bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance of a short version of the Everyday Cognition scale (ECog‐12) to detect cognitive impairment
Authors: Manjavong Manchumad , Diaz Adam , Eichenbaum Joseph , Ashford Miriam T. , Aaronson Anna , Miller Melanie J. , Kang Jae Myeong , Mackin Scott R , Tank Rachana , Landavazo Bernard , Truran‐Sacrey Diana , Farias Sarah Tomaszewski , Weiner Michael S. W. , Nosheny Rachel L.
Published: January 2025

Background

The Everyday Cognition questionnaire is a sensitive tool for measuring decline in activities of daily living and can differentiate dementia from normal cognition. There is limited data on comparing the ECog‐12 performance by raters (self vs. informant/study‐partner) and scoring systems (continuous average score vs. a categorical grouping) to differentiate cognitive statuses.

Method

ECog‐12 data were extracted from the 39‐item version collected in the Alzheimer’s Disease Neuroimaging Initiative. Participants (n = 1593) were divided into subgroups based on diagnosis. The average and categorized ECog‐12 scores were calculated. Logistic regression was used to evaluate the ECog‐12 performance in five different diagnostic groups, including discriminating between cognitively unimpaired (CU; n = 666) vs. cognitive impairment (CI; MCI and AD), CU vs. MCI (n = 707), CU vs. AD (n = 220), AD vs. MCI, and CI with amyloid pathology (n = 532) vs others. Simple logistic regression models with the ECog‐12 score as the sole independent variable were used to evaluate the association with CI, and multiple logistic regression models with participant characteristics included as covariates. This procedure was repeated for self/participants (PT) and study‐partners (SP; n = 1571) reports.

Result

ECog‐12 cut‐off scores of 1.36 (PT) and 1.45 (SP) distinguish CU from CI with AUC 0.7 (0.68‐0.73) and 0.78 (0.76‐0.8). Adding a memory‐concern question to the ECog‐12 of PT increased the AUC to 0.78. Any consistent SCD (categorized scores) of PT and SP provided AUC 0.69 (0.67‐0.71) and 0.78 (0.76‐0.8). Average ECog‐12 of PT and SP can differentiate between MCI and CU (AUC: 0.69, 0.75), AD and CU (AUC: 0.74, 0.93), AD and MCI (AUC: 0.57, 0.77), and amyloid‐positive CI and others (AUC: 0.65, 0.75). Average ECog‐12 of SP had a higher association with CI than PT (OR 35.45 vs. 8.79, 95%CI 22.41‐58.03 and 6.32‐12.43, respectively).

Conclusion

The ECog‐12 of SP showed higher performance in differentiating between the different cognitive statuses and higher prognostic value than that of PT. A memory concern question enhanced the performance of ECog‐12 of PT. The ECog‐12 (PT and/or SP) could be a valuable tool for quickly (and potentially remotely) assessing a person’s cognitive status for research studies and in clinical practice.
Cognitive screening in the emergency department: Agreement between the patient‐ and caregiver‐completed AD8
Authors: Galske James , Sather Anna , Chera Tonya , Hwang Ula , Carpenter Christopher R , Gettel Cameron
Published: January 2025

Background

Impaired cognition is prevalent in older adults in the emergency department (ED), but many cases go unrecognized. The Ascertain Dementia 8 (AD8) is a validated, self‐administered screening tool that can be used by patients and caregivers to assess for early cognitive changes associated with dementia. However, little is known regarding the degree of alignment between respondents in the ED setting. Our objective was to assess the agreement between the patient‐(pAD8) versus caregiver‐completed AD8 (cAD8).

Methods

We conducted a prospective observational study of community‐dwelling older adults aged 65+ years seeking emergency care and their caregivers between October 2021 and November 2023. Patients with a diagnosis of dementia indicated in the electronic health record were excluded. Collected by trained research assistants, AD8 scores ranged from 0‐8, with scores 2+ indicating cognitive impairment. Patients and caregivers were blinded to the others’ AD8 rating. The intraclass correlation coefficient (ICC) was used to assess the agreement of the presence or absence of cognitive impairment based on pAD8 and cAD8 scores.

