bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Motor Learning to Predict Cognitive and Functional Decline in Mild Cognitive Impairment and Alzheimer’s Disease
Authors: Koppelmans Vincent , Duff Kevin , Schaefer Sydney Y
Published: January 2025

Background

Predicting decline over the course of Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD), especially on relatively short time frames, is vital for appropriate treatment planning and to tailor patient and support systems’ expectations. The current study tested if a functional upper limb motor learning task could predict one‐year change in cognition and daily function.

Method

Cognitively unimpaired (n = 61), MCI (n = 35), and AD (32) older subjects (age: 74.6 ±5.7 years) completed a simulated feeding task (SFT) at baseline for which they used a plastic spoon to scoop two raw kidney beans at a time with their non‐dominant hand from a central cup and transport them to one of three distal cups. They completed this sequence five times for a total of 15 out‐and‐back movements. Time was recorded as outcome measure, and 6 trials of the test were completed. This test was completed 6 times with trial time as the outcome measure for each trial. At baseline and one‐year follow‐up visits, the Mini Mental Status Examination (MMSE) was administered to assess cognition and a knowledgeable collateral completed the Quick Dementia Rating System (QDRS) to assess daily functioning. Linear regression analysis, adjusted for age, sex, and years of education, was used to test the association between SFT performance over the six trials (mean/sd) and regression‐based one‐year change scores on the QDRS and MMSE.

Result

SFT performance speed and variability significantly predicted change in performance on the QDRS (total score, cognitive domain score, and behavioral domain score; p = .013‐.024). SFT variability (a measure of learning), but not average performance, over six trials predicted change on the MMSE (p = .031). These effects were small to medium in size (eta^2 = 0.04‐0.05).

Conclusion

Speed and variability on a brief, easy‐to‐administer (∼5‐7 minutes), cost‐efficient functional upper limb motor learning task predicted cognitive and functional change over one year across the AD spectrum. These promising results suggest that the SFT could be used in clinical practice to help predict disease progression, as well as a screening tool in clinical trials in MCI and AD.
Cytoplasmic expression of TDP‐43 in aged mice display hippocampal sclerosis‐like degeneration and neuronal loss with reduced lifespan
Authors: Anderson Ashley J. , Dopler Matthew B , Arezoumandan Sanaz , Osei‐KanKam Damian , Davis Stephani A. , Ajroud Kaouther , Lilek Jaclyn N , Bambakadis Eva , Shapiro Rachel , Gitcho Michael A. , Flanagan Margaret E , Cairns Nigel J
Published: January 2025

Background

TDP‐43 is a multifunctional heterogeneous nuclear ribonucleoprotein and is the major pathological protein in motor neuron disease. Previously, TDP‐43 pathology has been described in up to 50% of those with Alzheimer’s disease. Recent evaluation of this cohort revealed a distinct pathological staging of TDP‐43 proteinopathy in an aged population, called Limbic predominant age‐related TDP‐43 encephalopathy

(LATE). Hippocampal sclerosis of aging (HS‐A) is an age‐related neuropathology characterized by severe neuronal loss and gliosis, also seen as a co‐pathology in AD and LATE. HS‐A is evident in ∼80% of cases in the hippocampal region of cases that are positive for phosphorylated TDP‐43.

Method

We examined aged mice that selectively express human TDP‐43 and TDP‐43 with a defective nuclear localization signal (ΔNLS) in the hippocampus in an APP/PSEN1 background, six genotypes of interest were evaluated; WT, APP/PS1, Camk2a/TDP‐43, Camk2a/TDP‐43ΔNLS, Camk2a/TDP‐43/APP/PS1, and Camk2a/TDP‐43ΔNLS/APP/PS1 in 24 month old mice. A sample size of n = 3 was used for each genotype. Protein lysates as well as fixed tissues were prepared and analyzed.

Result

These 24‐ month‐ old mice display severe neuronal loss in the hippocampus, a decrease in beta‐amyloid plaque deposition, an increase in neuroinflammation, and reduced survival.

Conclusion

This aged hippocampal sclerosis‐like model may provide a greater understanding of the pathogenesis of neurodegeneration seen in TDP‐43 proteinopathies.
Potentially heritable biomarkers of neurodegeneration in a marmoset model of Alzheimer’s disease
Authors: Kumar Sonal , Spruce Catrina , Haber Annat , Schultz Laura , Huhe Hasi , Murai Takeshi , Choi Sang‐Ho , Hachem Stephanie , Mou Yongshan , Ha Seung‐Kwon , Park Jung Eun , Bailey Lauren , Mongeau Lauren , DeSana Andrew , Stein Brianne , Schaeffer Lauren K Hayrynen , Homanics Gregg E , Silva Afonso C , Rizzo Stacey J Sukoff , Carter Gregory W
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common global cause of dementia, with no real cure available. Despite extensive genetic findings from large‐scale genetic associations and similar studies, our understanding of AD is largely hindered by its long, asymptomatic progression with limited access to human brain tissue. Animal models like the marmoset allow for longitudinal analysis of disease by enabling the assaying of disease‐specific phenotypes that mimic human pathophysiology. Here, we have analyzed genetic associations with disease biomarkers in a cohort of wild type and PSEN1 C410Y mutant marmosets.

Method

Whole genome sequencing was carried out for a cohort of largely wild‐type and a few PSEN1 mutant carriers. A wide variety of disease associated biomarkers were analyzed to assess for the progression of neurodegeneration. The correlation structure underlying collected biomarkers and related phenotypes was calculated, separating for sex. Composite phenotypes were computed based on correlation strength, and genetic associations studied via QTLs for composite and individual phenotypes.

