bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenome‐Wide‐Association‐Scan Reveals Epigenetic Profile Changes Using Neurofilament Light as a Neurodegeneration Proxy Biomarker in Mexican Americans
Authors: Housini Mohammad , Zhou Zhengyang , Reid Danielle M , Daniel Ann Abraham , Silzer Talisa , O'Bryant Sid E. , Phillips Nicole , Barber Robert , Pathak Gita
Published: December 2023

Background

Recent literature shows Alzheimer’s Disease (AD) has both genetic and epigenetic components resulting in disease manifestation. Furthering our prior work on AD epigenetics in the Health and Aging Brain Study – Health Disparities (HABS‐HD) participants, we seek to identify differential CpG methylation profiles of Neurofilament Light (NfL) as a proxy for neurodegeneration in Mexican‐American participants with Normal Cognition (NC) or Mild Cognitive Impairment (MCI).

Method

Using data from the Epigenome Wide Association Scan (EWAS) that our group already published for 90 Mexican Americans in HABS‐HD (formerly Healthy Aging in Latino Elders Study [HABLE]), we conducted preliminary analysis in 32 individuals (NC = 21, MCI = 11) to assess the role of epigenetic markers in neurodegeneration among Mexican Americans. We performed the EWAS using the AT(N) biomarker, Neurofilament Light (NfL), as the outcome in our pilot group of 32 Mexican Americans. We first tested if the NfL data was normalized using the Shapiro Test, then tested NfL differences between NC and MCI with a Wilcox Test. We further tested CpG sites with NfL using a disease‐stratified and unstratified model with linear regression modelling and adjusted for covariates, such as age, gender, and education.

Result

Results of our analysis for the association between CpG methylation profiles and NfL showed 14 down‐regulated CpG sites and 1 up‐regulated CpG site with significant P values after multiple testing. These significant CpG sites residing in LRP4 (Chr11p11.2), ABCB9 (Chr12q24.31), and KIAA (Chr13q14.13) are implicated in the CpG methylation profile changes. These genes have been implicated in AD pathogenesis by other molecular studies. When we stratified NfL count by disease subtype, we did not find any significance in this dataset. We are expanding our ongoing work to identify methylation profiles of NfL in a larger cohort.

Conclusion

Our pilot findings are critical in understanding epigenetic profiles of biomarkers for neurodegeneration. Results suggest that epigenetics play a major role in the pathophysiology of AD development and manifestation, and that this effect may be different by ethnicity. Future studies will include a larger sample size, longitudinal analyses, and additional ethnic groups to help bridge the health disparities gap in the literature.
Pervasive biases in GWAS using family history of Alzheimer’s disease as proxy phenotypes
Authors: Sun Zhongxuan , Wu Yuchang , Fletcher Jason M , Lu Qiongshi
Published: December 2023

Background

Using family health history as proxy phenotype has become a common approach in genome‐wide association studies (GWAS) of Alzheimer’s disease (AD). This approach leverages large samples in population biobanks where most mid‐aged participants do not have any AD diagnosis. However, methodological issues in GWAS‐by‐proxy (GWAX) and quality of its association results have not been carefully investigated.

Method

We performed GWAX on parental AD history in UK Biobank (N = 48,031 proxy cases and 315,286 controls). We then applied GWAS‐by‐subtraction to obtain the non‐AD component underlying AD GWAX. We computed genetic correlations of AD case‐control GWAS, AD GWAX, and the non‐AD component underlying GWAX with a suite of complex traits. We also explored the impact of various quality control procedures and additional covariates in AD GWAX analysis.

Result

AD GWAS and GWAX showed drastically different genetic correlations with several other complex traits especially cognitive abilities (Figure 1). AD GWAX had a surprising genetic correlation with higher education (rg = 0.167, p = 1.7e‐11) as opposed to the negative AD‐education correlation observed for GWAS (rg = ‐0.133, p = 2.4e‐5). The positive genetic correlation between AD and cognition is explained by the non‐AD component in AD GWAX (rg = 0.260 with education, p = 5.2e‐11). The non‐AD component in GWAX also showed correlations with lower risks of health outcomes such as coronary artery disease (rg = ‐0.136, p = 2.8e‐3) and diabetes (rg = ‐0.206, p = 2.8e‐3), indicating substantial survival bias in samples reporting parental AD history. Adjusting for parental age in GWAX substantially reduced but did not fully remove the genetic correlation of AD and higher education (rg = 0.013, p = 0.67), hinting at additional unaccounted factors in the current GWAX practice. We also provide evidence that genetic correlation between family health history awareness and education (rg = 0.285, p = 1.4e‐10) leads to these biases in GWAX associations.

Conclusion

GWAX based on parental health history introduces substantial and systematic biases in AD genetic associations due to the non‐representativeness of the biobank health history survey. Naively combining GWAX with regular case‐control GWAS will lead to misleading results both at the single variant level and in genome‐wide analyses such as genetic correlation estimation and polygenic risk score applications.
Older people with mild cognitive impairment exhibit lower semantic noise after six months of frequent social conversations
Authors: Chen Liu , Dodge Hiroko H , Asgari Meysam
Published: December 2023

Background

Semantic noise (SN) is a linguistic measurement that quantifies how well the conversation focuses on topics they are discussing. We hypothesized that by engaging in high frequent conversation which aimed to enhance cognitive reserve, the SN observed in older people’s conversations with mild cognitive impairment (MCI) would resemble those with normal cognition (NC).