Results

Our analytic sample included 538 dyads, of which 34.7% of patients were male with a mean age of 73.5. A total of 132 (24.5%) patients scored themselves as cognitively impaired versus 201 (37.4%) patients were scored as cognitively impaired by their caregivers. Between groups, an ICC of 0.519 (95% CI 0.454‐0.578) demonstrated moderate agreement in identifying cognitive impairment based on pAD8 and cAD8 scores.

Conclusion

Approximately 1 in 4 older adults without a dementia diagnosis in the emergency department identified themselves as having cognitive impairment, with caregivers even more likely to identify cognitive impairment in accompanied older adult patients. With current guidance suggesting that the pAD8 be used in the absence of the cAD8, these findings highlight important differences to account for based on the respondent when screening for cognitive impairment.
APP Gene Duplication Unraveled: A Unique Case of Atypical Dementia with Prominent Psychiatric Concerns in a Hispanic Male
Authors: Castro Julia , Velazquez Sandra Azareli Garcia , Kautz Tiffany F. , Mendoza Crystal , Salardini Arash , Seshadri Sudha , Parker Alicia S. , Sullivan A. Campbell
Published: January 2025

Background

APP duplications are a rare form of familial Alzheimer’s disease (AD). Research has shown variability in clinical presentation with full duplications. There is limited information on those with partial duplications, especially in underrepresented minorities.

Methods

A 64 y/o Hispanic male presented with a 2.5 year history of anxiety, restlessness, coarsening behavior, cognitive and functional decline, and motor changes. We present findings from neuropsychological evaluation, neurological exam, neuroimaging, and genetic testing. Plasma‐based biomarkers are pending.

Results

The clinical course is notable for rapid onset of anxiety at age 62 with intrusive thoughts, delusional beliefs, and repeated psychiatric hospitalizations. Motor changes include myoclonic jerks, increased restless with pacing and rocking, and bradykinesia. The family described a 30lb weight loss without dieting, dietary changes with a preference for sweets, withdrawal from social interactions, and poor judgment. DaT scan was positive; synuclein biopsy was negative. Brain MRI revealed remote left basal ganglia lacune and superficial parietal atrophy. Neuropsychological assessment revealed prominent executive dysfunction, and amnestic verbal learning and recall, with preserved visual learning. Family history included late‐onset forgetfulness in his mother and abnormal behaviors in maternal half‐cousins.

Genetic sequencing uncovered a partial APP gene duplication (exons 1‐11, including the initiator codon). Illumina SNP chromosomal microarray confirmed a 21q duplication also including the CYYR‐1 and CYYR1‐AS1 genes, with the partial APP duplication defined as “uncertain” per ACMG guidelines.

Conclusion

This case study describes an atypical dementia syndrome in a 64 y/o Hispanic male with a partial APP gene duplication. The clinical syndrome is notable for neuropsychiatric symptoms and parkinsonism. This report is consistent with recent work highlighting atypical dementia among a small proportion of those with APP duplications. However, our findings show the ramifications of a partial duplication within an underrepresented population, emphasizing the need for further exploration.
Brain Barrier Aging is Associated with Changes in Brain Plasticity and Decline in Processing Speed: A Proteomic Study of Human Cerebrospinal Fluid
Authors: Elahi Fanny
Published: January 2025

Background

Protective brain barriers, such as blood‐brain barrier, become dysfunctional with age. The BBB is a dynamic and selective barrier, gating the passage of molecules and cells to and from the brain. The function of this barrier is critical for the maintenance of brain homeostasis. BBB dysfunction has been reported in aging and disease states, with downstream consequences on long‐range neuro‐glial networks subserving emotions, cognition, movement, and sensations. The molecular mediators of the effect of BBB leakage on neuro‐glial networks is not well understood.

