bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic factors modify the effect of chronic viral infections on Alzheimer disease risk
Authors: Tejeda Marlene , Farrell John J. , Zhu Congcong , Wetzler Lee , Lunetta Kathryn L. , Bush William S. , Martin Eden R. , Wang Li‐San , Schellenberg Gerard D. , Pericak‐Vance Margaret A , Haines Jonathan L. , Farrer Lindsay A. , Sherva Richard
Published: January 2025

Background

Several viruses have been linked to Alzheimer disease (AD) by independent lines of evidence.

Method

Whole genome and whole exome sequences (WGS/WES) derived from brain (3,404 AD cases, 894 controls) and blood (15,612 AD cases, 24,544 controls) obtained from European ancestry (EU), African American (AA), Mexican (HMX), South Asian Indian (IND), and Caribbean Hispanic (CH) participants of the Alzheimer’s Disease Sequencing Project (ADSP) and 276 AD cases 3,584 controls (all EU) from the Framingham Heart Study (FHS) that did not align to the human reference genome were aligned to viral reference genomes. A genome‐wide association study (GWAS) for viral DNA load was conducted using PLINK software and regression models with covariates for sex, age, ancestry principal components, and tissue source. A second GWAS tested association of the interaction of SNPs with total viral read count and specific viruses previously linked to AD (HSV‐1, HPV‐71, TTV‐10, and herpes and TTV clusters) with AD risk in five population ancestry groups. Results across subgroups (cohort, WES vs. WGS, tissue source, and ancestry) were combined by meta‐analysis using METAL software. P‐values for previously established AD risk SNPs were corrected for 83 tests and a standard genome‐wide significant (GWS) threshold of 5 × 10‐8 was used for GWAS analyses.

Result

HSV‐1 was associated with an increased risk of AD in EUs (OR = 1.20, P = 3.23 × 10‐6) and AAs (OR = 1.18, P = 9.46 × 10‐6), but was protective in CHs (OR = 0.43, P = 5.06 × 10‐62). HPV‐71 was associated with a reduced risk of AD in EAs (OR = 0.94, P = 0.035). No significant virus‐AD associations were observed in individuals of HMX or IND ancestry. The interaction of a known AD risk SNP (rs6489896) in TPCN1 with HSV‐1 was significantly associated with AD risk (OR_interaction = 1.11, P = 5.67 × 10‐4) in the trans‐ethnic meta‐analysis of all WGS samples. We identified GWS associations of 16 variants with viral reads in AAs. Several of these genes are involved in memory formation (KMT2A), synaptic transmission (SLC28A2), and immune response (FCN2 and CLEC12A).

Conclusion

These findings provide further evidence for the role of viral infections, particularly herpes viruses, in AD pathogenesis and highlight the importance of genetic factors in modulating these associations.
Subjective Cognitive Concerns and High Frequency Mobile App Based Cognitive Assessment in Older Adults: Relationship to Adherence, Satisfaction, and Cognitive Performance
Authors: Nester Caroline O , De Vito Alyssa N. , Kunicki Zachary J. , Strenger Jennifer , Harrington Karra D , Roque Nelson A. , Sliwinski Martin J. , Thompson Louisa I.
Published: January 2025

Background

Subjective cognitive concerns (SCC) are possibly one of the earliest clinical symptoms of dementia. There is growing interest in applying mobile app‐based assessment to remotely screen for cognitive status in preclinical dementia, but the relationship between SCC and relevant mobile assessment metrics remains unclear. To address this gap, we characterize the relationship between SCC and adherence, satisfaction, and performance on digital cognitive assessment in cognitively unimpaired older adults.

Method

Participants (N = 122, Table 1) completed 8 assessment days using Mobile Monitoring of Cognitive Change (M2C2), an app‐based testing platform, with brief daily sessions within morning, afternoon, and evening time windows (24 total testing sessions). M2C2 includes working memory, processing speed, and episodic memory tasks. Participants provided feedback about their satisfaction and motivation related to M2C2. SCC was assessed via the Cognitive Function Instrument (CFI). Regression analyses evaluated the association between SCC and adherence, satisfaction, and performance on M2C2, controlling for age, sex, and loneliness (UCLA Loneliness Scale). Linear‐mixed effects models evaluated whether SCC predicted M2C2 subtest performance longitudinally over the 8‐day testing period, controlling for covariates.

Result

SCC was not associated with adherence to M2C2, app satisfaction, or protocol motivation. SCC endorsement significantly predicted worse overall episodic memory performance (ß = ‐0.011, p = .021, 95% CI ‐0.02, ‐0.00), but was not associated with overall working memory or processing speed (Table 2). A trend was revealed between SCC and slow processing speed at day 1. There was a significant interaction between SCC and processing speed over the 8‐day period, such that SCC was associated with initially slow, then progressively faster processing speed.

Conclusion

SCCs are associated with objective cognitive performance on mobile app‐based assessments, but do not impact metrics related to protocol engagement (e.g., adherence, satisfaction, and motivation), suggesting that mobile app assessments may be sensitive to early neurodegenerative changes. Results provide reassurance that SCCs do not impact the feasibility of mobile app‐based assessments in older adult samples. Future research in larger, more diverse samples which follow cognitive functioning longitudinally will be essential next steps to understand the utility of SCC to predict cognitive decline via mobile app.
SPARC‐related modular calcium‐binding proteins (SMOC1 and 2) as a modulator of amyloid pathology in Alzheimer’s Disease
Authors: Afroz Kazi Farhana , Levites Yona , Ryu Danny , Ran Yong , Gadhavi Joshna Dharmendrabhai , Liu Xuefei , Seyfried Nicholas T , Golde Todd
Published: January 2025

Background

Recently, a highly significant brain proteome divergent modules change between Alzheimer’s disease (AD) and CRND8 APP695NL/F transgenic mice has been found. The M42 module is the module in human AD most highly correlated with amyloid and tau pathologies and cognitive decline. Among all proteins in this module, the (SPARC‐related modular calcium‐binding protein 1) SMOC1 is emerging as a robust biomarker of amyloid deposition in CSF. It increases in CSF in parallel with the Ab42:40 ratios’ decrease. SMOC1 is also markedly increased in the late‐onset AD CSF, suggesting its role as a robust biomarker. Our preliminary data have shown that i) recombinant SMOC1 inhibits Aβ aggregation in vitro and ii) both SMOC1 and its homolog SMOC2 bind amyloid structures. Furthermore, SMOC1 and 2 appear to be components of a subset of senile plaques and CAA.