Method

We analyzed transcriptions from a behavioral intervention randomized controlled trial, I‐CONECT (NCT02871921), which involved semi‐structured conversations between facilitators and participants. In the project, the experimental group engaged in 30‐minute semi‐structured conversations (four times per week for 6 months) via video‐chats. Every video‐chat is oriented to a predefined topic which was provided in a standardized order (e.g., dancing is the 1st conversation topic in the 2nd week). Out of 186 subjects randomized into the trial, 64 participants were randomized into the experimental group. Among them, 52 participants (26 MCI and 26 normal based on NACC D1) with sufficient recording quality during the 2nd week of the intervention (baseline) and during the last week (i.e., 24th) before the month 6 (M6) post‐intervention assessments (post‐trial assessments at M6) were used in this analysis. We utilized an automatic speech recognition (ASR) system to transcribe these recordings and measured each transcription’s SN. We analyzed the statistical difference of MSN (mean SN) between participants with MCI and those with NC at baseline (2nd week) and M6 (24th week).

Results

Using two‐tailed t‐test, we found that at the baseline, MSN in MCI group was significantly higher than NC group (MCI: 2.09(0.34), NC: 1.87(0.35), p‐value: 0.024). After six months of social interaction, MCI and NC group were not significantly different (MCI: 1.81(0.47), NC: 1.95(0.47), p‐value: 0.280). Moreover, in MCI group, baseline’s MSN was significantly higher than M6’ (p‐value: 0.017), while, in NC group, there was no significant difference between baseline and M6 (p‐value: 0.465).

Conclusions

We showed that, through six months of social interaction, MCI group’s MSN reduces from significantly higher than NC group at the baseline to not significantly different from NC group at M6. This indicates that the high dosage of interactive conversations reduces MSN in the MCI group.
Resilience in aging: characterizing social and emotional pandemic stress with age in a multi‐ethnic sample of middle‐aged and older adults
Authors: Schuck Lauren A , Arentoft Alyssa , Cham Heining , Oleas Denise S. , Breen Elizabeth Anne , Slaughter Alexander W. , Camuy Alicia M , Talavera Sandra , Mindt Monica Rivera
Published: December 2023

Background

COVID‐19 pandemic stress differentially affects older adults and persons from minoritized, underrepresented populations (URPs; e.g., Black, Latinx), yet potential protective factors are not well understood. This study aimed to evaluate whether pandemic‐related social and emotional stressors negatively affect functional capacity, mental health, and cognitive outcomes in an ethnoculturally diverse sample of middle‐aged and older adults.

Method

Cross‐sectional data were obtained from adults (55± years) participating in SALUD, an ongoing study examining risk and resilience factors for dementia in diverse populations. Participants completed a well‐validated, comprehensive battery of questionnaires and cognitive assessments. Aggregate scores of social and emotional pandemic stressors (e.g., more anxiety, loneliness) from Item 3 of the Pandemic Stress Index (PSI‐3) were examined in association with demographics, Patients Assessment of Own Functioning Inventory (PAOFI; self‐reported functional status measure), and Patient Health Questionnaire‐2 (PHQ‐2; self‐report depressive symptomatology measure). Demographically‐adjusted norms were used to compute Global Neurocognition (NC) and eight domain‐specific NC average T‐scores (e.g., learning, memory). Spearman’s correlations, Kruskal‐Wallis, Mann‐Whitney U‐tests were used for non‐normal variables.

Result

The sample included 110 adults (37.3% Non‐Latinx Black [NLB], 33.6% Latinx, and 29.1%, non‐Latinx White [NLW]; 63% female; M
age = 65.27 [SD = 7.11]; M
ed = 13.89 [SD = 3.07]). Age was negatively correlated with the PSI‐3 (rs = ‐.25, p<.01), but education (rs= ‐.05, p = .59) and gender (U<.01, p = .99) were not. PSI‐3 differed across ethnocultural groups (H = 8.00, p = .02), such that Latinx participants had the highest PSI‐3 scores. However, this relationship became non‐significant after accounting for age (p = .11). PAOFI impairment scores (rs = .37, p = .01) and PHQ‐2 scores (rs = .29, p = .01) were positively related to the PSI‐3, but Global NC and domain‐specific NC average T‐scores were not significant (rs = ‐.08 ‐ .10, ps> .05).

Conclusion

In this ethnoculturally diverse sample, findings suggest older adults may be more resilient to pandemic‐related stress. Older age was associated with lower social and emotional pandemic stress, while greater functional impairment and depression were moderately associated with higher pandemic‐related stress. As pandemic‐related increases in psychosocial stressors (e.g., worry and depression) continue to affect middle‐aged and older adults, longitudinal research should investigate the risk and resilience factors that may buffer against developing these negative outcomes.
Grumpy old men: agitation, aggression, and impulsivity in older adults and risk of incident dementia
Authors: Ghahremani Maryam , Ismail Zahinoor
Published: December 2023

Background

Impulse dyscontrol, i.e., excessive motor activity and/or physical and verbal aggression is common in dementia. However, impulse dyscontrol can also emerge in advance of dementia, but is often normalized due to age, or framed as a psychiatric condition. Thus, the association between these symptoms and incident dementia is unclear. Mild behavioral impairment (MBI) leverages risk associated with later‐life emergent and persistent neuropsychiatric symptoms (NPS) to identify a high‐risk group for incident dementia. Impulse dyscontrol is one of five MBI domains. Here, in dementia‐free participants, we assessed risk of progression to dementia in MBI‐impulse dyscontrol and conventionally‐measured impulse dyscontrol symptoms (Conv‐ID).

