bluuebunny/crossref_metadata_2025 huggingface dataset:
Driving Behavior as a Functional Biomarker of Preclinical Alzheimer Disease
Authors: Wisch Julie K. , Morris John C. , Benzinger Tammie L.S. , Ances Beau , Babulal Ganesh M.
Published: January 2025

Background

Trip chaining occurs when a driver departs from an origin and travels to multiple locations before returning. Increased trip complexity may require higher levels of executive function, memory, and navigational abilities. Subtle behavioral changes are apparent before a clinical diagnosis of Alzheimer Disease (AD); however, the correspondence between preclinical AD pathology (amyloid deposition, tauopathy, neurodegeneration), cognition, and changes in trip chaining behavior is unknown.

Method

46 individuals enrolled in the DRIVES study (µEnrollment = 2.7 years, ơEnrollment = 1.1 years) at Washington University in St. Louis completed longitudinal amyloid PET imaging and converted from amyloid negative (A‐) to amyloid positive (A+). All data were ordered temporally relative to date of conversion. We fit changepoint models to the average number of segments per departure and average number of trips away from home per month over time. After identifying key windows‐of‐change in trip‐related behavior, we extended our analysis of neuroimaging and cognitive data to all Knight Alzheimer Disease Research Center participants. We used a published analytical model to estimate time from A+ for all participants with amyloid PET (N = 1082). Then, we evaluated the spatial deposition of tau for individuals imaged within the time window‐of‐interest identified via changepoint model (N = 34). We applied linear mixed effects models to compare measures of brain structure and cognition between A‐ controls (N = 752, 195 respectively) and individuals within the window‐of‐interest (N = 105, 66).

Result

The total number of departures declined 6.3 (95% CI: 4.2, 6.7) years after becoming A+, and the number of segments per trip declined 8.2 (95% CI: 7.0, 9.3) years after becoming A+ (Figure 1). Within this key window (4.2 – 9.3 years post‐A+), tau was elevated in the earliest anticipated regions (Braak I/II), and 24/34 individuals were tau positive (Figure 2). Neurodegeneration was observable in the cortex, hippocampus, and regions associated with allocentric navigation but not egocentric navigation. Cognitive changes are not seen globally but were seen in attention and episodic memory (Figure 3).

Conclusion

Changes in amyloid burden, tauopathy, and neurodegeneration have real‐world effects on daily driving behavior even before global cognitive impairment is observed.
Does COVID‐19 Infection Accelerate Age‐Related Cognitive Decline?
Authors: Woods David L. , Hall Kathleen , Pebler Peter , Williams Garrett , Herron Timothy J , Blank Michael , Geraci Kristin , Johnson David K , Schendel Krista , Lwi Sandy J. , Chok Jas M. , Kahly Omar , Spinelli Maria G , Jaramillo Isabella , Baldo Juliana
Published: January 2025

Background

Similar neuroimaging abnormalities are reported in post‐COVID patients and patients with AD. Moreover, COVID‐19 and Alzheimer’s Disease (AD) share genetic vulnerabilities and have similar cognitive symptoms of COVID (e.g., memory impairment, mental fatigue, anosmia, etc.). These findings raise the concern that COVID infection may increase the risk that older patients will develop Alzheimer’s disease.

Method

Self‐reported COVID histories were recorded from 415 older participants (mean age 70.1 years), including 310 participants longitudinally tested beginning in 2022. The effects of COVID on cognitive performance were assessed with 32 computerized subtests of the California Cognitive Assessment Battery (CCAB). Omnibus z‐scores were averaged over 70 test measures at enrollment, and again at 6‐month and 18‐month post‐enrollment in the 310‐participant sample.

Result

Significant demographic differences were seen between COVID+ and COVID‐ groups (Table 1). COVID+ patients performed worse than COVID‐ patients overall (Figure 1, t(85) = ‐2.80, p<0.01) and when analyzed with a conventional model using Age, Education, and Gender (AEG) as regressors (t(85) = ‐3.07, p<0.005, Figure 2). However, inter‐group differences failed to reach significance (t(85) = ‐0.97, NS) when analyzed with a comprehensive 15‐factor model that factored out additional demographic influences including vocabulary, comorbidities, depression, anxiety, functional status, and race. In contrast, COVID infection severity (estimated from augmented WHO scores) correlated significantly with omnibus z‐scores when analyzed with the comprehensive model (r = ‐0.30, t(64) = ‐2.52, p<0.02) but correlations failed to reach significance when analyzed with the conventional (AEG) model.

The effect of incidental “breakthrough” COVID infections in participants (97.35% were vaccinated prior to retest) was analyzed at 6‐months (38 cases) and 18‐months (50 cases). Breakthrough infections prior to 6‐month retest were paradoxically associated with improved 6‐month Omnibus scores (t(49) = 2.74, p < 0.01), while no significant differences were observed for breakthrough infections prior to the 18‐month retest (t(90) = 0.95, NS).

Conclusion

These preliminary results suggest that infections with Wild Type and Delta variants early in the COVID pandemic produced cognitive deficits among older participants, particularly among patients hospitalized with COVID. In contrast, post‐inoculation breakthrough infections caused no significant decline in cognitive performance.
Can MBI‐C scores predict time‐to‐cognitive worsening in CU, SCD, and MCI participants? Evidence from the CompAS study
Authors: Mallo Sabela Carme , Juncos‐Rabadán Onésimo , Lojo‐Seoane Cristina , Pérez‐Blanco Lucía , Felpete Alba , Moreno‐Carretero M. José , Rojo‐Pantoja Águeda , Nieto‐Vieites Ana , Rozas Arturo X. Pereiro
Published: January 2025

Background

The role of neuropsychiatric symptoms (NPS) as early markers of cognitive impairment progression along the cognitive impairment continuum needs further research. Our objective was to estimate to which extent NPS, measured with the Mild Behavioral Impairment Checklist (MBI‐C), predict time‐to‐cognitive‐worsening during follow‐up in a sample of older adults recruited from primary care centers while controlling for other related variables (i.e., age, gender, years of education, comorbidity, and cognitive complaints).

