bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical profile and serum Vitamin D level among dementia patients: An Insight from Ethiopia
Authors: Zewde Yared Z
Published: January 2025

Background

Vitamin D deficiency is linked with the risk of developing dementia and Alzheimer disease. There is paucity of data on serum vitamin D level among patients from tropical countries such as Ethiopia. The objective of this study is to determine the prevalence of vitamin D deficiency and associated factors among Alzheimer disease and related dementia patients in Ethiopia.

Method

An institution‐based cross‐sectional study was conducted among patients presented with cognitive complaints and diagnosed with Alzheimer’s disease or Alzheimer’s disease related dementia at Lancet General Hospital in Addis Ababa, Ethiopia from November 1 – August 30, 2023. Sociodemographic and clinical data were obtained at presentation with serum vitamin D level determined subsequently. Cognitive test was assessed using the Montreal Cognitive Assessment‐Basic (MOCA‐B). Descriptive and inferential statistical analysis were done and measures of estimated crude and adjusted odds ratio with95% CI were constructed and a p value <0.05 was considered statistically significant.

Result

A total of 60 adult patients with dementia were enrolled. The mean (SD) age of dementia patients was 69.4 (1.56) years and 56% were male. The prevalence of vitamin D deficiency was 70% and the mean serum vitamin D level was 23.94 (1.55) ng/ml. Amnestic variant AD was detected in 45% of the participants followed by vascular dementia (35%) and Parkinson disease dementia (10%). HIV associated dementia was diagnosed in 6% of the participants. Hypertension was the most prevalent (45%) comorbidity reported in our dementia cohort. Severe vitamin D deficiency (serum vitamin D level < 10 ng/ml) was negatively association with disease severity (p = 0.01) and increased age (p = 0.003).

Conclusion

Vitamin D deficiency was prevalent in Ethiopian dementia patients. There were strong associations between severe vitamin D deficiency and dementia severity and increment in age.
Contextual discrimination and representation in APP NL‐G‐F knockin mice
Authors: Hopkins Maya D , Oleru Amarachi , Basu Jayeeta
Published: January 2025

Background

The entorhinal cortex and hippocampus are loci of early vulnerability in AD. These areas are crucial for episodic memory processing for space and contexts. The majority of AD model mouse imaging and electrode studies utilize simple tasks such open field and linear track. During these paradigms, place cells in hippocampal CA1 remain functionally intact and only demonstrate perturbations later in disease progression. However, restricting behavior to these low cognitive load tasks may mask more nuanced changes in place cell activity that occur earlier in the disease. We have selected cognitively demanding tasks that recruit both episodic memory and/or odor context discrimination to reveal early‐stage deficits in task acquisition and recall.

Method

In APP NL‐G‐F knock‐in homozygotes, we examined hippocampal CA1 activity through 2‐photon calcium imaging and head‐fixed behavior. Mice were aged to a “young” group (3‐5 months) or an “old” group (7‐9 months). Mice underwent two behavioral paradigms to probe episodic context discrimination. (1) A low cognitive load task where mice were exposed to new physical environments and trained to navigate to two different reward zones or (2) a high cognitive load task where mice were exposed to the same physical environment, but different contexts were established using olfactory cues and reward zones. CA1 cell bodies were imaged through viral GCaMP6f expression in excitatory cells and tracked longitudinally throughout learning. We examined the quality, flexibility, and stability of CA1 place cells in these task regimes. Finally, by targeting neuromodulatory systems that modulate GABAergic circuits, we are testing potential pharmacological rescue of functional and behavioral deficits.

Result

Preliminary findings suggest an impairment in the learning rate of the high cognitive load task in homozygotes compared to wild‐type controls. Analysis is ongoing for the functional imaging of place cell activity including the stability of cells across days, the ability to remap between contexts, calcium event rate, and the proportion of reward cells.

Conclusion

APP KI model mice can learn head‐fixed navigational tasks of varying cognitive loads, but learning acquisition may be impaired. We predict impairment of contextual representation within CA1 for both task regimes in the APP mice.
Cognitive resilience to Alzheimer’s disease characterized by cell‐type abundance estimates
Authors: O'Neill Nicholas K , Stein Thor D. , Olayinka Oluwatosin A , Empawi Jenny A , Hu Junming , Tong Tong , Zhang Xiaoling , Farrer Lindsay A.
Published: January 2025

Background

Some subjects exhibit AD pathology but remain cognitively intact. This resilience has been associated with cell‐type abundance changes, particularly in neurons. We investigated the molecular basis of cognitive resilience by deconvoluting bulk RNA sequencing (RNA‐seq) data into multiple brain cell types derived from three brain regions.

Methods

Cell‐type abundance in human brain bulk RNA‐seq data from 2,457 samples among three brain regions (744 anterior caudate (AC), 1,141 dorsolateral prefrontal cortex (DLPFC), and 572 posterior cingulate cortex (PCC)) obtained from ROSMAP Study participants (434 AD cases, 318 cognitively resistant (CR) AD cases and 188 controls (CT) was estimated by deconvolution using snRNA‐seq cell‐type signatures and DeTREM software. Abundance of six major cell types and eight neuronal subtypes were compared between pairs of diagnostic groups and for three AD clinicopathological traits (amyloid‐β burden and neurofibrillary tangles quantified by immunohistochemistry, and MMSE score) using a generalized linear model including covariates for cell‐fraction, age, sex, and post‐mortem interval. We also conducted a genome‐wide association study (GWAS) for abundance of each cell‐type and brain region using a model that included a polygenic random effect, genetic relationship matrix, and the covariates listed above.