Method

Dementia‐free National Alzheimer Coordinating Centre participants were included. Neuropsychiatric Inventory Questionnaire irritability, agitation, and aberrant motor behavior items were used to identify impulse dyscontrol. MBI‐impulse dyscontrol was operationalized by symptom presence at more than two‐thirds of pre‐dementia study visits (symptom persistence criterion) in those with no history of psychiatric disorders (symptom emergence criterion). Conv‐ID required symptoms only at baseline without consideration of past psychiatric history. Kaplan‐Meier survival curves and Cox proportional hazards models, adjusted for age, sex, education, race, and APOE‐e4 status, were generated to compare survival probability and dementia incidence rates of MBI‐impulse dyscontrol and Conv‐ID to No‐NPS.

Results

The sample comprised 1,884 MBI‐impulse dyscontrol (age = 74.5±9.7; 40.9% female), 3,676 Conv‐ID (age = 71.0±9.4; 47.0% female), and 6,362 No‐NPS participants (age = 71.0±10.3; 64.7% female) (Table 1). MBI‐impulse dyscontrol had lower dementia‐free survival (p<0.0001) and 2.23‐fold greater dementia incidence compared to No‐NPS (CI:1.99‐2.50, p<0.001, Figure 1(A)); Conv‐ID had lower dementia‐free survival (p<0.0001) and 1.39‐fold greater dementia incidence compared to No‐NPS (CI:1.25‐1.54, p<0.001, Figure 1(B)).

Conclusion

Compared with a conventional approach to assess agitated and impulsive behaviors, MBI‐impulse dyscontrol was associated with greater dementia incidence. Applying the MBI criteria of later‐life emergence and persistence of symptoms provides a more specific approach to identify those at risk for incident dementia, who might otherwise be dismissed due to normalization of these behaviors in older persons or labelled with a psychiatric condition. This approach may allow for earlier implementation of preventative measures, pharmacological and non‐pharmacological, improving outcomes and quality of life for patients and their caregivers.
Investigating the role of GPNMB in modulating LPS mediated inflammation in progranulin‐deficient macrophages
Authors: Gillett Drew A , Neighbarger Noelle , Huarte Oihane Uriarte , Tansey Malu Gámez
Published: December 2023

Background

Progranulin (PGRN) is a glycosylated holoprotein that is critical to endo‐lysosomal health and regulating inflammatory responses over the lifespan. Insufficient PGRN due to nonsense mutations in the GRN gene has been linked to increased risk of developing Frontotemporal Dementia (FTD) and Neuronal Ceroid Lipofuscinosis (NCL‐11). The precise mechanism(s) behind the onset and progression of disease is unclear, and no disease‐modifying treatment exists. Previous work has identified increased glycoprotein non‐metastatic B (GPNMB) in both the cortex and plastma of Grn−/− mice relative to Grn+/+ mice, and our lab has recently identified different GPNMB expression in PGRN‐deficient immune cell populations, but it remains unclear how this increase in GPNMB modifies the inflammatory response(s) with PGRN deficits. This work seeks to investigate GPNMB expression over the course of the immune response in PGRN‐deficient cells, and the extent to which GPNMB modulates inflammation.

Method

To investigate the role(s) of GPNMB in PGRN‐deficient myeloid cells, we isolated peritoneal macrophages (pMacs) from Grn+/+,and Grn−/− mice and quantified GPNMB protein before and after lipopolysaccharide (LPS) stimulation with western blot. We also determined the extent to which exposure to the GPNMB extracellular domain (ECD) modifies LPS‐elicited markers of inflammation in both Grn+/+and Grn−/‐ pMacs via qPCR. Finally, we determined how markers of inflammation were altered in pMacs from Grn−/−Gpmnb−/‐ relative to Grn+/+and Grn−/‐ with and without LPS stimulation.

Result

We determined that the additional loss of GPNMB in Grn−/−Gpmnb−/− pMacs altered the expression of inflammatory markers after LPS challenge relative to both Grn−/−and Grn+/+ pMacs. We also discovered that GPNMB is dynamically regulated during and after LPS challenge in both Grn+/+ and Grn−/− pMacs. Finally, we determined that the addition of GPNMB ECD before and during LPS treatment ameliorated the altered expression of inflammatory markers during LPS challenge.

Conclusion

The increase of GPNMB expression in Grn−/‐ myeloid cells is a significant modulator of inflammatory responses and may be a potential target in the development of therapeutics.
Assessing amyloid plaque burden in aging marmosets and genetically engineered PSEN1 mutation carriers using 11C‐PiB PET
Authors: Schaeffer David J , Dubberley Lauren R , Schaeffer Lauren K Hayryren , Park Jung Eun , Homanics Gregg E , Strick Peter L , Carter Gregory W , Rizzo Stacey J Sukoff , Silva Afonso C
Published: December 2023

Background

There is an urgent need to develop novel animal models to investigate the underlying cellular and molecular root causes of the pathogenesis and progression of AD. Our group has worked to establish the common marmoset as the first primate‐specific model of AD to reveal the earliest cellular and molecular events of AD processes and allow charting of AD progression from its inception. For this, we established a colony of outbred marmosets and used genetic engineering techniques to generate marmosets carrying the PSEN1‐C410Y and PSEN1‐A426P mutations that cause early‐onset, familial AD. The present study aims to use PET imaging to access and track the progression of Ab plaque burden non‐invasively and longitudinally in our marmoset models of AD.

Method

Marmosets anesthetized with isoflurane delivered via a facemask were placed in a preclinical PET/CT scanner customized with marmoset‐specific beds. Respiratory rate, heart rate, arterial O2 saturation, and rectal temperature were monitored and maintained at normal physiological values. Our PET imaging protocol follows the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The amyloid‐binding 11C‐Pittsburgh Compound B (11C‐PiB) was delivered intravenously in doses varying from 18.5 – 185 MBq (0.5 – 5 mCi). A 90‐min dynamic acquisition was performed immediately following the radiotracer injection, followed by a 3D CT scan acquired at 200 µm isotropic resolution. After the PET/CT neuroimaging scan, the marmosets were recovered from anesthesia and returned to their home cages.