Result

Females showed greater correlations between disease specific biomarkers like total tau (tTau), neurofilament light protein (NfL), the astrocytic marker GFAP, and β‐amyloid peptides with 40 and 42 amino acids, as well as the Aβ42:Aβ40 ratio. Correlations between markers were found to be weaker but still significant in males. Variants predicted to be pathogenic were found for many genetic loci implicated by human genome‐wide association studies. Standing genetic variation in the marmosets was found akin to what is seen in humans, but overall population structures varied significantly between the two species.

Conclusion

Correlations between AD‐relevant biomarkers in marmosets exceeded those observed in humans, which were not explained by age. This suggests a strong potential genetic contribution. Leveraging possible heritable associations with disease markers discovered in the marmosets to explain the progression of neurodegeneration could directly provide insights into human AD biology from a genetic point of view.
Elucidating the phenotypic landscape of neurodegeneration using multiplexed single‐cell sequencing of defined neuronal co‐cultures in vitro
Authors: Vaikunthan Mathini , McFaline‐Figueroa José
Published: January 2025

Background

Many putative factors may contribute to the neurodegeneration seen in Alzheimer’s Disease (AD), including the build‐up of toxic amyloid‐beta plaques and the aberrant reactivity of non‐neuronal cell types such as astrocytes and microglia. However, the precise contribution of these factors to normal and disease states of neurons remains poorly defined.

Method

We employed in vitro rat neural co‐culture models to determine how changes in cell interactions alter the transcriptional response of neural cell types to agents associated with neurodegeneration. We performed single‐cell RNA‐seq using the 10x Genomics Chromium on neuron‐enriched (Neu) fractions alone or with the addition of an astrocyte‐enriched (Ast) fraction or both astrocyte‐ and microglia‐enriched (Ast + Mic) fractions. We then exposed different cell‐type composition conditions to AD‐related (i.e., Aβ42 aggregates), oxidative/nitrosative (hydrogen peroxide, sodium nitroprusside), and inflammatory/anti‐inflammatory (tumor necrosis factor ɑ, transforming growth factor β, interleukin‐4, lipopolysaccharides, short chain fatty acids) compounds, yielding 20 conditions (including controls). We use multiplexed sci‐RNA‐seq to process all conditions within one experiment. Ongoing work includes gene knockouts of AD relevant genes with CRISPR‐Cas9 Ribonucleoprotein particles before exposure to compounds.

Result

The initial coculture experiment yielded transcriptomes for ∼12k cells. We show that variations in cell‐type composition led to changes in the expression of genes associated with neurodegeneration, including 11 late‐onset AD (LOAD) genes, suggesting that neurodegenerative gene expression changes can occur as a function of altered neural cell interaction alone. Changes in early‐onset AD (EOAD) genes in specific cell‐types were also observed, including increasing Psen1 expression in neurons upon cell‐type composition changes. Our multiplexed 20‐condition experiment yielded ∼40k transcriptomes. MultiNicheNet–a pipeline for analyzing cell‐cell interactions over multiple conditions–inferred downregulation of LOAD‐associated receptor‐ligand pairs such as Apoe‐Sorl1 in the context of the “high microglia” coculture model over a number of exposures, recapitulating a transcriptional phenotype seen in AD patients.

Conclusion

By enacting simple perturbations to cell‐type composition and exposures in a neuronal model, we have modeled a subset of the phenotypes displayed in AD patients. This study can help elucidate the order of events of changes observed in AD, including those likely to directly induce neuronal cell death.
Relationship between brain stiffness, microstructural integrity, beta‐amyloid accumulation, and cognitive decline in beta‐amyloid positive individuals
Authors: Triolo Em , Langan Mackenzie , Khegai Oleksandr , Diaz Aislinn , Binder Sarah , Hedden Trey , Balchandani Priti , Kurt Mehmet
Published: January 2025

Background

Leveraging non‐invasive ultra‐high field, 7 Tesla (7T) MRI, with increased signal‐to‐noise ratio and improved soft tissue contrast afforded by 7T allows us to accurately map tissue microstructure. We aim to use 7T MR Elastography (MRE), 7T Diffusion Tensor Imaging (DTI), 3T amyloid‐PET, and Preclinical Alzheimer Cognitive Composite (PACC) score to determine the relationships between these metrics in a cohort of older individuals with either normal cognition (CN), mild cognitive impairment (MCI), or Alzheimer’s Disease (AD).

Methods

7T MRE, 7T DTI, 3T PET (Fig. 1A), and PACC test were performed on CN 14 subjects (Avg. age 70.3±5.2 years), and 6 subjects (Avg. age 70.0±9.4 years) with MCI/AD (Clinical Dementia Rating >4.0 in the Clinical Dementia Rating Scale Sum of Boxes). We performed multiple Shapley Regressions in subjects with amyloidosis (average SUVR above the region threshold, described in Bullich, et al.) in five PET‐relevant cortical regions with the imaging metrics acquired and PACC score.

Results

We found significant differences (p<0.05) between the CN and AD/MCI groups in complex shear stiffness (|G*|) of the hippocampus and frontal lobe, and SUVR of all brain regions investigated. A significant negative correlation was found between average SUVR and |G*| in multiple brain regions (Fig. 1B). We also found significant correlations between SUVR and mean diffusivity (MD), and |G*| and MD in the temporal cortex (Fig. 1C). There was a significant negative correlation between SUVR and PACC, and positive correlation between |G*| and PACC, in all regions.

Excluding PACC, |G*| was the best predictor of SUVR in subjects with amyloidosis, apart from in the temporal and parietal cortexes, where MD was a better predictor (Fig. 2 A, B). Again, excluding PACC, SUVR was the best predictor of |G*|, apart from the temporal cortex.

