bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma metabolomic profiles of aged, humanized APOE mice and behavioral correlates
Authors: McLean John W. , Bhattrai Avnish , Simmons Hannah , Wiegand Jean‐Paul L. , Raikes Adam C. , Kaddurah‐Daouk Rima F. , Brinton Roberta Diaz
Published: December 2023

Background

Apolipoprotein E (APOE) plays a critical metabolic role by facilitating the binding of lipid complexes to cell surface receptors, providing tissues with energy substrates. The APOE‐ε4 (APOE4) polymorphism is the predominant genetic risk factor for late‐onset Alzheimer’s Disease (LOAD), while APOE3 is considered risk‐neutral. Female biological sex also nearly doubles LOAD risk. This study utilizes the JAX humanized APOE knock‐in mouse model to investigate the contributions of chromosomal sex and APOE genotype to plasma metabolic profiles, along with potential correlates to cognitive performance in a novel objection recognition (NOR) task.

Method

Male and female mice aged 23‐25 months old (37M/32F) with humanized APOE3/3, APOE3/4, and APOE4/4 genotypes underwent blood plasma extraction and subsequent metabolic profiling via mass spectrometry using the Biocrates MxP® Quant 500 platform. A subset of animals (34M/28F) additionally performed an NOR paradigm prior to metabolic profiling. Two‐way ANOVA and post‐hoc t‐tests were utilized to determine data significance.

Result

Metabolomic analyses indicated that male mice exhibited relatively higher levels of glucogenic amino acids, including glycine, asparagine, and histidine. In contrast, female mice had higher levels of TMAO and ADMA along with lower levels of phosphatidylcholines, cholesteryl esters (CE), and triglycerides. In males, APOE3/4 and APOE4/4 genotypes were associated with lowered CE levels. APOE3/4 female mice had the lowest CE plasma concentrations. Female APOE4/4 mice had increased concentrations of several diglyceride and triglyceride species, relative to APOE3/3 and APOE3/4 female mice. Behavioral correlates indicated that triglyceride levels negatively correlated with locomotion throughout the NOR paradigm. Memory performance, as determined by the discrimination index, positively correlated with plasma concentrations of glycine and negatively correlated with hydroxy acylcarnitine levels.

Conclusion

In mice aged to resemble a ∼70‐year‐old human population, these results suggest that biological sex affects peripheral metabolic profiles greater than APOE genotype. Male metabolism was characterized by elevated glucogenic amino acid levels; female metabolic profiles demonstrated increased TMAO and lower phosphatidylcholines and triglycerides, suggesting differences in lipid metabolism. APOE3/4 genotype was associated with lowered CE in both sexes while APOE4/4 females had higher triglycerides, indicating potential sex‐genotype interactions upon metabolism that may confer elevated LOAD risk and influence behavior.
Salivary lactoferrin for detection of early stage Alzheimer’s disease
Authors: Bunprakop Saowalak
Published: December 2023

Background

As the global population ages, the incidence of dementia is projected to increase significantly in the coming years, with Alzheimer’s disease (AD) being the leading cause. To address this impending public health crisis, there is a critical need to identify simple and reliable biomarkers for early AD diagnosis. While current diagnostic approaches include cerebrospinal fluid analysis and positron emission tomography (PET), they are often unavailable in resource limited settings. Recent research has highlighted the potential utility of salivary lactoferrin (Lf) as a promising biomarker for AD diagnosis. In this study, we aim to assess salivary Lf levels in early‐stage AD patients in comparison to non‐demented elderly controls, with the goal of further elucidating the diagnostic utility of this biomarker.

Method

A total of 81 saliva samples were collected from 28 early‐stage AD patients and 53 nondemented elderly controls. The diagnosis of AD was made clinically using the current guidelines (Jack et al., 2018; Dubois et al., 2021) and 70.4% of participants underwent biomarker testing using amyloid‐PET or plasma phosphorylated tau181 (p‐tau181). Salivary Lf levels were compared between the two groups and the diagnostic performance of Lf was evaluated in these early‐stage patients.

Result

Among 81 participants included, 53 (65.4%) were female. The median age was 69 years (interquartile range: 62.8‐76.0). Salivary Lf levels decreased significantly among early‐stage AD patients compared to controls (median: 5.03 vs 26.85, P<0.01). Salivary Lf showed strong correlation with plasma p‐tau181 (Spearman Rho = ‐0.51, P<0.01) but not with age (Spearman Rho = ‐0.17, P = 0.15). For diagnosing AD in early‐stage patients, salivary Lf levels demonstrated an area under the curve of 0.93 (95% confidence interval 0.82‐0.98).

Conclusion

Consistent with prior findings, diagnostic performance of salivary Lf is substantial. Further research endeavors should conduct a comprehensive assessment of this biomarker against a robust, biomarker‐based reference diagnosis. If validated, the ease of saliva collection could potentially make it an attractive option for population‐wide screening and early identification of undiagnosed individuals with AD in its early stages.
Abnormalities in Occipital Cortical Sources of Resting‐State EEG Rhythms in Patients with Epileptiform Activity and Mild Cognitive Impairment due to Alzheimer’s Disease
Authors: Salamone Enrico Michele , Noce Giuseppe , Tucci Federico , Jakhar Dharmendra , Lopez Susanna , Lizio Roberta , Percio Claudio Del , Babiloni Claudio
Published: December 2023

Background

Alzheimer’s Disease (AD) patients present a higher risk of developing epilepsy compared to the age‐matched general population. Neurodegenerative cognitive disorders in general are closely linked with epilepsy and subclinical Epileptiform Electroencephalographic Activity (EEA). Furthermore, AD with Mild Cognitive Impairment (MCI) patients present abnormalities in posterior cortical sources of resting‐state eyes‐closed EEG rhythms at delta (< 4 Hz) and low‐frequency alpha (8‐10 Hz) rhythms. This retrospective study tested the hypothesis that ADMCI patients with EEA (ADMCI‐EEA) may be characterized by specific disease‐related abnormalities in delta and alpha rsEEG source activities compared with ADMCI patients without EEA (ADMCI‐noEEA) and noADMCI controls.