Result

We observed positive 11C‐PiB binding and retention in the brains of aging outbred marmosets and in marmosets harboring PSEN1 mutations. Significant 11C‐PiB retention was observed in the cortex and white matter tracts. The areas with the highest 11C‐PiB retention were the lateral frontal cortex, anterior cingulate cortex, and temporal lobe regions.

Conclusion

This study demonstrates using 11C‐PiB to track Ab plaque burden in the brains of aging marmosets and marmosets harboring PSEN1 mutations. As observed in human patients of AD, the amount of 11C‐PiB bound (measured in SUV and SUVR units) varied from animal to animal, and we are currently performing group analysis to investigate the dependence of 11C‐PiB retention on age and sex.

This research was funded by NIH/NIA grants R24AG073190 and U19AG074866.
Gene co‐expression network analyses in Mild cognitive impairment
Authors: Dorsant‐Ardon Valerie , Sanjay Apoorva Bharthur , Rocha Luis M , Correia Rion Brattig , Apostolova Liana G.
Published: December 2023

Background

Multiomic data analysis has been extensively developed in recent years. Particularly, microarray data can be used as biomarkers of disease of progression specially in pathologies as cancer, autoimmunity and others. (Dahinden et al., 2010; Soleimani Zakeri et al., 2020). This modality of data analysis can also be employed in other multifactorial diseases as Alzheimer’s disease including the progression from normal cognition to mild cognitive impairment and finally to dementia. These genes work in intricate relationship with each other. The establishment of computational gene interaction networks shows the intricacy of the biological systems but increases the complexity of the analysis, for this reason, the removal of redundant edges leaves a network backbone revealing important driver nodes that are essential for the observed interactions, reducing the number of genes of interest and narrowing potential diagnostic or therapeutic targets. (Gates et al., 2021)

Methods

We used data from the ImaGENE study and the Weighted gene co‐expression network analysis (WGCNA) pipeline to analyze gene‐gene interactions of mRNA transcripts obtaining hierarchical clustering of genes and eigengenes in a sample of 160 individuals (Table 1). The backbones were obtained using the shortest path computation. (Gates et al., 2021; Simas et al., 2021). Gene ontology was used to classify processes associated with these genes.

Results

We identified 42 hubs of differentially expressed genes and we analyzed the top 5 groups with the strongest association with amnestic mild cognitive impairment (MCI) phenotype (pfdr<0.0001). This cluster consisting of 46 genes was further classified according to function and interactions with other nodes in the backbone identifying processes like calcium signaling, nucleotide excision repair, fatty acid metabolism among others.

Conclusion

There is an identifiable difference in gene expression in individuals with MCI compared to normal controls. The analysis of the backbone of the gene hubs allowed to reduce the number of genes of interest. This approach can help to elucidate important biological interactions, potential therapeutic targets and could eventually be used as risk factors markers for the development of MCI and AD.
The role of aquaporin‐4 localization in glymphatic impairment and tau aggregation in post‐traumatic neurodegeneration
Authors: Braun Molly , Sevao Mathew , Gino Elizabeth , Keil Samantha A , Pedersen Taylor J , Agarwal Sanjana , Jang Jay , Swierz Justyna , Sanderson Keith , Jansson Deidre , Iliff Jeffrey J
Published: December 2023

Background

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide and has been established as a risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD). Neurofibrillary tangles (NFTs), aggregates of intracellular tau, are hallmarks of AD and are observed in the post‐TBI brain; however, the mechanisms that contribute to tau aggregation and accumulation are not well understood. One key mechanism that may contribute to this tau aggregation is decreased clearance by the glymphatic system, a perivascular pathway that clears solutes, including tau, from the brain.

Method

PS19 mice with tau pathology were crossed with Aqp4−/− mice lacking the astroglial water channel aquaporin‐4 (AQP4) or Snta1−/− mice lacking perivascular localization of AQP4. Behavioral tests were performed on the PS19Aqp4 transgenic crosses at 4 months or 6 months of age. Brain tissue was collected and stained for markers of p‐tau pathology.

A mild closed‐skull controlled cortical impact TBI model was established and validated. Sham or TBIs were performed on PS19Snta1 transgenic crosses at 3 months of age. Behavioral testing was performed at 4 months (1 month post‐TBI) or 6 months (3 month post‐TBI). Brain tissue was collected and stained for markers of p‐tau pathology.

Result

We confirmed the previous finding that glymphatic influx is impaired following a closed‐head controlled cortical impact TBI. We also observed that Aqp4 deletion was sufficient to exacerbate tau pathology in PS19 mice at 6 months old, in the absence of TBI, and more advanced tau pathology was observed in PS19+Snta1−/‐ mice at 6 months old (3 months post‐TBI) compared to PS19+Snta+/+ that also received a TBI.