Conclusions

The Shapley regression analyses demonstrated that SUVR and |G*| were the most interrelated imaging covariates for multiple brain regions, which is promising for finding correlates of PET through MRE. Additionally, correlations between SUVR or |G*| and MD, but not SUVR and |G*| in the temporal cortex may be indicative of cascades which contribute to Aβ deposition, microstructural damage, and tissue softening and degradation.
Incidence of early neurodegenerative disease pathology in a forensic cohort
Authors: Hunter Mikayla L , Williamsen Hannah R , Cooper Benjamin J , Pierson Samantha R , Marcinkiewcz Catherine A , Hefti Marco M , Fiock Kimberly L
Published: January 2025

Background

It is increasingly apparent that tau pathology in Alzheimer’s disease (AD) begins in the brainstems of middle‐aged patients, decades before the onset of symptoms. Most studies are, however, based on brain‐bank cohorts and focus on patients dying of natural causes. The true incidence of tau pathology in the brainstem thus remains unclear. In this study, we report a systematic characterization of Alzheimer’s disease and related dementia (ADRD) pathology in the brainstems of a statewide cohort of patients coming to forensic autopsy.

Method

Postmortem human brain samples were obtained from asymptomatic forensic deaths in the state of Iowa (n = 12; 6 male and 6 female). Formalin‐fixed, paraffin embedded tissue samples were stained by immunohistochemistry (IHC) on the dorsal raphe (DR), locus coeruleus (LC), and hippocampus (HPC) to assess the presence of tau (AT8), α‐synuclein, and beta amyloid pathology. All stains were independently evaluated by two experienced neuropathologists, with discrepancies resolved by consensus.

Result

We identified a total of 12 cases in our initial cohort (median age 51, range 25‐74). Six of the 12 cases contained tau pathology in the HPC, five of 12 contained tau in the DR, and five of 12 contained tau in the LC. Additionally, one case contained beta amyloid in neocortex and alpha synuclein in the DR. All cases positive for pathology were greater than 50 years of age.

Conclusion

Our data suggests that incidental ADRD pathology is extremely rare in younger adults, with alpha‐synuclein and beta‐amyloid only seen in a single 74‐year‐old patient. These findings suggest such pathology is less common than previously thought and emphasizes the unique advantage of studying it in forensic cohorts dying of non‐natural causes, which better represents the population as a whole.
AD pathology‐independent effects of astrocyte‐ or microglia‐specific replacement of APOE4 with APOE2
Authors: Nolt Georgia L , MacLean Steven M , Golden Lesley R , Stephens Isaiah O , Hernandez Gabriela , Siano Dahlia , Woodward Ellen , Moses Joshua , Morganti Josh M. , Johnson Lance A
Published: January 2025

Background

Compared with the E3 allele of Apolipoprotein E (APOE), E4 increases late‐onset Alzheimer’s Disease (AD) risk up to 15‐fold, while the E2 allele substantially decreases risk. In the CNS, ApoE is predominantly synthesized by astrocytes and microglia, making these two cell types promising targets for ApoE‐directed therapeutic approaches. Our lab has generated an inducible “switch” mouse model (APOE4s2) in which we can conditionally replace E4 with the protective E2 in a cell‐specific manner. To elucidate potential mechanisms by which astrocytes and microglia expressing E2 or E4may modulate AD risk, we characterized the immuno‐metabolic response of astrocyte‐ and microglia‐specific “switch” mice to a variety of CNS‐related challenges.

Method

Aged APOE4s2 mice were administered tamoxifen to induce an in vivo transition from expression of E4 to E2 selectively in astrocytes (Aldh1l1‐CreERT2) or microglia (Tmem119‐CreERT2). A separate cohort of APOE4s2 mice received LPS to induce an inflammatory response 24 hours prior to tissue collection. Immunohistochemical analysis of gliosis (GFAP, IBA1), cytokine measurements, and targeted metabolomics and lipidomics were performed on brain tissue from these groups. Additionally, a cohort of 6‐week‐old microglia‐APOE4s2 mice were administered lysophosphatidylcholine (LPC) via intracranial injections to promote demyelination. Mice were sacrificed 10 days post‐LPC injection, and myelin content and glial reactivity were quantified via staining of myelin basic protein (MBP), degraded MBP (dMBP), and Luxol Fast Blue (LFB).

Result

As measured by plasma and brain cytokine levels, the inflammatory response was not modified by glial E2 expression in either age or LPS. However, aged E4 mice in which only astrocytes selectively expressed E2 showed decreased microglia reactivity (Iba1 immunoreactivity) compared to mice expressing E4 in all cell types. In contrast, aged mice in which only the microglia express E2 showed increased microglia reactivity relative to E4 expressing controls. Interestingly, a similar increase in Iba1 signal was noted in mice expressing only astrocytic E2 following an acute exposure to LPS. Finally, E2 expressing microglia appear to have higher levels of myelin following LPC injections compared to E4 expressing microglia.

Conclusion

Glial cell‐specific expression of E2 alters microglia reactivity in response to various pathological challenges, including aging, inflammatory stimuli, and demyelination.
NFT maturation and tau mediated neurodegeneration in Alzheimer’s disease with concomitant LATE
Authors: Arezoumandan Sanaz , Emrani Sheina , Capp Noah , Ohm Daniel T , Phillips Jeffrey S , McMillan Corey T , Lee Eddie B , Wolk David A , Irwin David J
Published: January 2025

Background

Limbic predominant age‐related TDP‐43 encephalopathy (LATE) is a common co‐pathology in Alzheimer’s disease (AD) and is associated with advanced cognitive impairment and severe atrophy in limbic regions. In AD, various maturation stages for tau neurofibrillary tangles have been characterized and can be selectively marked by monoclonal tau antibodies, providing insight into disease progression. Indeed, AD tau pathology progresses from an early “paperclip” conformation, marked by the MC1 epitope to a C‐terminally truncated form of tau, marked by MN423 epitope. Moreover, MC1‐reactive inclusions in AD largely take the form of pre‐tangles/threads and are less prominent in patients with more advanced AD, where there is a higher burden of MN423‐reactive inclusions that largely take the form of extracellular ghost tangles. In this study we tested the hypothesis that hippocampal tau maturation is more advanced in AD with concomitant LATE compared to the pure AD.