Method

We hypothesized that Smoc1 and Smoc2 overexpression will inhibit amyloid deposition and even promote clearance of aggregated Aβ. To test the hypothesis, we cloned both genes into AAV and injected newborn CRND8 amice with rAAV2/8‐Smoc1‐Flag and rAAV2/8‐Smoc2‐Flag, aged them and assessed amyloid deposition in the brain by immunohistochemical and biochemical methods.

Result

Immunohistochemical analysis showed that Smoc1 overexpression resulted in significantly lower amyloid plaque count and SDS‐soluble Aβ1‐42 and Aβ1‐40 levels in the brain, as compared to non‐injected controls. Soluble Aβ1‐42 and Aβ1‐40 levels were not changed as a result of Smoc1 overexpression. Staining with astrocyte‐specific glial fibrillary acid protein (GFAP) and microglia‐specific ionized calcium‐binding molecule‐1 (IBA‐1) antibodies showed that Smoc1 overexpression did not affect astrocytosis, but significantly increased the activated microglia cell counts. Additionally, we are currently examining the effects of Smoc1 and Smoc2 overexpression on pre‐existing plaques in aged CRND8 mice.

Conclusion

Our data suggest that Smoc1, in addition to being an early and sensitive fluid biomarker, is acting as an inhibitor of amyloid formation and can potentially lead to a novel therapeutic approach. Although Smoc1 and Smoc2 prevent Aβ aggregation, the specific mechanism of this action is yet to be identified. Our findings will pave the road to establishing SMOC proteins as a potential therapy for AD.
Single‐nuclei transcriptomic identifies type‐specific neuronal cell vulnerability in Amnestic and Logopenic Variant Primary Progressive Aphasia Alzheimer’s disease
Authors: Pereira Felipe Luiz , Lew Caroline , Li Song Hua , Rizzi Liara , Araujo Igor Prufer Q C , Soloviev Alexander V. , Spina Salvatore , Rexach Jessica E , Seeley William W. , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Newell Kathy L , Ghetti Bernardino , Murray Melissa E. , Grinberg Lea T.
Published: January 2025

Background

Individuals meeting neuropathological criteria for Alzheimer’s disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1. In contrast, logopenic variant primary progressive aphasia (lvPPA) cases have a higher tau burden in the superior temporal gyrus (STG). Single‐cell technology enables investigations on the molecular basis of differential neuronal vulnerability in AD. Consequently, we delved into the factors that underlie this selective vulnerability by analyzing brain samples from individuals exclusively afflicted with AD but exhibiting diverse clinical manifestations.

Method

snRNA Sequencing using the Chromium Single Cell 3′ (10X Genomics, USA) on nuclei cells extracted from the CA1 sector and posterior STG of postmortem brain tissue of 48 individuals either meeting pathological criteria for AD (A3B3C3; 24 amnestic and eleven lvPPA) and healthy controls (A≤1B≤1C≤1; n = 13) (Table 1, Fig. 1A/B). Bioinformatics analyses were conducted using Cell Ranger and R software. Comparisons between cell subpopulations were conducted with the Wald statistical test, and p‐values < .05 were considered significant.

Result

After quality control, we recovered more than 250k nuclei with a mean of 2,130 genes per nuclei. Upon cross‐sample alignment and t‐stochastic neighborhood embedding clustering (Fig. 1C), we found 21 excitatory neuronal subpopulations (Exc‐sub) in CA1 and 26 in STG, and 22 and 25 inhibitory neuronal subpopulations (Inh‐sub) in CA1 and STG, respectively; 16 astrocytes subpopulations in both areas and 20 microglia subpopulations in CA1 and 17 in STG (Fig. 2). One STG Exc‐sub, expressing CUX2 and LAMP5 genes showed vulnerability in lvPPA patients. Also, one STG Inh‐sub, expressing the ADARB2 gene, showed vulnerability for all AD patients.

Conclusion

Our preliminary study identified a vulnerable population of excitatory neurons related to lvPPA. We are conducting validation studies using quantitative pathology to confirm these results. Furthermore, analysis of a higher number of cases is ongoing and will continue to inform on factors associated with neuronal vulnerability.
Reducing tau acetylation rescues cognitive deficits in a mouse model of traumatic brain injury‐induced acceleration of Alzheimer’s disease
Authors: Barker Sarah , Vázquez‐Rosa Edwin , Caradonna Salvatore , Kornblit Ryan , Apostolakis Aristotle , Dou Lijun , Shin Min‐Kyoo , Corella Sofia , Tripathi Sunil Jamuna , Chakraborty Suwarna , Chaubey Kalyani , Franke Kathryn , Cintrón‐Pérez Coral , Sridharan Preethy , Woo Jung A , Kang David E. , Gan Li , Wilson Brigid M. , Cheng Feixiong , Paul Bindu D , Pieper Andrew A.
Published: January 2025

Background

TBI is the 3rd greatest risk factor for developing AD, behind genetics and aging. TBI is associated with a 3‐4 year earlier onset of cognitive impairment, and increased cortical thinning and amyloid plaques in people with AD. The underlying mechanisms of this relationship are not understood, and as a result there are no treatments that protect patients from accelerated AD after TBI. We reported that tau is pathologically acetylated after TBI. Acetylated tau is significantly more elevated in the brains of human AD subjects with a history of TBI, compared to AD alone and healthy controls. Therefore, we hypothesized that early tau acetylation after TBI is mechanistically involved in the acceleration of AD.