Method

A multivariate Cox proportional hazard regression model was performed using the ‘Enter method’. Two hundred twenty‐six participants from the Compostela Aging Study (CompAS) were included in the analyses (none censored). Participants were diagnosed at baseline as Cognitively Unimpaired (CU = 144), Subjective Cognitive Decline (SCD = 37), and Mild Cognitive Impairment (MCI = 45) (Table 1). The event was defined as stability or worsening in cognitive status over a follow‐up of 17‐75 months, during which three evaluations were performed. Stability was considered when the diagnosis remained stable and worsening when progression to MCI or dementia occurred. The groups at baseline (CU, SCD, MCI) were entered into the model as strata. MBI‐C total score at baseline was introduced as a covariate and adjusted by age, gender, years of education, comorbidity, and SCCs from participants and informants.

Results

The tested model was statistically significant [overall significance: ‐2 Log Likelihood = 1620.73, χ2
= 17.63, df = 7, p < .014]. MBI‐C total score was the only significant variable [β = .038, SE = .014, Wald = 7.77, p < .005]. Its corresponding hazard ratio was 1.039 (95% CI 1.011‐1.068), indicating that for one unit increase in the MBI‐C total score, the risk of worsening increases by 1.039 for a month (Table 2).

Figure 1 shows the survival function using covariates for each group. The greatest differences were observed in the time interval 20‐60 months, and especially between the MCI and CU. SCD curve remained stable during that period and was more similar to the MCI curve.

Conclusion

Our results indicated that MBI‐C can significantly predict time to worsening along the cognitive impairment continuum. Further, differences between MCI and CU participants' trajectories were especially pronounced around 40‐60 months, with SCD falling between the two groups.
Apolipoprotein E4 contributes to Alzheimer’s disease neuropathology in Down syndrome
Authors: Dooling Breanna , Summers Rose , Quang Daphne , Joshi Molishree , Esquer Hector , Potter Huntington , Johnson Noah R
Published: January 2025

Background

Adults with Down syndrome (DS) develop Alzheimer’s disease (AD) brain pathology by their 40s due to triplication of the amyloid precursor protein (APP) gene on chromosome 21, and most develop clinical symptoms by age 50‐60. Inheritance of the apolipoprotein E (apoE) ε4 allele (APOE4) is the strongest risk factor for AD besides age, whereas the ε3 allele (APOE3) does not change AD risk. The APOE4 genotype is associated with earlier and more rapid cognitive decline in both typical AD and DS‐associated AD (DS‐AD); however, understanding of the associated mechanisms is lacking.

Method

We developed cerebral organoids (COs) from trisomy 21 (T21) and disomy 21 (D21) APOE3/3 human induced pluripotent stem cell (hiPSC) lines. We then used CRISPR‐Cas9 editing to modify our hiPSCs from an APOE3/3 genotype to APOE4/4 in DS hiPSCs and in matched control hiPSCs disomic for chromosome 21. We differentiated these hiPSCs into COs as well as into monolayer cultures of astrocytes and microglia.

Result

There was a significant decrease in size from D21 COs to T21 COs. T21 COs also accumulated more apoE and Aβ than D21 COs and at earlier timepoints. T21 and APOE4/4 each resulted in increased microglial size and decreased microglial roundness. T21 astrocytes accumulated more apoE than D21 astrocytes. T21 APOE4/4 astrocytes exhibited increased cell death compared to T21 APOE3/3 astrocytes at an early timepoint.

Conclusion

APOE4/4 further accelerates and enhances AD neuropathologies in people with DS. Understanding the molecular and cell type‐specific changes caused by APOE4 as compared to APOE3 in DS‐AD will aid in the development of more targeted and proactive therapies to alleviate dementia risk in individuals with DS.
Local ancestry in Apoe3: Friend or Foe?
Authors: Moura Sofia , Celis Katrina , Nasciben Luciana Bertholim , Rajabli Farid , Rivero Joe , Hamilton‐Nelson Kara L. , Whitehead Patrice L. , Gearing Marla , Bennett David A. , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Scott William K. , Davis David A. , Vontell Regina T , Schuck Theresa , Dykxhoorn Derek M. , Pericak‐Vance Margaret A. , Griswold Anthony J. , Young Juan I , Vance Jeffery M.
Published: January 2025

Background

Non‐Hispanic White APOE4 carriers have a higher risk of developing AD compared to African American APOE4 carriers. The local ancestry (LA) surrounding the APOE region was previously shown to be the primary factor in this risk difference. APOE4 carriers of European LA (ELA) have been found to have higher APOE4 expression and chromatin accessibility compared to African LA (ALA). We sought to investigate whether the LA around APOE3 has the same effect between ancestries. Differences between alleles could provide insight into ancestry‐specific regulatory areas controlling the APOE4 expression.

Method

We identified AD autopsy samples by GSA, all homozygous for APOE3 and LA from 4 ADRC brain banks: Miami, Emory, Duke, and Rush. We performed single nuclei RNA sequencing (snRNA‐seq) on eight frozen frontal cortex (B9 area) samples using 10x Genomics.