Method

We analysed data from an international database (www.pdwaves.org) comprising clinical, neuropsychological, rsEEG (25‐30 minutes), cerebrospinal fluid (CSF), and structural magnetic resonance imaging (sMRI) data in n = 42 ADMCI and n = 32 noADMCI patients without a diagnosis of epilepsy. The database also included clinical, neuropsychological, and rsEEG data of n = 38 matched cognitively unimpaired elderly (Nold) persons, used as additional controls in the present study. The rsEEG traces were reviewed by expert epileptologists blinded to the diagnostic status. EEA was detected in n = 8 ADMCI and n = 13 no‐ADMCI patients (Table 1). Individual alpha frequency peak (IAF) was used to determine the rsEEG delta, theta, and alpha bands. Regional rsEEG cortical sources were estimated using the eLORETA freeware.

Result

Compared to the Nold and noADMCI‐noEEA groups, the noADMCI‐EEA group showed greater temporal rsEEG delta cortical source activity. Conversely, compared to the Nold and ADMCI‐noEEA groups, the ADMCI‐EEA group showed greater temporal and occipital rsEEG delta cortical source activity (Figure 1). Notably, CSF amyloid (but not sMRI‐based cortical atrophy) burden was greater in the ADMCI‐EEA than in ADMCI‐noEEA patients (Table 2).

Conclusion

The abnormal temporal rsEEG delta cortical source activity in the ADMCI‐EEA and noADMCI‐EEA groups may reflect an unspecific susceptibility of the temporal lobe to slowing rsEEG activity for several neuropathological processes. Instead, the abnormal occipital rsEEG delta cortical source activity in the ADMCI‐EEA over the control groups may reflect a specific susceptibility of the occipital lobe to slowing rsEEG activity for AD‐related neuropathological processes in the cholinergic tract to the occipital cortex.
Signalling pathways associated with impaired angiogenesis in Alzheimer’s Disease
Authors: Tsartsalis Stergios , Sleven Hannah , Fancy Nurun N , Wessely Frank , Willumsen Nanet , Michal Rokicki , Chau Vicky , Ifie Eseoghene , Khozoie Combiz , Ansorge Olaf , Owen David R , Webber Caleb , Jackson Johanna , Cader Zameel , Matthews Paul M
Published: December 2023

Background

Brain perfusion and blood brain barrier (BBB) integrity are reduced in Alzheimer’s disease (AD). We hypothesized that b‐amyloid (Aβ) induces dysfunction of pathways in vascular cells that regulate angiogenesis.

Method

We performed single nucleus RNA sequencing (snRNAseq) of vascular cells isolated from post mortem samples from multiple cortical regions from AD patients (Braak V‐VI) and non‐diseased controls (NDC, Braak 0‐II). We developed a meta‐analytic approach to integrate these data with related publicly available datasets. We performed differential gene expression (DGE) analyses as a categorical comparison of AD vs NDC and as a confound‐controlled regression of transcriptomic alterations by regional total Aβ. We also performed cell‐specific gene co‐expression analyses identify modules differentially expressed in AD relative to NDC.

Result

Our results describe differential expression of genes central to pathways sustaining angiogenesis, proliferation and migration of endothelial cells and the integrity of the BBB with either AD or greater pathological protein load. HIF1A and FGF2, proangiogenic molecules which both induce VEGF, are upregulated in EC, consistent the parenchymal hypoxic response shown repeatedly in prior studies. However, components of signalling pathways downstream of VEGFR2 are downregulated, suggesting a pathological block to angiogenesis with greater Aβ load. While the proangiogenic stimuli promote the expression of genes such as PPP3CA and ITPR1, coding for calcineurin, which contribute to VEGF signalling through the PLCγ‐Ca2+ signalling pathway are upregulated in AD, expression of RAC1 and RHOJ, which enable cellular migration and adhesion, is downregulated. While ANGPT2 expression is also upregulated, the angiopoietin receptor (TIE2, coded by TEK) is downregulated. Downregulation of ADAM10 in AD and upregulation of other NOTCH pathway genes with greater Aβ load suggests altered NOTCH signalling.

Conclusion

Overall, a hypoxic tissue environment in AD is accompanied by dysfunctional angiogenesis related to Aβ load. Evidence for multiple sites of dysfunction were identified, involving impaired angiopoietin responses, vascular cell migration and NOTCH signaling.
A study on the sample representativeness of the Wisconsin Alzheimer’s Disease Research Center Clinical Core participants versus the Wisconsin state population
Authors: Ma Yue , Pinzon Maria C Mora , Buckingham William R. , Bersch Andrew , Powell W. Ryan , LeCaire Tamara J. , Ennis Gilda E. , Deming Yuetiva , Jonaitis Erin M. , Reuter Leah , Shi Fangfang , Spalitta Alice , Wahoske Michelle L , Bevis William B. , Blazel Hanna M. , Chin Nathaniel A. , Edwards Dorothy F. , Walaszek Art , Okonkwo Ozioma , Chappell Richard J , Johnson Sterling C , Asthana Sanjay , Gleason Carey E. , Kind Amy J. , Bendlin Barbara B , Carlsson Cynthia M
Published: December 2023

Background

Understanding how representative a research sample is compared to the population can help inform future recruitment planning, data analysis strategies, and interpretation of the generalizability of the findings. We compared the demographics, rural residence, neighborhood socioeconomic disadvantage, and vascular risk factors between the Wisconsin Alzheimer’s Disease Research Center (ADRC) Clinical Core participants versus the Wisconsin state adult population.