Results

Parvalbumin positive (PVALB+) inhibitory neuron abundance was negatively associated with cognitive status and tau pathology in DLPFC and PCC (all comparisons padj<0.001, Figure 1) and the most reduced neuronal subtype in AD cases compared to controls in the DLPFC (padj = 8.4 × 10‐7) and PCC (padj = 0.0015) regions (Figure 2). The proportions of astrocytes and RORB expressing neurons in the PCC were significantly increased (padj = 0.047) and decreased (padj = 0.024), respectively, in CR AD cases compared to non‐CR AD cases. We also identified a genome‐wide significant association of neuron abundance with TMEM106B SNP rs13237518 in PCC (p = 6.08 × 10‐12). This variant was also associated with levels of amyloid‐β (p = 0.0085) and tangles (p = 0.0073) in the same region (Figure 3).

Conclusion

High abundance of PVALB+ neurons and lack of astrocytosis may be markers of cognitive resilience among persons with a pathological diagnosis of AD. Variants in TMEM106B are associated with neuron abundance and, hence, may specifically influence resilience to cognitive decline independent of AD pathology.
Identification of genetic risk loci and prediction for β‐amyloid deposition in the East Asian population
Authors: Kim Jun Pyo , Jung Sang‐Hyuk , Ali Muhammad , Cruchaga Carlos , Jang Beomjin , Raj Towfique , Won Hong‐Hee , Seo Sang Won
Published: January 2025

Background

Previous Alzheimer’s disease GWAS studies were mostly based on the European population, and the β‐amyloid (Aβ) status was not considered. We performed a meta‐GWAS using East Asian and European genomics data and performed prediction of Aβ status using the identified variant. We utilized single‐cell transcriptome data to identify the differentially expressed gene that is affected by the variant.

Method

In our discovery dataset, genotype data of 3,387 participants from Korea‐Registries to Overcome and Accelerate Dementia research cohort, who underwent amyloid PET were included in our analysis. Additionally, we utilized summary statistics from a recent multi‐ethnic amyloid PET GWAS using genome data from 13 cohorts. We performed a meta‐analysis to identify risk loci for cerebral Aβ deposition. We used 606 independent Korean participants for replication and prediction of Aβ positivity. Finally, post GWAS analysis was performed using Columbia ROSMAP(N = 402) and Samsung Hospital Brain Bank (N = 9) single‐cell transcriptome data.

Result

In our meta‐GWAS analysis, we identified 16 SNPs showing genome‐wide significant associations near SORL1. The SNP rs76490923 (MAF in East Asians = 0.21) showed the most significant association (p = 3.12⨉10‐11). This SNP was associated with Aβ positivity in the replication samples (OR(95% CI) = 0.71(0.52‐0.96), p = 0.025). When we stratified the replication dataset by APOE e4 carrier status and SNP rs76490923, the risk of Aβ positivity was significantly impacted in e4 carriers. (OR = 2.30 in rs76490923 homozygotes, OR = 8.41 in rs76490923 non‐carriers). The single‐cell eQTL results from Columbia ROSMAP database showed that rs76490923 was associated with the expression level of SORL1 in microglia (p = 3.86⨉10‐6). Furthermore, in SMC Brain Bank autopsy cases, SORL1 was differentially expressed in microglia (logFC = ‐1.335, FDR = 3.81⨉10‐83) between Aβ positive and negative individuals.

Conclusion

While variants related to SORL1 have not been identified in a recent multi‐ethnic amyloid PET GWAS, our analysis including greater proportion of East Asian population identified significant SNPs near SORL1. This association might have been undetected in previous studies due to Europeans' low minor allele frequency (0.023). Our finding supports the importance ethnic diversity, which has been increasingly recognized recently in AD genomics studies.
Characterization of the A1527G variant of ABCA7 in an animal model for late‐onset Alzheimer’s disease
Authors: Bernabe Cristian S , Kotredes Kevin P , Pandey Ravi S , Carter Gregory W , Sasner Michael , Oblak Adrian L , Howell Gareth R , Lamb Bruce T. , Territo Paul R ,   MODEL‐AD consortium
Published: January 2025

Background

Genome‐wide association studies (GWAS) identified the ATP binding cassette subfamily A member 7 (ABCA7) gene as increasing risk for Alzheimer’s disease (AD). ABC proteins transport various molecules across extra and intra‐cellular membranes. ABCA7 is part of the ABC1 subfamily and is expressed in brain cells including neurons, astrocytes, microglia, endothelial cells and pericytes. However, the mechanisms by which variations in ABCA7 increase risk for AD are not known.

Method

The IU/JAX/PITT MODEL‐AD Center identified the A1527G variant in ABCA7 (ABCA7*A1527G) as a putative LOAD risk factor. CRISPR/CAS9 was first used to introduce Abca7*A1527G variant to B6.APOE4.Trem2*R47H (LOAD1) mice to assess the transcriptional profiling on brain hemispheres from different ages. The Abca7*A1527G was then incorporated into B6.APOE4.Trem2*R47H.hAb (LOAD2) mice to further evaluate its contribution to LOAD. Female and male LOAD2.Abca7*A1527G and LOAD2 mice were characterized at 4, 12, and 24 months using the following phenotyping pipeline: behavior, PET/CT, multi‐omics, fluid biomarkers, electrophysiology, cognition, and neuropathology.

Result

Brain transcriptional profiling showed that Abca7*A1527G induced changes in gene expression that are similar to some of those observed in human AD (e.g., granulocyte/neutrophil migration, and insulin receptor signaling). LOAD2.Abca7*A1527G showed no aging cognitive deficit but did show significant sex‐ and region‐dependent increases in brain glycolysis paralleled by reduced tissue perfusion yielding progressive age‐related uncoupled phenotypes between 4‐12 and 4‐24 months. While multi‐resolution consensus clustering of regional covariance matrices revealed an increase in cluster number and organization in LOAD2.Abca7*A1527G over LOAD2 for both sexes at 4 months, the cluster number and complexity were reduced by 24 months. Importantly, LOAD2.Abca7*A1527G, but not LOAD2, displayed a similar age‐dependent reduction in cluster number for both sexes. Consistent with the uncoupled phenotype, IL6, IL10, and TNFα were elevated in plasma with genotype, but were not age dependent. Conversely, brain levels of IL4, IL12, TNFα, and CXCL1 were decreased, whereas IL2 and IL10 were elevated in LOAD2.Abca7*A1527G relative to LOAD2. Lastly, assessment of plasma levels of Ab40‐Ab42 revealed an age‐dependent increase in both genotypes.

