bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial nitric oxide synthase deficiency exacerbates SARS‐CoV‐2 induced neuropathology in a mouse model of vascular dementia
Authors: Ismael Saifudeen , Umar Meenakshi , Bix Gregory J
Published: January 2025

Background

SARS‐CoV‐2 causes a variety of neurological sequelae in COVID‐19 survivors, including fatigue and cognitive dysfunction. Endothelial dysfunction is the unifying and central mechanism of COVID‐19 illness and a major risk factor for vascular dementia (VaD). Endothelial dysfunction stems, in part, from an imbalance between nitric oxide (NO) generated by the endothelial nitric oxide synthase (eNOS) and reactive oxidant species produced by uncoupled‐eNOS. Clinical observations suggest that decreased NO bioavailability appears as a likely pathogenic factor of endothelial dysfunction in COVID‐19 patients. We hypothesize that eNOS deficiency contributes to brain endothelial dysfunction in SARS‐CoV‐2 infection and SARS CoV‐2 infection promotes early onset VaD in eNOS deficient mice.

Methods

6‐month‐old WT/eNOS± male mice were infected with 1 × 104‐pfu mouse‐adapted (MA10) SARS‐CoV‐2 intranasally and animals were evaluated acutely out to 3 days‐post‐infection (3dpi) for changes in body weight and clinical signs of illness. Genomic and sub‐genomic viral copy numbers were also quantified. RNA was isolated whole‐brain and was analyzed for quantitative PCR and immunofluorescence for markers of inflammation and blood‐brain barrier permeability.

Results

MA10 infection induced significant weight loss in WT and eNOS± mice. eNOS± mice exhibited more disease‐associated weight loss (∼15%) than WT‐infected mice, but no infection‐induced mortality was observed in either group. We then confirmed MA10 viral copy in the lungs of infected, but not uninfected, WT MA10 and eNOS± mice at 3 dpi (noted to be similar in both groups). However, we did not detect the virus in the brains of the MA10‐infected WT and eNOS± mice. Real‐time PCR analysis of mouse whole brain‐isolated mRNA showed that the proinflammatory mediators CCL2 and IL‐6 were elevated in both the WT and eNOS± mice (eNOS± > WT) following MA10 infection. Immunofluorescent analysis showed increased Iba1 (microglia marker) fluorescent intensity in the cortex of eNOS± mice following MA10 infection than WT mice (mock or MA10 infected) and eNOS± mock mice.

Conclusions

The eNOS± mice experience worsened acute SARS‐CoV‐2‐associated morbidity indicated by increased weight loss, glial activation, and neuroinflammation than WT mice despite a similar pulmonary viral load. This is the first experimental evidence investigating a link between eNOS and neuropathology associated with SARS‐CoV‐2.
Longitudinal cognitive outcomes are strongly correlated with the Alzheimer’s Disease microbiome
Authors: Zeamer Abigail L , Sanborn Victoria , Drake Jonathan D , Haran John P , Bucci Vanni
Published: January 2025

Background

It has been shown that dysbiosis, or dysfunction of the gastrointestinal (gut) microbiome is associated with Alzheimer’s disease (AD). Here, we aimed to expand on beyond our previously reported findings of the gut microbiome associating with AD and explore if the gut microbiome is predictive of cognitive performance in individuals with AD. We sought to identity what cognitive domains are associated with the microbiome in our cohort of AD patients and healthy controls without dementia.

Method

Older individuals residing in the general community of central Massachusetts were enrolled in our study. At each visit, fecal samples and clinical variables were collected in addition to cognitive testing using the ADAS‐Cog‐13 tool, such as delayed memory, word recall, recognition etc. Metagenomic profiling was performed on longitudinal fecal samples. Z‐scores for different cognitive domains, including memory, executive function and language were generated for the study population. Mixed‐effect random forest regression (MERFR) models were created to identify metagenomic features informative of cognitive performance across these different cognitive tests and domains.

Result

Replicating our previous work, among AD diagnosed individuals, MERFR models predicted performance on ADAS‐Cog 13 from microbial abundance and pathways with a strong accuracy. The ADAS‐Cog 13 was not well predicted by the microbiome in the healthy controls. Additionally, in our new analysis across different cognitive domains, Z‐Scores were well predicted by MERFR models using microbial abundance and encoded pathways.

Conclusion

Not only is the gut microbiome composition highly predictive of AD diagnosis, but there is also a strong correlation of the gut microbiome and cognitive functioning. This is true across the multiple domains of cognition including memory, executive function and language, however different bacterial species were significant in associating with each domain. This work highlights the complexity of the microbiome‐gut‐brain axis and how the microbiome community makeup might play a role in cognitive decline.
Recurring genetic variant in LEADS
Authors: Rumbaugh Malia C. , Nudelman Kelly N. , Dage Jeffrey L. , Eloyan Ani , Hammers Dustin B. , Carrillo Maria C. , Dickerson Bradford C. , Rabinovici Gil D. , Apostolova Liana G. , Foroud Tatiana M. ,   the DIAN/DIAN‐TU Clinical Genetics Committee, and the LEADS Consortium
Published: January 2025

Background

The Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) is analyzing the genetic etiology of early onset (40‐64 years) cognitive impairment, including amyloid‐positive early‐onset Alzheimer’s disease (EOAD) and amyloid‐negative early‐onset Alzheimer’s disease (EOnonAD). One goal of this investigation is to identify novel or under‐characterized genetic variants.