Method

Individuals with neuropathological diagnoses of pure AD (N = 63) and AD+LATE (N = 66) were selected. Hippocampal sections were immunohistochemically stained with MC1 and MN423. We measured percent area‐occupied by tau pathology in CA1 of hippocampi by employing validated digital histopathology methods. Additionally, we used ordinal ratings (0‐3) of TDP‐43 pathology from adjacent sections to test the association between tau and TDP‐43 pathology in the AD+LATE group. We compared pathology burden between groups using linear regression models controlling for age, disease duration, sex, and Braak stage.

Result

There were lower levels of early conformations of tau detected by MC1 in the AD+LATE group in contrast to the pure AD group (p = 0.01). Moreover, we found a similar burden of late conformation of tau associated with ghost tangles between the AD+LATE and pure AD group (p = 0.2) (Fig. 1A). However, among individuals with AD+LATE, higher TDP‐43 pathology was associated with greater burden of MN423 immunoreactive tau (p = 0.03) (Fig. 1B).

Conclusion

The presence of increasing TDP‐43 pathology in AD+LATE is associated with maturation of tau NFT and could potentiate tau‐mediated neurodegeneration.
Association between remote Traumatic Brain Injury and AD pathology, vascular injury, and cognitive decline among Veterans and non‐Veterans
Authors: Van Hulle Carol A. , Zylstra Hanna , Betthauser Tobey J. , Du Lianlian , Cole Aleshia , Cronin Katherine , Rivera‐Rivera Leonardo A. , Gleason Carey E. , Johnson Sterling C. , Zetterberg Henrik , Carlsson Cynthia M.
Published: January 2025

Background

Each year, millions of Americans experience mild traumatic brain injury (mTBI). Current research on the long‐term effects of mTBI vary considerably. Several mechanisms linking mTBI to dementia have been proposed including amyloid plaque formation and cerebrovascular injury following mTBI. Veterans have higher rates of mTBI than non‐Veterans. As efforts to increase Veteran enrollment in clinical trials and studies related to Alzheimer disease expand, it is critical to understand the potential impact of mTBI on cognitive ability and factors related to risk for AD. This study leveraged two cohorts to examine the association between history of mTBI and white matter hyperintensity lesion volume (WMLV), CSF pTau181, total tau, and Aβ42, and cognitive ability.

Method

The sample comprises, N = 131 VA eligible Veterans without memory impairment enrolled in the Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE) clinical trial (NCT02719327) and N = 320 participants in the Wisconsin ADRC clinical core, including n = 36 identified as Veterans. BRAVE participants reported if they had experienced symptoms of mTBI (e.g. loss of consciousness, dizziness, headache). ADRC participants indicated if they had a recent or remote mTBI; participants with a recent mTBI were excluded (n = 6).

CSF samples were assayed using elecsys® beta‐Amyloid(1_42) CSF II, phopho‐Tau (181P), and Total tau assays (Roche Diagnostics International, Switzerland) and log‐transfomed prior to analyses. WMHLV adjusted for TIV was binarized to WMH presence or absence. Separate Preclinical Alzheimer’s Cognitive Composite scores were created for BRAVE and were analyzed separately. Regression models included gender, age at study visit, clinical status and education level (PACC only) as covariates.

Result

Demographics and study outcomes stratified by cohort and Veteran status are shown in Table 1 and 2. Veterans had higher rates of mTBI than non‐Veterans. History of mild TBI status was unrelated to study outcomes (see Figure 1; WMH presence: p = .06; CSF biomarkers: ps = .50 to .88; BRAVE‐PACC: p = .15, ADRC‐PACC, p = .48).

Conclusion

History of mild TBI had no long‐term impact on cerebrovascular dysfunction, AD biomarkers or baseline cognitive performance. Further analyses will explore severity of TBI (with or without loss of consciousness) on study outcomes as well asexamine the impact of mTBIon change in cognitive performance and biomarkers of neuroinflammation.
Investigating the stability of SuperAging over time
Authors: Loxton Caitlin C , Fong Tamara G. , Jones Richard N , Marcantonio Edward R , Schmitt Eva M , Katsumi Yuta , Barrett Lisa F , Touroutoglou Alexandra , Dickerson Bradford C. , Inouye Sharon K. , Wong Bonnie
Published: January 2025

Background

“SuperAgers” (SA) are older adults who perform significantly better than their peers and comparable to young adults on objective memory measures. Longitudinal studies show that many do not maintain their SA status over time. The fluctuation in SA stability may reflect changes in executive functioning, hypothesized to contribute to variance of episodic memory scores in SA. In the present study we analyzed longitudinal neuropsychological performance of SAs in the Selective Aging After Elective Surgery (SAGES) study to examine SA stability. We hypothesized that losing SA status over time will reflect a decline in executive function.

Methods

17 SAs (criteria defined by Katsumi, Wong et al., 2022) (mean age 75.4, 12 females) identified in the SAGES Study were tested annually (up to 84 months). Neuropsychological data for baseline and follow‐up at years 1, 2, and 3 were analyzed. Performance of SAs who no longer met SA criteria after baseline (non‐stable SAs) were compared to that of SAs who maintained their status (stable SAs). A mixed factorial ANOVA was run with Trail Making Test B (TMTB) scores as the dependent variable to determine differences over time between stable and non‐stable SAs.