Conclusion

Data collected to date support a model whereby variations in ABCA7 exert risk for AD through interactions between cerebrovasculature, microglia, and peripheral immune cells.
Identifying genetic risk factors driving cerebral amyloid angiopathy using novel mouse models
Authors: Marola Olivia J , Onos Kristen D , Diemler Cory , Keezer Kelly J , Sasner Michael , Howell Gareth R ,   the IU/JAX/PITT MODEL‐AD Center
Published: January 2025

Background

Cerebral amyloid angiopathy (CAA) co‐occurs with neurodegeneration in Alzheimer’s disease (AD). CAA is absent in many AD mouse models, rendering CAA difficult to study. Previous work has shown wild‐derived WSB/EiJ (WSB) mice over‐expressing APP/PS1 had increased CAA, and thus may be useful in investigating CAA‐causing mechanisms. Here, genetic backgrounds with CAA susceptibility (WSB.APP/PS1) and resilience (B6.APP/PS1) are leveraged to map CAA‐susceptibility loci.

Furthermore, blood brain barrier (BBB) compromise has been hypothesized to impair amyloid clearance and promote vascular deposition. Endothelial TIE2 deactivation was shown to weaken BBB integrity in other models, and therefore may drive CAA. TIE2 activation (pTIE2) is inhibited by endogenous antagonists ANGPT2 and PTPRB, which can be manipulated to bolster pTIE2. Here, the efficacy of pTIE2 elevation in preventing CAA in AD is investigated.

Methods

To determine the onset and therapeutic window of CAA, WSB.APP/PS1 mice (n≥3/sex) were aged to 4, 6, 8, 14, and 18M. CAA was assessed using immunohistochemistry (X34+ plaques within CD31+ vessels). To map CAA‐susceptibility loci, B6.APP/PS1 and WSB mice were crossed, generating BXW.APP/PS1 (F1) offspring. To determine haplosufficiency of these alleles, CAA was evaluated in BXW.APP/PS1 mice (n = 6/sex). F1 mice were intercrossed to generate heterogeneous F2 progeny (n = 50/sex), which were assessed for CAA.

To elevate pTIE2 in models of CAA/AD, Angpt2 heterozygous (Angpt2±) and Ptprb loss‐of‐function (PtprbD57N) alleles were bred to generate CAA‐susceptible mice with TIE2 modulation. Western blot analysis is employed to confirm elevated pTIE2, and CAA amelioration will be evaluated.

Results

WSB.APP/PS1 mice developed significant CAA by 8M. CAA was significantly more advanced in BXW.APP/PS1 compared to founder strains at 8M, and F2 mice had varying CAA severity. Late‐onset AD mice (LOAD2, JAX #033867) with PtprbD57N/D57N exhibited pTIE2 elevation at 12M.

Conclusions

Robust BXW.APP/PS1 CAA suggests heterozygous loci promote CAA. F2 CAA variability suggests CAA‐susceptibility loci are likely mappable. F2 SNP analysis and R/qtl2 software is being employed to identify candidate loci corresponding with CAA. Furthermore, BXW.APP/PS1 is a novel CAA model to study the therapeutic potential of pTIE2 enhancement. To this end, BXW.Angpt2±APP/PS1 and BXW.Ptprb+/D57NAPP/PS1 mice are aging and will be evaluated for pTIE2 elevation and CAA attenuation.
Differential patient selection for amyloid‐targeting immunotherapies in Alzheimer’s disease
Authors: Rosen Jurij , Jessen Frank
Published: January 2025

Background

Anti‐amyloid beta (Aβ) immunotherapies have recently evolved as promising treatment options in patients with early symptomatic Alzheimer’s disease (AD). Meanwhile, accurate patient selection for these treatments might be challenging mirrored by strict selection criteria of the hitherto published clinical trials. Based on a real‐world tertiary care sample of post‐mortem validated cases, we aimed to identify the patients matching these selection criteria and their proportion showing post‐mortem AD pathology.

Method

This study is based on data from The National Alzheimer‘s Coordinating Center‐Uniform and Neuropathology Data Set. Patients with available post‐mortem report of AD pathology were selected by the published selection criteria of clinical trials evaluating efficacy and safety of aducanumab, lecanemab and donanemab. The resulting samples were scrutinized for a potential overlap and their proportion showing post‐mortem AD pathology.

Result

Of 44359 patients in the dataset, 3343 had an available report of post‐mortem AD pathology. Of these, 887 patients were potential candidates for an anti‐Aβ immunotherapy as they presented an amnestic AD syndrome at the baseline visit. Applying selection criteria of clinical trials on these patients resulted in 91, 306, and 192 patients that would be suitable for immunotherapy with aducanumab, lecanemab and donanemab, respectively. These patient samples showed a partial overlap. In these samples, 83, 288, and 184 patients showed post‐mortem AD pathology.