Methods

Cognitively impaired (CI) LEADS participants, including amyloid‐positive and amyloid‐negative early‐onset cases, were whole exome or genome sequenced (N = 361). Genetic and copy number variants in APP, PSEN1, PSEN2, GRN, MAPT and C9ORF72 were assessed. Variants in these genes were annotated with Annovar and assessed for potential pathogenicity with criteria including 1,000 genomes population frequency, computational functional prediction, and reported disease occurrence in databases including ClinVar and the Human Gene Mutation Database. Variants were reviewed manually as well as with VarSome and evaluated for pathogenicity using the American College of Medical Genetics criteria. Patient information for carriers of likely pathogenic variants not reported as pathogenic in ClinVar or included in the Dominantly Inherited Alzheimer Network Trial Unit (DIAN‐TU) Trial Eligible list were reviewed.

Results

Three CI participants were found to carry the p.I227L variant in PSEN1 (3/361, 1%), with no other pathogenic variants identified in these individuals in the six genes analyzed. This variant was previously described in a single individual. It is classified as likely pathogenic by Varsome based on In‐Silico predictors; however, it is listed as “Pathogenicity Not Classified” in AlzForum and as a Variant of Unknown Significance in ClinVar due to the lack of reported cases. The variant is not included in the DIAN‐TU Trial Eligible List. We describe the family history, demographic and clinical data for these three participants.

Conclusions

The PSEN1 variant p.I227L was identified in three LEADS CI participants and warrants further investigation as a potentially pathogenic variant.
Organizing Alzheimer’s Disease Endophenotypes Into Subdivisions of Biological Domains Improves Therapeutic Target Hypothesis Selection
Authors: Keegan Stephen , Cary Gregory A. , Wiley Jesse C , Leal Karina , Butler Robert R. , Greenwood Anna , Carter Gregory W ,   The Emory‐Sage‐SGC TREAT‐AD Center
Published: January 2025

Background

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

Method

Utilizing a top‐down expert curation approach of organizing Gene Ontology terms into endophenotypes of AD, we developed 19 biological domains. To provide more functional insight of these biological domains impacts on AD, we recreated the process to make 80 subdomains. The biological domain describes the endophenotype, the subdomain describes the important functions of that endophenotype. The gene lists of these clusters are turned into protein‐protein interaction networks.

Result

Using the structures of the Gene Ontology, biological domains, and subdomains, it’s possible to identify a genes relationship to an endophenotype and its impact on other genes implicated in AD. Analyzing your target at a biological domain level connects endophenotypes and at the subdomain level it connects the functions that lead to the endophenotype.

Conclusion

A layered knowledge approach of investigating the impact a gene has on an endophenotype provides insight into how a potential therapeutic target would interact with other areas of disease biology. TREAT‐AD investigators will validate these targets in cell models and generate experimental resources to support further target development.
Distribution of cognitive domains and neuropathology of cases with mild cognitive impairment
Authors: Ho Andrew , Choudhury Parichita , Adler Charles , Shprecher David , Mehta Shyamal , Shill Holly , Driver‐Dunckley Erika , Belden Christine , Serrano Geidy E , Beach Thomas G. , Atri Alireza , Tremblay Cécilia
Published: January 2025

Background

Mild Cognitive Impairment (MCI) is a pre‐dementia state where impaired cognitive domains (memory, executive, visuospatial processing, language) may predict underlying pathology, e.g. Alzheimer’s disease(AD), Lewy body (LB), and other. Delineating neuropathological heterogeneity in MCI and their associations with neuropsychological profiles are important in identifying individuals at risk of further deterioration. We aimed to characterize the neuropathological heterogeneity in cases with a diagnosis of MCI.

Method

Cases with a final consensus cognitive diagnosis of MCI (n = 128) prior to death were selected from the Arizona Study of Aging and Neurodegenerative disorders (AZSAND). Groups were divided into amnestic (aMCI) and non‐amnestic MCI (naMCI), single and multi‐domain impairment, and specific domain impairment (executive, language, visuospatial) was explored. Presence and severity of neuropathology including AD, LB, cerebral white matter rarefaction (CWMR), cerebral amyloid angiopathy (CAA), cerebral infarcts and microinfarcts (cortical and subcortical), TAR DNA‐binding protein 43 (TDP‐43), and apolipoprotein E (ApoE) status were compared between MCI subtypes.

Result

The number of cases meeting neuropathological criteria for AD was not different between aMCI (36.4%) and naMCI (22.6%) while co‐existent PD was less frequent in aMCI (19.5% vs 38.7%). When compared to naMCI (n = 31), the aMCI (n = 85) group had an older age of death (p = 0.001), less educational years (p = 0.04), a higher number of subcortical infarcts (p = 0.012), a higher regional density of neurofibrillary tangles (p = 0.027) and a lower density of LB (p = 0.015) in the temporal lobe, and CWMR in tended to be more severe in the frontal lobe (p = 0.052). Those with single domain aMCI had less CWMR (p = 0.001) compared to the multidomain. Within the naMCI group, those with single domain MCI had higher proportions of CAA (p = 0.042), and lower LB density (p = 0.019) compared to multidomain. CWMR was more severe (p = 0.026) in

Conclusion

A high heterogeneity was observed between MCI subtypes. While AD pathology was similar between groups, regional anatomical differences were observed. Vascular pathology including subcortical infarcts, CWMR and CAA appear to be commonly associated with both aMCI and naMCI respectively while CWMR was associated with executive dysfunctions. CWMR, CAA and LBs appear to be more frequent in multidomain aMCI and naMCI respectively.
Clinical Recognition of Frontotemporal Dementia with Right Anterior Temporal Predominance; Recommendations of the International Working Group
Authors: Ulugut Hulya
Published: January 2025

Background

Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized as a separate FTD subtype, a uniform description of the syndrome is still missing. This multicenter study, led by an international working group (IWG), aims to establish a cohesive clinical phenotype and lay the groundwork for consensus on terminology and diagnostic standards.