Method

The ADRC participant sample (n = 678) included all active participants as of November 30, 2021. The state population statistics were estimated using multiple national and state data sources. Differences between the sample versus the population were tested using the one‐sample z‐test, the one‐sample Wilcoxon signed rank test, the exact binomial test, and the exact Monte Carlo multinomial test. Except for age, comparisons were performed for two age groups: 45‐64 years and ≥ 65 years, separately.

Result

The ADRC participants are older than the state population. For each age group, compared to the state population, the ADRC participants include more women and greater proportions of Black and American Indians, have higher levels of educational attainment, have smaller percentages living in rural areas and more disadvantaged neighborhoods, and show lower vascular risks. The sample versus population differences are greater for the ≥ 65 years group (the group at higher risk for AD) than the 45‐64 years group for most metrics, however, are smaller for sex and neighborhood disadvantage.

Conclusion

The ADRC targets recruiting middle‐aged and older adults with dementia, mild cognitive impairment, or increased risk for AD. Thus, the participants are not a suitable sample for epidemiology studies on AD prevalence. Oversampling underrepresented racial groups would alleviate the lack of statistical power associated with small or unbalanced sample sizes and increase the precision in effect size estimates for studies on racial disparities. Future recruitment should endeavor to include participants from a broader range of educational backgrounds and more residents in rural areas and disadvantaged neighborhoods. These subpopulations have inequitable access to quality health care and are at greater risk. Properly representing them in research would allow conclusions to be generalizable to these subpopulations and support policy making to meet their needs.
Assessing the functional effect of the Presenilin‐1 G206A variant on age of onset of Alzheimer Disease in the Puerto Rican population
Authors: Celis Katrina , Rajabli Farid , Griswold Anthony J. , Adams Larry D. , Tejada Sergio J. , Sanchez Jose Javier , Simon Shaina A. , Hamilton‐Nelson Kara L. , Gomez Nicholas R , Whitehead Patrice , Mena Pedro R. , Arvizu Jamie , Golightly Charles G. , Silva Concepcion , Acosta Heriberto , Cuccaro Michael L. , Vance Jeffery M. , Beecham Gary W. , Feliciano‐Astacio Briseida E. , Dykxhoorn Derek M. , Young Juan I. , Pericak‐Vance Margaret A.
Published: December 2023

Background

The variant G206A in Presenilin‐1 (PSEN1) gene has been identified almost exclusively in Alzheimer Disease (AD) Puerto Rican families. This variant represents a founder effect on the African background. The G206A variant associates with extreme variability in age of onset (AOO), ranging from 30 to 90 years. In contrast, other variants at the same amino acid of PSEN1 (G206N, G206S) have a tighter range of AOO (30‐35 years). We aim to identify the molecular mechanisms involved in the AOO variability between G206A carriers through functional analysis of induced pluripotent stem cells (iPSCs).

Method

Genotyping data were phased using SHAPEIT to identify local ancestry and RFMix to estimate genetic ancestry. p‐Tau181 levels were tested from plasma using Simoa (Quanterix HD‐X). iPSCs of G206A carriers with different AOO were reprogrammed using non‐integrating Sendai virus. These clonal lines were assessed for pluripotency and chromosomal stability Isogenic construction of G206A iPSC lines is currently in progress.

Result

We screened for G206A carriers using whole genome from 896 individuals (182 families) and identified 43 carriers (39 AD and 4 cognitively unimpaired <65 years) from 8 families and 3 isolated cases. 55% of AD G206A carriers had AOO <65. A single African haplotype was identified in all G206Acarriers. We observed higher pTau181 levels in AD G206A carriers with early age of onset, compared to those with late onset. Association analysis did not identify APOE4 or SYNJ1 polymorphisms as contributing to the differences in AOO within G206A carriers. To perform functional studies, we selected three with early (<65) and three with late (>65) AOO AD peripheral blood mononuclear cells (PBMCs)that were reprogrammed into iPSC lines. G‐band Karyotype, factor loss analyses, genetic finger printing, immunocytochemistry (ICC) and qRT‐PCR for intracellular and surface pluripotency markers was confirmed in the iPSC lines.

Conclusion

The PSEN1 G206A variant, originating in African ancestry haplotype revealing a founder effect, is an important contributor to AD in an underserved population. Understanding the role of the G206A variant in AD pathogenesis and the factors that influence its effect on AOO will provide insight on AD pathogenesis, age of onset variation and identification of potential novel therapeutic targets.
Rare cause of dementia in childhood
Authors: Dubey Shubham , Dubey Ayush
Published: December 2023

Background

Dementia is rare in paediatric age group. While inborn errors of metabolism account for majority of the causes, structural abnormalities are also responsible for cognitive decline in few patients. We present such a rare case here.

Method

An eight year old female presented to Neurology department with complaints of decline in memory, poor judgement and social disinhibition since two months with three episodes of focal with impaired awareness seizures. On examination, she had MMSE score of 8/30 and no motor weakness or abnormal reflexes. She was evaluated for her symptoms.