Method

We developed a mouse model of TBI‐mediated acceleration of AD‐like pathology and cognitive impairment in 5xFAD mice. Our unique blast mediated multimodal TBI model is reproducible and clinically relevant. 8‐week‐old male and female 5xFAD and WT littermates underwent sham/TBI and were assessed after two weeks via Morris water maze, immunohistochemistry, western blot, and single nuclear RNA sequencing. For treatment studies, the FDA‐approved non‐steroidal inflammatory drug diflunisal, which inhibits the p300‐CBP acetyltransferase enzyme that acetylates tau, or vehicle was initiated 24 hours after TBI and continued daily. To investigate potential mechanisms, we developed an in vitro TBI model with Hela cells that stably express amyloid precursor protein or tau.

Result

TBI causes learning deficits in young 5xFAD mice that do not occur in sham 5xFAD mice or in TBI‐injured WT littermates. TBI accelerates amyloid plaques in 5xFAD mice. 5xFAD mice show greater elevation of acetylated tau after TBI, compared to WT mice. Hippocampal snRNA sequencing showed that TBI or 5xFAD mutations alone primarily perturb neurons. By contrast, TBI in 5xFAD mice drastically alters transcription in multiple cell types. Diflunisal treatment reduces acetylated‐tau and rescues behavior deficits after TBI in 5xFAD mice. Amyloid precursor protein and tau expressing cells are more susceptible to in vitro TBI, compared to wild type cells.

Conclusion

TBI accelerates onset of AD‐like pathologies in 5xFAD mice. Preliminary evidence shows that pharmacologically reducing acetylated tau rescues TBI‐induced cognitive deficits in 5xFAD mice.
CNS‐active drugs for neuropsychiatric disorders differentially modulate the risk of AD development
Authors: Cortes‐Flores Helena , Torrandell‐Haro Georgina , Brinton Roberta Diaz
Published: January 2025

Background

Neuropsychiatric disorders including depression, insomnia, epilepsy, schizophrenia, and attention‐deficit and hyperactivity disorder (ADHD) have been associated with a neurodegenerative process and linked to increased risk for Alzheimer’s Disease (AD). Because of the shared biological mechanisms of AD and neuropsychiatric disorders, we hypothesized that pharmacologic treatment for neuropsychiatric disorders could impact the risk for AD. CNS drugs that are first‐line therapies for neuropsychiatric disorders (including antidepressants, sedatives, anticonvulsants, antipsychotics, and stimulants) were investigated for impact on AD incidence.

Method

To address this hypothesis, we conducted a retrospective medical informatics analysis of insurance claims of patients aged 60 years and older, with and without exposure to CNS drugs. To reduce health status and demographic bias, we utilized propensity score matching to adjust for age, gender, Charlson comorbidity index (CCI), and comorbidities. The propensity score matched population was surveyed for AD diagnosis following at least 1 year of exposure to CNS drugs.

Result

Exposure to CNS drugs was associated with a decreased risk for AD (RR [95%CI]: 0.50 [0.47–0.53]; P<.0001), and women (RR [95%CI]: 0.46 [0.42–0.50]; P<.0001) exhibited a slightly greater risk reduction compared to men (RR [95%CI]: 0.55 [0.50–0.61]; P<.0001). Drug stratification indicated that antidepressant, sedative, anticonvulsant, and stimulant treatment were associated with reduced AD risk, while antipsychotics were associated with increased risk for AD. Additional analysis indicated that the combination of two CNS drugs was associated with a greater reduction of AD risk compared to monotherapy for most drugs assessed. Age and sex emerged as modulators of rate of disease conversion, with females older than 70 years receiving the greatest benefit.

Conclusion

Collectively, these results indicate that antidepressants, sedatives, anticonvulsants, and stimulants are beneficial as risk modifiers for AD, while antipsychotics appear to increase the vulnerability of the brain to AD development. The potential use of combination therapy with antipsychotics could mitigate the risk conferred by these drugs. These findings have the potential to contribute to advancing neuropsychiatric treatment that could impact the risk of Alzheimer’s disease.
Enhancing Alzheimer Disease risk prediction using machine learning for Pathway Polygenic Risk Scores (p‐PRS)
Authors: Rajabli Farid , Aguiar‐Pulido Vanessa , Scott Kyle , Feliciano‐Astacio Briseida E. , Hamilton‐Nelson Kara L. , Adams Larry D. , Mena Pedro R. , Celis Katrina , Sanchez Jose Javier , Whitehead Patrice L. , Prough Michael B. , Acosta Heriberto , McInerney Katalina F , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W , Pericak‐Vance Margaret A
Published: January 2025

Background

Polygenic Risk Scores (PRS) are important in predicting disease risk and are usually rely on markers selected by thresholding p‐values from genome‐wide association studies (GWAS). In traditional approaches, one single model is built to calculate risk scores, employing effect size to determine additive risk. However, this traditional method overlooks potential interactions between genetic loci resulting in reduced prediction power. To overcome these limitations, we propose an interpretable machine learning approach based on pathway‐level PRS (p‐PRS). Our approach improves prediction accuracy of PRS and generates both pathway specific and overall PRS considering possible nonlinear interactions. This advancement opens new avenues in personalized medicine, enabling more accurate disease prediction and prevention strategies.