Results

7/17 non‐stable SAs were identified. Analyses revealed a significant group x timepoint interaction [F(3, 39) = 3.152, p < 0.05]. Assessment of the coefficient of variation calculated across time points revealed that non‐stable SAs showed greater variability in TMB performance (M = 0.21, SD = 0.059) than stable SAs (M = 0.15, SD = 0.064). A significant difference was found between stable SA and non‐stable SA for TMT‐B performance [F(1, 13) = 13.237, p < 0.01. Both groups were similar in age at baseline (p < 0.19).

Conclusions

These findings suggest that current SA definitions need refinement as SA reflects more than superior memory. Ongoing analyses include 7‐year data from the current sample, replication of findings in an independent SA cohort, and examination of the neuroanatomical correlates of the observed differences between stable and non‐stable SAs. Enhancing our understanding of SAs will deepen our knowledge of resilience to decline in aging.
The Impact of Test‐Scoring Models on MCI Diagnosis
Authors: Woods David L. , Baldo Juliana , Hall Kathleen , Blank Michael , Geraci Kristin , Miranda Miranda , Chok Jas M. , Lwi Sandy J. , Jaramillo Isabella , Schendel Krista , Spinelli Maria G , Herron Timothy J , Johnson David K
Published: January 2025

Background

Cognitive‐test scores in the bottom 7% of a normative distribution (z‐score < ‐1.50) are an essential component of the diagnosis of Mild Cognitive Impairment (MCI). However, different patients show MCI‐compatible performance when evaluated using scoring models that account for the influences of different demographic variables (e.g., Age only, Age and Gender, Age, Education, and Gender). Most conventional models exclude many factors (e.g., vocabulary, comorbidities, race, functional impairment, emotional status, etc.) that correlate significantly with test scores. As a result, they reduce score precision, inflate racial disparities in MCI classification, and compromise the detection of MCI in high‐functioning individuals.

Method

415 older participants (mean age 70.1 years) completed three 90‐minute enrollment test sessions using the California Cognitive Assessment Battery (CCAB). Omnibus z‐scores were obtained by averaging z‐scores from 70 performance measures. Stepwise linear regression was used to identify factors that contributed significantly (p<0.01) to the solution, after outliers (typically ∼3% of scores) were eliminated. We compared MCI classification using unadjusted performance scores and models with different predictors including (1) Age, (2) Age and Gender; (3) Age, Education, and Gender (AEG), and (4) a Comprehensive model that included 15 demographic factors (see Table 1). All models were tested for heteroskedasticity, multicollinearity, and normality.

Result

Table 1 shows Pearson correlations with omnibus z‐scores (averaged over test scores) of the 15 demographic factors included in the Comprehensive model. The five factors that contributed significantly (p< 0.01) and independently to the model were included in the final model solution. Figure 1 shows omnibus z‐scores calculated with AEG and Comprehensive models. Table 2 shows the model root mean squared error and the racial bias of MCI classification for each of four models, along with the percentage of patients with identical MCI classifications on the different models. Less than one‐third of participants with MCI‐level performance on the Comprehensive model showed MCI‐level performance on other models.

Conclusion

MCI classification is strongly influenced by the model used to score performance. Compared to other models, a Comprehensive model accounted for more variance, reduced racial bias in MCI classification, and identified different participants with performance in the MCI range.
Preservation amidst decline: wake‐promoting histaminergic system provides a novel target to mitigate sleep/wake dysfunction in Alzheimer’s disease
Authors: Satpati Abhijit , Pereira Felipe Luiz , Soloviev Alexander V. , Mladinov Mihovil , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Rodriguez Roberta Diehl , Paes Vitor Ribeiro , Walsh Christine M , Spina Salvatore , Seeley William W. , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Neylan Thomas C. , Grinberg Lea T.
Published: January 2025

Background

Excessive daytime sleepiness is a common and early symptom of Alzheimer’s disease (AD). The subcortical wake‐promoting neurons in the lateral hypothalamic area, tuberomammillary nucleus (TMN), and locus coeruleus synchronize to maintain wakefulness/arousal. Although significant neuronal decline occurs in wake‐promoting regions, the TMN histaminergic neurons remain relatively more intact than orexinergic and nor‐adrenergic neurons. The preserved histaminergic neurons could be a potential target for addressing sleep dysfunction when neurons in the wake‐promoting system degenerate. We aimed to map neuropathological and molecular events in poorly understood histaminergic neurons across AD progression in the human TMN to help understand pathogenic features and guide therapeutic strategies.

Method

We used unbiased stereology and double‐immunohistochemistry to quantify pTau (CP13) accumulation, the number of histaminergic, and total neurons in the TMN in subjects across progressive Braak stages (n = 20). Data were analyzed using the Wilcoxon signed‐rank test. We used a customized Neuropathology nCounter® (Nanostring) panel for proteomic analysis. Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when the p‐value was <0.05.

Result

TMN total neuronal count remained constant across Braak groups (BG), underscoring TMN’s resilience to AD compared to other wake‐promoting neurons. Histaminergic (HDC+CP13‐) neurons declined between BG 0‐2 and 5‐6 (p = 0.013). The number, proportion, and density of pTau inclusions in histaminergic and total TMN neurons increased across BG (p<0.05) (Fig. 1, Table 1). In Braak 5‐6 over 0‐2, we found 284 differentially expressed genes in TMN, of which 171 were upregulated. Gene ontology analysis demonstrated upregulation of cytokine‐cytokine receptor interaction pathways (p = 0.015). In Braak 5‐6 over 0‐2, histamine decarboxylase (HDC) expression was downregulated (lfc = ‐0.819, p = 0.37) with increased expression of histamine receptors HRH1 (lfc = 1.26, p = 0.028) and HRH2 (lfc = 1.76, p = 0.019) (Fig. 2).