Method

Retrospective clinical data were systematically collected across 18 dementia centers. The harmonized data were interpreted by 90 FTD experts across over 30 centers. Visual assessments of initial neuroimaging identified study cases, culminating in a cohort of 360 FTD patients with predominant RATL atrophy.

Result

Common symptoms were mental rigidity and preoccupations (78%), disinhibition (74%), naming/word‐finding difficulties (70%), memory deficit (67%), apathy (65%), loss of empathy (65%), and face recognition deficit (60%), based on the chart reviews. Reviewing case notes beyond clinicians' interpretations unveiled impairments in identifying landmarks, smells, sounds, tastes, and bodily sensations, and altered reactions to those stimuli (74%). These symptoms, while not explicitly queried or examined, were often categorized under language, memory, behavioral, psychiatric, or other/unclassified problems by various centers. Available cognitive test scores indicated impairments in emotion, people, social interactions, and visual semantics related domains. Secondly, the IWG interpreted symptoms within three main domains; (i) semantic deficit for predominant non‐verbal information including people, taste, smell, sound, landmarks, bodily sensations, socioemotional information/ concepts/ facts (ii) socioemotional dysfunction including altered emotional expressivity, and emotional apathy, (iii) altered thought process including mental rigidity, hyper‐focused specific interests and altered hedonic valuation and prioritization. Lastly, 67 patients had genetic and/or pathological confirmation for FTLD, and 21 had amyloid positivity. Of note, caution is advised in interpreting amyloid positivity, and the distinct clinical nuances associated with each molecular subtype are emphasized by the IWG.

Conclusion

This collaborative effort represents the first international initiative to establish the largest RATL cohort, resolving contradictions in the field and shedding light on challenges in recognizing RATL impairment in clinical practice. Our ultimate goals are reaching a consensus on diagnostic criteria that will facilitate the recognition of FTD associated with RATL atrophy and differentiate the syndrome from other dementia subtypes and psychiatric disorders.
Association Between Age and Cognitive Severity in Early‐Onset AD: Extension of preliminary findings in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS)
Authors: Hammers Dustin B. , Eloyan Ani , Taurone Alexander , Thangarajah Maryanne , Kirby Kala , Wong Bonnie , Dage Jeffrey L. , Nudelman Kelly N. , Carrillo Maria C. , Rabinovici Gil D. , Dickerson Bradford C. , Apostolova Liana G. ,   LEADS Consortium
Published: January 2025

Background

Widespread cognitive impairments have previously been documented in Early‐Onset Alzheimer’s Disease (EOAD) relative to cognitively normal (CN) same‐aged peers or those with cognitive impairment without amyloid pathology (Early‐Onset non‐Alzheimer’s Disease; EOnonAD; Hammers et al., 2023). Prior preliminary work has similarly observed worse cognitive performance being associated with earlier ages in EOAD participants enrolled in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS; Apostolova et al., 2019). It is unclear, however, if these age effects are seen across early‐onset conditions, and whether cognitive discrepancies among diagnostic groups are uniform across the age spectrum. The objective of the current study is to more‐extensively examine the impact of age‐at‐baseline on cognition within LEADS, with emphasis placed on the influence of diagnostic group on these associations.

Method

Expanded cross‐sectional baseline cognitive data from 573 participants (CN, n = 97; EOAD, n = 364; EOnonAD, n = 112) enrolled in the LEADS study (aged 40‐64) were analyzed. Multiple linear regression analyses were conducted to investigate associations between age‐at‐baseline and cognition for each diagnostic group – and their interaction among diagnoses – controlling for gender, education, APOE ε4 status, and disease severity.

Result

See Table 1 for demographic characteristics of our sample. Linear regression showed a significant interaction effect for the cognitive domain of Executive Functioning (p = .002). Specifically, while the EOAD group displayed a positive relationship between age‐at‐baseline and Executive Functioning performance (β = 0.08, p = .02; Figure 1), the CN group displayed a negative relationship (β = ‐0.04, p = .008) and the EOnonAD group displayed no relationship (β = ‐0.01, p = .50). A similar main‐effect for age was observed for the EOAD group when examining Visuospatial Skills (β = 0.12, p = .04), however no other age effects were evident across other diagnostic groups or cognitive domains (Episodic Memory, Language, or Speed/Attention; Table 2).