Conclusion

The present results might influence both differential patient selection for upcoming anti‐Aβ immunotherapies and interpretability of potential differences of clinical trial results.
Sex Specific Association of Apolipoprotein E Alleles with Autopsy Measures of Arteriolosclerosis and Atherosclerosis among Older Adults
Authors: Gomez Melisa Lara , Beecham Gary , Montine Thomas J. , Cuccaro Michael L. , Toga Arthur W. , Keene C Dirk , Crane Paul K. , Mukherjee Shubhabrata , Panizzon Matthew S. , Biber Sarah A , Kukull Walter A. , Bennett David A. , Barnes Lisa L. , Schneider Julie A. , De Jager Philip L. , Menon Vilas , Hohman Timothy J. , Dumitrescu Logan C.
Published: January 2025

Background

Cerebrovascular disease (CVD) is a major cause of mortality in females, while two‐thirds of Alzheimer’s disease (AD) patients are female. AD and CVD share many genetic risk factors, one of them being apolipoprotein E (APOE) genotype. Sex differences in APOE and AD are well‐established; it is unclear if associations between APOE and CVD are sex‐specific.

Method

Autopsy data (females = 3,464; males = 3,130) from three AD cohorts included measures of arteriolosclerosis and atherosclerosis (levels for each: none [0], mild [1], moderate [2], and severe [3]) harmonized as part of the AD Sequencing Project Phenotype Harmonization Consortium. Non‐Hispanic White (NHW) individuals >60 years at age of death were included (average age at death = 85±9; 58% AD dementia). Linear analyses assessed sex‐stratified and APOE*sex interactions on CVD outcomes covarying for age at death. APOE‐ε4 and APOE‐ε2 were modeled additively and dominantly, respectively.

Result

Females were older on average and included more APOE‐ε2 and less APOE‐ε4 carriers when compared to males. Among males and females, APOE‐ε2 was not related to arteriolosclerosis (p = 0.90) or atherosclerosis (p = 0.30), while APOE‐ε4 related to higher arteriolosclerosis (β = 0.07 p<0.001) and atherosclerosis (β = 0.04, p = 0.03). There was a significant APOE‐ε2*sex interaction on arteriolosclerosis (p = 0.02) whereby the ε2 allele was associated with less arteriolosclerosis among females (β = ‐0.05, p = 0.27) and more arteriolosclerosis among males (β = 0.08, p = 0.13), although neither stratified effect reached statistical significance. Similarly, the ε4 allele was associated with more arteriolosclerosis among females (β = 0.11, p<0.001), but not among males (β = 0.04, p = 0.16), although the APOE‐ε4*sex interaction did not reach statistical significance (interaction‐p = 0.052). The ε4 allele was associated with more atherosclerosis among females (β = 0.07, p = 0.01), but not males (β = 0.01, p = 0.56), but again the APOE‐ε4*sex interaction did not reach statistical significance (p = 0.28).

Conclusion

We provide evidence that the ε4 allele is related to higher levels of arteriolosclerosis and atherosclerosis, while providing modest evidence of a sex difference in the association between the ε2 allele and arteriolosclerosis. Future work will seek to better characterize these sex‐specific effects within the context of other neurodegenerative pathologies in the aging brain, and more fully characterize sex‐specific clinical consequences of APOE and CVD.
African origin haplotype protective for AD in APOEe4 carriers: exploring potential mechanisms
Authors: Nasciben Luciana Bertholim , Nuytemans Karen , Vasquez Marina Lipkin , Rajabli Farid , Young Juan I , Dykxhoorn Derek M. , Wang Liyong , Scott William K. , Davis David A. , Vontell Regina T , Pericak‐Vance Margaret A , Griswold Anthony J. , Vance Jeffery M.
Published: January 2025

Background

The effect size of APOE4 varies across genetic ancestries with African (AFR) local ancestry conferring a lower risk when compared to other ancestries. Recently, we identified a strong effect of the A allele of rs10423769 (with a minor allele frequency of 0.12 in AFR and 0.003 in Europeans), which lowers the risk of AD by 71% in APOE4 carriers. rs10423769 is 2 MB from APOEe4 in a region of segmental duplications (SD) containing a cluster of pregnancy specific beta‐1 glycoprotein genes (PSGs) and a lncRNA. To gain insights into the mechanism of protection, we characterized the haplotype harboring the variant and investigated differences in methylation and structural variation (SV) between haplotypes.

Method

We used the Alzheimer’s Disease Sequencing Project (ADSP) short read sequencing database to fine map and extend the protective haplotype using Haploview 4.2. In addition, long read sequencing (LRS) with the Oxford Nanopore PromethION was performed on 16 samples of individuals carrying one or two copies of rs10423769_A. LRS was used for SV calling with Sniffles2 and differential methylation analysis using Nanomethphase.

Result

The minimum shared haplotype harboring rs10423769_A allele was ∼21kbp (chr19:43099521‐ 43120243). Though the region is rich in SDs, high quality LRS reads mapped uniquely to the region around the A allele confirming that the haplotype is unique and not duplicated elsewhere in the genome of the sequenced individuals. Moreover, the rs10423769_A haplotype harbors 23 differential CpG sites (fdr<0.05) compared to rs10423769_G, although no differential methylated region was identified. LRS revealed a 140bp insertion of repetitive MEF2 binding motifs. Initial examination demonstrated that the insertion was present in 80% of the A allele carriers.

Conclusion

We have identified an AF‐specific haplotype protective against AD risk conferred by APOE ε4. Considering the distance from APOE and the complexity of the highly SD region where the variant is located, we have identified the minimum shared haplotype from AFR origin and are investigating the potential effects of SVs and differential CpG sites. Ongoing analyses include 3D chromatin structure and LRS at higher coverage to assemble and resolve the complex genomic context of the allele.
Effects of chaducanumab‐mediated plaque removal on amyloid‐tau synergy
Authors: Welikovitch Lindsay A , de Gerando Anastasie Mate , Khasnavis Anita , Bhavsar Harshil , Meltzer Jonah C , Buee Luc , Bussière Thierry , Hyman Bradley T. T
Published: January 2025

Background

Amyloid‐targeting antibodies have been shown to be remarkably effective at clearing amyloid plaques from the Alzheimer’s disease (AD) brain. To date, preclinical assessments have used animal models that develop only amyloid pathology, whereas AD patients present with tau pathology, neuroinflammation, and other concurrent neuropathologies. Deciphering how successful anti‐amyloid therapies impact the synergistic interplay of amyloid and tau will be critical in determining which secondary disease processes can be slowed, interrupted, or reversed by amyloid‐targeting immunotherapies.