Conclusion

Loss of AQP4 or loss of perivascular AQP4 promotes tau pathology in a mouse model of tau pathology. These studies may provide a mechanistic basis for the vulnerability of the post‐traumatic brain to tau aggregation and neurodegeneration and suggest that targeting glymphatic dysfunction may be useful in the prevention and treatment of neurodegeneration.
Gut microbiota genus network reflects Alzheimer’s disease clinical stages
Authors: Lima Amanda Muliterno Domingues Lourenço , Rosa Morghana Machado , Machado Luiza Santos , Salgaço Mateus Kawata , Cassia Pessotti Rita , Saverio Stephani , Guimarães Cristiano Ruch Werneck , de Freitas Miller Nunes , Sivieri Katia , Bastiani Marco Antônio De , Zimmer Eduardo R.
Published: December 2023

Background

Bidirectional communication through the gut‐brain axis is fundamental to maintaining physiological functions. Imbalance in the intestinal microbial composition due to taxonomic or functional dysbiosis may be related to increased deposition of amyloid‐β plaques and tau tangles, which are the main hallmarks of Alzheimer’s disease (AD). We hypothesized that dysfunctional associations between the bacterial groups of the gut microbiota could be associated with AD clinical stages. Thus, we compared gut‐microbiota networks in cognitively unimpaired (CU), mild cognitive impaired (MCI), and AD dementia individuals.

Methods

We selected 16S rRNA gene sequencing data from fecal samples of CU, MCI and AD (n = 30, per group) available at NCBI repository (PRJNA489760). Individuals of both sexes aged between 57 and 73 years were included in the study. Adaptors were removed from the FASTQ files using the Trimmomatic tool for each sample and submitted to the DADA2 pipeline. Briefly, after filter and trimming, amplicon sequence variants (ASVs) were inferred using the dada function, taxonomic assignment was implemented using the SILVA resource and normalized by rarefaction without replacement. Afterward, normalized centered‐log ratio transformed abundance data were used to construct correlation networks between genus for CU, MCI, and AD.

Results

We observed different correlation patterns between bacterial genera in CU, MCI, and AD. More especially, we found a progressive increase in network density toward AD clinical progression. Genus reportedly associated with cerebral amyloidosis and tau show few connections in the CU individuals (Figure 1A), which are increased in MCI (Figure 1B) and highly connected in AD (Figure 1C). Interestingly, we also noted that the opportunistic pathogen Escherichia_Shigella, strongly associated with AD pathology, was exclusively present in the AD network and showed a negative correlation with Faecalibacterium, a reportedly indicator of health.

Conclusion

Microbial association networks at the genus level reflect different pathological stages of AD and could provide insights into preventive therapeutic strategies aiming to delay disease progression through the modulation of the gut microbiota.
Pregnancy‐Related Cardiometabolic Disease and Dementia Risk: A Twin Study
Authors: Foret Janelle T , Saelzler Ursula G , Gatz Margaret , Gillespie Nathan A. , Panizzon Matthew S.
Published: December 2023

Background

Pregnancy related complications such as gestational diabetes mellitus (GDM) and pregnancy‐induced hypertension (PIH) have been shown to increase risk of cardiometabolic disease and may subsequently contribute to all cause dementia. While GDM and PIH have been genetically associated with their later life, non‐pregnancy related counterparts, it remains to be seen if these conditions independently contribute to dementia risk. This study investigated the degree to which GDM and PIH are genetically associated with dementia.

Method

Data were analyzed from 5,930 females in the Swedish Twin Registry who reported at least one pregnancy. Traditional twin analyses were conducted to determine the degree to which GDM and PIH are genetically influenced, as well as the degree of genetic and environmental overlap with the non‐pregnancy related variant of these conditions. Survival analyses examined relationships between 1) GDM and dementia and 2) PIH and dementia. Hypertension and diabetes outside of pregnancy were included in their respective models as covariates.

Result

For individuals who reported having been pregnant, risk of later life cardiometabolic risk factors were significantly increased if the similar conditions were experienced during pregnancy (P<.001). Both GDM and PIH showed evidence of significant familial associations, with a higher OR in MZ twins for both conditions (GDM OR = 6.74; 95% CI, 1.06 to 2.76; PIH OR = 8.27; 95% CI, 1.89 to 2.38). The survival models indicated that while neither pregnancy‐related condition was independently associated with dementia risk, diabetes outside of pregnancy was associated with a more than three‐fold increase in dementia risk (HR = 3.77, 95% CI = 1.17 – 1.63).

Conclusion

In this large, population‐based cohort we found significant associations between pregnancy conditions and their respective cardiometabolic conditions. Cross‐twin associations further indicated that the association between pregnancy and non‐pregnancy cardiometabolic risk factors was driven by genetic influences. However, GDM and PIH did not appear to convey risk for dementia. These findings suggest that mechanisms driving diabetes and hypertension during pregnancy, while related to their later‐life counterparts, do not increase risk of neurocognitive decline.
Digital pathology analysis reveals TDP‐43 pathology as a strong predictor of glial activation in Alzheimer’s disease
Authors: Kouri Naomi , Frankenhauser Isabelle , Boon Baayla D.C. , Labuzan Sydney A. , Peng Zhongwei , Tranovich Jessica F. , Lesser Elizabeth R. , Crook Julia E. , Lachner Christian , Ertekin‐Taner Nilufer , Duara Ranjan , Graff‐Radford Neill R. , Dickson Dennis W. , Carter Rickey E. , Murray Melissa E.
Published: December 2023

Background

Glial activation plays a critical role in Alzheimer’s disease (AD) pathogenesis and is associated with amyloid‐β plaques and neurofibrillary tangles composed of phosphorylated tau (phospho‐tau). With approximately 40%‐60% of AD cases having limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), TDP‐43 pathology has become more the rule than the exception in AD brains. However, the effect of LATE‐NC in AD‐related glial activation is unknown.