Conclusion

Building off preliminary work, our results suggest that executive functioning may be disproportionately impacted earlier in the disease course in participants with EOAD relative to other diagnostic groups. This finding appears to be unique to executive functioning, as it was absent in other cognitive domains and remained after accounting for disease severity. This highlights the need for further investigation into executive dysfunction early in the course of EOAD.
Identification of genetic risk factors for brain amyloid deposition
Authors: Patel Maulikkumar P , Fan Kang‐Hsien , Johnson Matthew , Cetin Arda , Ali Muhammad , Western Daniel , Liu Menghan , Gorijala Priyanka , Budde John P. , Cohen Ann D , Lopez Oscar L. , Feingold Eleanor , Pottier Cyril P , Kamboh M. Ilyas , Cruchaga Carlos
Published: January 2025

Background

Amyloid PET imaging is a promising biomarker to track the accumulation of parenchymal amyloid beta (Aβ) deposits in the brain. Recent large‐scale genome‐wide association studies (GWAS) reported common risk factors associated with amyloidosis, suggesting that this endophenotype is driven by genetic variants. We hypothesized that genes with multiple variants with deleterious effect are associated with Aβ accumulation. To address this issue, we performed whole‐genome sequencing (WGS) on a large cohort of individuals with amyloid PET imaging.

Method

In this study, we carried out a (GWAS) on European‐ancestry individuals with amyloid PET imaging from two cohorts [MAP (Memory & Aging Project), and Pitt (University of Pittsburgh)]. WGS was performed using Illumina Hiseq followed by GATK variant calling as well as extensive variant and ‐individual level quality check. Functional annotation was performed using snpEff and dbNFSP. Only variants predicted loss of function (stop loss/gain, splicing, and frameshift variants), defined as high effect; or with Combined Annotation Dependent Depletion score greater than 25, defined as moderate effect, were included. The amyloid PET harmonized z‐score was used as a quantitative phenotype in our SKAT‐O gene based analyses.

Result

After quality control, we retained 1,228 participants (52% female). Gene‐based analyses identified a study‐wide significant association for APOE (p‐value = 1.82 × 10‐09), and eight additional genes with suggestive significance association (p‐value<7.5 × 10‐04) including MPDZ, SEC16A, PLBD1, GLB1L2, KCNMB4, ELOVL5, SCART1 and SCN7A. According to the GTEx portal, five of these candidate genes are expressed in the brain. MPDZ encodes for a modular scaffold protein that was recently reported to be associated with Alzheimer’s disease in African‐Americans, supporting its involvement in amyloidosis risk (Ray et al., MedRxiv, 2023)

Conclusion

We present the first time, a gene‐based association study assessing the effect of potentially deleterious variants on amyloidosis. Importantly, we show that variants located in the APOE gene have a strong effect on this endophenotype. Interestingly, we point out additional candidate genes such as MPDZ that are potentially associated with amyloidosis. Additional replication, however, is required to validate our findings.
ABCA1 missense mutations are associated with Lewy body dementia
Authors: Ray Anindita , Reho Paolo , Logroscino Giancarlo , Barmada Sami , Ross Owen A. , Scholz Sonja W , Consortium International LBD Genomics
Published: January 2025

Background

Lewy body dementia (LBD) is the second most prevalent dementia in the United States after Alzheimer’s disease (AD). Recent studies have implicated rare mutations in two lipid transport genes, ABCA1 and ATP8B4, in Alzheimer’s disease. Substantial co‐pathology and shared risk factors indicate an intersectional genetic architecture between LBD and AD; therefore, we investigated the association of rare mutations in ABCA1 and ATP8B4 with LBD. Additionally, we examined rare mutations in 25 genes involved in ABCA1‐related lipid‐specific pathway with risk of developing LBD.

Method

We annotated rare missense and loss‐of‐function (LOF) mutations in ABCA1 and ATP8B4 genes, using Ensembl Variant Effect Predictor, in previously published whole‐genome sequence data from 2,591 LBD cases and 4,027 healthy controls of European ancestry. To test the association with LBD risk, we applied the optimized sequence kernel association test (SKAT‐O), followed by single‐variant association test (Fisher’s exact test), and multiple testing (Bonferroni correction). Additionally, we evaluated rare coding variants of 25 genes in ABCA1‐related positive regulation of the cholesterol efflux pathway (GO: 0010875) by performing single‐gene burden and gene‐set burden analyses.

Results

We found a significant enrichment of rare ABCA1 missense mutations in LBD (SKAT‐O p = 2.68E‐02). However, no significant associations were found between LBD and ABCA1 LOF, and ATP8B4 LOF or missense mutations. Interestingly, the single‐variant analysis identified two ABCA1 missense variants, c.5398A>C; p.N1800H (Fisher’s test: p‐value = 1.16E‐04) and c.3544G>A; p.A1182T (p‐value = 4.29E‐02), with the p.N1800H substitution surviving Bonferroni multiple testing. The p.N1800H variant is reported to be pathogenic, and it was observed in twelve LBD patients and one control, with an odds ratio of 18.48 (95%CI = 2.4‐142.8). This mutation is reported to be pathogenic, in our LBD cohort, six out of twelve ABCA1 p.N1800H carriers also carry the APOE ε4 risk allele. However, neither a single‐gene burden nor a gene‐set burden analysis in 25 genes in the positive regulation of the cholesterol efflux pathway revealed any significant associations with LBD.