Method

To establish whether interrupting Aβ plaque deposition or clearing existing plaques could halt the progression of tau pathology and downstream disease events, we treated APP/PS1xTau22 mice with a murine chimeric analog of Aducanumab (chAdu) targeting human oligomeric and fibrillar Aβ species. Equal concentrations of chAdu and isotype Control IgG were administered weekly for 12 weeks by intraperitoneal injection at a dose of 30mg/kg beginning at 6 months of age.

Result

Following 3 months of immunotherapy, APP/PS1xTau22 mice treated with chAdu had lower Aβ plaque burden in both the hippocampus and cortex. Although amyloid expression accelerates the formation of tau neurofibrillary tangles as early as 6 months of age in the APP/PS1xTau22 transgenic model, inhibiting further plaque deposition using chAdu had no effect on the abundance of AT8+ or AT100+ neurofibrillary lesions in any brain region analyzed. While regional phospho‐tau deposition was similar between isotype‐IgG and chAdu‐treated animals, we observed a reduction in the number of AT8+and SMI312+ axonal dystrophies in mice that had undergone 3 months of immunotherapy.

Conclusion

Within a more‐complex neuropathological environment, amyloid immunotherapy influences plaque‐related secondary disease events, but does not directly impact tau deposition in the APP/PS1xTau22 mouse model. Identifying which aspects of the AD pathology remain resistant to amyloid immunotherapy will provide insight into how mono‐ or combination therapies can be developed or improved.
Large‐scale proteomic approach to stable isotope labeling kinetics (SILK) for studying protein turnover in blood and cerebrospinal fluid in Alzheimer’s disease
Authors: Lehmann Sylvain
Published: January 2025

Background

Protein metabolism and turnover can be monitored using tracer methods, notably stable isotope labeling kinetics (SILK) based on 13C‐leucine incorporation. This approach has been used in Alzheimer’s disease, specifically analyzing the turnover in cerebrospinal fluid of biomarkers of interest, including amyloid peptides, leading to major pathophysiological insights (Nature medicine 12:856‐861). This was achieved using immunoprecipitation mass spectrometry, which enables to track a small number of targets present in low concentration. Complementarily, we have recently validated a new large‐scale SILK proteomics workflow and bioinformatics pipeline capable of assessing the turnover of hundreds of proteins (Analytical chemistry 91:15500‐15508). Here, we use this workflow on SILK blood and CSF samples to generate a comprehensive model of protein dynamics that can potentially be used to compare samples generated in amyloid‐positive and amyloid‐negative patients.

Methods

We analyzed blood and CSF samples collected for up to 36 hours, every 3 hours, after a 9‐hour infusion of 13C‐leucine. After depletion of major proteins, samples were reduced, alkylated and digested before C18 fractionation. LC‐MS acquisitions were performed on Evosep coupled to TIMS TOF HT (Bruker Daltonics). Data acquisition generated a list of peptides uploaded and process on skyline. We used a Bayesian hierarchical model to provide robust and comprehensive data of protein turnover (doi.org/10.1101/2023.10.30.564713).

Result

In a first series of analyses CSF MS data covered 3,156 proteins and 22,842 distinct peptides, of which 16,913 contained at least one leucine. 2,417 distinct peptides usable for dynamics modelling determined the dynamics of 869 proteins in CSF. In plasma, the same process led to 1,260 proteins covered by 9,243 peptides, 6,788 of which contained at least one leucine, enabling the dynamics of 271 proteins in plasma to be estimated. The number of proteins detected with dynamics data in both plasma and CSF was 194. We report an accurate 3‐biological compartment model able simultaneously account for the protein dynamics observed in plasma and the CSF including a hidden central nervous system compartment.

Conclusion

The models developed and optimized for 3‐biological‐compartment system has now been implemented and will be applied to a SILK cohort generated in amyloid‐positive and amyloid‐negative patients.
Examining the associations between Alzheimer disease, Lewy body, and TDP‐43 neuropathology with mild behavioral impairment: a clinicopathological study of older adults
Authors: Sharif Sergio Fernandez , Guan Dylan X. , Smith Eric E. , Ismail Zahinoor
Published: January 2025

Background

The utility of neuropsychiatric symptoms (NPS) for early detection of AD and/or other neuropathologies is not fully understood, with concerns regarding specificity. Mild behavioral impairment (MBI) is a syndrome identifying persons at risk for incident cognitive decline and dementia by leveraging risk associated with later‐life emergent and persistent NPS. Here, in dementia‐free individuals at baseline, we examined whether AD, Lewy body (LB), and/or transactive response DNA‐binding protein 43 (TDP‐43) pathology at autopsy were associated with the presence of MBI five years before death.

Method

National Alzheimer’s Coordinating Center participants (n = 1016) were included. Using the Neuropsychiatric Inventory–Questionnaire, three NPS statuses were derived: MBI, NPSnoMBI, or noNPS. Proteinopathy presence/absence was determined using published guidelines. Adjusted multinomial logistic regressions modeled pathology‐NPS status associations. Adjusted Cox proportional hazards regressions modeled hazard for AD‐dementia at each NPS status level, including interaction terms with cognitive status and each co‐pathology.