Method

We used whole genome sequencing data from 652 individuals from the Puerto Rican Alzheimer’s Disease Initiative (PRADI). First, we selected Alzheimer disease (AD)‐related pathways and genes based on those reported in the largest non‐Hispanic White AD GWAS to date (Bellinguez et al. 2021). Then, we applied the Clumping and Thresholding (C+T) PRS approach using Bellinguez et al. summary statistics within each pathway (±20Kb for each gene). Finally, we used random forest with pathway‐level PRS values as input to classify AD vs. control. We assessed the performance of the p‐PRS model based on area under the receiver operating characteristic curve (AUC) using a 70%/30% split for training/testing. The outcomes were compared to a traditional C+T PRS model (AD∼PRS+APOE).

Result

p‐PRS improves the performance of the traditional PRS model by 4.2% (p = 5.54E‐32). Performance is centered around AUC = 0.689(SE = 0.0022) for p‐PRS and 0.647(SE = 0.0024) for traditional PRS. PRS by pathway enables determining individual‐level important pathways for accurate classification. Top pathways obtained are related to processes implicated in cognitive deficit, neuroinflammation, neurodegeneration and vesicle mediation.

Conclusion

Utilizing the innovative p‐PRS approach has improved the estimation of AD risk in the PR cohort. The application of interpretable machine learning approaches allows identifying the most relevant pathways for effective risk prediction and classification. Importantly, improved precision will provide more effective actionable risk mitigation strategies, optimize the selection process for clinical trials, and contribute to the development of more personalized treatment interventions.
Sex differences in the response to high pulse pressure in APOE4 mice
Authors: Ferguson Skylyn J , Isakharov Lazar N , Walker Ashley E
Published: January 2025

Background

Elevated arterial pulse pressure (PP) is associated with cognitive decline and Alzheimer’s disease (AD). High PP damages the brain vasculature by causing endothelial cell dysfunction. Stiffer cerebral arteries have an impaired ability to dampen PP, which transmits the pulsatility further into the microvasculature, where it can damage brain tissue. At the same time, the APOE4 genotype is associated with cerebrovascular dysfunction; however, it is unknown if elevated PP amplifies this risk. Furthermore, female APOE4 carriers are at a higher risk for developing AD than males. Thus, we hypothesized that female APOE4 mice would be more vulnerable to high PP and have greater cerebral artery stiffness and cognitive impairments compared with male mice.

Method

In male and female mice homozygous for APOE4 and humanized Aβ1‐42 (APOE4/hAβ, n = 26, 6 months), we assessed ex vivo endothelium‐dependent vasodilation by the dose‐responses to acetylcholine in isolated posterior cerebral arteries (PCAs) following exposure to static pressure (50 mmHg), low PP (50‐75 mmHg), or high PP (37.5‐87.5 mmHg). PCA endothelium‐independent vasodilation was measured by the response to sodium nitroprusside, and stiffness was measured during the high PP condition. We assessed cognition by the Morris Water Maze.

Result

Under static pressure, PCA endothelium‐dependent vasodilation was similar between male and female mice (p = 0.13). In females, PCA endothelium‐dependent vasodilation was similar between static and low PP (p = 0.37), while exposure to high PP resulted in a 38% decline in endothelium‐dependent vasodilation (p = 0.004 vs. static). In contrast, PCA endothelium‐dependent vasodilation in male mice was similar between static and PP conditions (p>0.05). Endothelium‐independent vasodilation did not differ between sexes (p>0.05). Female mice also exhibited a higher PCA β‐stiffness index than male mice (p = 0.03). Additionally, during the Morris Water Maze probe trial, females crossed the platform area significantly fewer times than males (p = 0.048).

Conclusion

Our data indicate that high PP is detrimental to cerebral artery endothelial function in female, but not male, APOE4/hAβ mice. Additionally, female APOE4/hAβ mice have stiffer cerebral arteries and poorer spatial memory than male APOE4/hAβ mice. Our findings suggest that sex may influence the interactive effect of APOE4 and PP on cerebrovascular and AD‐related outcomes.
Comparing the diagnostic performance of the INECO Frontal Screening in illiterate vs. literate older adults with cognitive impairment in Lima, Peru
Authors: Custodio Nilton , Malaga Marco , Montesinos Rosa , Ruiz‐Yaringaño Arturo Jhonny , Baca Fiorella , Chambergo‐Michilot Diego , Verástegui Graciet , Agüero‐Flores Katherine , Cruzdel Castillo Rossana , Cuenca José , Huilca José Carlos , Lanata Serggio , Bustamante‐Paytan Diego
Published: January 2025

Background

Rising dementia prevalence in Low and Middle‐Income Countries (LMICs), fueled by socio‐economic disparities, necessitates accessible brief cognitive tests. The INECO Frontal Screening (IFS) proves effective for detection of Mild Cognitive Impairment (MCI) and early dementia. It prioritizes executive functions, is suitable for low‐educated or illiterate individuals, and robust diagnostic capacity.

Method

We conducted a secondary analysis of a prior patient cohort. Illiterate participants met the following criteria: proficiency in Spanish for over 10 years, age ≥ 60, less than 1 year of formal education, and inability to read and write. Literate patients were aged 60 or older, Spanish speakers, and had a minimum of 6 years of formal education. A clinical evaluation with three consecutive phases was used as gold standard diagnosis, resulting in a final classification based on international criteria. The IFS was applied to all participants. To compare the diagnostic performance of the IFS, a Receiver‐Operator Curve (ROC) analysis was conducted. The average scores for each IFS domain were compared among all groups in each cohort using a Wilcoxon test.