Methods

Using large‐scale proteomics and targeted ELISA assays to interrogate over 7000 proteins in cerebrospinal fluid (CSF) of highly phenotyped aging older adults, we interrogated signatures of BBB dysfunction in aging and AD. Our analytical workflow consisted of principal component analysis, linear modeling, and ontology analyses.

Results

We identified distinct CSF‐proteomic signatures for leaky BBB and demonstrate associations with markers of synaptic dysfunction and slowed processing speed. We found several associations between BBB leakage and upregulation in pathways classically thought to be neurodevelopmental including Ephrin and neuropilin signaling. We validated our findings in an independent Alzheimer’s disease dataset.

Conclusion

This study presents a multivariate approach for investigating large‐scale omics data and provides insights into the potential mechanisms for vascular cognitive aging, with a focus on aging of the brain’s barriers.
Psychosis in Neurocognitive Disorder for Ethnoculturally Diverse Older Persons
Authors: Isaac Estevana Juanita , Federman Alex , Sano Mary , Siu Albert , Mindt Monica Rivera , Zhu Carolyn W.
Published: January 2025

Background

There is longstanding evidence that the presence of psychosis in neurocognitive disorders is associated with faster deterioration of cognitive function. These reports also describe greater care partner burden, higher rates of institutionalization and functional decline, especially among ethnoculturally diverse persons. The goal of this study is to examine the association of race/ethnicity with rates of psychosis in neurocognitive disorders among ethnoculturally diverse older persons.

Method

Data are from the National Alzheimer’s Coordinating Center Uniform Dataset, a longitudinal dataset with annual patient assessments from ∼40 National Institute of Aging funded Alzheimer’s Disease Research Centers. Participants aged 40‐95 years as of June 2023 with mild cognitive impairment (MCI) or dementia were included. Psychosis was defined as clinician diagnosed visual or auditory hallucinations or delusions. Race and ethnicity were self‐reports categorized as non‐Hispanic White (NHW), NH‐Black/African American (AA), Hispanic/Latino, Asian, and American Indian/Native Alaskan (AI/NA). Associations between race/ethnicity and psychosis were estimated using multivariable generalized estimating equation (GEE) models with repeated measures of outcomes and covariates (severity of cognitive impairment, age, sex, history of anti‐psychotic medication use and history of mood disorder). Analyses stratified by age of cognitive impairment onset (40‐65 years and 65‐95 years) were also performed.

Result

25,731 participants had a mean age 72.5±9.7, 51% female, 76% NHW, 12% NH‐Black/AA, 8% Hispanic/Latino, 3% Asian and 1% AI/NA (Table 1). At baseline, 15,646 (60.8%) had MCI and 10,085 (39.2%) had dementia. The rate of psychosis was highest among Hispanic/Latino (15.7%), AI/NA (14.7%) and Black/AA (12.5%) (Graph1). In adjusted analysis, NH‐Black/AA had significantly greater odds of psychosis (OR 1.73, 95% CI 1.17‐2.19), including visual hallucinations (OR 1.33, 95% CI 1.18‐1.51), auditory hallucinations (OR 1.69, 95% CI 1.41‐2.03) and delusions (OR 1.73, 95% CI 1.56‐1.92) (p<0.05) (Table 2). Hispanic/Latino and AI/NA participants had even greater odds of psychosis than NHWs (Table 2). Only Black/AA and Hispanic/Latino participants with early‐onset neurocognitive disorder (40‐65 years) had greater odds of psychosis than NHWs (Table 2).

Conclusion

Black/AA, Hispanic/Latino and AI/NA individuals were more likely to be diagnosed with psychosis in neurocognitive disorders when compared to NHWs. More research is needed to explore psychosocial, neuropathology and genetic factors involved.
Global and local process on the Rey Complex Figure Test in older adults
Authors: Seo Eun Hyun , Yoon Hyung‐Jun , Kim Seung Gon , Choi Kyu Yeong , Ha Jung‐Min , Kim Hoowon , Lee Kun Ho
Published: January 2025

Background

Recent studies have shown that the Rey Complex Figure Test (RCFT) is useful for early detection of Alzheimer’s disease (AD). While RCFT is known as a test for visuoconstruction and memory, it demands executive components during copying and recalling of the complex figure. This study aims to explore which features of executive function are involved in RCFT performance and which of them are clinically significant indicators in older adults.