Result

MRI showed elongated curvilinear altered signal intensity structure consistent with fat at inter‐hemispheric fissure, pericallosal in location, adjacent to body, isthmus and splenium of corpus callosum indicating pericallosal lipoma (curvilinear type).

Conclusion

Pericallosal lipoma is a rare congenital malformation of brain that can be associated with dysgenesis or agenesis of the corpus callosum. It is usually asymptomatic, but can manifest with seizures, dementia, paralysis or headaches. CT and MR imaging play an important role in making this diagnosis.
Multimodal music therapy intervention for engagement and agitation reduction for persons with severe dementia: Study protocol of a pilot randomized cross‐over trial
Authors: Reschke‐Hernandez Alaine E. , Ross Meghan , Davis Hayley Rene , Latham Emma Foret , Veblen Nora Bryant
Published: December 2023

Background

Music‐based interventions may support the well‐being of persons with dementia (PWD). However, limited empirical evidence exists regarding the optimal use of such interventions for specific outcomes and at different disease stages. Project goals are to 1) demonstrate proof‐of‐concept and feasibility of a music therapy intervention for care facility residents with severe dementia and 2) obtain preliminary data. Here, we describe the study protocol.

Method

The multimodal intervention, led by a music therapist, uses live participant‐preferred music and progressively layers singing and rhythmic instrument playing concurrent with participant behavioral responses. It is grounded in the “Clinical Practice Model for PWD,” a person‐centered framework that presents a schema regarding why particular care strategies are important and how to implement them (Reschke‐Hernández, 2019; 2021). This randomized cross‐over design has 4 blocks: Baseline, 3‐week treatment period, 1‐week washout (no intervention), and 3‐week treatment period. The comparison treatment consists of short stories read aloud, using the same non‐music strategies, small group format (3‐5 people per group), and dosage (2x/week for 30 minutes) as the combined music interventions. Outcomes include ratings of engagement (primary outcome), agitation, and arousal. To evaluate our study design within the care milieu, we will perform semi‐structured interviews with up to 10 caregivers at participating facilities. The Menorah Park Engagement Scale (Camp et al., 2015) and Observed Emotion Rating Scale (OERS; Lawton et al., 1999) are used to measure engagement and agitation, and the Neuropsychiatric Inventory‐Nursing Home (Wood et al., 2000) to measure agitation and occupational disruptiveness. The OERS, data on functional transfers, pulse oximetry, and a wearable activity tracker (including sleep data) are used to measure arousal.

Results

Planned enrollment is 20 PWD. Recruitment will occur in partnership with care facilities from January to May 2023, with active data collection beginning in February. Preliminary data will be available in March with results in July 2023.

Conclusion

Progressive layering of musical stimuli coupled with purposeful activity, matched to participants’ cognitive capacity, may promote purposeful engagement, thereby supporting arousal regulation and reducing agitation. A key deliverable will be enhanced practical understanding of how to measure effectiveness of music‐based interventions for PWD.
Phosphorylated tau in the Down syndrome brain: Age related increases and comparison to late‐onset Alzheimer’s Disease
Authors: Pascual Jesse R. , Nguyen Halyma , Ngo Phong , Andrews Elizabeth J. , Kofler Julia , Ikonomovic Milos D , Lai Florence , Phelan Michael J. , Head Elizabeth ,   Alzheimer Biomarkers Consortium — Down Syndrome (ABC‐DS)
Published: December 2023

Background

Individuals with Down Syndrome (DS) have an increased risk of developing Alzheimer’s Disease (AD) with nearly all individuals exhibiting neuropathological changes in the brain by age 40 years, and with a mean diagnosis of dementia by age ∼55 years. The purpose of this postmortem study was to characterize the age‐associated burden of several tau phosphorylation epitopes, including threonine (pT) 181, 217, and 231 by immunohistochemistry in the frontal cortex. We hypothesized that cerebral pT burden would increase with age in DS but not in controls and be higher in DS with AD neuropathology (DSAD) compared to late‐onset AD (LOAD).

Method

We examined 117 brains from: controls (non‐DS n = 53; ages 1‐91), DS without AD (n = 13; ages 1‐48), DSAD (n = 31; age 43‐68), and LOAD (n = 20; ages 63‐96). Serial sections from the frontal cortex were cut at 30µm and immunostained for phosphorylated tau pT181, pT217 and pT231. Whole slide images were digitized and analyzed by Aperio ImageScope software. The % area for each type of tau was quantified using positive pixel counts. Spearman rank correlations on log‐transformed data were used to test for positive age associations and t‐test was used to compare pT between DSAD and LOAD.

Result

In control cases, there was a positive correlation of age with pT181 (r = 0.47 p<0.001) but not with pT217 or pT231. In DS cases across the lifespan (DS and DSAD combined) displayed a positive correlation of age with pT181 (r = 0.70 p<.001), pT217 (r = 0.70 p<.001), and pT231 (r = 0.42 p = 0.005). DSAD cases had significantly higher pT181, pT217 and pT231 (p<.001) than late‐onset AD and control cases.

Conclusion

These results suggest that tau phosphorylation for these epitopes is more positively correlated with age in people with DS than people without DS. Although pT181 increased with age in both cohorts, pT217 and pT231 showed a positive correlation with age in people with DS but not controls. Fluid biomarker studies focused on pTau in longitudinal cohorts of people with DS with subsequent brain donation will help reveal the link between peripheral and central pTau levels.
COVID‐19 vaccination hesitancy among people with dementia
Authors: Ciopleias Bogdan , Ungureanu Larisa , Rusu Diana , Diaconu Stefania , Irincu Laura , Despa Irina , Falup‐Pecurariu Oana , Zarnoveanu Anca , Opritoiu Bianca , Murasan Iulia , Kakucs Cristian , Cusnir Malina , Falup‐Pecurariu Cristian
Published: December 2023

Background

people with dementia is a vulnerable category during COVID‐19 pandemic. COVID‐19 vaccination hesitancy was one of the main issues during pandemic with multiple factors involved. Aim of the study: to evaluate COVID‐19 vaccination hesitancy among people with dementia and factors involved.