Result

We performed snRNA‐seq in a total of 51,462 nuclei from eight brains (4 ELA and 4 ALA). We identified 35 distinct cell clusters at a resolution of 0.6. The proportion of cells per cluster between ELA and ALA samples was similar for all clusters, except for cluster 32 (Excitatory Neurons) which had a greater than 2‐fold difference in ALA. Our data shows that APOE3 carriers with ELA have a significantly higher APOE expression in Excitatory Neurons (cluster 7) than those of ALA and contrary to our previous observations in APOE4 carriers (Griswold, A. et al, (2021)), APOE3 carriers of ALA express higher APOE in astrocytes (cluster 2) and Microglia (cluster 6). However, overall, comparison of APOE3 vs APOE4 carriers in this study demonstrated that APOE3 alleles have significantly lower gene expression than APOE4 carriers of the same LA.

Conclusion

Our preliminary data suggest that the LA surrounding APOE3 is associated with different effects on APOE expression compared to APOE4 allele. Further, within the same LA, we observed that, overall, the different cell types express less APOE in APOE3 carriers compared to APOE4 carriers. Altogether, this may provide additional insight into the regulatory mechanisms affecting APOE4 expression.
Association of grip strength and gait speed with structural brain volume in older adults with and without cognitive impairment.
Authors: Cole Keith R , Full Kelsie M , Shi Hui , Pechman Kimberly R. , Shashikumar Niranjana , Davis L. Taylor , Hohman Timothy J. , Jefferson Angela L.
Published: January 2025

Background

Growing evidence supports that measures of overall physical health are related to incidence and progression of Alzheimer’s disease and related dementias (ADRD). In particular, measures of gait speed and grip strength independently predict incident dementia and cognitive decline in older individuals. Less is known regarding their relationship with structural brain volume in the presence of cognitive impairment. This study examined the relationship between gait speed and grip strength, and regional brain volumes in older adults with and without cognitive impairment.

Methods

Participants included 570 adults (59% males; n = 412 cognitively unimpaired; n = 158 mild cognitive impairment) aged 50‐92 years (M = 69.0, SD = 9.0) from the Vanderbilt Memory and Aging Project. Participants underwent 3T brain magnetic resonance imaging (MRI) at study enrollment. Cross‐sectional multivariate linear regression models were used to determine the associations between gait speed (usual walking pace over 15 ft) and grip strength (greatest of three maximum effort trials) with hippocampus and frontal, temporal, parietal, and occipital lobe volumes. Covariates included age, biological sex, ethnicity, education, BMI, global depression scale, Framingham Stroke Risk Profile, APOE ε4 status, cognitive status, and intracranial volume. The model included interaction terms of gait speed and grip strength each with biological sex and cognitive status.

Results

In fully adjusted models, poorer grip strength was only associated with lower hippocampal volume (F(13,491) = 26.3, R2adjusted = 0.4, p = 0.001). Sex interacted with grip strength (p = 0.03) on hippocampal volume such that the association was present among male (p = 0.006) but not female participants (p = 0.46). Slower gait speed was only associated smaller frontal lobe volume (F(12,488) = 51.0, R2adjusted = 0.56, p = 0.04) without interaction with sex (p = 0.95). There was no evidence of interaction with cognitive status in any model (all p’s>0.05).

Conclusion

Grip strength and gait speed, both quick and easy clinical measures, are differentially related to structural brain volume. Grip strength is related to hippocampal volume only in male older adults with and without cognitive impairment, indicating potential influence of biological sex. Gait speed, however, is related to frontal lobe volume in both males and females. Changes in distinct measures of physical health of those with and without cognitive impairment may indicate changes in different regions of the brain.
Procedural practice effects in remote digital memory assessment
Authors: Basche Kristin E , Berron David , Peterson Amanda , Rosario Hannah , Johnson Sterling C. , Düzel Emrah , Clark Lindsay R.
Published: January 2025

Background

Frequent and remote cognitive assessment may improve sensitivity to subtle cognitive decline associated with preclinical Alzheimer’s disease (AD). However, repeated testing can result in unintended inflation of scores, due to practice effects. The objective of this study is to evaluate the extent of sessions with non‐identical stimuli on performance and determine if study design or amyloid PET status moderates the impact of practice.

Method

Participants were recruited from longitudinal aging cohorts to complete medial temporal lobe‐based memory paradigms (Object‐In‐Room Recall [ORR], Mnemonic Discrimination for Objects and Scenes [MDT‐OS 1‐back and 2‐back], Complex Scene Recognition [CSR]) using the neotiv application at repeated intervals over one year. Participants were randomized to a task schedule (biweekly 1 task or bimonthly burst) for a total of 24 ten‐minute remote sessions. In both groups, participants completed each task 6 times; the interval between identical tasks was eight weeks (Table 1). Linear mixed effects models were used to assess the impact of practice on task performance and the interaction of practice with (1) task schedule group or (2) amyloid status. Models contained person‐level random intercepts and covariates of age, gender, education, and device type (tablet or smartphone).

Results

Task schedule group did not differ by demographic characteristics (Table 2, n = 133, mean age = 68.2, 67% female, 87% white, 97% cognitively unimpaired). The interaction of practice x task schedule group was only significant for the MDT‐OS (Table 3, β = 0.01, p = 0.032). The main effect of practice was significant for the ORR (β = 0.20, p = 0.002) and CSR (β = 0.001, p<0.001) tasks. The interaction of practice x amyloid PET result was not significant in any models. The main effect of practice was significant in all models (Table 3, ORR: β = 0.21, p = 0.004; CSR: β = 0.01, p<0.001; MDT‐OS: β = 0.01, p = 0.034).