Result

We included 114 controls, 101 MCI patients, and 105 all type dementia patients. Median age was 68 (67‐71), 69 (66‐71) and 72 (71‐75), respectively, and female participants accounted for 45.6%, 47.5% and 45.7% for each group, respectively. An excellent diagnostic performance was found when we evaluated the IFS Total score for discrimination between controls, MCI, and dementia patients across both groups (Fig. 1). The analysis based on the Youden index showed that, the optimal cut‐off points for MCI (22 vs 23.7), and dementia patients (17.6 vs 18.3), was lower in illiteracy participants (Table 1). Finally, when evaluating each IFS domain among control patients in both groups, statistically significant differences were found in Digits backward and the Hayling test (p‐value <0.001) (Table 2).

Conclusion

The IFS seems to be useful in assessing both illiterate and literate older adult patients for the presence of MCI and dementia in LMIC settings.
Multi‐tissue multi‐omic trans QTL mapping identified novel causal and druggable targets and gene‐gene interactions
Authors: Cruchaga Carlos
Published: January 2025

Background

The integration of quantitative trait loci (QTLs) with disease genome‐wide association studies (GWAS) has proven successful at prioritizing candidate genes at disease‐associated loci. Most of QTL studies are focusing on expression QTLs in plasma and brain and cis‐signals.

Method

Here we analyzed a large proteomic (Somalogic 7K) and metabolomic (Metabolon HD4) CSF (n = 3, 000) and plasma (African (AFR, N = 400) and European (EUR, N = 2,300) ancestry, respectively) to identify novel QTLs. We integrated with FUSION, colocalization and Mendelian Randomization approaches to identify novel causal and druggable targets.

Result

In CSF we identified 2,316 significant pQTLs (1,247 in cis and 1,069 in trans) for 1,960 proteins, of which 1,228 were not observed in plasma. For metabolomics we identified 219 independent associations (59.8% novel) for 144 CSF metabolites. In plasma, we identified 2,400 pQTL in EUR and 881 pQTL in AFR. In EUR and AFR metabolomics, we reported 403 and 60 metabolites with at least one significant QTL, respectively. Approximately 40% of these findings were novel associations compared to previous studies Through PWAS, we identified 473 CSF proteins associated with AD risk. MR prioritized 40 proteins as causal and colocalization identified 158 proteins that share genetic etiology. 42 of these overlap between at least two of these methods and are enriched in immune and lysosomal pathways. Multiple (including PILRA, PRSS8, and SIRPA) represent novel candidate proteins. We also identified novel regulators for TREM2 including TGBR2 and NECTIN2, which represent novel therapeutic targets for AD.

Conclusion

We have developed the largest CSF proteomics and metabolomics data. Through a rigorous approach combining three methods, we have identified high‐confidence proteins involved in AD that confirm previously reported candidate genes and prioritize new ones at GWAS loci. Our findings offer insights into Alzheimer’s disease biology that were missing when using plasma analyses, supporting the development of tissue‐specific proteomics databases in neurologically‐relevant tissues.
ABCA1 rare variants interact with APOE isoforms to confer Alzheimer’s Disease risk
Authors: Peña‐Tauber Andrés , Arriaza Ricardo Hernandez , Guen Yann Le , Khosla Chaitan , Greicius Michael D
Published: January 2025

Background

Several lines of evidence now suggest that ABCA1 plays a role in Alzheimer’s disease (AD). Rare variants on ABCA1 increased AD risk in a large genetic study, and mouse models suggest that increasing ABCA1 activity can reverse signs of AD pathology. While there is growing consensus that ABCA1 and ApoE directly interact, it is unclear how APOE genotype affects this interaction in the context of neurodegeneration.

Method

We conducted burden tests of rare variants (MAF < 1%) on ABCA1 either causing loss of function or having a REVEL score above 0.75 in European‐ancestry participants from ADSP whole‐genome (WGS), whole‐exome (WES) sequencing, and UK Biobank WES datasets. All analyses were adjusted for sex, PCs 1‐4, and sequencing platform. Stratifying by APOE genotype, we tested the association between ABCA1 variant carrier status and AD using logistic regression, then meta‐analyzed the results with fixed‐effect inverse‐weighted variance. To test directly for an APOE interaction with ABCA1, we analyzed all APOE genotypes together adding interaction terms ε2*ABCA1 and ε4*ABCA1, and additionally adjusted for APOE ε2/ε4 dosages.

Result

Carrying an ABCA1 variant was associated with increased AD risk in APOE ε2/ε3 and ε3/ε3 cohorts. In contrast, the association was not significant in ε3/ε4 or ε4/ε4 (Fig. 1). Models including cross‐terms in the whole‐APOE cohort supported an interaction between ABCA1 variants and APOE ε4 dosage diminishing risk compared to having an ABCA1 variant by itself (Table 1). Analysis of missense variants by themselves showed a significant protective effect for extracellular domain mutations in ε3/ε4, whereas they increased risk in ε3/ε3 and showed no effect in ε2/ε3 (Fig. 2). Conversely, ε2/ε3 saw a risk‐increasing association only with nucleotide‐binding domain mutations.

Conclusion

ABCA1 rare variants are associated with AD risk and the effect size appears to be modulated by APOE genotype, showing significant interaction with ε4 dosage. This suggests an interplay between ABCA1 and different ApoE isoforms in contributing to AD, highlighting a potential pathogenic mechanism. Further, as extracellular domain mutations show diverging impacts on AD risk depending on APOE genotype, this domain may play a critical role in the pathogenic interaction between ABCA1 and ApoE.
Unveiling the Role of A2AR Dysregulation in Olfactory Dysfunction and Amyloidogenesis in Alzheimer’s Disease
Authors: AILIYA AILIYA , BAO Ligao , XIJIRI XIJIRI , KAKUTA Shigeru , Eerdunfu Eerdunfu
Published: January 2025

Background

Alzheimer’s Disease (AD) manifests early in the olfactory system, yet its precise role in the pathophysiology of AD remains elusive. This study aims to elucidate the progression of olfactory dysfunction in AD by investigating the dysregulation of the adenosine 2A receptor (A2AR) and its potential involvement in the formation of abnormal plaques and tangles. A2AR plays a pivotal role in modulating synaptic transmission and neuroinflammation by regulating both neurons and glial cells. Its regulatory impact on olfactory function prompted the hypothesis that A2AR tightly binds to the Amyloid Precursor Protein (APP), influencing the formation of Amyloid β‐Protein (Aβ).