Conclusion

Stereological data revealed that the decline in histaminergic neurons is associated with pTau accumulation and reduced histamine synthesis rather than neuronal loss. This is corroborated by a decrease in HDC expression and an upregulation of histaminergic receptor expression (potentially compensatory) in late Braak stages. Interventions focused on pTau removal may succeed in reinstating histaminergic neuro‐transmission/‐modulation, improving cognition, and restoring sleep‐wake dysfunction in AD patients.
Behavioral and metabolic profiles in an aged, humanized APP/APOE mouse model of Alzheimer’s Disease risk
Authors: McLean John W. , Bhattrai Avnish , Brinton Roberta Diaz
Published: January 2025

Background

Research into Alzheimer’s Disease (AD) pathomechanisms frequently utilizes animal models with dominant mutations; however, the vast majority (>95%) of AD cases are idiopathic. Animal models with AD risk factors represent an approach with potentially greater translational validity. The predominant genetic risk factor for AD is the Apolipoprotein E ε4 (APOE4) polymorphism, with APOE4 homozygosity conferring approximately 15‐fold higher risk relative to the normative APOE3/3 genotype. Additionally, women are nearly twice as likely to develop AD. To address the translational validity of a risk factor model approach for AD research, we investigated behavioral and metabolic differences in a novel mouse model with homozygous expression of humanized (h) amyloid precursor protein (hAPP), encoding the precursor of the major protein in amyloid plaques, and replacement of murine Apoe with humanized hAPOE3 or hAPOE4.

Method

Aged (22‐24 months) hAPP/APOE3 and hAPP/APOE4 mice underwent open field (OF), novel object recognition (NOR), EchoMRI body composition analysis, fasting blood glucose (FBG) and ketone body (FKB) determinations. Data were analyzed by 2‐way ANOVA for effects of biological sex and APOE genotype followed by post‐hoc t‐tests and considered significant at p<0.05.

Result

Female mice traveled significantly farther and for a greater percentage of time during both OF and NOR, and interacted more with both familiar and novel objects during NOR. There were no group differences in either thigmotaxis or novelty recognition. EchoMRI body composition analysis revealed significant weight reduction in both male and female APP/APOE4 mice. While weight loss included a decline in both lean and adipose mass, greater loss of adipose tissue in APP/APOE4 mice resulted in lower body fat percentage and was the major contributor to weight loss.

Conclusion

Metabolically, female mice had lower FBG and higher FKB relative to males. The sex difference was greater in APP/APOE4 females, which had the lowest FBG and highest FKB. The hAPOE4‐driven reduction in body weight, especially in adipose tissue, further indicates a metabolic consequence in mice expressing the AD risk gene. Collectively, this program of research contributes to the determination of the translational validity of the humanized APOE and APP mouse model for preclinical target identification and therapeutic development for AD.
Brain Health Screening in Israel’s Diverse Population
Authors: Haddad Rafi , Ben‐Hayun Rachel , Ayoub Rawan , Natalya Yarovinsky , Shihada Essam , Shor Merav , Levavi Michal , Fisher Tali , Aharon‐Peretz Judith , Tanne David
Published: January 2025

Background

Israeli population is primarily comprised of Jews (74%) and Arabs (21%). Previous studies suggested a higher incidence of cerebrovascular risk factors (CVRF) and dementia among Israeli Arabs. We evaluated potential cognitive disparities between community‐dwelling Arabs and Jews diagnosed with at least one CVRF.

Method

96 participants (age: 66.6± 5.3; education: 14.8± 4.1), 52 Arabs (age: 64.4± 5; education: 15.3±2.6), and 44 Jews (age: 69.1± 4.4; education: 14.8± 4.1) without known cognitive impairment and with at least one CVRF were prospectively enrolled. All participant completed a cognitive symptoms questionnaire (in their primary language) and underwent the Montreal Cognitive Assessment (MoCA) and the Tablet‐based Cognitive Assessment Tool (TabCAT) Brain Health Assessment (BHA) battery, including the TabCAT Favorites (associative memory), Match (executive functions and processing speed) and Line Orientation (visuospatial skills) tasks. Demographic and clinical characteristics were analyzed using the Student’s t‐test for continuous variables and Chi‐squared tests for categorical data.

Results

Arab participants were younger (p≤0.001) than Jews, education was similar (p = 0.26). Cognitive complaints were reported by 32 (33%) participants, (24% Arab,9% Jews). Participants with cognitive complaints exhibited significantly lower scores on Match (p = 0.005), but not on Favorites (p = 0.28), Line Orientation (p = 0.48), and MoCA (p = 0.62). Arabs scored significantly worse on Match (p = 0.006) while Jews scored worse on Line Orientation (p = 0.004). Performance was similar on the Favorites (p = 0.4) and MoCA (p = 0.2). When focusing on participants with cognitive complaints Arabs exhibited significantly lower scores on Match (p = 0.036) while Jews had lower scores on Line Orientation (p = 0.06). No significant differences were observed on Favorites (p = 0.4) or MoCA (p = 0.2). Among participants without cognitive complaints no significant differences were observed between Jews and Arabs on Match (p = 0.29), Favorites (p = 0.99) or MoCA (p = 0.65). Jews had lower scores on Line Orientation (p = 0.04).