Method

prospective study on 134 patients (60.44% females) with a mean age of 73.45 ± 17.12 years. We used a standardised questionnaire to assess the attitude and risk factors of COVID‐19 vaccination hesitancy. There were two assessment periods: 1.) 01.07.2021 – 31.09.2021 and 2.) 01.02.2022‐ 31.04.2022.

Result

a total of 25 (18.65%) people with different form of dementia were vaccinated during the first study period. For the remaining 110 patients, vaccination hesitancy involved (one or multiple factors): vaccine insufficient tested (61 patients, 55.45%), possible serious side effects (25 patients, 22.72%), safety of COVID‐19 vaccine over dementia (74 patients, 67.27%), and worsening of cognition symptoms (63 patients, 57.27%). A number of 51 patients (46.36%) were advised by the family and relatives to wait, not to vaccinate in that period. Intention to vaccinate in the future was expressed by 39 patients (35.45%): 10 very likely (25.64%) and 29 (74.35%) likely. Patients with dementia living in rural parts, with relatives with high frequency of vaccination hesitancy are more likely to hesitate to vaccinate. They get the information especially from family members and TV.

Conclusion

COVID‐19 vaccination hesitancy among people with dementia involve concerns related to possible side effects of the vaccine and risk of worsening of dementia symptoms.
The NIA Genetics of Alzheimer’s Disease Data Storage Site API: a toolkit for exploring Alzheimer’s disease genetics and genomic annotations
Authors: Greenfest‐Allen Emily , Kuska Pavel P. , Lee Wan‐Ping , Leung Yuk Yee , Valladares Otto , Wang Li‐San
Published: December 2023

Background

NIAGADS is a repository for genotypic data relating to the study of the genetics of Alzheimer’s disease and related dementias (AD/ADRD). To facilitate access to unrestricted data in the repository and support research collaborations with the AD Sequencing Project (ADSP), NIAGADS has created several public databases. Programmatic access to these resources is essential for many bioinformatics applications exploring AD/ADRD genetics. These databases include: the Alzheimer’s GenomicsDB, an interactive knowledgebase for mining NIAGADS summary statistics datasets that provides detailed reports of AD/ADRD‐risk associations for >250 million annotated variants and their potential gene targets; the AD Variant Portal (ADVP), a catalog of AD/ADRD genetic associations curated from recent literature in the context of both genes and variants; VariXam, which reports variants detected from the ADSP’s whole‐genome and whole‐exome sequencing data; and FILER, an indexed database of harmonized functional genomics and gene/variant annotations containing ∼80k searchable data tracks.

Method

We have created a RESTful Application Programming Interface (REST API) to support integration of NIAGADS datasets and annotations assembled in these public resources into software applications. Calls to the API are based on simple URLs that specify the feature type (e.g., gene, variant, or locus), feature identifier(s) and filter criteria (e.g., NIAGADS resource, or dataset and bio‐source properties), defining an intuitive interface for programmatic access. API calls for gene or variant records return functional annotations as well as genetic evidence for AD/ADRD‐risk. Queries can also be made against FILER or the GenomicsDB to retrieve functional annotations and risk‐associated variants within a genomic span of interest across one or multiple datasets. The API supports both single‐lookups and batch queries, with paginated results to improve query and response times.

Result

The NIAGADS API establishes a simple framework for sharing and integration of NIAGADS datasets and annotated gene and variant records into analysis pipelines. Use of the API requires only a HTTPS library and JSON parser, permitting large‐scale programmatic access independent of any specific programming language.

Conclusion

The NIAGADS REST API promotes data sharing and reuse among the AD/ADRD research community. Information about accessing this toolkit as it becomes available can be found on the NIAGADS website (https://www.niagads.org).
Plasma biomarkers as stand‐alone tests in the diagnosis of Alzheimer’s disease
Authors: Therriault Joseph , Benedet Andrea Lessa , González Escalante Armand , Jonaitis Erin M. , Ashton Nicholas J. , Karikari Thomas K , Tissot Cécile , Servaes Stijn , Rahmouni Nesrine , Lussier Firoza Z , Stevenson Jenna , Milà‐Alomà Marta , Pascoal Tharick A. , Vitali Paolo , Gauthier Serge , Zetterberg Henrik , Johnson Sterling C. , Blennow Kaj , Suarez‐Calvet Marc , Rosa‐Neto Pedro
Published: December 2023

Background

Several recent studies have provided evidence for high diagnostic performance of plasma biomarkers for AD, with Area Under the Curve values sometimes exceeding 90%. However, positive and negative predictive values are rarely reported yet are critical for interpreting individual‐level screening test results.

Method

We determined positive and negative predictive values of plasma biomarkers (p‐tau181, p‐tau217, p‐tau231, GFAP and NfL) for biological AD (A+T+, determined either with PET or CSF) in the TRIAD, WRAP, ALFA+, BIODEGMAR, ADNI and McGill memory clinic cohorts (total n = 2219). We also determined positive and negative predictive values for specific clinical scenarios: MCI and mild AD – two populations that may benefit from disease‐modifying therapies in AD. Prevalence estimates of biological AD in these groups were taken from the Mayo Clinic Study of Aging.