Result

Participant characteristics are presented in Table 1. AD+ individuals were 88.4% more likely to be MBI+ in the five years before death than AD‐ (odds ratio (OR):1.88, 95% confidence interval (CI):1.29‐2.75, p<0.01); NPSnoMBI did not differ from noNPS (OR:1.22, CI:0.90‐1.66, p = 0.20). No significant associations were seen for either co‐pathology, even in an AD‐only stratum. Among MBI progressors to dementia (n = 137), 43.8% were solely AD+ and 32.8% were mixed AD+/LB+. MBI individuals had a 2.03‐fold greater progression rate to AD‐dementia than noNPS (CI: 1.60‐2.57, p<0.01). NPSnoMBI did not differ from noNPS (OR:1.22, CI:0.90‐1.66, p = 0.20). Progression rates to AD‐dementia among MBI+ who had limbic LBs at autopsy were significantly greater than those without (HR:2.56, CI:1.09‐6.06, p<0.05). No significant interaction was noted for TDP‐43. Progression rates to dementia were higher in MCI, but the effect of MBI on progression was greater for NC (HR:3.05, CI:1.37‐6.80, p<0.01) vs. MCI (HR:1.93, CI:1.51‐2.47, p<0.01).

Conclusion

These findings suggest that those with autopsy‐confirmed AD—but not other common proteinopathies—are more likely to be preceded by MBI than by NPSnoMBI or noNPS in the five years before death. Among those with MBI, the presence of LB might serve as an important co‐pathology in the development of AD dementia. By extension to postmortem diagnosis, these results reinforce the utility of MBI in AD‐related dementia prognostication.
Identification of differentially expressed genes in post‐mortem tissue from African American Alzheimer disease cases and controls
Authors: Logue Mark W. , Labadorf Adam Thomas , O'Neill Nicholas K , Dickson Dennis W. , Flanagan Margaret E , Franklin Erin E. , Frosch Matt P. , Gearing Marla , Jin Lee‐Way , Kofler Julia , Lee Eddie B , Mayeux Richard , McKee Ann C. , Miller Carol A , Murray Melissa E. , Nelson Peter T , Perrin Richard J. , Schneider Julie A. , Stein Thor D. , Teich Andrew F , Troncoso Juan C , Wang Shih‐Hsiu Jerry , Mez Jesse , Farrer Lindsay A.
Published: January 2025

Background

Although the rate of Alzheimer’s disease (AD) in African‐ancestry (AA) Americans is higher than that of persons from European‐ancestry (EA) populations, AA participants have been underrepresented in AD neuropathological studies.

Method

Utilizing the AD Research Centers (ADRC) infrastructure, we obtained AA donor pre‐frontal cortex (PFC) tissue from brain repositories of 12 ADRC and generated bulk RNA sequencing (RNA‐seq) data for 179 samples that met QC and inclusion criteria. Previously generated PFC RNAseq data were obtained for 28 additional AA donors from the Columbia University ADRC. Differential gene expression was evaluated among 125 donors with a neuropathological diagnosis of AD (NIA‐Reagan intermediate or high likelihood) and 82 neuropathologically confirmed controls using regression models including covariates for age at death, sex, cell‐type frequencies, and RNA integrity number (RIN) calculated with Limma. FDR‐corrected p‐values (padj) were calculated to control for the 33,611 genes examined.

Result

A total of 482 genes surpassed the multiple‐testing threshold. The most significant, ADAMTS2 (p = 2.96 × 10‐8, padj = 0.001), showed increased expression in AD cases (see Table/Figure). We note that ADAMTS2 was differentially expressed in a prior EA study of neuropathologically confirmed AD cases and controls (Panitch et al. Molecular Psychiatry 2021). Additionally, a recent analysis of cognitive resilience in EA neuropathological AD cases identified a strong association with ADAMTS2 (See Li et al. AAIC2024 abstract). Of the differentially expressed genes observed in the Panitch et al. EA study, 385 (35%) were nominally significant,65 (5.8%) were corrected significant, and most (89%) of these genes had the same effect direction in the AA cohort. Some of the observed associations appear to be AA specific (e.g., EFR3B, IRS4, and CA12; see Table). Additionally, we found nominally significant (p<0.05) associations with expression of APOE (Log2 fold change [L2FC = ‐0.20, p = 0.012) and several other established AD genes including SORL1 (L2FC = ‐0.10, p = 0.014) and IGF1R(L2FC = 0.11, p = 0.0013).

Conclusion

This largest‐ever (to our knowledge) gene expression study of AD in postmortem brain tissue from AA donors implicates many more genes as having a role in AD in this population than previously identified in genome‐wide association studies and provides insight into trans‐ancestry differences risk for AD.
Fatty Acid Amide Hydrolase Single Nucleotide Polymorphism rs324420A/C Associations with Alzheimer’s Disease
Authors: Mori‐Fegan Daniel K , Wong Yuen Yan , Noor Shiropa , Wu Che‐Yuan , Ross Ruth A , Swardfager Walter
Published: January 2025

Background

The endocannabinoid system has demonstrated roles in Alzheimer’s Disease (AD), such as modulation of inflammation. Fatty Acid Amide Hydrolase (FAAH) is the enzyme responsible for the rapid inactivation of the endocannabinoid anandamide into arachidonic acid and ethanolamine. In doing so, FAAH modulates the concentration of anandamide and influences neurobehavioral functions and physiological conditions such as nociception and inflammatory responses. A missense single nucleotide polymorphism in the FAAH gene rs324420‐A>C (Minor allele frequency = 26.4%) is associated with higher levels of anandamide, reduced susceptibility to PTSD and increased risk of substance use disorders. However, the relationship between rs324420 and AD progression has not been explored. In AD, FAAH methylation is lower resulting in increased activity, and FAAH inhibition is suggested to drive microglial polarisation towards anti‐inflammatory phenotypes. rs324420 increases proteolytic degradation, thus reducing functionality of FAAH. Due to lowered FAAH activity, we hypothesise that rs324420 minor allele carriers will have slower neurodegeneration and slower cognitive decline in AD.