Conclusion

Practice effects were present, indicating that procedural practice benefited task scores, despite non‐repeating stimuli. The MDT‐OS group x practice interaction indicated that participants in the burst design group had lower scores at their initial MDT‐OS visit, but increased performance with practice at a higher rate. No main effects or interaction of amyloid result was observed, possibly due to limited availability of data and few elevated participants.
The cellular prion protein mediates Tau oligomer‐induced memory impairment in mice
Authors: Forloni Gianluigi , Balducci Claudia , Orsini Franca , Cerovic Milica , Masone Antonio , Raimondi Ilaria , Lavigna Giada , Zucchelli Chiara , Beeg Marten , Colombo Laura , Musco Giovanna , Gobbi Marco , Chiesa Roberto , Fioriti Luana
Published: January 2025

Background

The role of oligomeric forms of various proteins as direct responsible of neuronal dysfunction in neurodegenerative disorders has been supported by numerous findings at experimental level and, more recently, by histological examinations in human material. The cellular prion protein (PrPC) has been proposed to mediate the neurotoxicity of β‐amyloid, α‐synuclein and tau oligomers. We demonstrated that although amyloid‐β oligomers (AβOs) bind with high affinity to PrPC, the memory deficit induced by intracerebroventricular (ICV) administration of AβOs in mice was not mediated by PrPC. Moreover, we did not confirm the reported interaction between α‐synuclein oligomers and PrPC, and found that their effect on memory did not depend on PrPC expression. In this study, we examined the interactions between tau oligomers (TauOs) and PrPC by chemico‐physical and functional studies.

Method

TauOs were prepared in the presence of arachidonic acid and analyzed by atomic force microscopy; the interaction between TauOs and PrPC was investigated by surface plasmon resonance (SPR); the cellular localization of TauOs was studied in HEK293 cells expressing different levels of PrPC; the effect of TauOs on memory function was assessed by the novel object recognition test (NORT) after ICV injection (1µM 7.5 µl) in wild type (wt) and PrP knockout (KO) mice; the effect of TauOs on long‐term potentiation (LTP) was analyzed in hippocampal slices.

Result

SPR demonstrated a high‐affinity binding between TauOs and PrPC with a Kd in the range of 20‐50 nM. Immunofluoresce analysis showed a PrPC dose‐dependent association of TauOs with the plasma membrane of HEK293 cells, and their co‐localization with PrPC. ICV application of TauOs induced memory impairment in wt but not in PrP KO mice. Accordingly, TauOs inhibited hippocampal LTP in a PrPC‐dependent fashion.

Conclusion

In contrast to our previous findings with Aβ and α‐synuclein oligomers, we demonstrate that PrPC interacts with TauOs and this binding has functional consequences. This interaction might represent an interesting therapeutic target in Alzheimer’s disease and other tauopathies.
Cognitive Domains and Functional Assessment Questionnaire (CDFAQ): Accuracy Across Educational Levels
Authors: Maia Isabelle de Aguiar , Tavares Caio Peixoto , Moro Giovanna Correia Pereira , de Souza Aline Siqueira , Ferreira Jéssica Diniz , Burgos Ivonne Carolina Bolaños , Engelmann Gabriela Tomé Oliveira , Diniz Maissa Ferreira , Romano‐Silva Marco Aurélio , de Paula Jonas Jardim , Bicalho Maria Aparecida Camargos , Viana Bernardo de Mattos
Published: January 2025

Background

The Cognitive Domains and Functional Assessment Questionnaire (CDFAQ) assess cognitive and functional decline for Neurocognitive Disorders based on the DSM‐5 criteria (1). It’s accuracy to the Informant Questionnaire on Cognitive Decline in the Elderly ‐ Long Version (IQCODE‐LV) has been assessed (2), and was translated and validated into English. The informant version (CDFAQ‐IV) assess: Complex Attention (CA), Executive Functions (EF), Learning and Memory (LM), Language (L), Perceptual‐Motor (PM) and Social Cognition.

Methods

To evaluate the CDFAQ‐IV’s accuracy to IQCODE‐LV across participant’s educational levels. Both questionnaires were applied to 196 informants of older adults. Older adults were stratified by educational levels into three groups: 73 participants had low educational level (0‐3 years), 71 had middle educational level (4‐7 years), and 52 with high educational level (8 or more years). Accuracy assessment was made by Receiver Operating Characteristic (ROC) and cut‐off values defined by Youden’s J statistic. This study was approved by the ethics committee of UFMG.

Results

The low educational group had good accuracy (Area Under the Curve = 0.879) for the CDFAQ‐IV total score, excellent accuracy for the EF domain (AUC = 0.907), good accuracy for LM domain (AUC = 0.822) and poor accuracies for other domains. For the middle educational group, CDFAQ‐IV (AUC = 0.908) and LM domain (AUC = 0.914) showed excellent accuracies, while CA (AUC = 0.876), L (AUC = 0.832) and SC (AUC = 0.814) domains showed good accuracies. The others domains showed poor accuracies. For high educational group, LM domain (0.924) had excellent accuracy, while CDFAQ’s total score (AUC = 0.894) and L domain (AUC = 0.898) showed good accuracy. Poor accuracies were found for the other domains.