Method

We included 4540 participants (2384 cognitively normal, 272 subjective cognitive decline, 1662 mild cognitive impairment, 222 dementia) from the GARD Cohort in Korea. Based on the qualitative analysis by Cherrier et al (1999), we further divided the RCFT score into six groups (gestalt/ detail/ left/ right/ upper/ lower) to explore specific executive component. The RCFT subscores were compared between groups using ANCOVAs. Partial eta squared (η2p
) was calculated for effect size. Linear regression analysis with stepwise selection was performed to examine associations between the RCFT subscores and other neuropychological scores.

Result

The six subscores from copy, immediate recall, and delayed recall trials were all significantly different among CN, SCD, MCI, and dementia groups. Based on η2p, ‘detail’ score on copy trial (η2p, = 0.228) ‘gestalt’ scores on memory trials (η2p, = 0.185 for delayed; η2p, = 0.213 for delayed) showed largest effects. In terms of relations to cognitive domain, for copy trial, both ‘gestalt’ and ‘detail’ scores were associated with tests of psychomotor (ß = 0.074∼0.193, all p <0.0001), delayed verbal memory (ß = 0.067∼0.077, all p <0.0001), and executive functions (ß = ‐0.176∼‐0.185, all p <0.0001). For memory trials, ‘gestalt’ scores were mainly associated with tests of executive functions (ß = ‐0.069∼‐0.100, all p <0.0001), whereas, ‘detail’ scores were mainly associated with tests of psychomotor and attention (ß = ‐0.073∼‐0.144, all p <0.0001).

Conclusion

Our results suggest that the RCFT performance involves cognitive process regarding strategic planning and organization of a fractional figure into whole object. In particular, local process on copy trial, measured by ‘detail’ score and global process on memory trials, measured by ‘gestalt’ score may be a useful indicator of early cognitive impairment. It may be necessary to collect procedural features during RCFT performance to capture perceptual organisation strategies.
Does Apolipoprotein E polymorphism play a role in familial Alzheimer’s Dementia
Authors: Vinod Pratibha , Sen Somdatta , Jayasankar Pavithra , Janardhanan Meghana , Paul Pradip , Viswanath Biju , Jain Sanjeev , Harbishettar Vijaykumar , Sivakumar Palanimuthu Thangaraju , Purushottam Meera
Published: January 2025

Background

Apo E4 is the best studied genetic risk factor for sporadic Alzheimer’s disease. Apo E2 homozygosity is associated with a lower risk of Alzheimer’s disease. While rare and common variants in genes encoding APP metabolism are strongly linked to familial dementia, however family history and ApoE 4 genetic risks have been found to co‐occur.

Aim to evaluate the frequency of Apo E polymorphisms and their relationship with the of family history and clinical characteristics in a cohort of 483 patients with Alzheimer’s dementia.

Method

Persons with Alzheimer’s dementia were identified from a tertiary care center in India. Their family history status, and detailed clinical characteristics were collected. Genotyping was done at the apolipoprotein E (Apo E) locus using real time PCR.

Result

Of the 483 patients analyzed; 142 patients had a family history of Alzheimer’s dementia in at least one first degree relative. Absence of Apo E2 homozygosity was noted in the sample. Patients with family history had a higher likelihood of an Apo E4 carrier status (OR = 1.6071; Confidence Interval 1.0840 to 2.3829 p = 0.00182).

The Apo E4 frequency in the overall sample was 25.05%.

