 12; SD = 1.41), and subjective stress burden score of 8.43/20 (Range = 5 to 16; SD = 2.72) as well as a range of perceive conversation difficulties (M = 42.34/154, Range = 6 to 105, SD = 22.88). Higher conversation difficulties were associated with higher ratings of caregiving burden for objective burden (p < 0.001) and subjective stress burden (p = 0.010). Significant mediating variables included activities of daily living and CP depression scores.

Conclusion

The current study shows an association between both subjective and objective caregiving burden and conversation difficulties. Given this relationship, it will be important to determine whether interventions that successfully address conversation difficulties may also decrease caregiving burden.
Clinical utility of plasma biomarkers to identify preclinical Alzheimer’s disease in the community
Authors: Lage‐Martinez Carmen , López‐García Sara , Martínez María García , Martínez‐Dubarbie Francisco , Pozueta Ana , Arroyo Juan Martin , Pardo Andrea Corrales , Irure‐Ventura Juan , Rodríguez Eloy Rodríguez , Sanchez‐Juan Pascual
Published: December 2022

Background

Several plasma biomarkers have shown good correlation with brain amyloidosis measured by CSF biomarkers and PET, but their utility to identify subjects with Alzheimer’s disease(AD) brain pathology at the community level is not well known. Neuropsychological tests might be a more accessible alternative.

Method

Our aims were to assess the utility of plasma p‐tau231, plasma GFAP, and plasma NFL to identify individuals with preclinical AD, and to compare it with the utility of current neuropsychological tests for early AD detection: Preclinical Alzheimer's Cognitive Composite 5(PACC5), Spanish version of Face‐Name Memory Exam(S‐FNAME), Logical Memory Test (LMT‐WMSIII), and Free and Cued Selective Reminding Test(FCSRT). Our study population was a community‐based cohort that enrolls individuals older than 55 living in Cantabria, a region in northern Spain. Exclusion criteria include a diagnosis of dementia or other cognitive disorders. AD+ status was defined by abnormal levels of both CSF amyloid‐β1‐42/1‐40 ratio and CSF p‐tau181. General linear models were used to compare biomarker and cognitive results between AD+ subjects and the rest of the population, with age and sex as covariates. ROC curves were built to compare the utility of each test to identify AD+ cases.

Result

The total sample included 156 individuals, 30 of them AD+. AD+ subjects showed significantly higher levels of GFAP (mean difference 78.04, p<0.00001) and p‐tau231 (mean difference 5.53, p 0.00040), but not NFL (mean difference 1.16, p 0.63), compared to non‐AD (table 1). After adjusting by age, sex, APOE4 carrier status, and AD status, age and sex were still independent predictors of GFAP levels, but not of p‐tau231 (table 2). FCSRT delayed recall and LMT‐WMSIII total score were significantly lower in AD+ than in non‐AD cases, but not S‐FNAME nor PACC5 (table 1). Both plasma GFAP and p‐tau231 showed an AUC of 0.75 to identify AD+ individuals (table 3, figure 1). Neuropsychological tests obtained non‐significantly smaller AUC than plasma biomarkers.

Conclusion

In our community‐based population, plasma GFAP and p‐tau231 were useful to identify individuals with preclinical AD, but not plasma NFL. Although probably with a lower performance, early detection cognitive tests may also be helpful to identify AD cases in the community.
Alzheimer’s Disease modeling using hiPSC neurons and microglia
Authors: Gordon Kara L. , Rines Christine G. , Handley Cherie , Basa Ranor C. B. , Price Jeffrey H. , McDonough Patrick M.
Published: December 2022

Background

Neuroinflammation is an important topic in neurodegenerative disease research. Scientists have established multiple protocols for differentiating microglia, neurons, and astrocytes from human iPSCs, which enable the study of neuroinflammation in vitro. Here we describe the use of Vala Sciences’ imaging platform, the IC200 Kinetic Image CytometerTM (KIC), to develop screening assays for Alzheimer’s Disease (AD) in cultures with hiPSC‐derived microglia and neurons.

Method

We cultured iCell Glutaneurons with microglia in 384‐well dishes. To detect microglia phagocytosis, we cultured microglia with pHrodo‐Red Zymosan beads or β‐amyloid fragments and then acquired timelapse videos over 5‐24 hours. To measure neuronal activity, we loaded cells with Rhod‐4 calcium dye and imaged at 4fps. We also fixed and immunolabeled cells for neurite and synapse analysis. All assays were scanned using the IC200 KIC. We developed algorithms for our CyteSeer image analysis software to automate neurite tracing, synapse detection, analysis of calcium activity, and microglia phagocytosis and morphology for single cells in a co‐culture system.

Result

In microglia, we demonstrated an increase in uptake of pHrodo‐Red labeled Zymosan beads with increasing concentration of Zymosan particles and in response to IL‐4. We also demonstrated differential engulfment of β‐amyloid 1‐40 and β‐amyloid 1‐42 by microglia. While investigating the effects of microglia on neuronal health, we observed increased neuronal survival, neurite outgrowth, and pre‐synapse count in glutamatergic neurons co‐cultured with microglia when compared to glutamatergic neurons cultured alone. In neuron‐microglia co‐cultures exposed to increasing doses of β‐amyloid 1‐42 fragments, we observed neuronal hyperactivity (increased calcium event frequency), which may reflect disease‐associated stress.

Conclusion

Our data demonstrate that healthy microglia regulate neuronal heath. Our system can serve as a model for testing inflammatory insults related to AD. To further our research with genetic variants with AD susceptibility, we have created an isogeneic panel of ApoE variants using CRISPR‐Cas9, and plan to characterize them in the culture systems developed above to validate a disease model from these lines.