Conclusion

TabCAT‐BHA proved superior to MoCA in depicting subtle cognitive impairment in people with CVRF. Despite being younger, Arabs exhibited higher prevalence of cognitive complaints and were more impaired on executive functions while Jews on visuospatial tasks.
Multi Site Comparison of Participant Profiles in the South Texas Alzheimer’s Disease Research Center
Authors: Bosque Jennifer G Del , Wang Chen‐Pin , Fernandez Roman A. , Tanner Jeremy A. , Sullivan A. Campbell , Savoia Sarah E. , Parker Alicia S. , Salardini Arash , de Erausquin Gabriel A. , Goss Monica , Trevino Hector A , Patel Aishwarya N. , Katragadda Haritha V. , Seidl Amaya M , Saklad Amy R. , Werry Amy , Gonzales Mitzi M. , Pirela‐Mavarez Rosa P. , Mejia‐Arango Silvia , Lavigne Shannon , Hromas Gabrielle , Santiago‐Mejias Stephanie , Satizabal Claudia L , Hilsabeck Robin C. , Maestre Gladys E. , Seshadri Sudha , LaRoche Ashley
Published: January 2025

Background

Hispanic adults comprise 19% of the US population, yet <8% of Alzheimer’s Disease and Related Dementia (ADRD) research cohorts. Hispanic adults in the US are 1.5 times more likely to develop ADRDs compared to Non‐Hispanics. Considering the projected growth in Hispanics in the US, a >400% increase in ADRDs in this population is anticipated over the next twenty‐five years. Knowledge is limited on the prevalence and influence of social determinants of health (SDoH) and modifiable risk factors on cognition in ethnically diverse groups. The South Texas Alzheimer’s Disease Research Center (STAC, P30AG066546) is a collaboration between UT Health San Antonio (UTHSA) and UT Rio Grande Valley (UTRGV) with a primary aim to better understand ADRDs in Hispanic adults. Our objective is (1) to describe differences in SDoH, modifiable risk factors, and cognitive performance in cognitively unimpaired adults in STAC, and (2) to assess differences between sites to better understand the risk factors in ADRDs in Hispanics by location.

Method

Participants in San Antonio, Tx, and Rio Grande Valley, Tx completed cognitive testing and questionnaires of medical history, SDoH, and modifiable ADRD risk factors. The two sites were compared between sites with Wilcoxon and T‐Tests. Differences in neurocognitive performance was further assessed with linear regression adjusting for age, sex, and education.

Result

Cognitively unimpaired adults were enrolled at UTHSA (n = 180, mean(SD) age 71(10), 36% male, 47% Hispanic) and UTRGV (n = 45, age 63(12), 33% male, 71% Hispanic). Participants at UTRGV were younger and more frequently identified as Hispanic. Site differences were seen on Trails B (p < 0.001), and Number Span Total Forward (p = .001) and Total Backward (p = 0.009) after adjusting for age, sex, and education. Sites showed differences in risk factors including hyperlipidemia (p = <.001), hearing loss (p = .022), Sleep Apnea (p = .006), and alcohol use (p = .022). Other risk factors were similar across sites.

Conclusion

Overall, there were significant differences in the risk factors between locations, supporting the value of recruiting participants at both sites to assess the spectrum of risk factors and SDoH in Hispanic adults.
Vitamin D and donepezil intervention in ovariectomized rats: modulating neuroinflammation in the aging brain
Authors: Danielski Lucineia , Medeiros Eduarda Behenck , Fenilli Gabriela Piovesan , Zabot Gabriel Casagrande , Vargas Adrielly , Boaventura Amanda L , Lumertz Mariana Cardoso , Bobinski Franciane , Giridharan Vijayasree V , Barichello Tatiana , Budni Josiane
Published: January 2025

Background

Aging is a natural, irreversible process that can be successful or pathological, resulting in chronic degenerative diseases such as Alzheimer’s disease. Low levels of estrogen characterize menopause. Research reveals that the lack of these hormones may be related to dementia and that vitamin D (vit D), when supplemented, has a neuroprotective and neuromodulator effect.

Method

60‐ or 120‐day‐old Wistar rats were subjected to ovariectomy (OVX) for either 1 or 8 months, treatment with oral administration of Vit D (42 or 420 IU/kg) and/or DONE (1 mg/kg) spanned 21 days. On the 22nd day of the protocol, 24 hours post the final administration, the prefrontal cortex and hippocampus were dissected for cytokine analysis, including interleukin 10 (IL‐10), IL‐1 β, and tumor necrosis factor α (TNF‐ α), conducted through enzyme immunoassay.

Result

In 60‐day‐old rats undergoing one month of ovariectomy (OVX), elevated IL‐1β and TNF‐α levels were observed in the brain. The optimal dose for mitigating these effects was found to be vitamin D (Vit D) at 420 IU/kg, either alone or in combination with DONE. This dosage successfully reversed the increased IL‐1β levels in the frontal cortex and normalized the elevated TNF‐α levels in the hippocampus. Similarly, in rats subjected to OVX for eight months, the most effective dose for reversing increased IL‐1β levels in the frontal cortex and hippocampus was Vit D at 420 IU/kg. However, in this protocol, TNF‐α levels remained unchanged, emphasizing the selective impact of this particular dosage. Additionally, the optimal dose for modulating IL‐10 levels in the frontal cortex, particularly in the context of increased IL‐10 following OVX, was Vit D at 420 IU/kg.