Conclusions

CDFAQ’s total score shows good accuracy in samples of low and high educational levels and excellent accuracy in samples with 4 to 7 years of schooling. Interestingly, the LM domain shows excellent accuracy (AUC > 0.9) in samples with higher levels of education. Brazilian older adults have lower educational levels and more heterogeneity in schooling quality compared to those from high‐income nations. Assessment of psychometric properties according to education is needed, as well as more scenarios such as studies in community and clinical settings.
Analysis of the production in a connected speech task in patients with language impairment
Authors: Redondo Santiago , Paolantonio Patricia , Romanelli Sofía , Andreotti Daniela , Matar Lourdes , Vita Luciana , Vivas Leticia
Published: January 2025

Background

Neuropsychological language assessment batteries usually include connected speech tasks (e.g. the description of a picture). These tasks are assessed using different indicators that cover various levels of language: phonetic and phonological, lexico‐semantic, syntactic and discourse. Objective: to analyze linguistic and acoustic indicators for the picture description task of the Minlinguistic State Examination (MLSE) in its Argentinean version.

Method

The sample included 22 patients with aphasia due to focal and degenerative etiologies (10 APP, 1 DCB, 11 post‐stroke aphasia) classified into three clinical profiles: fluent, anomic and non‐fluent (according to Grossman, 2018) and 23 healthy participants. The task consisted of an oral description of the MLSE picture for 1 minute and it was audio recorded. Acoustic indicators were analyzed using the Praat software.

Result

Regarding acoustic indicators, significant differences were observed in the duration of pauses between the three clinical groups and the control group, while the differences in vocalization and silence segments were significant between the non‐fluent and the control group. Regarding linguistic indicators, a significant difference was observed between the clinical and control groups in the number of nouns, words/time ratio, number of semantic units, the density of semantic units, speaking average, and number of complete utterances; while significant differences were observed between the control group and the non‐fluent and anomic groups in number of adverbs, non‐noun words, closed words, number of verbs, average number of nouns, utterances higher and lower number of words, mean length of utterance, and utterance rate. Besides, significant differences were observed between the fluent aphasia and the control groups in semantic errors and density of ideas; and between the no fluent aphasia and the control groups in number of total utterances and index of discourse. Among the clinical groups, significant differences were observed between the non‐fluent and fluent groups in the number of semantic errors; and between the anomic and non‐fluent groups in the noun/number of words relationship.

Conclusion

These results illustrate how the use of linguistic and acoustic indicators in a connected speech task can provide additional information to identify the type of difficulties presented by aphasia patients.
Examining APOE4 overexpression effects in iAstrocytes across European and African ancestries
Authors: Dykxhoorn Derek M. , Oron Oded , Trittipo Jack , Adams Larry D. , Starks Takiyah D. , Acosta Heriberto , Feliciano‐Astacio Briseida E. , Byrd Goldie S. , Pericak‐Vance Margaret A , Griswold Anthony J. , Vance Jeffery M. , Young Juan I
Published: January 2025

Background

The Apoliproprotein E (APOE) e4 allele is the most significant genetic risk factor for late‐onset Alzheimer disease (AD). However, the risk associated with the APOE e4 allele differs across populations with individuals of African ancestry having a reduced risk than individuals of European (EU) ancestry. Further, single‐nuclei RNAseq analysis in autopsy samples from AD APOEε4 homozygotes with EU Local Ancestry (LA) had a significantly increased APOEε4 expression compared to those with African LA, particularly in astrocytes. To test the functional consequences of elevated APOE4 expression on astrocytes, we examined the effect of APOE4 overexpression in inducible pluripotent stem cell (iPSC) derived astrocytes (iAstrocytes).

Method

iPSC were derived from European and African LA AD individuals homozygous for APOEε4/ε4. These APOEε4/ε4 iPSC were differentiated into astrocytes (iAstrocytes) which were transduced with a lentiviral construct overexpressing APOEε4 or a control vector. RNAseq analysis was performed to identify differentially expressed genes followed by pathway analyses.

Result

iPSC lines were derived, validated for pluripotency, and differentiated into iAstrocytes. Preliminary analysis of transcriptional effects ofApoEe4 overexpression in iAstrocytes showed alterations in gene expression patterns, including the down regulation of the inflammatory markers THBS1 and CLDN11 which had both been shown to be downregulated in AD, the mitochondrial‐related gene NDUFA4L2 shown to be dysregulated in AD, as well as SFRP2 (Wnt modulator involved in TREM2 processing). Upregulated genes included RGMA (accumulates in amyloid plaques), as well as TNC and CECR2. Pathway analysis showed an enrichment for extracellular matrix (ECM)‐receptor interaction, PI3K‐Akt signaling, and TGF‐beta signaling pathways. Interestingly, the transcriptional response to APOEε4 overexpression has an ancestry‐specific component in these iAstrocytes; with some genes dysregulated exclusively in African ancestry iAstrocytes such as ZBTB4 and PRND, and others only in European iAstrocytes, including MYBPHL and VWF.

Conclusion

The overexpression of APOEε4 in iAstrocytes resulted in alteration in gene regulatory patterns, including the ECM and key signaling pathways across ancestries (EU and AF). In addition, gene expression differences were identified between ancestries. Further analyses of these ancestry‐specific transcriptional differences may help to elucidate the mechanisms that drive the differential AD risk seen in APOEε4 individuals across ancestries.
Modulating dynamic brain networks and episodic memory in amnestic mild cognitive impairment using 40 Hz precuneus transcranial alternating current stimulation
Authors: Koomen Annel P. , Stam Cornelis J. , Pijnenburg Yolande A.L. , de Haan Willem
Published: January 2025

Background

Worldwide, 32 million Alzheimer’s disease (AD) patients contribute to a large economic burden, making effective and safe therapies that slow or prevent the progression from pre‐dementia or mild cognitive impairment (MCI) to AD of high priority. Transcranial alternating current stimulation (tACS) is a safe and patient‐friendly non‐invasive brain stimulation technique that serves as a potential candidate for slowing and/or reducing cognitive impairment. Application of tACS in the gamma (30‐45 Hz) frequency range, specifically around 40 Hz, has been studied in patients with (pre‐dementia) AD. In these patients, a single session of 40 Hz tACS at the precuneus region showed to improve episodic memory and to increase relative power of higher frequencies such as gamma, as measured with EEG. These findings will be replicated in the current study in pre‐dementia AD patients, using magnetoencephalography (MEG) to study brain network dynamic changes with greater temporal and spatial detail.