Conclusion

Our findings reveal significant enrichment of ABCA1 missense mutations in LBD emphasizing the genomic complexity surrounding LBD and AD.
Whole blood DNA methylation profiles of Alzheimer’s disease differ across ancestrally diverse populations
Authors: Gu Tianjie , Gomez Lissette , Mews Makaela , Whitehead Patrice L. , Hamilton‐Nelson Kara L. , Sanchez Jose Javier , Adams Larry D. , Mena Pedro R. , Starks Takiyah D. , Silva‐Vergara Concepcion , Illanes‐Manrique Maryenela Z. , Cuccaro Michael L. , Vance Jeffery M. , Cornejo‐Olivas Mario , Byrd Goldie S. , Feliciano‐Astacio Briseida E. , Haines Jonathan L. , Beecham Gary , Pericak‐Vance Margaret A , Bush William S. , Griswold Anthony J.
Published: January 2025

Background

Prior studies have shown differences in the genetic etiology and clinical presentation of Alzheimer’s Disease across populations. For example, for multiple genetic loci associated with AD, effect sizes can vary drastically between individuals of different ancestral backgrounds. Few investigations into differences in epigenetic features like DNA methylation have been conducted in AD, particularly in diverse individuals. These studies are critical to identify and further characterize mechanisms of disease allowing for development of therapeutic interventions.

Method

As part of an ongoing study of the genetics and epigenetics of AD in diverse populations, we performed a methylome analysis of 626 individuals. DNA from whole blood was analyzed using the Illumina MethylationEPICv2.0. The cohort consisted of both AD and cognitively unimpaired (CU) individuals of European (68 AD, 67 CU), African (98 AD, 106 CU), or Hispanic (Puerto Rican (85 AD, 76 CU); Peruvian (41 AD, 41 CU); Cuban (22 AD, 22 CU)) backgrounds. We analyzed data using the SeSAMe R package for quality control and statistical analysis. We performed differential methylation analysis between AD and CU in the overall dataset and within each ancestral population using linear models with covariates sex, age of exam, batch effect, global ancestry and estimated immune cell type proportions.

Result

878,853 CpG sites were tested for differences between AD status. In a preliminary analysis of these data, we identified 563 CpG sites with nominally significant differences (p‐value ≤ 0.001) between AD and CU. Within each ancestral group, the number of differentially methylated sites differed: European – 442 sites, African – 217 sites, Hispanic – 475. Notably, however, the markers within the ancestral group did not overlap, implying that the AD disease process may be quite different across populations.

Conclusion

While these results are preliminary, and expansion of the dataset may reveal convergence of methylation patterns across ancestral populations, our analyses suggest the possibility of ancestry specific whole blood DNA methylation patterns as signatures of AD pathogenesis. Ultimately, combining these methylation profiles with existing genomic and transcriptomic data may reveal distinct genes but similar underlying pathological processes contributing to AD across individuals of diverse ancestries.
Accuracy of Figure Memory Test of the Brief Cognitive Screening Battery to predict amyloid status in older adults with Subjective Cognitive Decline
Authors: Neto Adalberto Studart , Coutinho Artur Martins , Carneiro Camila de Godoi , Moraes Natália Cristina , Spera Raphael Ribeiro , Yassuda Monica Sanches , Brucki Sonia Maria Dozzi , Buchpiguel Carlos Alberto , Nitrini Ricardo
Published: January 2025

Background

Some older adults with subjective decline (SCD) had a positive amyloid biomarker indicating a preclinical stage of Alzheimer’s disease.

Objectives

To assess the accuracy of Delayed Recall of Figure Memory Test (DR‐FMT) of Brief Cognitive Screening Battery to predict amyloid status in SCD older adults.

Method

The sample consisted of 45 older adults classified as SCD and 25 as cognitively unimpaired (mean age of 76.4 and 73.5, respectively, p = 0.138). They were evaluated with BCSB and a standard neuropsychological battery (which includes MMSE, MoCA, RAVLT, Logical Memory and DR of Rey Complex Figure). Subjects were underwent PIB‐PET to assess their amyloid status and images were classified based on visual and semi‐quantitative analyses with 3D‐SSP methodology.

Result

Twelve SCD older adults (27.3%) were positive amyloid against six in the controls (23.1%). In SCD group, DR‐FMT was the only memory test that correlated with SUV in amyloid PET (r = ‐0.514, p < 0.001). Only DR‐FMTshowed significant area under the curve (AUC) in the ROC curve in SCD older adults (AUC = 0.771, 95% CI 0.621 ‐ 0.921). Among SCD older adults, DR‐FMT < 8.0 had a sensitivity of 83.3%, a specificity of 68.7% and an accuracy of 72.7%.

Conclusion

FMT proved to have a good sensitivity and accuracy to predict amyloid status in SCD older adults.
Visual memory is primarily impacted by tau load in the right hemisphere
Authors: Arias Jaime Fernandez , Therriault Joseph , Servaes Stijn , Macedo Arthur C. , Wang Yi‐Ting , Rahmouni Nesrine , Socualaya Kely Monica Quispialaya , Aumont Etienne , Trudel Lydia , Hosseini Seyyed Ali , Hall Brandon J , Chan Tevy , Kunach Peter , Mathotaarachchi Sulantha , Vitali Paolo , Rosa‐Neto Pedro
Published: January 2025

Background

Classical literature has pointed at lateralization of the relationship between memory scores and cerebral hemisphere injury. Epilepsy studies have suggested an association between left hippocampal damage and verbal memory deficits, and between right hippocampal damage and visual memory deficits. We aimed to explore this concept in the context of tauopathy due to Alzheimer’s disease.