Method

To explore the impact of A2AR dysregulation in the olfactory system of AD, we examined A2AR expression patterns in the olfactory bulb, striatum, and hippocampus of single amyloid precursor protein knock‐in (APPNL‐G‐F) mice. Additionally, in vitro experiments like RNAi knockdown using SH‐SY5Y cell line were conducted to mimic the regulatory effects of A2AR on APP and Aβ, providing insights into the pathological mechanisms.

Result

Our findings revealed an age‐dependent increase in A2AR expression in the olfactory bulb, hippocampus, and striatum in APPNL‐G‐F mice. Notably, A2AR expression precedes APP expression in the olfactory bulb, suggesting A2AR has a regulatory role in amyloidogenesis. Furthermore, co‐expression analysis revealed a significant association between A2AR and APP, underscoring their potential interaction in AD pathology. The APP expression pattern will be led by A2AR expression from glomerular layer to the granule cell layer of the APPNL‐G‐F mice olfactory bulb. Additionally, modulating A2AR expression alters cellular responses to caffeine and adenosine on SH‐SY5Y cell line and regulating APP expression, implicating its involvement in synaptic transmission and amyloid pathology.

Conclusion

This study underscores the pivotal role of A2AR dysregulation in olfactory dysfunction associated with AD. The observed tight binding of A2AR with APP implies its direct involvement in Aβ formation. These findings highlight the significance of A2AR dysregulation in olfactory dysfunction and amyloidogenesis, suggesting novel therapeutic targets and early diagnosis for AD intervention.
Fukushimura Brain Bank ‐Nursing home based brainbank project in Japan‐
Authors: Kaneda Daita , Ogawa Norihiro , Kanesaka Takeshi , Hishida Chie , Sakurai Keita , Akatsu Hiroyasu , Yamamoto Sakon , Yamamoto Takayuki , Yoshio Hashizume
Published: January 2025

Background

The Fukushimura (welfare village), located in Toyohashi city, Japan, is a unique complex of various nursing home facilities including dementia homes, Day‐care houses, homes for disabled and mentally retarded, and the Fukushimura Hospital. This village is totally managed by private sector, the Sawarabi Medical Cooperative. About 800 elderly people reside in this area. The hospital plays a pivotal role within the village and acts as the central facility for each nursing homes.

Fukushimura BrainBank (FBB) was established in 1990. The neuropathological investigation of FBB was initially conducted by Kenji Kosaka, who initially reported cortical Lewy bodies. Our research institute was approved in 2004 by the Ministry of Education, Culture, Sports, Science and Technology, as one of the non‐governmental institutes which is permitted to apply for governmental grants.

Method

Detailed serial imaging tests including MPRAGE T1 volume datas and diffusion tensor imaging (DTI) using 1.5T MRI (Siemens) are perfomed in the clinical setting. Clinical datas including behavioral and psychological symptoms are collected from medical records and each nursing homes at the autopsy. Donation of retina is an optional offer at the autopsy.

For collecting CNS specimens, the brains are separated into two hemispheres, one for neuropathological analyses with using several antibodies for beta‐amyloid, phosphorylated tau, alpha‐ synuclein, and TDP‐43. Modified gallyas‐silver staining is applied for evaluating argyrophilic grain disease. The other hemispheres are stored for frozen sections.

Result

At the end of 2023, 841 of frozen brains with detailed medical record are stored in FBB and readily available for research. 56 brains with DTI scans are collected. The number of consents for retinal donation became 146, which is expected as one of the largest Asian retinal tissue bank of post‐mortem. We already have over 20 collaborators and supply our samples for more than 30 research institutes in Japan.

Conclusion

The challenge of FBB will play a unique and important role to clarify cliniconeuropathological correlation of the nursing home residential with various geriatric conditions.
Unravelling neurodegenerative effects of SARS‐CoV‐2 infection in Alzheimer’s disease‐ brain organoids
Authors: Gonzalez Laura Garcia , Sarrias Andrea Martí , Puertas Maria Carmen , Turpin Isabel , Gil Ángel Bayón , Infante Patricia Resa , Picado Javier Martinez , Navarro Arcadi , Acosta Sandra
Published: January 2025

Background

The increased vulnerability of Alzheimer’s disease patients to severe SARS‐CoV‐2 infection raises crucial concerns, especially with the potential transition of the COVID‐19 pandemic to an endemic state. Given the rising prevalence of Alzheimer’s in an aging world‐wide population, elucidating whether SARS‐CoV‐2 infection may induce or accelerate neurodegeneration becomes imperative.

Method

To investigate the neurodegenerative effects of SARS‐CoV‐2 infection, we generated brain organoids using human induced pluripotent stem lines from one non‐demented control, one with sporadic Alzheimer’s, and one with familial Alzheimer’s. After 6 months of differentiation, aged organoids were infected with SARS‐CoV‐2 in duplicates (n = 4 organoids/each). Post‐infected organoids were analyzed systematically 6 weeks post‐infection in order to simulate long‐lasting viral effects. We collected cell media, and fixed the brain organoids to monitor cellular infection, the status of neurons, the reactivity of astrocytic glia, and the presence of neurodegeneration markers.