Method

In this double‐blind, randomized, sham‐controlled, cross‐over trial, 30 pre‐dementia AD (biomarker‐confirmed amnestic MCI) patients will undergo concurrent tACS‐MEG. At two sessions separated by a week, 48 minutes of either gamma (40 Hz) or sham tACS will be applied at the precuneus region. Cognitive outcome measures assessed pre and post‐tACS are the Rey Auditory Verbal Learning (RAVL) test and Face‐Name Association Task (FNAT) score. In addition, resting‐state spectral and functional connectivity MEG measures will be extracted from the pre‐ and post‐tACS data to determine tACS‐induced network effects.

Result

An increase in RAVL test and FNAT score after 40 Hz but not sham tACS is expected, as well as an increase of relative power and global connectivity in higher frequencies (alpha [8‐13 Hz], beta [13‐30 Hz] and gamma [30‐45 Hz]). Furthermore, a positive correlation is expected between these quantitative MEG measures and cognitive outcome following 40 Hz tACS.

Conclusion

We expect 40 Hz precuneus tACS to improve episodic memory and to counteract the slowing of oscillatory activity and reduction of brain communication in AD. This will support the notion that this approach can temporarily improve cognitive impairment by normalizing disturbed brain function, and encourages the use of tACS in clinical studies of AD.
Effects of BDNF and COMT variants on cognitive decline in Early‐Onset Alzheimer’s Disease
Authors: Hammers Dustin B. , Foroud Tatiana M. , Kim Hee Jin , Musema Jane , Dage Jeffrey L. , Eloyan Ani , Carrillo Maria C. , Dickerson Bradford C. , Rabinovici Gil D. , Apostolova Liana G. , Nudelman Kelly N. ,   LEADS Consortium
Published: January 2025

Background

Early‐Onset Alzheimer’s Disease (EOAD) is a rare condition that affects only 5% of patients with Alzheimer’s Disease (AD). At present, only basic information is known about the impact of AD risk variants on EOAD, and the effects of more subtle genetic contributions to cognitive decline have yet to be investigated. Genetic variants for brain derived neurotrophic factor (BDNF) and catechol‐O‐methyltransferase (COMT) have both been implicated in cognitive change (Fiocco et al., 2010; Ferrer et al., 2019), consequently the aim of the current study was to examine the role of these genetic variants on cognitive decline in EOAD.

Method

Data from 88 amyloid‐positive EOAD participants enrolled in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS; aged 40‐64) were analyzed. Exploratory multivariate analyses of covariance (MANCOVA) were conducted to investigate differences in 12‐month cognitive decline as a function of BDNF rs6265 (p.V66M) and COMT rs4680 (p.V158M) variants using dominant genetic models (Val/Val versus Val/Met or Met/Met). Cox Regression analyses were also conducted to consider the effect of genetic variants on age of onset.

Result

See Table 1 for demographic characteristics of our sample. MANCOVA, controlling for age, education, sex, and race/ethnicity, showed significant effects for BDNF p.V66M on domains of Memory (p<0.001) and Executive Functioning (p = 0.04; Table 2). Specifically, greater 12‐month cognitive decline was observed for the CRAFT Immediate and Delayed Story Memory, with worse performance associated with BDNF minor alleles (ps. = 0.007 to 0.02). Conversely, worse decline was observed for the reference group for RAVLT Immediate Memory (p<0.006) and Digit Span Backwards (p<0.02). No significant effects were evident for domains of Language, Speed/Attention, or Visuospatial skills (ps = 0.34‐0.97), nor for any analyses of COMT carrier status (ps = 0.26‐0.87). Cox Regression analyses, controlling for race and ethnicity, were not significant for BDNF or COMT carrier status (ps = 0.59‐0.64; Figure 1).

Conclusion

Results suggest subtle effects of BDNF p.V66M carrier status on memory decline in EOAD participants, which was not observed for disease progression/age‐of‐onset. No effects for COMT p.V158M carrier status were observed. Future investigation will replicate these effects in larger samples, permitting stratification of additional covariates including APOE genotype.
Aβ re‐wires CSF1R‐induced MAPK pathway activation in MMC microglia
Authors: Bitarafan Sara , Uhlig Zachary C. , Tobin Brendan R , Armentrout Owen S , Rangaraju Srikant , Wood Levi B
Published: January 2025

Background

Mitogen activated protein kinase (MAPK) signaling is a critical regulator of microglial phenotype, including phagocytic function, cytokine expression, and motility, among others. Importantly, both canonical and non‐canonical MAPK signaling is directly activated by RTKs, including Interestingly, CSF1R, is activated by two agonists, CSF1 and IL‐34, which have been shown to activate the receptor in different ways that can lead to However, little is known about how the affect microglial MAPK signaling, and whether their effects are dependent on disease state/Aβ exposure. In this study, we hypothesized that IL‐34 and CSF‐1 elicit distinct patterns of MAPK signaling activation in microglia and MAPK activation would be dependent on whether the cells were exposed to Aβ.