Method

we assessed 132 cognitively unimpaired (CU) older adults, and 44 cognitively impaired (CI), amyloid‐β positive individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. All participants had amyloid‐PET with [18F]AZD4694 and tau‐PET with [18F]MK6240, verbal memory assessments with Rey Auditory Verbal Learning Test (RAVLT), and visual memory assessments with Aggie Figures Learning Test (AFLT). We conducted voxel‐wise analyses to explore the relationship between tau PET and memory modality. In addition, we run regression models with right or left tau temporal metaROI as predictor and memory scores as outcome variables. We entered global amyloid (PET), sex, age, years of education, ApoE status, grey matter volume and handedness as covariates. Finally, we used the laterality index (LI) to investigate correlations with memory modality. Right laterality is indicated by an LI below 0, while left laterality would be signaled by an LI above 0.

Result

voxel‐wise analyses suggested a lateralized relationship between tau and visual memory scores on the right hemisphere, whereas tau and verbal memory scores were bilaterally associated. Regression analyses showed a trend towards a stronger relationship between temporal tau on the right and visual memory scores. The LI was significantly associated with visual memory performance. Further analyses showed that this relationship seems to be driven by tau positive individuals.

Conclusion

visual memory performance might be more prominently affected by tau load on the right hemisphere in Alzheimer’s disease. Furthermore, a hemispheric imbalance in the amount of tau is related to visual, but not verbal, memory scores.
Exploring the relationship between neuropsychiatric symptoms, cognitive test performance, and brain abnormalities in a cohort of older adults in rural South Africa
Authors: Gao Sarah , Bassil Darina T. , Farrell Meagan T. , Wagner Ryan G. , Manly Jennifer J. , Brickman Adam M. , Tollman Stephen , Berkman Lisa F.
Published: January 2025

Background

People with Alzheimer’s Disease (AD) often have neuropsychiatric symptoms. The Neuropsychiatric Inventory (NPI) is a validated tool for assessing the severity of these symptoms, but its applicability in a South African context remains unexamined. This study evaluated NPI‐Q, a brief version of the NPI, in relation to cognitive performance and markers of brain atrophy and emotional regulation among older South African adults.

Method

Data were from Cognition and Dementia in the Health and Aging in Africa: A Longitudinal Study in South Africa (HAALSI‐HCAP), a population‐based nested cohort study in Agincourt, South Africa. The survey included a cognitive battery, clinical examination, and informant interview to assess perceived cognitive and functional changes in respondents. During the informant interview, the NPI‐Q was completed, and a severity score was derived from the cumulative sum of reported individual symptom scores (range: 0‐36). The final sample included 626 participants (71.9±11.3 years‐old, 35.6% men, 56.6% without formal education), of whom 185 underwent MRI scans. Pairwise correlations assessed the relationship between informant reported symptom severity with cognitive measures and MRI‐generated bilateral amygdala volume.

Result

A total of 95 informants (15.2%) reported any neuropsychiatric symptoms, averaging 2.48 per participant among those who reported any symptom. Hallucinations were the most common symptom (5.4%), while disinhibition was the least (1%). Among those who reported symptoms, average symptom severity score was 4.28 (SD: 3.65). Severity was significantly correlated (p‐value<0.001) with most cognitive measures assessing general cognition (β: ‐0.27, ‐0.17), episodic memory (β: ‐0.26, ‐0.17), language (β: ‐0.28, ‐0.12), and executive function (β: ‐0.26, ‐0.12). However, no relationship was observed between neuropsychiatric symptoms and visuospatial functioning or amygdala volume, possibly attributable to high rate of missingness for visuospatial measures (30%), and the small MRI sample size reporting symptoms (n = 26).

Conclusion

NPI‐Q symptoms were associated with lower cognitive performance, revealing a significant relationship between symptom severity and cognitive performance across all measures of the HAALSI‐HCAP cognitive battery, except for those evaluating visuospatial function. Associations between neuropsychiatric symptoms and bilateral amygdala volume were less evident. These results contribute to understanding the impact of neuropsychiatric symptoms on cognitive health in aging South African populations.
Accuracy of cognitive and functional screening tests to Clinical Dementia Rating in an Outpatient Memory Clinic
Authors: Moro Giovanna Correia Pereira , de Souza Aline Siqueira , da Silva Viana João Vitor , Engelmann Gabriela Tomé Oliveira , Burgos Ivonne Carolina Bolaños , Dias Bruna Fugêncio , Moreira Carolina Mizerani Couto , Kosac Karoline Freire , de Oliveira Hansen Erika , Romano‐Silva Marco Aurélio , Viana Bernardo de Mattos , Bicalho Maria Aparecida Camargos
Published: January 2025

Background

Short screening tools designed to detect cognitive impairment are important for clinical and research. The Clinical Dementia Rating (CDR) is the main used categorization system, which classifies from no dementia, to questionable dementia/mild cognitive impairment (MCI) and three severities of dementia.

Objective

To conduct an accuracy analysis of different short screening tests to predict CDR scores on a cohort of a Memory Clinic.

Methods

This is a cross‐sectional study, using data from the Cog‐Aging cohort study in 2023. Participants go through a comprehensive clinical, neuropsychological and neuroimaging assessment to determine the diagnosis and CDR. Eighty participants were recruited: 11 controls, 43 MCI, and 26 Dementia. Mini Mental State Examination (MMSE), Figure Memory Test’s delayed recall in the Brief Cognitive Screening Battery (FMT‐BCSB), The Consortium to Establish a Registry for Alzheimer’s Disease’s word list delayed recall (DR‐CERAD) and Short‐version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were used to distinguish the CDR scores. Participants were classified based on CDR (0; 0.5; and 1‐2). We performed a Receiver Operating Characteristic (ROC) curve and cut‐off values defined by Youden’s J statistic comparing: CDR 0 x CDR 0,5; CDR 0,5 x CDR 1‐2; CDR 0 x CDR 1‐2. This study was approved by the ethics committee of UFMG.