Conclusion

There is a correlation between Apo E4 carrier status and the likelihood of a positive family history. It remains to be known whether family history effects are separable from Apo E4 related effects.
Poor sleep quality as a potential trigger for cognitive deficits
Authors: Carnes Anna , Piñol‐Ripoll Gerard , Ariza M , Cano N , Segura Barbara , Junqué Carme , Garoellda M
Published: January 2025

Background

In the present study we aimed to assess the cognition of post‐COVID condition (PCC) participants regarding their sleep quality, and to analyse different possible moderators of this effect, such as quality of life (European Quality of Life‐5 Dimensions, EQ‐5D), fatigue (Chadler Fatigue Questionnaire, CFQ), cognitive reserve (Cognitive Reserve Questionnaire, CRC), and subjective cognitive complaints (Memory Failures of Everyday Questionnaire, MFE‐30).

Method

We included 373 individuals with PCC and 126 healthy controls (HCs) from the NAUTILUS Project (NCT05307549 and NCT05307575) that were assessed with a comprehensive neuropsychological battery and different questionnaires.

Result

We included 373 individuals with PCC and 126 healthy controls (HCs) from the NAUTILUS Project (NCT05307549 and NCT05307575) that were assessed with a comprehensive neuropsychological battery and different questionnaires. We found that PCC participants with poor sleep quality have a 4.3% greater risk of having immediate verbal memory deficits the greater the MFE‐30 score (Odd Ratio (OR) 1,043; Confidence Interval (CI) 1,023‐1,063). Also, they multiply their risk of having immediate verbal memory disorders by 2.4 when the EQ‐5D is low (OR 0,33; CI 0,145‐0,748), and they have less risk of having delayed visual memory deficits the greater the CRC (OR 0,963; CI 0,929‐0,999). With processing speed performance, PCC participants and poor sleep quality have a 6.7% greater risk of having deficits the greater the MFE (OR 1,059; CI 1,024‐1,096) and the risk of slowing processing speed triples the lower the EQ‐5D (OR 0,021; CI 0,003‐0,141).

Conclusion

These results indicate that poor subjective sleep quality plays a role as a potential trigger for cognitive deficits. Therapeutic strategies to maximize sleep quality would be reducing not only sleep disturbances, but perhaps also cognitive impairment in PCC participants.
Functional connectivity associations with markers of disease progression in GRN mutation carriers
Authors: Flagan Taru M. , Chu Stephanie A. , Häkkinen Suvi , Zhang Liwen , McFall David , Heller Carolin , Rohrer Jonathan D. , Brown Jesse A. , Lee Alex Jihun , Fernhoff Kristen , Pasquini Lorenzo , Mandelli Maria Luisa , Tempini Maria Luisa Gorno , Yokoyama Jennifer S. , Sturm Virginia , Appleby Brian , Dickerson Brad C , Domoto‐Reilly Kimiko , Foroud Tatiana M. , Geschwind Daniel H. , Ghoshal Nupur , Graff‐Radford Neill R , Grossman Murray , Hsiung Ging‐Yuek Robin , Huang Eric J. , Huey Edward D. , Kantarci Kejal , Karydas Anna M. , Kaufer Daniel , Knopman David S. , Litvan Irene , MacKenzie Ian R , Mendez Mario F. , Onyike Chiadi U. , Petrucelli Leonard , Ramos Eliana Marisa , Roberson Erik D , Rojas Julio C. , Tartaglia Maria Carmela , Toga Arthur W. , Weintraub Sandra , Forsberg Leah K. , Heuer Hilary W. , Boeve Brad F. , Boxer Adam L. , Rosen Howard J. , Miller Bruce L. , Moreno Fermin , Seeley William W. , Lee Suzee E. ,   the ARTFL/LEFFTDS Consortia
Published: January 2025

Background

Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.

Method

Utilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity.

Result

NfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers.

Conclusion

In presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.
Moving along the ALS‐bvFTD spectrum: changes in MEG‐based brain network topology
Authors: Govaarts Rosanne
Published: January 2025

Background

Amyotrophic lateral sclerosis (ALS) with only motor impairment (ALS‐pure motor) and the behavioral variant of frontotemporal dementia (bvFTD) are hypothesized to be the extreme ends of the ALS‐bvFTD spectrum. This spectrum also encompasses ALS patients with mild to severe cognitive impairment (ALSci) and/or behavioral impairment (ALSbi), including ALS with concomitant bvFTD.