Method

We analyzed the effect of TDP‐43 pathology on glial activation in three AD subtypes: hippocampal sparing (HpSp) AD, typical AD, and limbic predominant AD. Twenty cases of each subtype (n = 60 total) were selected from the FLorida Autopsied Multi‐Ethnic (FLAME) cohort. Cases were immunohistochemically evaluated on serial sections of the hippocampus in the CA1 and subiculum subsectors, and superior temporal, inferior parietal, and mid‐frontal cortices with antibodies to CD68 (phagocytosis), GFAP (astrogliosis), GT‐38 (conformation‐specific AD‐type tau), 6F/3D (amyloid‐β), and phospho‐Serine 409/410 of TDP‐43 (pTDP‐43). Digital pathology was employed to quantify immunohistochemical staining. Multivariable regression modeling was utilized to understand the relationship between glial activation and AD pathologies.

Result

The level of glial activation, defined as % of immunoreactive surface area for CD68 and GFAP, was lowest in HpSp AD (0.54%, 13%), whereas typical AD (1.3%, 33%) and limbic predominant AD (1.3%, 30%) had similar levels suggesting a ceiling effect, or plateau, of gliosis levels (both p<0.001). HpSp AD was more often male (p<0.001) and younger at disease onset (p<0.001) compared to both typical AD and limbic predominant AD. Multivariable regression modeling of CD68 (subiculum R2 = 0.60) identified advanced tau to be a significant predictor of CD68 in all brain regions. LATE‐NC stage predicted increased CD68 levels in limbic brain regions. Multivariable regression modeling of GFAP (CA1 R2 = 0.60) showed that Aβ was the strongest predictor of astrogliosis in CA1 and subiculum (p<0.001). Advanced tau in CA1 and parietal cortex, LATE‐NC in subiculum and temporal cortex, and APOE4 genotype in CA1 predicted a significant increase in GFAP.

Conclusion

These findings highlight the significant role TDP‐43 pathology plays in affecting the microenvironment and interplay between neuroinflammation and neurodegeneration and have important implications for therapeutic strategies in AD with co‐morbid LATE‐NC.
Age‐associated biomarker profiles in a non‐human primate model of sporadic CAA
Authors: Karimi Sohail , Patel Akash G , Nehete Bharti P , Nehete Pramod N , Debure Ludovic , Levine Dafna T , Cho Olivia , Rami Dina , Soliman Muhammad T , Llanos Michael , Gray Stanton B , Hopkins William D , Wisniewski Thomas , Scholtzova Henrieta
Published: December 2023

Background

Advancements of novel therapeutic interventions for Alzheimer’s disease (AD) have been hindered by a lack of animal models in preclinical research that naturally recapitulate the pathologic features of disease with age. Our prior work demonstrated the utility of squirrel monkeys (SQMs), a non‐human primate (NHP) model of sporadic AD pathology with abundant cerebral amyloid angiopathy (CAA), as an opportune species to assess the potential therapeutic outcomes and safety profile of our novel immunomodulatory approach using TLR9 agonist CpG‐ODN. Here we provide the first longitudinal and cross‐sectional study on aging and disease pathogenesis in SQMs by characterizing blood/CSF biomarker signatures of AD/CAA pathology.

Method

SIMOA, ELISA, and Luminex platform immunoassays were utilized to investigate age‐associated profiles of plasma and CSF biomarkers involved in neurodegeneration (NfL, GFAP), brain and peripheral inflammation/glia activation (YKL‐40/CHI3L1, sTREM2), and cerebrovascular dysfunction/BBB integrity (albumin index, bFGF, VCAM‐1, MMPs).

Result

Cross‐sectional analysis revealed statistically significant differences in plasma NfL and GFAP levels between age groups ranging from 6 to 23 years old (NfL: one‐way ANOVA, f(6,84)) = 6.395, p<0.0001; GFAP: one‐way ANOVA, f(6,84)) = 8.111, p<0.0001). Preliminary assessments revealed significantly higher plasma YKL‐40/CHI3L1 and MMP1 levels, while VCAM‐1, bFGF, and MMP2 levels were significantly lower in the geriatric SQMs when compared to the young group. CSF analyses demonstrated significantly higher YKL‐40/CHI3L1 and bFGF levels, and an elevated albumin index among the geriatric cohort when compared to young monkeys. Moreover, a longitudinal follow‐up of a separate SQM cohort over three years (19‐22 years old) revealed a significant increase in plasma sTREM2 levels; neurogranin levels appeared to increase, but differences were not significant (p = 0.0625, Wilcoxon signed‐rank test). Further characterizations of fluid biomarker trajectories and their relationships with age‐associated changes in cognition and neuroimaging markers are forthcoming.

Conclusion

SQMs present a valuable opportunity to evaluate biomarker signatures associated with aging and the development of cerebrovascular amyloid pathology. The use of this advantageous model is important to enhance the translational potential of novel therapeutics for human benefit.
MRI CHANGES FOLLOWING TREATMENT OF GLP‐1 ANALOGUE, LIRAGLUTIDE IN ALZHEIMER’S DISEASE
Authors: Edison Paul , Femminella Grazia Daniela , Ritchie Craig , Nowell Joseph , Holmes Clive , Walker Zuzana , Ridha Basil H , Williams Gareth , Lawrence Robert M , McFarlane Brady , Archer Hilary , Coulthard Elizabeth , Underwood Benjamin , Koranteng Paul , Karim Salman , Perneczky Robert , Prasanna Aparna , Junaid Kehinde , McGuinness Bernadette , Nilforooshan Ramin , Donaldson Andrew , Thacker Simon , Russell Gregor , Mate Vandana , Knight Lucy , Kshemendran Sajeev , Holscher Christian , Mansouri Anita , Chester‐Jones Mae , Holmes Jane , Harrison John E , Tadros George , Passmore Anthony Peter , Ballard Clive G
Published: December 2023

Background

Preclinical evidence in transgenic models of Alzheimer’s disease (AD) suggests that liraglutide, a GLP1 analogue, exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and reducing insulin resistance, and increasing the proliferation of neuronal progenitor cells. ELAD is a 12‐month, multi‐centre, randomised, double‐blind, placebo‐controlled, phase IIb trial of liraglutide in participants with mild to moderate AD conducted at 24 centres in the UK.