Results

Participants had a mean age of 77.7 yr. (SD 6.9) and median 6.1 years of education (IQR 5.25). The DR‐CERAD had the best area under the curve (AUC) (0.863) to distinguish CDR 0 to 0.5, with 88% sensitivity with cut‐off points of 5 / 6. Comparing CDR 0.5 to 1‐2, IQCODE had the largest AUC (0,884) with 92% sensitivity with cut‐off ≥ 3,78. Comparing CDR 0 to 1‐2, the DR‐CERAD had the largest AUC (0.987), with 88% sensitivity with cut‐off points of 3 / 4.

Conclusion

These findings suggest that DR‐CERAD is the most accurate to distinguish MCI to normal cognition, and normal cognition to dementia in this sample. IQCODE presented as the best to distinguish MCI to dementia. These are preliminary results and more studies with years of education and a larger sample are necessary.
A Multi‐Omic Analysis of Molecular Risk and Resilience Factors in Late‐Onset Alzheimer’s Disease in APOEe4 Carriers
Authors: Markov Yaroslav , Priyanka Ahana , Higgins‐Chen Albert
Published: January 2025

Background

While the apolipoprotein E (APOE) ε4 allele is a well‐known risk factor for late‐onset Alzheimer’s disease (LOAD), not all carriers develop the condition, suggesting the presence of resilience and/or risk factors. The molecular signatures of resilience/risk in the brain, however, have not been thoroughly described, partly due to the scarcity of healthy APOEe4 carriers. This study addresses this gap using a novel multi‐tissue, multi‐omic dataset from the Religious Order Study and Memory and Aging Project cohorts highly enriched in APOEe4 carriers with and without LOAD.

Method

Our dataset encompasses post‐mortem samples from three brain regions – superior temporal gyrus (ST), prefrontal cortex (PFC), and cerebellum (CBM) – which exhibit varied susceptibility to AD pathology. Utilizing Illumina EPIC arrays for DNA methylation profiling, deep whole exome sequencing, and label‐free mass spectrometry for protein quantification, we analyze samples from 23 APOE 2/4, 197 APOE 3/4, 17 APOE 4/4, and 96 APOE 3/3 carriers (age range 65 to 108, median 89). This diverse cohort includes 78 individuals without cognitive symptoms, 81 with mild cognitive impairment, and 174 with clinically diagnosed AD dementia, further stratified by NIA Reagan scores, allowing us to rigorously define AD diagnosis based on both clinical and post‐mortem assessments.

Result

We delineate molecular changes associated with resilience/risk to AD specifically in APOEe4 carriers within each brain region. For example, we find sets of 76, 43, and 74 mutated genes strongly associated with AD resilience/risk in ST, PFC, and CBM respectively, featuring an enrichment in genes important for the extracellular matrix. Mutations in these genes, alongside with alterations in DNA methylation and protein levels, may potentially reflect an array of influences, including genetic, environmental, and aging effects, and could provide crucial insights into intervention strategies. For the next phase of this project we will integrate these molecular signatures identified at individual ‐omic levels using a multimodal machine learning approach to further investigate their relevance and interplay in the context of AD resilience/risk.

Conclusion

This comprehensive study illuminates the molecular landscape of Alzheimer’s disease resilience and risk factors in APOEε4 carriers, setting the stage for future integrative, multi‐omic analyses.
Longterm Protective Effects of Complement C3 Lowering in Adult APP‐KI Mice
Authors: Singh Brijendra , Spooner Emma , Batista Andre F. , Saido Takaomi C. , Carroll Michael , Lemere Cynthia A.
Published: January 2025

Background

Previously, we found that germline C3 deletion protected cognition and hippocampal synapses in aged APP/PS1dE9 mice, despite increasing Aß plaques. Here, we crossed our C3 inducible conditional mouse model to APPNL‐G‐F/NL‐G‐F knockin mice to determine whether global C3 lowering in an adult amyloid mouse model would be protective.

Methods

C3fl/fl;Rosa26‐Cre‐ERT2 (C3iKO) mice were crossed to C3fl/fl;APPNL‐G‐F/NL‐G‐F mice to generate APP;C3iKO mice, which received 75 mg/kg tamoxifen (TAM; n = 16) or corn oil (CO; n = 15) for 5 days at 3.6 months of age. Serum was collected after 30 days and at the termination of the study to measure C3 protein levels by ELISA. Behavioral testing was conducted at 15 months after which the mice were euthanized, and brain tissue harvested. ELISAs, immunofluorescent staining, qPCR and unbiased RNAseq of prefrontal cortical tissue were performed.