In a previous study, using magnetoencephalography (MEG), in early symptomatic ALS patients we showed resting‐state functional connectivity changes in frontal, limbic and subcortical regions that overlap considerably with bvFTD. These findings showed the potential of MEG to detect brain changes in early symptomatic phases of ALS and contribute to our understanding of the disease spectrum, with ALS and bvFTD at the two extreme ends.

In our current study we used MEG in a longitudinal design, to investigate the changes in brain network topology of ALSci/bi over time as compared to ALS‐pure motor and bvFTD patients.

Method

Resting‐state MEG was recorded in ALS‐pure motor (n = 9), ALSci/bi (n = 16) and bvFTD (n = 16) at baseline and mean (SD) 5.4‐month (0.8) follow‐up, and projected to source‐space. The corrected version of the amplitude envelope correlation (AECc) was applied to compute frequency‐band specific functional connectivity between brain regions, from which the backbone of the functional networks was constructed using the Minimum Spanning Tree (MST) approach. Reference MSTs were computed based on the average functional connectivity matrix for either ALS‐pure motor or bvFTD, against which the networks of ALSci/bi were compared. Post‐hoc, measures of global and local network topology were compared (i.e. tree hierarchy, leaf fraction, diameter and betweenness centrality).

Result

At baseline, ALSci/bi patients’ theta‐band brain networks resembled those of ALS‐pure motor more than those of bvFTD. At follow‐up, ALSci/bi patients appear to shift towards the bvFTD group in the beta band. This was reflected by the fact that ALSci/bi patients moved away from ALS‐pure motor patients overtime and their beta‐band networks resembled those of bvFTD at follow up. No significant differences in global or local network topology were found.

Conclusion

Our findings suggest that brain networks of ALSci/bi patients move along the ALS‐bvFTD spectrum over time and become closer to bvFTD‐like topology.
Modeling tau aggregation through optogenetics
Authors: Profes Marcos Schaan , Zou Lyucheng , Farrell Kurt W. , Crary John F.
Published: January 2025

Background

The molecular etiology of tau‐derived neurodegeneration remains poorly understood, reflected in the low success rate of clinical trials. Hence, aquiring a better understanding the molecular basis of tauopathies is a critical need.

Objective

To develop a versatile and reproducible system to study tau aggregation with high spatiotemporal control through optogenetics that will aid in investigating the differences in tau aggregation kinetics, the burden the burden of tau isoforms, and mutations and that will be suitable for high‐throughput analysis of tauopathy‐related mechanisms.

Method

We engineered an optogenetic cellular model using the CRY2 protein that when light‐activated enables spatiotemporal control over tau aggregation. A panel of CRY2‐tau constructs expressing all six neuronal isoforms and known mutations was created to assess aggregation kinetics and cellular burden due to imbalances in tau proteoforms. Tauopathy‐associated factors will be assayed with biochemistry, and challenge optogenetic tau aggregation with their overexpression and knockdown. Experiments in patient‐derived human induced pluripotent stem cell models will be performed supporting the project’s translational nature.

Result

HEK293 and SH‐SY5Y cells expressing our constructs showed mCherry stable tau inclusions after light stimulation, which are not present when the backbone alone is transfected and are less frequent without light stimulus. These inclusions where positive for phosphorylation markers consistent with Alzheimer disease when assessed by immunocytochemistry. Western blotting analysis confirmed the presence of high molecular weight tau molecules consistent with dimmers and higher aggregates and live‐imaging assessments of different tau proteoforms suggest different CRY2‐tau inclusion formation kinetics.