Methods

This retrospective, longitudinal, observational study used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Patients diagnosed with mild cognitive impairment or mild AD (MCI or AD) from ADNI2/GO/3 were selected. Linear regression models evaluated baseline differences between rs324420 minor allele carriers (AC/CC) and major allele homozygotes (AA) controlling for sex, age, baseline cognitive status, APOE‐e4 status and baseline intracranial volume. Longitudinal associations were assessed as interactions between SNP and visit number (baseline to 48 months) in mixed models.

Results

In Aβ‐positive patients with AD or MCI, carrying the rs324420 minor allele was associated with smaller nucleus accumbens volume (F(1,311) = 15.7, p = 0.018) at baseline. Longitudinally, several brain regions showed less volumetric decline in minor allele carriers over 48 months: caudal anterior cortex (F(1,163) = 5.18, p = 0.024), fusiform gyrus (F(1,85.6) = 5.28, p = 0.024), rostral anterior cortex (F(1,59.9) = 6.41, p = 0.014) and nucleus accumbens (F(1,84.7) = 4.75, p = 0.032). Carriers of the minor allele also showed less decline MMSE score over 48 months (F(1,544.15) = 5.13, p = 0.024).

Conclusions

Slower rates of cognitive and neuroanatomical decline in amyloid positive patients with MCI or mild dementia due to AD suggest a potential protective role of the rs324420 minor allele in the FAAH gene. Further investigation is warranted, including cognitive, anatomical, fluid biomarker and neuropsychiatric symptom profiles.
Genome‐wide association analysis and admixture mapping suggest an Alzheimer disease risk locus on chromosome 12 in a Puerto Rican cohort
Authors: Akgun Bilcag , Feliciano‐Astacio Briseida E. , Rivero Joe , Hamilton‐Nelson Kara L. , Scott Kyle , Celis Katrina , Adams Larry D. , Sanchez Jose Javier , Valladares Glenies S , Silva‐Vergara Concepcion , Rodriguez Vanessa C , Mena Pedro R. , Whitehead Patrice L. , Prough Michael B. , Acosta Heriberto , Griswold Anthony J. , Dalgard Clifton L. , McInerney Katalina F , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W , Rajabli Farid , Pericak‐Vance Margaret A
Published: January 2025

Background

Hispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. The Puerto Rican (PR) population, a three‐way admixed (European, African, and Amerindian) population is the second‐largest Hispanic group in the continental US. We performed a genome‐wide association study (GWAS) in the PR population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.

Method

652 individuals (349 AD; 303 cognitively unimpaired), ascertained through the Puerto Rico Alzheimer Disease Initiative (PRADI), were included in the analyses. We performed GWAS on the Whole Genome Sequencing (WGS) dataset with a generalized linear‐mixed model adjusting for sex, age, and population substructure as fixed effects and genetic relationship matrix as a random effect. To infer local ancestry, we merged the target PR dataset with appropriate population samples from the HGDP and 1000G reference panels. Subsequently, we conducted univariate admixture mapping (AM) analysis. We also assessed the polygenic risk score (PRS) using the effect sizes from summary statistics from the non‐Hispanic White (NHW) study.

Result

We identified a suggestive significant (p<5 × 10‐6) signal (rs11183403; P = 4 × 10‐6) within the SLC38A1 gene on chromosome 12. Univariate African AM analysis identified one suggestive (p<4 × 10‐5) ancestral block located in the same region on chromosomes 12q13.1 (p = 7.2 × 10‐6). We replicated eight known AD loci– APOE, ABCA7, CLU, FERMT2, GRN, PRDM7, SEC61G, and TREM2. Admixture analysis revealed proportions of 68% European, 20% African, and 12% Amerindian in the PR cohort. NHW‐derived PRS has a good prediction power (AUC = 0.62) in the PR dataset.

Conclusion

PR GWAS and AM identified a suggestive AD risk locus in the SLC38A1 gene. This region overlaps with an area of linkage of AD in previous studies (12q13). The SLC38A1 gene is associated with ischemic brain damage and its transcription is affected by amyloid‐beta peptide. Our study replicated 8 known AD loci previously identified in European studies and showed good predictive power with NHW‐derived PRS which is likely due to the high European background of the PR population. Including underrepresented populations in genetic studies is important for identifying health disparities and developing effective treatments for AD in all groups.
The influence of APOEε4 on the pTau interactome in sporadic Alzheimer’s disease
Authors: Thierry Manon , Ponce Jackeline , Ariza Mitchell Marta , Askenazi Manor , Faustin Arline , Leitner Dominique , Pires Geoffrey , Kanshin Evgeny , Drummond Eleanor , Ueberheide Beatrix , Wisniewski Thomas
Published: January 2025

Background

APOEε4 is the major genetic risk factor for sporadic Alzheimer’s disease (AD). Although APOEε4 is well known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology.

Method

To elucidate this potential effect, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4), using a combination of anti‐pTau PHF1 (pS396/pS404) immunoprecipitation and mass spectrometry. This proteomic approach was complemented by a neuropathological analysis of anti‐pTau PHF1 and anti‐Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOEε3/ε3 and n = 10 APOEε4/ε4).

Result

Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOEε3/ε3 and APOEε4/ε4 groups (FC ≥ 1.50, IPPHF1
versus IPIgG ctrl). We identified 80 and 68 proteins as pTau interactors in APOEε3/ε3 and APOEε4/ε4 groups, respectively (SAINT score ≥ 0.80; FDR ≤ 5%). A total of 47/80 proteins were identified as pTau interactors only for APOEε3/ε3 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as pTau interactors only for APOEε4/ε4 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A comprehensive characterization of Tau pathology in the frontal cortex showed a higher density of plaque‐associated neuritic crowns, made of dystrophic axons and synapses, in APOEε4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOEε4/ε4 cases.