Result

P‐tau217 had the highest positive and negative predictive values of all biomarkers in all cohorts, with above 80% positive and negative predictive values. In individuals with MCI, an etiologically heterogeneous syndrome, plasma p‐tau217 had sufficiently high performance to rule out biological AD in differential diagnosis. In mild AD dementia, plasma p‐tau217 could rule in biological AD, but follow‐up with PET/CSF will likely be needed to confirm the absence of AD.

Conclusion

Plasma biomarkers have the potential to be used as stand‐alone diagnostic tools in specific clinical scenarios. In MCI, a negative plasma p‐tau217 could rule out AD as a cause of cognitive impairment, but a positive result should be followed up with PET/CSF. In mild AD dementia, a positive plasma p‐tau217 result can rule in biological AD, but a negative result should be followed up with PET/CSF.
Drivers of underreport of memory loss in mild cognitive impairment due to Alzheimer’s and vascular disease
Authors: Briggs Anthony Q , Tall Sakina Ouedraogo , Bernard Mark A , Masurkar Arjun V.
Published: December 2023

Background

We examined self‐ and informant‐based report of memory loss in mild cognitive impairment due to Alzheimer’s disease (AD‐MCI) and vascular disease (Va‐MCI). We hypothesized that drivers of underreport would differ based on etiology and participant characteristics.

Method

This retrospective cross‐sectional study included participants with AD‐MCI (n = 2874) and Va‐MCI (n = 376) in the National Alzheimer’s Coordinating center dataset (NACC). Report of memory loss by the participant and informant was recorded as a binary (yes/no) value. We examined the role of demographic variables (age, sex, education, race, ethnicity) and neuropsychological variables (anxiety, depression on NPI‐Q) in driving underreporting of memory loss using Fisher’s exact test.

Result

Compared to AD‐MCI, Va‐MCI was associated with significantly more underreport of memory loss by participants (24.5% vs 19.7%, p = 0.031) and informants (31.4% vs 21.6%, p<0.0001). Black/African American participants displayed higher rates of underreport in both AD‐MCI (27.1% vs. 18.4%, p<0.0001) and Va‐MCI (37.8% vs. 20.8%, p = 0.0022). Informant underreport was increased in both AD‐MCI and Va‐MCI for participants who were female (AD: 24.3% vs 18.6%, p = 0.0002; Va:38.1% vs 22.2%, p = 0.0011) and Black/African American (AD: 35.1% vs 19.3%, p<0.0001; Va: 48.8% vs. 26.5%, p = 0.0002), and in AD‐MCI for participants who had less than 16 years of education (AD: 23.9% vs 20.3%, p = 0.0262). In both AD‐MCI and Va‐MCI, anxiety associated with less underreport in both participants (AD: 13.1% vs 22.0%, p<0.0001; Va: 15.91% vs. 31.2%, p = 0.0071) and informants (AD: 10.8% vs. 25.5%, p<0.0001; Va: 15.9% vs. 37.4%, p = 0.0002). Underreport was similarly lowered with depression in participants (AD: 14.7% vs 21.4%, p<0.0001; Va: 15.1% vs 28.3%, p = 0.0146) and informants (AD: 11.5% vs 25.2%, p<0.0001; Va: 17.4% vs. 36.8%, p = 0.0008).

Conclusion

Persons with MCI and who have likely vascular presentations, or who are female, Black/African American, or have lower education are at increased risk for self‐ and/or informant‐based underreport of memory loss. Affective symptoms appear to increase the likelihood of correctly reporting memory loss. These factors may be particularly important in influencing interview‐based MCI detection and would suggest extra vigilance in persons at‐risk for self‐ or informant‐based misreport.
Biological Domain Network Analysis Identifies Potential Triadic Interaction between Mitochondria, Nuclear Epigenetics, and Synaptic Viability
Authors: Wiley Jesse C , Cary Gregory A. , Levey Allan I. , Carter Gregory W , Greenwood Anna K
Published: December 2023

Background

The AD endophenotypes initially described in the Common Alzheimer’s Disease Research Ontology (CADRO) were augmented and transformed into computationally implementable definitions for 19 discrete Biological Domains. These AD biological domains were employed in the development of molecular interaction networks depicting the signaling and protein‐protein interaction as a central bioinformatics resource for the TREAT‐AD consortium.

Method

19 AD biological domains were identified by iterative literature culling and model testing based on gene set enrichment analysis and gene ontology term identification. All 19 biological domains are defined by an exhaustive set of GO terms, allowing scientists everywhere to use the same criteria to define their large datasets in an unbiased manner. Network models were constructed from the leading‐edge genes from all AD‐risk enriched GO terms within each biological domain. The network models incorporate data from over 1700 transcriptomic brain studies and 1100 proteomic brains studies examining shifts in gene expression. These are employed as a reference tool for the formulation of specific hypotheses.

Result

The analysis of mitochondrial gene expression changes at both the transcriptomic and proteomic level identify deficits in both mitochondrial energy production and metabolism along with a decrease in acetyl‐CoA production, a necessary element for many reactions including histone acetylation. This suggests that mitochondrial metabolic tone may modify epigenetic regulation through lysine acetyltransferase (KATs) independently from ATP production. Examination of decrements in KAT activity from other model systems suggest a particularly robust impact on synaptic gene expression, implying a potential interaction between mitochondrial metabolism and synaptic gene expression independent of energy production. Intriguingly, some elements of a protein module identified by TREAT‐AD large‐scale deep proteomic analysis found to be most tightly associated with AD pathology and cognitive decline, are tightly associated with this model.