Method

As a part of this study, a total of 204 Alzheimer’s participants were randomised to receive either liraglutide or placebo as a daily subcutaneous injection for 12 months. All subjects underwent volumetric MRI scans at baseline and during follow up. Volumetric changes from baseline to follow up in MRI scans were evaluated using both regional volume analysis and voxel based morphometric analysis

Result

MRI analysis demonstrated that temporal lobe volume, total grey matter volume and frontoparietal volume change was lower in liraglutide treated patients compared to the placebo group. Voxel based morphometry (VBM) analysis demonstrated that liraglutide‐treated participants showed a slower reduction in whole cortical grey matter, frontal, temporal and parietal lobe volume in participants treated with liraglutide compared to placebo.

Conclusion

In the ELAD study, participants with mild to moderate AD who received liraglutide had slower reduction in MRI volume and cognition compared to the placebo demonstrating a potential benefit of liraglutide in the treatment of Alzheimer’s disease. These findings highlight the potential of GLP‐1 analogues in the treatment of Alzheimer’s disease
The Sporadic Early‐Onset Alzheimer’s Disease Signature of Regional Atrophy
Authors: Touroutoglou Alexandra , Katsumi Yuta , Brickhouse Michael , Eloyan Ani , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Vemuri Prashanthi , Dickerson Brad C.
Published: December 2023

Background

In EOAD, the localization of neurodegeneration is often more prominent in posterior lateral temporal, lateral and medial parietal, frontal, or occipital cortex relative to the medial and ventral temporal cortical localization of typical LOAD. Convergently, neuropathological investigations have identified a “hippocampal‐sparing” form of AD that is often present in younger patients. For these reasons, imaging biomarkers of neurodegeneration in EOAD, such as Magnetic Resonance Imaging (MRI) measures of atrophy, likely need to be different than those of neurodegeneration in typical LOAD. Although prior neuroimaging work has advanced our understanding of anatomical abnormalities in EOAD, these studies have included small samples, most composed of amnestic EOAD dementia and none focused on developing an MRI biomarker specific to EOAD. Such a disease‐signature MRI biomarker has been established and validated in LOAD dementia and has proven to be powerful in predicting progressive decline in people with MCI or who were cognitively unimpaired and in predicting molecular biomarker status. An a priori‐defined regional atrophy signature may also be helpful in constraining the analysis of MRI data in studies of putative disease‐modifying therapies.

Method

LEADS is an observational study which includes annual MRI. In this analysis, we used FreeSurfer to define the sporadic EOAD atrophy signature in a small sample of MGH EOAD patients, and investigated its reproducibility in LEADS, as well as the magnitude of atrophy and its relationship to clinical measures.

Result

The EOAD signature is robustly reproducible across the two independent patient cohorts, with prominent atrophy in caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortex, with relative sparing of medial temporal lobe structures. Comparing patients to controls, Cohen’s d effect sizes within various regions ranged from 0.99 to 1.98.

Conclusion

This study demonstrates the specific cortical regions with most prominent atrophy in patients with sporadic EOAD; this signature of regional atrophy will be used to examine longitudinal change.
The association between anxiety and Alzheimer’s disease plasma biomarkers across stages
Authors: Bernard Mark A , Boutajangout Allal , Debure Ludovic , Briggs Anthony Q , Vedvyas Alok , Marsh Karyn , Osorio Ricardo S , Wisniewski Thomas , Masurkar Arjun V.
Published: December 2023

Background

Anxiety is associated with faster progression of Alzheimer’s disease (AD) and related imaging biomarkers. However, the association of anxiety with plasma biomarkers of AD is unclear. We investigated the relationship between various plasma AD biomarkers and anxiety at different AD stages.

Method

The study included 192 older adults evaluated at the NYU Alzheimer’s Disease Research Center with a consensus diagnosis of cognitively normal (CN, n = 99), mild cognitive impairment (MCI, n = 52), and mild AD dementia (AD, n = 41). Anxiety and depression were measured by study partner report via the Neuropsychiatric Inventory Questionnaire (NPI‐Q). Plasma levels of Aβ40, Aβ42, neurofilament light (NfL) and total tau were measured using ultra‐sensitive, single‐molecule array (SIMOA) technology. Secondarily‐calculated measures included Aβ42/Aβ40 and tau/Aβ42 ratios.

Result

Anxiety had a prevalence of 14%, 48%, and 24% at CN, MCI, and AD, respectively. Comparing plasma biomarkers from participants with and without anxiety within each stage, anxiety associated with a significantly higher plasma tau/Aβ42 ratio in AD (p = 0.0127). In contrast, while depression had a higher prevalence of 37% at the AD stage, it was not associated with a significant difference in tau/Aβ42 ratio (p = 0.6459). Comparing stages, plasma tau/Aβ42 was significantly elevated in AD versus CN only among participants with anxiety (p = 0.034). In contrast, plasma NfL was significantly elevated in AD versus CN among participants with (p = 0.0475) and without (p < 0.0001) anxiety.