Method

We applied agonists of CSF1R (i.e., IL‐34, CSF1) to the mouse microglial cell (MMC) line, either pre‐treated with 500nM of Aβ1‐42 or vehicle (1% NH4OH) for 48hr. Cells were serum starved (1hr), stimulated with each agonist for 5min, then lysed for Luminex quantification of a panel of 10 MAPK phosphoproteins.

Result

In the absence of Aβ1‐42, both CSF1R and IL‐34 stimulated both canonical (ERK) and non‐canonical (p38, JNK) MAPK signaling phospho‐proteins (Wilcox test, p<0.05 vs control). While Aβ1‐42 pre‐treatment resulted in diminished activation in canonical MAPK signaling (i.e., MEK, ERK) following either CSF1 or IL‐34 stimulation, CSF1 stimulation of non‐canonical MAPK signaling through p38 and JNK was preserved with Aβ1‐42 pre‐treatment. These findings indicate that CSF1‐induced signaling is robust regardless of Aβ1‐42 exposure. Furthermore, different agonists of the same receptor distinctly activate non‐canonical MAPK pathway signaling (p38). Collectively, this finding supports the overall hypothesis that CSF‐1R‐induced signaling is dependent on Aβ and Aβ pre‐treatments shift the canonical ERK signaling to non‐canonical p38 signaling.

Conclusion

These findings show that different agonists of CSF1R can provoke distinct profiles of canonical and non‐canonical MAPK pathway signaling in the presence of Aβ1‐42. Understanding differences in agonist‐specific microglial signaling in healthy and diseased microglia will be essential to designing microglial‐targeted therapeutics for treatment of AD.
snRNA‐seq analysis of human brains suggests cell type‐specific synergistic effects of APOE4 and TREM2‐R47H and potential drug targets in Alzheimer’s Disease
Authors: Zajac Diana J , Xu Jielin , Cheng Feixiong
Published: January 2025

Background

Alzheimer’s Disease (AD) risk variants APOE4 and TREM2‐R47H have been shown to impact glial cell functions and transcriptional profiles. We hypothesize that TREM2‐APOE may have synergistic effects in driving pathogenesis and disease progression of AD in a cell type‐specific manner.

Methods

We investigated cell‐type specific transcriptional changes associated with APOE4‐ and TREM2‐R47H‐carrier status. We conducted single‐nuclei RNA‐sequencing (snRNA‐seq) analysis, including cell type clustering and annotation, and identification of differentially expressed genes (DEGs). We used integrative genomic analysis for pathway enrichment and drug‐target network inference. Our investigation was between APOE‐TREM2 groups: APOE4‐carrier+TREM2‐R47H (E4‐R47H) (n = 18) vs non‐APOE4+R47H (nonE4‐R47H) (n = 6), APOE4‐carrier+TREM2‐common variant (E4‐CV) (n = 16) vs nonE4‐CV (n = 6), E4‐R47H vs nonE4‐R47H, and E4‐CV vs nonE4‐CV.

Results

We found that APOE‐TREM2 status had synergistic effects on cell abundance in several cell types, especially in oligodendrocytes, excitatory neurons and pericytes. Pathway enrichment analysis suggests a possible APOE4‐ and TREM2‐R47H‐dependent regulation of cell type‐specific pathway signaling. Of note, preliminary analysis suggests an APOE4‐dependent regulation of TREM2‐R47H‐associated PI3K‐Akt signaling in microglia such that APOE4‐R47H carriers had significantly upregulated PI3K‐Akt signaling but nonAPOE4‐R47H carriers had comparatively downregulated PI3K‐Akt signaling. Oligodendrocyte clusters show R47H‐dependent effects of APOE4‐carrier status on relevant signaling pathways as well. Oligodendrocytic signaling pathways for long‐term depression and serotonin/anxiety events, as well as sleep regulation and circadian entrainment have R47H‐dependent regulation between APOE4 vs non‐APOE4 carriers. We employed integrative network‐based analysis of single‐nuclei transcriptomic and drug‐gene signatures and identified an FDA‐approved drug clidinium bromide, a treatment for irritable bowel syndrome and enterocolitis, to be a possible antagonist of the synergistic R47H‐APOE4 effects in microglia.

Conclusion

In summary, this study suggests possible synergistic effects of APOE4‐carrier and TREM2‐R47H‐carrier status on cell type abundance and cell type‐specific specific signaling pathways. Hence, further classification of differences between joint APOE‐TREM2 genotypes will improve our understanding of glial cell alterations in AD, and could lead to novel microglia‐targeted therapeutic interventions. Such findings enhance our knowledge of druggable therapeutic targets and support the need for precision and personalized medicine. Independent cohort validation and functional observations of candidate targets and treatments are warranted.
Semantic control across different phenotypes of Alzheimer’s disease: a cognitive study
Authors: Armas Pilar , Zsadanyi Sara E , Morcillo‐Nieto Alejandra O. , Illán‐Gala Ignacio , Marques‐Kiderle Sonia Karin , Ciongoli Francesco , Rubio‐Guerra Sara , Lleo Alberto , Fortea Juan , Grasso Stephanie M , Binney Richard J , Calabria Marco , Hernando Javier , Bejanin Alexandre , Santos‐Santos Miguel A
Published: January 2025

Background

While the functioning of semantic memory has been extensively documented in Alzheimer disease (AD), little is known about semantic control capacities that monitor and modulate semantic representations. The present study used a task to assess semantic control in typical and atypical AD patients.