Result

Sustained low‐level virus replication was detected in the organoids medium for 6 weeks. We observed a higher proportion of infected cells in Alzheimer’s‐derived organoids compared to the control organoids (Fig. 1A and Fig. 1B). In addition, neuronal infection rates surpassed astrocytes across all genotypes (Fig. 1C). RNA expression analysis of SARS‐CoV‐2 receptors expression showed no significant differences between different genotypes, suggesting that the differences in infection rates is not solely attributable to receptor expression. We found no significant differences in the total number of neurons or astrocytes, nor the proportion of caspase‐3 positive cells. However, an increase in β‐amyloid peptide counts and particle area along with an elevated Aβ42/ Aβ40 ratio was observed after infection (Fig. 2). Regarding Tau phosphorylation levels, there were no clear differences between genotypes or conditions.

Conclusion

Our research reveals a heightened susceptibility of Alzheimer’s disease‐derived brain organoids to SARS‐CoV‐2 infection together with a notable accumulation of Aβ peptides. These findings suggest a potential link between viral exposure and exacerbation of neurodegenerative markers in Alzheimer’s disease, underscoring the urgent need for further exploration of this relationship amid the evolving landscape of the COVID‐19 pandemic.
Synaptic density in the hippocampal and parahippocampal subregions and its association with the severity of axonal damage and cognitive decline in Alzheimer’s disease
Authors: Bouwman Maud M.A. , Frigerio Irene , Reijner Niels , van de Berg Wilma D.J. , Jonkman Laura E.
Published: January 2025

Background

The hippocampus is highly vulnerable to amyloid‐b (Aβ) and phosphorylated tau (p‐tau), and shows synaptic loss in Alzheimer’s disease (AD). Moreover, the loss of synapses correlates strongly with cognitive decline and leads to neuronal network dysfunction. Here, we aim to map the selective synaptic loss in hippocampal and parahippocampal subregions in AD and its association to the severity of neuropathology, axonal damage and cognitive decline.

Method

We included (para)hippocampal tissue of 26 AD and 17 age‐matched control donors. Synaptophysin puncta was measured using multiple measurements per subregion, distinguishing superficial and deep cortical layers in the parahippocampus. Aβ and p‐tau load, and NfL immunoreactivity were quantified in manually segmented hippocampal and parahippocampal subregions. Clinical Dementia Rating (CDR) scores were retrieved from the clinical reports. Group differences were analysed using linear mixed models and correlations between synaptic and pathological measures and cognitive scores were studied using linear regression, correcting for age, sex and post‐mortem delay.

Result

The AD (para)hippocampus tended to have a lower synaptic density compared to controls (‐5.6%, p = 0.270). Within hippocampal and parahippocampal subregions, we observed synaptic loss in the entorhinal cortex in AD vs controls (‐8.9%, p = 0.028) and a trend for the subiculum (‐8.8%, p = 0.069) (Fig. 1). Synaptic degeneration was most pronounced in the deeper layers of the enthorinal cortex (layer V‐VI) (Fig. 2). Synaptic loss was not correlated with Aβ and p‐tau load, however higher NfL immunoreactivity associated with synapse loss in the fusiform gyrus (r = ‐0.467, p = 0.008). Synaptic degeneration in the CA1 (r = ‐0.769, p = 0.023), entorhinal cortex (r = ‐0.700, p = 0.035) and fusiform gyrus (r = ‐0.762, p = 0.014) was strongly correlated with higher CDR scores (Fig. 3).

Conclusion

The entorhinal cortex is vulnerable to synapse degeneration in AD. Moreover, our results confirm the strong relation between (para)hippocampal synaptic loss, axonal damage and cognitive decline in AD, while neuropathological load (Aβ and p‐tau) could not explain differences in vulnerability across donors. These results suggest that the synaptic integrity in these regions seem to be important for cognitive function. A better understanding of the selective vulnerability of hippocampal subregions would provide insight into their intricate connections and functions, underpunning their involvement in cognitive decline.
Genetic proxies for predicting plasma protein levels reveal TIMP2 role in human cognitive performance
Authors: Anastasi Federica , Genius Patricia , Rodríguez‐Fernández Blanca , Escalante Armand González , Hernández‐Villamizar Luis Felipe , Lorenzini Luigi , del Campo Marta , Sánchez‐Benavides Gonzalo , Yang Chengran , Timsina Jigyasha , Minguillón Carolina , Esteller Manel , Navarro Arcadi , Cruchaga Carlos , Suarez‐Calvet Marc , Vilor‐Tejedor Natalia
Published: January 2025

Background

Murine studies have identified blood proteins that influence brain aging, but translating these findings to humans remains challenging. We used an innovative approach to investigate whether genetically predicted blood levels of proteins linked to brain aging in animal models are associated with cognitive performance in individuals at risk of Alzheimer’s disease (AD) [Figure 1].

Method

Through systematic review, we identified 13 circulating proteins with an aging/rejuvenating effect on the mouse brain. We retrieved summary statistics of protein quantitative trait loci (pQTLs) associated with these proteins in human plasma from the Fenland study (Pietzner et al., 2021). We validated their predictive capacity by computing protein‐based genetic scores (protPRS) in 1,380 cognitively unimpaired (CU) individuals from the Knight‐ADRC cohort and analyzing their association with plasma protein levels (measured by Somalogic). We also computed the protPRS for 410 CU individuals at risk for AD from the ALFA+ study (60% women, 55% APOE‐ε4 carriers; Table 1) and assessed their associations with cognitive performance through linear models adjusted by age, sex, and years of education. Stratified models by sex, APOE‐ε4 carriership, and Aβ status were also assessed. pQTLs included in the significant scores were annotated to explore their biological significance.