Conclusion

The administration of vitamin D either alone or in combination with DONE (a specific treatment) demonstrated favorable outcomes in the rats, effectively mitigating the inflammatory response.
Microglial extracellular vesicles’ proteome sheds light on the mechanisms underlying Alzheimer’s disease progression
Authors: Gabrielli Martina , Tonoli Elisa , Battocchio Elisabetta , Coveney Clare , Boocock David , Arancio Ottavio , Verderio Elisabetta A M , Verderio Claudia
Published: January 2025

Background

We recently demonstrated that large extracellular vesicles (EVs) released by Aβ‐loaded microglia and carrying Aβ (Aβ‐EVs) propagate synaptic dysfunction in the mouse brain by moving at the axon surface (Gabrielli et al., Brain, 2022; Falcicchia et al., Brain Commun, 2023). Compared to ctrl‐EVs, not carrying Aβ, a higher number of Aβ‐EVs move along axons and travel longer distances through a yet undefined mechanism. Our previous work indicates that large EVs motion can be passively driven by neurons, via EV interaction with a neuronal receptor linked to the cytoskeleton, or may happen autonomously when EVs contain actin filaments and ATP in their lumen. To get insights into the mechanisms underlying higher extracellular Aβ‐EVs motion, we here analysed microglial EVs proteome.

Method

Aβ‐EVs were obtained from primary microglia exposed to Aβ42. High‐resolution accurate‐mass spectrometry SWATH™‐MS followed by DIA‐NN quantitative analysis was employed to identify differentially expressed proteins in Aβ‐ vs. ctrl‐EVs, which may justify Aβ‐EVs empowered motility and describe the molecular mechanisms underlying EVs extracellular motion. Western blot and optical manipulation coupled to time‐lapse imaging were also employed to explore the involvement of additional candidate molecules, such as transglutaminase 2 (TG2).

Result

A total of 148 proteins were upregulated in Aβ‐ compared to ctrl‐EVs, while 169 were downregulated. Panther GO analysis showed that terms enriched in large Aβ‐EVs include cytoskeletal protein binding (GO:0008092) and ATP hydrolysis activity (GO:0016887), suggesting that a higher fraction of Aβ‐EVs may undergo independent motion. STRING analysis revealed a high protein‐protein interaction (PPI) among Aβ‐EVs enriched molecules, some of which are differentially expressed also in EVs from AD/MCI patients or AD mouse models, validating the relevance of our findings.

Conclusion

Our data suggest that Aβ‐EVs higher motility and capability to propagate synaptic dysfunction may be due to their augmented capacity to undergo active motion, and identify novel proteins potentially involved in EVs motion. Further analysis will be necessary to validate these findings in AD.

Fundings: 2018‐AARF‐588984, Horizon2020#874721PREMSTEM.
Predicting Objective Cognitive Impairment on MMSE with CDFAQ
Authors: Tavares Caio Peixoto , Maia Isabelle de Aguiar , 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 , de Mattos Viana Bernardo
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 (3). 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 predict objective cognitive impairment on Mini‐Mental State Examination (MMSE) with CDFAQ‐IV. Both instruments were applied in 196 older adults and their informants. The cut‐off points on MMSE were 19/20 for illiterates and 23/24 for those with one year or more of formal education (4). A multiple logistic regression was made to assess the CDFAQ likelihood to predict a performance below the cut‐off points on MMSE controlled by years of age and of education. This study was approved by the ethics committee of UFMG.

Results

The median age of the older adults was 73 years (IQR = 13.25), median years of education of 4 years (IQR = 5), median CDFAQ‐IV score of 64 (IQR = 9), and median MMSE score of 23 (IQR = 9). One hundred and six participants (54.08%) had impaired results on MMSE. When controlled by age and education, the Odds Ratio (OR) of one point increase in CDFAQ had an OR of 1.039 (p = 0.029) to predict an objective cognitive impairment on MMSE. A one‐year increase in formal education, had a decreased OR of 0.862 (p < 0.001). Age was not associated to the prediction of an objective cognitive impairment on MMSE, when controlled by education and CDFAQ performance (p = 0.106).

Conclusions

Years of education and CDFAQ scores were related to the prediction of objective cognitive impairment measured by MMSE. These are still preliminary studies, but these results point to the need of considering the importance of years of education for future norms of the CDFAQ.
Androgen receptor upregulation regulates tau pathology in a female tauopathy mouse model
Authors: Munoz‐Mayorga Daniel , Lyu Xinchen , Tao Yuren , Kauffman Alexander S. , Rissman Robert A. , Chen Xu
Published: January 2025

Background

According to data from the Alzheimer’s Association, more than two‐thirds of patients living with Alzheimer’s disease (AD) in the United States are women. The interplay between aging and hormone depletion during menopause has been proposed as a leading cause, but the molecular underpinnings of this vulnerability are not fully understood. On the one hand, approaches that seek to supplement estrogens to rescue pre‐menopausal hormonal levels have had contradictory outcomes in clinical trials. On the other hand, androgen effects in women in a neurodegeneration context are dramatically understudied. Furthermore, the number of XX chromosome individuals using androgens for sex‐reassignment purposes has steadily increased. Whether androgens can regulate tau pathology and how is poorly understood, especially in the context of female physiology.

Method

We performed a dihydrotestosterone (DHT) supplementation paradigm in 5‐6 month old P301S female mice and harvested brain tissue at 9 months of age. Pathological and biochemical tau markers, as well as androgen receptor content were evaluated in the hippocampus and cortex.

Result

Here, we report an exacerbation of tau pathology in tauP301S female mice treated with DHT, an androgen receptor (AR)‐specific ligand, in the hippocampus, as evaluated by AT8 and MC‐1 immunostaining. Furthermore, we report upregulation of AR almost exclusively in neurons upon DHT treatment, potentially mediating our observations.

Conclusion

Our results implicate AR activation in females as a potential risk factor for tau pathology. Overall, the AD field will benefit from a more thorough understanding of neurodegeneration in women and transmasculine individuals, facilitating the identification of different risk and protection factor, paving the way to the development of novel and targeted therapies, and better addressing the health issues of our diverse society.