Conclusion

The presence of anxiety uniquely modulates the levels of specific plasma biomarkers depending on stage, as well as the ability of specific biomarkers to distinguish AD stages. These results highlight a complex relationship between neuropsychiatric symptoms and plasma biomarkers that warrants further study.
A Comprehensive, Community‐Engaged Recruitment Strategy to Increase Minority Representation in New IDEAS – an Amyloid Imaging Study
Authors: Wilkins Consuelo H. , Dilworth‐Anderson Peggye
Published: December 2023

Background

Although Black and Hispanic/Latino people have higher rates of clinical Alzheimer disease (AD), evidence indicates lower proportions and odds of positive amyloid positron emission tomography (PET). This may indicate differences in etiology of cognitive impairment, which has implications for prevention and treatment (ie, anti‐amyloid treatments). Unfortunately, Black and Hispanic/Latino people are underrepresented in AD research.

Method

To evaluate amyloid PET in a diverse sample, we designed culturally‐informed, community‐engaged recruitment strategies for New IDEAS (Imaging Dementia—Evidence for Amyloid Scanning), an observational, open‐label, longitudinal cohort study of beta‐amyloid PET. New IDEAS intends to recruit 7,000 U.S. Medicare beneficiaries with mild cognitive impairment (MCI) or dementia including 2,000 Black/African American and 2,000 Latino/Hispanic individuals. To ensure diversity, we developed a comprehensive recruitment strategy using a diverse, culturally‐trained staff that includes

:

• Identifying Dementia Specialists experienced recruiting minorities

• Embedding high‐impact community engagement in select regions

• Increasing capacity of specialists and PET facilities to engage minorities

• Increasing pipeline of referrals to Dementia Specialists

• Creating a culturally‐informed awareness campaign

Result

New IDEAS has enrolled 4,524 participants including 954 (21.1%) Black/African American, and 842 (18.6%) Hispanic/Latinx. Median age is 76 years; 54% are female. More Black/African American (46.6%) and Hispanic/Latinx (42.6%) participants had a dementia diagnosis compared to the overall cohort (33.9%). More Black/African American (37.4%) and Hispanic/Latinx (37%) participants were enrolled in Medicare Advantage compared to the overall cohort (19.5%).

During implementation, we encountered additional barriers to minority participation including: dementia specialists and PET facilities located greater distance from minority neighborhoods, lack of transportation to visits, fewer academic medical sites registered, concerns about co‐pays, and dementia specialists not accepting new patients. New strategies are being implemented to address some of barriers including coverage of co‐pays and assistance with transportation.

Conclusion

New IDEAS has enrolled more Black/African American and Hispanic/Latinx participants than any amyloid PET study published to date. Despite some success with minority enrollment, recruitment has been hampered by underlying structural barriers such as lack of access to dementia care in minority communities and higher Medicare Advantage rates. Additional resources and policy changes are needed to allow more equitable access to research and dementia care.
Tau maturation in clinicopathological spectrum of Lewy body and Alzheimer’s disease
Authors: Arezoumandan Sanaz , Cousins Katheryn A Q , Ohm Daniel T , Lowe MaKayla , Phillips Jeffrey S , McMillan Corey T , Siderowf Andrew , Chen‐Plotkin Alice , Deik Andres , Spindler Meredith , Tropea Thomas F. , Weintraub Daniel , Wolk David A. , Grossman Murray , Lee Eddie B , Irwin David J.
Published: December 2023

Background

In Alzheimer’s disease neuropathologic change (ADNC), maturation of neurofibrillary tangles and tau pathology are characterized by posttranslational modifications of tau. ANDC and Lewy body disease (LBD) commonly co‐exist in aging brains and there are overlapping clinical syndromes and heterogeneity in clinical features among cases with mixed ADNC and LBD pathology. Given this clinical and pathological overlap, we examined the postmortem expression of tau conformational epitopes that mark various stages of tangle maturation in clinicopathologic spectrum of Alzheimer’s disease (AD) and LBD.

Method

Autopsy‐confirmed cases with diffuse neocortical LBD with/without ADNC (n = 59) were selected (Table1). We used digital histology methods to measure percent area occupied (%AO) with pathology in three regions (middle frontal, anterior cingulate, and superior temporal cortices) immunohistochemically stained with MJF‐R13 (α‐synuclein), NAB228 (beta‐amyloid), and tau monoclonal antibodies marking phosphorylated (AT8), early conformational (MC1, preferentially reactive in pre‐tangles), and C‐terminally truncated tau epitopes (TauC3, preferentially reactive in mature intracellular and ghost tangles). Linear models tested the group comparisons, and correlation between α‐synuclein or beta‐amyloid with outcome of average neocortical tau. In models, %AO were log‐transformed, and age and sex were included as covariates.

Result

α‐synuclein was strongly correlated with early tau epitopes labelled with AT8 (β = 1.37, p<0.001) and MC1 (β = 1.20, p<0.001), but not with mature tau epitopes detected by TauC3 (p = 0.38). There were significant positive correlations between all tau epitopes and beta‐amyloid, including TauC3 immunoreactive tau (p≤0.013) (Figure1). In the mixed pathology group, those with clinical LBD had a positive association between α‐synuclein and MC1 (β = 1.61, p = 0.014) and AT8 (β = 1.67, p = 0.005) positive tau, while those with clinical AD had no correlation between α‐synuclein and tau epitopes. There was greater MC1 (β = 3.40, p<0.001), AT8 (β = 3.59, p<0.001), and TauC3 (β = 1.43, p = 0.005) pathology in patients with clinical AD compared to clinical LBD.

Conclusion

In LBD, higher α‐synuclein is associated with greater phosphorylated and early tau conformations, but not later conformation of mature tau, which was selectively associated with beta‐amyloid pathology. Our findings suggest that tau pathology may modify the clinical expression of synucleinopathies and C‐terminal truncation of tau may be more closely related to AD pathophysiology than synucleinopathy.