Conclusion

The biological domains were constructed as a computational resource to facilitate hypothesis generation within the TREAT‐AD consortium, and here are implemented to highlight one emerging interaction between domains that may imply new mechanisms of disease regulation coupling between mitochondria and synaptic viability through shifts in epigenetic regulation.
Depression and the relationship between neurocognition and functional status and decline within ethnoculturally diverse middle and older adults
Authors: Breen Elizabeth Anne , Arentoft Alyssa , Cham Heining , Oleas Denise S. , Slaughter Alex W. , Camuy Alicia M , Schuck Lauren A , Hart Rebecca , Talavera Sandra , Mindt Monica Rivera ,   The Study of African‐Americans and Latinas/os for Understanding Dementia (SALUD)
Published: December 2023

Background

Ethnoculturally diverse (e.g., non‐Latinx Black (NLB), Latinx) older adults are up to twice as likely as non‐Latinx White (NLW) older adults to experience depressive symptoms. While the relationship between neurocognition (NC) and functional status (e.g., everyday functioning) in older adults is well‐established, the impact of depression remains unclear in diverse populations. We assessed the influence of depression on the relationship between NC and functional status in a sample of Latinx, NLB, and NLW middle‐aged/older adults.

Method

This cross‐sectional study included 50 NLB, 45 Latinx, and 38 NLW (N = 133) adults (59% female; 39% with HIV; M
age = 65.3, SD = 6.69; M
ed = 13.9, SD = 3.22) who completed the Beck Depression Inventory‐II (BDI‐II), Activities of Daily Living (ADL) scale, and a comprehensive NC battery. Demographically‐corrected T‐scores were used to compute global NC and domain average T‐scores (global cognition, executive function, learning, memory, verbal fluency). The BDI‐II Total Score (BDI‐tot), Cognitive‐Affective Subscale (BDI‐cog), Functional‐Somatic Subscale (BDI‐som), current functional status (ADL‐tot), and decline over time (ADL‐dec) were computed. A series of hierarchical linear regressions (HLRs; Step 1: BDI‐tot; Step 2: NC global/domain NP T‐scores) were computed to predict ADL‐dec in each ethnocultural group. To assess age effects in this relationship, additional HLRs (Step 1: BDI‐tot, age, BDI‐tot×age and Step 2: NC global T‐score) were computed.

Result

BDI‐tot, BDI‐cog, and BDI‐som were significantly correlated with ADL‐dec (r
s = .58‐.64, ps<.01) in NLW adults. However, in NLB adults, only BDI‐cog was correlated with ADL‐dec (r = .51, p<.01), while in Latinx adults, both BDI‐tot and BDI‐som were significantly related to ADL‐dec (r
s = .38, ps <.05). Within NLB adults, BDI‐tot accounted for 15‐16% of the variance in ADL‐dec (ps<.05), but NC scores did not uniquely contribute to the model/s (ΔR
2 = 0‐.11, ps>.05). Across ethnocultural groups, BDI‐tot×age did not significantly predict ADL‐dec. However, in the NLW group BDI‐tot×age was a significant predictor of ADL‐tot (ΔR
2 = .53, p<.05).

Conclusion

Depressive symptoms are associated with functional decline, particularly in NLB middle/older adults. Cognitive‐affective symptoms may better predict functional status in middle/older NLB adults, while somatic‐functional symptoms are associated with functional decline in Latinx middle/older adults. Future studies should examine the longitudinal impact of depression on functional status/NC within ethnoculturally diverse older adults.
Antidepressant exposure and long‐term dementia risk in a nationwide study on U.S. Veterans with major depressive disorder
Authors: Cejudo Jaime Ramos , Corrigan June , Zheng Chunlei , Swinnerton Kaitlin N. , Jacobson Sean R , La Jennifer , Betensky Rebecca A , Osorio Ricardo S , Madanes Sharon , Pomara Nunzio , Iosifescu Dan , Brophy Mary T , Do Nhan V , Fillmore Nathanael R
Published: December 2023

Background

Major depressive disorder (MDD) is associated with dementia risk. The use of antidepressants in MDD has been reported to influence long term risk of Alzheimer’s disease and related dementias (ADRD), but studies are conflicting.

Methods

We used inverse probability weighted Cox models with time‐varying covariates in a retrospective cohort study among Veterans with MDD within the US Veterans Affairs health‐care system from 1/1/2000 to 6/1/2022. We focused on patients receiving their first diagnosis of MDD at the age of 60 or above. Our outcome was incident ADRD and unrelated death was considered as a competing risk event. Exposed intervals were defined using prescription data. Models were weighted for the inverse probability of falling in each of the treatment arms (exposed or not) at the beginning of each treatment period based on demographic and clinical covariates updated with most recent information (1‐year prior). The cumulative effect of antidepressant exposure (No. days) was also studied.

Result

A total of 24,964 patients with MDD were identified, of which 45% were on antidepressants (Table 1). Median treatment time was 4.10 years [2.56, 6.10]. No relationship was observed between the number of days on antidepressants and the risk of ADRD (Figure 1). No significant associations were seen for the effect of being exposed to antidepressants (any) vs unexposed (HR = 0.94, 95%; CI: 0.81‐1.09) or exposed to each antidepressant drug classes vs unexposed (SSRI HR = 0.93, 95%; CI: 0.79‐1.10; NDRI HR = 0.80, 95%; CI: 0.42‐1.54; SNRI HR = 0.87, 95%; CI: 0.54‐1.41). (Table II). In sensitivity analysis stratified by sex, a reduction in risk due to antidepressant exposure was suggested in female patients, however the number of cases was small (HR = 0.30, 95%; CI: 0.12‐0.81; P = 0.02)).