Result

Most computed protPRS (10/13) significantly predicted plasma protein levels in the Knight‐ADRC cohort. In ALFA+, we found a significant association between genetic predisposition to elevated plasma TIMP2 (TIMP2‐protPRS) and better cognitive performance (PACC and episodic memory composites). Associations of TIMP2‐protPRS with PACC remained significant in stratified models [Figure 2]. TIMP2‐protPRS was associated with the actual plasma TIMP2 levels in ALFA+. The annotated pQTLs included in the TIMP2‐protPRS were associated with traits related with cognition and neuropsychiatric disorders. We also found an age‐dependent expression of genes regulating blood TIMP2 levels in the human brain.

Conclusion

Protein‐based PRS computation may overcome translational challenges encountered in animal studies. Through this method, we showed that genetically predicted levels of plasma TIMP2, known for its rejuvenating effect on mice’s brain, are linked to cognitive performance in CU at risk of AD. This highlights TIMP2 as a potential therapeutic target for age‐related brain diseases.
Evaluating the link between hearing loss and Alzheimer’s disease neuropathology: A systematic review and meta‐analysis
Authors: Chandra Avinash , Levett Benjamin Aaron , Waters Sheena , Hardy Chris JD , Warren Jason D , Marshall Charles R
Published: January 2025

Background

Various explanations have been proposed for how hearing impairment might be associated with increased risk of dementia. Several theories have proposed direct links with Alzheimer’s disease (AD) neuropathology, either due to shared aetiology (i.e. AD proteinopathies cause impaired hearing), or due to an interaction (i.e. functional brain changes due to impaired hearing drive pathogenic protein accumulation). We performed a systematic literature review and meta‐analysis to evaluate evidence associating AD neuropathology (amyloid‐β and tau) with hearing loss.

Method

Searches were conducted using electronic biomedical databases for articles published in the past 20 years. Studies evaluating hearing loss as an exposure and AD neuropathology using molecular biomarkers or histopathology as an outcome were included. Initial search identified 7,313 studies, which were screened, independently reviewed, and assessed for quality before being synthesised and meta‐analysed.

Results

Studies were highly heterogeneous, with mixed and inconsistent results. There was overall no strong evidence linking hearing loss with amyloid‐ β pathology, with some studies reporting weak effect sizes and others null results. Associations between hearing and tau pathology were more robust. Associations between hearing and neuropathology were stronger when hearing impairment was measured using more “central” tests of hearing than standard “peripheral” measures such as pure tone audiometry, suggesting that changes in the auditory brain may be a consequence of AD neuropathology.

Conclusion

There is no strong evidence to suggest that changes in peripheral hearing are associated with AD neuropathology. Tests of central auditory function may signal AD neuropathological changes in auditory cortical areas. These results suggest the need for caution in developing hearing‐targeted interventions, such as hearing aid use, for prevention of neuropathological change due to Alzheimer’s disease.
Differential Impact of Social Frailty, Physical Frailty and Intrinsic Capacity Profiles on 2‐year Cognition in Healthy Older Persons: A Cluster Analysis
Authors: Lim Wee‐Shiong , Tan Cai‐Ning , Yeo Audrey , Pek Kalene , Chia Jia Qian , Lim Jun Pei , Chew Justin
Published: January 2025

Background

Intrinsic capacity (IC) and frailty are inter‐related yet distinct constructs which encapsulate functional capacities of older adults. There is uncertainty how IC is related to and interacts with the social (SF) and physical (PF) dimensions of frailty to influence cognition. We aim to examine IC, PF and SF profiles and compare the association between identified subtypes with change in cognition at 2 years

Methods

We studied 230 healthy community‐dwelling older adults (age:67.2±7.4 years) from the GeriLABS‐2 cohort study. We assessed: 1) IC, using modified Integrated Care for Older Adults (ICOPE); 2) PF, using Fried Frailty Phenotype; 3) SF, via 8‐item Social Frailty Scale. To identify subtypes, we performed two‐step cluster analysis with age, PF, SF, IC and CFAB. Cluster associations with change in cognition [Chinese Mini Mental State Examination (CMMSE, range:0‐28) and Chinese Frontal Assessment Battery (CFAB, range:0‐18)] at 2 years were examined using hierarchical linear regression sequentially adjusted for age, gender and education (step 1); PF, SF or IC (step 2); and PF, SF and IC (step 3).

Results

Three distinct clusters were identified – C1: PF/High IC (N = 54, 24%); C2: SF/Low IC (N = 69, 30%); and C3: Robust (Physical/Social) /High IC (N = 106, 46%). There were more men in C1, whilst C2 was older with fewer years of education and scored lowest in CMMSE [C1 to C3, mean (SD): 26.20(1.58) vs 25.32(1.86) vs 26.60(1.53), p<0.001] and CFAB [17.20(0.86) vs 14.59(2.28) vs 17.26(1.04), p<0.001]. At 2 years, C1 experienced greatest improvement in CMMSE [0.69(1.60) vs 0.11(1.81) vs 0.03(1.70), p = 0.088) vis‐à‐vis C2 for CFAB [0.06(1.22) vs 1.21(2.07) vs ‐0.19(1.64), p<0.001). The association of CMMSE improvement in C1 became non‐significant when adjusted for PF (β = 0.63, P = 0.261), SF (β = 0.60, P = 0.058), or IC (β = 0.57, P = 0.072), but remained significant for CFAB improvement in C2 even in step 3 (β = 1.423, P = 0.004).

Conclusion

Amongst healthy community‐dwelling older adults, SF and IC are complementary to physical frailty measures for better profiling of at‐risk individuals with lower executive function beyond general cognition. Further research is required to explicate the differential longitudinal improvement between clusters in general cognition and executive function and the factors underpinning the improvement.