Method

11 patients with typical AD (ADtyp), 17 patients with logopenic variant of primary progressive aphasia (lvPPA, i.e. AD language variant), and 16 cognitively unimpaired subjects performed a task (from Corbertt et al., 2011) consisting of selecting the picture of an object that could be used to complete an everyday task (e.g. “kill a fly”). Each task was performed under 4 conditions (4 trials), that manipulated the difficulty of selecting a suitable object. For each trial, the target item was either a canonical object for completing the task (e.g. “flyswat”) or a noncanonical one (e.g. “magazine”); the target picture was presented alongside 5 additional pictures of either unrelated distractors (e.g. “toothbrush”) or distractors semantically related to the target (e.g. “mousetrap”). Semantic control measures were canonicity (associated with abstraction and flexibility capacities) and relatedness (associated with inhibition). Semantic control scores were computed as the difference between canonical and noncanonical conditions (canonicity scores), and unrelated and related conditions (inhibition scores) in accuracy and reaction time (RT); higher scores indicated greater semantic control impairment.

Result

Linear mixed‐model analyses showed that, across all groups, canonicity influenced RT and accuracy, whereas relatedness influenced accuracy only. Interaction analyses showed that the canonicity (but not the relatedness) manipulation resulted in slower RTs (but not lower accuracy) in both patient groups vs controls; lvPPAs unexpectedly showed faster RT in the condition theoretically demanding higher semantic control. Significant differences were found between controls and both patient groups in canonicity scores (both accuracy and RT) but not inhibition scores. No significant differences were observed between the patient groups.

Conclusion

Our results indicate that AD impacts semantic control capacity, with differences for canonicity and inhibition. Canonicity and inhibition semantic control abilities are similarly impaired in lvPPA and ADtyp groups. These results help us to identify different effects of semantic control capacities.
Translating Genetic Insights into Molecular Mechanisms in Alzheimer’s Disease: Innovative CRISPR Approaches Targeting Inflammasomes
Authors: Sher Falak
Published: January 2025

Background

The connection between inflammasomes and Alzheimer’s disease (AD) has garnered significant interest, with emerging evidence suggesting genetic associations and functional implications. Notably, studies have reported the upregulation of inflammasome components like NLRP1, NLRP3, and Caspase‐1 in AD patients. Moreover, genetic polymorphisms in inflammasome‐related genes are linked to increased AD risk. Inflammasome activation in microglia, key immune cells of the brain, contributes to the neuroinflammation characteristic of AD. This backdrop sets the stage for exploring inflammasomes as potential therapeutic targets using advanced genomic tools.

Methods

Addressing the critical need for robust, human‐centric research models, our study developed an optimized protocol to differentiate human induced pluripotent stem cells into microglia (iMG). Validating this model through single‐cell RNA sequencing (scRNA‐Seq), proteomics, and functional assays, we employed a novel CRISPR‐based approach. We conducted comprehensive CRISPR tiling across inflammasome protein coding sequences in iMG cells, coupled with affinity chromatography‐based mass spectrometry and functional guide RNA mapping. This allowed us to investigate the essential subcomplexes within the inflammasome protein family and identify key genetic and protein interactions relevant to AD.

Results

Our CRISPR‐based investigations revealed crucial insights into the inflammasome’s role in AD. We identified specific mutations in NLRP3 that separate its impact on cell health from inflammasome activation. Additionally, our study highlighted critical amino acids in the AD‐associated protein SORL1, offering potential targets for small molecule therapeutics that alter SORL1 function with minimal side effects.

Conclusion

This research marks a significant stride in translating genetic findings into a deeper understanding of molecular mechanisms in AD. By leveraging innovative CRISPR techniques on iMG models, we have elucidated the intricate roles of inflammasome pathways and their interactions with key AD‐associated proteins. Our findings pave the way for novel, targeted therapeutic strategies in Alzheimer’s disease, promising more effective interventions with higher precision.

Our findings offer a generalizable approach to uncover protein or protein‐complex features suitable for rational biochemical targeting
Tau ablation rescues vascular amyloid‐related deficits in a cerebral amyloid angiopathy model
Authors: Mardones Muriel D , Jury Nur , Juarez Enrique Chimal , Patel Henika , Martinez Jonathan , Vanderbosch Katie , Perkins Abigail , Marambio Yamil , Vidal Ruben , Reeves Cristian A Lasagna
Published: January 2025

Background

Close to 80 to 90% of subjects with AD also present cerebral amyloid angiopathy (CAA) a disease in which amyloid accumulation damages the vasculature an impairs blood flow. Since current AD therapies are targeting the disease focusing on amyloid, we are interested on determine how to decrease the accumulation of amyloid in the vasculature observed in CAA and our aim is to determine the impact of tau reduction in CAA pathogenesis.

Method

We crossed the Tg‐FDD mice CAA model with Mapt‐/‐ mice to decrease tau levels and analyzed the disease pathogenesis in the different genotypes though behavioral tests, histological and morphometric assays and transcriptomic analysis using the nCounter neuroimmflamation panel from Nanostring.

Result

We determined that tau ablation improved motor strength in the Tg‐FDD mice model, reduced amyloid deposition in the vasculature, decrease fibrinogen levels in the cortex, reduced astrocyte branching process associated to immunoreactivity. Nanostring analysis revealed that microglia function, oligodendrocyte and cytokine signaling are altered in the Tg‐FDD mice and that in the Tg‐FDD, Mapt‐/‐ mice there is an increase in this mechanisms restoring the values to the ones observed in wild type mice.

Conclusion

We are currently evaluating the pathways observed in the distinct inflammatory profile in microglia and oligodendrocytes. Our results suggest that tau ablation decreased CAA pathology in the Tg‐FDD mice model, which shows the potential therapeutic implications of targeting tau in CAA and related neurodegenerative diseases