Conclusion

Our study conducted in a large population and after accounting for confounders shows that antidepressant exposure has no effect on ADRD risk. Our result suggesting an association in female patients should be interpreted with caution due to a small sample size and deserves further attention. Replication of results in an external population with a larger representation of female patients is needed for further validation
Aging drives chronic exacerbated interactions of disease associated microglia and CD8+ T cells following traumatic brain injury
Authors: Gebhardt Jessica , Ashley Clair , Wendell Ben , Goulding Danielle S. , Schwartz James , Morganti Josh M.
Published: December 2023

Background

Aged individuals are highly susceptible to adverse outcomes following traumatic brain injury (TBI). Despite worsened correlates related to functional outcomes following injury, as well as increased likelihood to acquire a TBI, our understanding of the cellular mechanisms governing the poorer outcomes associated with aged individuals post‐TBI are not well‐characterized.

Method

In the current study, we examined microglial heterogeneity following TBI, in our mouse model of focal TBI across both acute (3d) and chronic (28d) intervals in both young (4m) and aged (18m) male C57B6J mice. At the appropriate interval, brains were collected and processed for single cell RNAseq (scRNAseq), spatial transcriptomics, and histology. A follow up study examining the interaction of TBI and aging upon T cell receptor (TCR) sequences was utilized to examine clonal expansion and lymphocyte heterogeneity in young and aged mice chronically after TBI.

Result

Our findings demonstrate that TBI drives diverse transcriptional heterogeneity of microglia in both the young and aged condition. Acutely at 3 days post injury an inflammatory response is seen both in the young and aged mice. However, chronically at 28 days post injury, the microglia from young animals more closely resemble their pre‐injury (i.e. Sham) phenotypes, in comparison to the aged brain where there is a persistence of Apoe‐linked ‘DAM‐like’ microglial response. Inferential analyses point toward these aging‐related chronic populations of microglia as having distinct transcription factor utilization and metabolic pathway enrichment, including Hif1α upregulation and interferon gamma (INFγ) signaling. Furthermore, linkage with chronically accumulated CD8+ T cells and interferon signaling may underlie these phenotypes. Using single cell TCR sequencing, we demonstrate stark contrasts in the responses due to aging and TBI in the clonal expansion of infiltrated CD8+ T cells chronically following TBI.

Conclusion

Our studies demonstrate that aging is a centrally associated with the persistence of chronically reactive microglia in the brain and that these responses are linked, in part, with the protracted accumulation of CD8+ T cells following TBI.
Regional patterns of pathological tau accumulation in sporadic early‐onset Alzheimer’s disease: Longitudinal tau‐PET in the LEADS Cohort
Authors: Schonhaut Daniel R , Mundada Nidhi S. , Insel Philip S. , soleimani‐Meigooni David N. , Zeltzer Ehud , Windon Charles , Tanner Jeremy A. , Heath Courtney Lawh , Shankar Ranjani , Amuiri Alinda , Aisen Paul S. S , Eloyan Ani , Koeppe Robert A. , Carrillo Maria C. , Dickerson Brad C. , Apostolova Liana G. , Rabinovici Gil D. , La Joie Renaud
Published: December 2023

Background

The longitudinal progression of tau pathology in sporadic early‐onset Alzheimer’s disease (EOAD, age‐at‐onset<65) has not been well established and may be key to its understanding and treatment. We utilized in vivo PET imaging to characterize regional patterns of pathological tau accumulation in the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS), an ongoing, large‐sample, multi‐site cohort.

Method

[18F]Flortaucipir tau‐PET was acquired 75‐105min post‐injection in 277 amyloid‐PET‐positive patients with sporadic EOAD and 90 healthy controls (Table 1). Patients had mild cognitive impairment (CDR‐SB = 0.5‐4, n = 206) or mild dementia (CDR‐SB = 4.5‐8, n = 71) at baseline. Longitudinal tau‐PET was collected in 126 patients (2‐4 scans/subject, 1.3 ± 0.4 years apart). Tau‐PET SUVRs were calculated in 72 FreeSurfer‐defined regions referenced against inferior cerebellar gray matter, and SUVRs were W‐scored within‐region to adjust for age and sex associations in controls (control W‐score mean = 0, SD = 1). Baseline tau‐PET W‐score differences between patients and controls were assessed using linear regression. Linear mixed‐effects models were used to calculate tau‐PET W‐score change rates among EOAD patients.

Result

Tau‐PET was significantly elevated in EOAD patients at baseline in every region examined (p<0.05, FDR‐corrected), with highest tau‐PET signal in lateral prefrontal, parietal, and posterior cingulate cortices bilaterally, and relative sparing of primary cortices (Figure 1a). In longitudinal analyses, tau‐PET increased significantly in 69/72 regions (p<0.05, FDR‐corrected; Figure 1b), and regions with higher tau‐PET at baseline had faster prospective accumulation rates on average (r = 0.47, p<0.0001; Figure 2). Exceptions were noted in posterior cingulate and parietal association regions, which had high tau‐PET at baseline but comparatively slow accumulation; and in anterior prefrontal and occipital regions with low‐to‐moderate tau‐PET at baseline yet rapid accumulation.

Conclusion

Tau pathology is present throughout cortex by the mild dementia stage in EOAD and is still accumulating globally, especially in anterior prefrontal and occipital cortices. Parietal association regions have high baseline tau but slower‐than‐expected prospective accumulation, suggesting these regions are early pathological foci that plateau early in the clinical disease stage.