Conclusion

Our study supports an influence of APOE genotype on pTau subcellular location in the human brain. These results are consistent with a facilitation of pTau progression in Aβ‐affected brain regions of APOEε4 carriers, paving the way to the identification of potential new therapeutic targets.
Distinct associations of excitatory‐inhibitory (E/I) imbalance in aging and in Alzheimer’s disease
Authors: Ranasinghe Kamalini G , Verma Parul , Kudo Kiwamu , Syed Faatimah , Rankin Katherine P. , Miller Bruce L. , Kramer Joel H. , Rabinovici Gil D. , Kirsch Heidi , Vossel Keith , Raj Ashish , Nagarajan Srikantan S
Published: January 2025

Background

Neural circuit hyperexcitability and impaired excitation‐to‐inhibition (E/I) activity is believed to be a key contributor to synaptic and network degeneration in Alzheimer’s disease (AD). Extensive preclinical research on transgenic animal models of AD have demonstrated neuronal and circuit level E/I imbalance mediated by amyloid‐beta (Aβ) and tau proteins. Synaptic and network deficits are also integral changes of aging. It is unknown whether the mechanisms of E/I imbalance in aging are distinct from that in AD. In this study we leveraged the aperiodic spectral slope measure, which represent the spontaneous neuronal firing, and which has been shown to indicate higher E/I as reduced slope values.

Methods

We used source reconstructed, high spatiotemporal resolution signals, from magnetoencephalography (MEG) for the spectral analysis and used the neural mass model (NMM) to estimate excitatory and inhibitory neuronal parameters, in patients with AD (n = 85) and age‐matched elderly‐controls (n = 45). The NMM estimates the time constants of excitatory (te) and inhibitory (ti) neuronal subpopulations and depicts E/I as 1/inhibitory‐neural‐gain (gii). We estimated the aperiodic slope from the spectral analysis (15‐50 Hz) and examined the correlations with NMM parameters. In a subset of AD patients, we recorded the presence or absence of epileptiform activity (EPI) and examined the associations of neuronal‐time‐contents and inhibitory‐neural‐gain in AD‐EPI+ (n = 20) vs. AD‐EPI− (n = 30).

Results

AD patients showed reduced inhibitory‐neural‐gains compared to elderly‐controls indicating increased E/I (Fig. 1.A). AD patients also showed increased neuronal‐time‐constants than controls (Fig. 1.B‐C). The spatial patterns of reduced inhibitory‐neural‐gains overlapped with AD vulnerable anatomic regions showing a posterior temporo‐parietal‐occipital distribution (Fig. 1.D). Greater reductions of aperiodic‐slope distinctly correlated with inhibitory‐neural‐gains in AD and with higher neuronal‐time‐constants in elderly‐controls (Fig. 1.G‐L). Moreover, AD‐EPI+ showed greater reductions in inhibitory‐neural‐gains than AD‐EPI−, but no differences in neuronal‐time‐constants (Fig. 1.M‐O).

Conclusions

Our findings identified impaired inhibitory synaptic activity as the strongest correlate of neural circuit hyperexcitability in AD. In contrast, impaired timing of both excitatory and inhibitory neurons were the best predictors of neural circuit hyperexcitability in aging. These results suggest different mechanisms of neural circuit hyperexcitability in AD vs. aging and have important implications to translational as well as clinical studies probing early network changes.
Preoperative Visual Attention Performance Predicts Postoperative Delirium
Authors: Chapin Benjamin A , Kimmett Faith , Garvan Cynthia , Tighe Patrick , Dekosky Steven , Williamson John B. , Price Catherine C.
Published: January 2025

Background

Preexisting cognitive impairment is a significant risk factor for post operative delirium (POD), and POD increases morbidity and mortality. Disturbances of attention (i.e., ability to direct, focus, sustain, and shift attention) and awareness (i.e., orientation to environment) are necessary for delirium diagnosis. This suggests dysfunction in frontoparietal networks which control visuospatial attention. However, preoperative visual attention has not been systematically investigated as a risk factor for delirium in at‐risk adults.

Methods

In this prospective observational study, participants aged 65 years and older undergoing elective orthopedic surgery completed preoperative measures of visuospatial attention, including horizontal line bisections and a preparation of the Posner cueing task in vertical and horizontal orientations. Our primary outcome was maximum POD severity, as measured by the Confusion Assessment Method Severity (CAM‐S) short form. Data were summarized (i.e., frequencies, mean (SD), and median [Q1, Q3]) and analyzed (i.e., Spearman correlational testing).

Results

The majority of the 28 participants were female (68%) and white (93%) with mean (SD) age of 75.0 (6.1) years of age and 15.6 (2.7) years of education. 75% were not delirious post‐surgery, 11% were classified as subsyndromal (CAM‐S > 0), and 14% were classified as having POD. The median [Q1, Q3] value for the delirium score was 0 [0, 1.5]. The median [Q1, Q3] values for cognitive measures were as follows: Montreal Cognitive Assessment (MoCA) was 24 [22,27], line bisection leftward deviation was 0.12 mm [‐.40,0.11], incongruent stimulus reaction time was 550 ms [488,616]. Correlations between delirium and age, education, and MoCA score were not found to be significant. The correlation coefficient (p‐value) between delirium and leftward deviation on line bisection was 0.39 (p = 0.038), and incongruent stimulus reaction time was 0.57 (p = 0.003).

Conclusion

We found that preoperative measures of visual attention predicted postoperative delirium. Further studies can help to determine how to apply these measures to better predict and monitor the effects of delirium on cognition and neurodegeneration. Understanding this relationship also provides a basis for future research on strategies to prevent, mitigate or rehabilitate the effects of delirium, improving hospital outcomes and potentially delaying or preventing dementia. Funding AACSF‐22‐928731; K07AG066813