Results

Serum C3 levels were significantly reduced ∼85% 30 days post‐TAM and ∼70% at the end of the study. The TAM‐treated APP;C3iKO mice performed significantly better on the Spatial Novelty Y Maze, Novel Object Recognition and Novel Object Location tests compared to CO‐treated mice. C3 mRNA expression and protein levels in brain were significantly reduced; C1q protein levels were also reduced in brain. No difference in overall amyloid load was seen by IHC or ELISA in APP‐KI;C3iKO mice. We found no changes in overall Iba‐1 and GFAP immunoreactivity between the two groups. However, plaques were associated with fewer Iba‐1+/CD68+ microglia and AQP4+/GFAP+ astrocytes in the TAM‐treated animals. PSD‐95 post‐synaptic staining was increased in hippocampal CA3 but no difference was seen in SYP pre‐synaptic staining. C3 lowering in the APP‐KI mice resulted in significantly reduced mRNA expression of C3, TNFa, IL‐10, CX3CR1 and AQP4 but only a trend for reduced C1q mRNA by qPCR. Unbiased bulk RNAseq of prefrontal cortex identified 1071 differently expressed genes (DEGs) including 569 upregulated genes and 502 downregulated genes in the APP;C3iKO mice. Further analysis of these DEGs is underway but thus far, many of the top hits are related to synaptic signaling.

Conclusion

Our data indicates that global C3 lowering in adult APP‐KI mice reduced inflammation and protected synapses and cognition.

Funding: NIH/NIA RF1 AG060057 (CAL)
The neutrophil to lymphocyte ratio associates with markers of Alzheimer’s disease pathology in cognitively unimpaired elderly people
Authors: Jacobs Tovia , Jacobson Sean R , Fortea Juan , Berger Jeffrey S , Vedvyas Alok , Marsh Karyn , Gonzalez Moses , Figueredo Luisa F , Plaska Chelsea Reichert , Blessing Esther M , Betensky Rebecca A , Rusinek Henry , Glodzik Lidia , Wisniewski Thomas , Osorio Ricardo S. , de Leon Mony J. , Cejudo Jaime Ramos ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2025

Background

An elevated neutrophil‐lymphocyte ratio (NLR) has been associated with Alzheimer’s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities.

Method

We explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and NYU Center for Brain Health (CBH). Specifically, we examined associations between the NLR and cross‐sectional measures of amyloid‐β42 (Aβ42), total tau (t‐tau), and phosphorylated tau181 (p‐tau181), as well as the trajectories of these CSF measures obtained longitudinally.

Result

A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p<0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p<0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p<0.001), and a greater percentage of Aβ‐positivity (34.2% vs. 20.0%, p = 0.009) (Table 1). In the ADNI cohort, we found cross‐sectional associations between the NLR and CSF Aβ42 (β = ‐12.193, p = 0.021), but not t‐tau or p‐tau181. In the NYU cohort, we found cross‐sectional associations between the NLR and CSF t‐tau (β = 26.812, p = 0.019) and p‐tau181 (β = 3.441, p<0.001), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t‐tau (β = 100.476, p = 0.037) compared to Aβ‐ subjects or the non‐stratified cohort (Figure 1). In both cohorts, the same associations observed in the cross‐sectional analyses were observed after incoporating longitudinal CSF data (Figure 2).

Conclusion

We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t‐tau and p‐tau181 in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD‐biomarkers may occur as part of immunosenescence.
Utility of mobility testing in early ADRD detection
Authors: Tolea Magdalena I , Rosenfeld Amie , Besser Lilah M , Galvin James E
Published: January 2025

Background

Gait and balance deficiencies may be important indicators of cognitive impairment, distinguishing dementia from normal cognition (NC). It is unclear whether this extends to pre‐dementia stages of disease. Study goals were to: assess patterns of mobility across early stages of disease and identify specific measures that distinguish individuals with subjective cognitive impairment (SCI) and mild cognitive impairment (MCI).

Method

We assessed whether mobility differentiates SCI (n = 35) from NC (n = 78) and MCI (n = 41). Using ANCOVA, we compared diagnostic groups on global (mini‐PPT; TUG) and individual (gait speed (GS), flexibility, balance, step length, single‐leg support) measures of mobility, controlling for age and baseline physical activity levels. Group separation was evaluated with logistic regression. Group differences in mobility while distinguishing between MCI etiology (AD vs non‐AD) and relationships between mobility and MRI cortical atrophy score (CAS) were analyzed and results validated against biomarker‐confirmed diagnoses (true controls/preclinical/MCI).

Result

Participants were 69±9yr old, highly educated (16±3y), mostly non‐Hispanic White (77%), and performed within normal parameters for mobility. Mobility performance decreased with disease stage (MCI>SCI>NC). All mobility measures distinguished MCI from NC (p<0.01). Dual task mobility distinguished MCI from SCI (e.g., ORTUG = 1.24, 95%CI:1.055‐1.457). AD vs non‐AD etiology accounted for most group differences in mobility. Higher mini‐PPT score was linked to lower odds of SCI vs NC (OR = 0.705 (0.543‐0.916)) stemming from significantly poorer balance in SCI (β = ‐0.3±0.1, p = 0.041). Lower GS explained MCI differences from NC (β = ‐0.1±0.03, p = 0.003) and SCI (β = ‐0.1±0.04, p = 0.027). Results were not explained by differences in age and physical activity. Small‐to‐moderate correlations between CAS and mobility (e.g., rTUG dual = 0.34, p<0.001) were found. In analyses using biomarker‐confirmed diagnoses, mobility was lower in MCI vs true controls (all p<0.01) and vs preclinical disease (p<0.05), with a trend for preclinical vs true controls (p = 0.054) validating findings on clinical diagnoses.

Conclusion

Mobility parameters can distinguish NC from SCI and MCI highlighting: 1) dual task testing and subtle changes in balance help detect early cognitive impairments; 2) changes in GS mark more significant cognitive impairment. Mobility testing may be an important tool in early detection of ADRD in the clinical setting and can help identify targets for early intervention.