Conclusion

These data support the feasibility of generating tau aggregates with pathological features in our cellular system. This approach has the potential to enhance the screening process of possible tau aggregation modulators allowing analysis in real time of tau aggregation in a precise manner with high spatiotemporal resolution while. This model may r be amenable to drug screening.
Associations between blood‐based biomarkers of Alzheimer’s disease and rate of global and domain‐specific cognitive decline in an elderly population with 15 years of follow‐up
Authors: Laukka Erika J , Ekström Ingrid , Grande Giulia , Valletta Martina , Qiu Chengxuan , Winblad Bengt , Fredolini Claudia , Fratiglioni Laura , Vetrano Davide Liborio
Published: January 2025

Background

Alzheimer’s disease (AD)‐related biomarkers assessed in blood have proved to be useful for detecting dementia and cognitive impairment in the memory clinic. However, less is known about their predictive value in the long‐term and in a community‐based setting.

Method

We examined six common serum‐derived biomarkers of AD (P‐tau181, T‐tau, Aβ42/Aβ40 ratio, P‐tau181/Aβ42 ratio, Nfl, and GFAP) from the baseline assessment of the population‐based Swedish National Study on Aging and Care in Kungsholmen (SNAC‐K; n = 2071, mean age at baseline = 72 years). At baseline, participants were free from dementia and neurodegenerative disorders and their cognitive level was within normal range (Mini‐Mental State Examination score > 23). Global cognition and performance in four specific domains (i.e., episodic and semantic memory, verbal fluency, and perceptual speed) were assessed regularly with a neuropsychological test battery across up to 15 years. Associations of AD‐related serum biomarkers with rate of cognitive decline across the follow‐up period were examined with linear mixed‐effects models.

Result

Effects on rate of change in all examined cognitive domains were observed for all biomarkers, except T‐tau. The strongest associations were observed for P‐tau181 (global cognition: β = ‐0.024, 95% CI: ‐0.029 to ‐0.020) and for individuals with relatively high biomarker concentrations (3rd or 4th quartile). Interactions were explored for age, sex, and APOE ԑ4‐carrier‐status.

Conclusion

To summarize, this study shows that higher concentrations of blood‐based biomarkers for neurodegeneration are associated with faster rates of cognitive decline in the general elderly population.
Defining the Problem History Heterogeneity in Patients with Alzheimer’s Disease: A Data‐Driven Approach
Authors: Mansel Clayton , Townley Ryan A , Honea Robyn A , Sardiu Mihaela E , Veatch Olivia J
Published: January 2025

Background

The medical and social history of patients with Alzheimer’s Disease is heterogeneous with many interacting genetic and environmental factors contributing to an individual’s risk. Moreover, a maternal family history (mFH) is a key risk factor for AD—raising the risk for disease onset by as much as nine times. However, a proportion of individuals do not have a complete knowledge of their family history. Determining which problem history profiles are common among individuals with a mFH of AD may help identify these high‐risk patients. Mitochondria are inherited matrilineally and certain haplogroups have been linked to an increased risk for AD. Subgrouping AD patients based on problem and family history using novel methods such as unsupervised machine learning (ML) may provide key insights into the pathogenesis of AD and could augment future clinical trial enrollment.

Method

In this cross‐sectional study of longitudinal clinical data from the National Alzheimer’s Disease Coordinating Centers (NACC), we used agglomerative hierarchical clustering on principle components to group subjects based on self‐reported medical history and substance use history. A total of 2,754 individuals who did not have AD at their initial visit but later developed AD were included in the final analysis. Secondarily, we tested whether these clusters were associated with a mFH of AD, mitochondrial haplogroup, APOE genotype, and various demographic factors.

Result

The final dataset had a mean age of 76±8.2 years and was 44.9% (n = 1,237) male, 84.9% (n = 2,337) white, 94.4% (n = 2,601) non‐Hispanic, and had 15.7±6.0 years of education. Three distinct problem history clusters were identified: minimal problem history (n = 1,380), substance use history (n = 1,038), and cardiovascular problem history (n = 336). The cardiovascular problem history cluster had a significantly lower proportion of subjects with a mFH of AD and an E4/E4 APOE genotype.

Conclusion

In this study, three distinct problem history subgroups were identified. The cardiovascular problem history cluster was not associated with an E4/E4 APOE genotype or a maternal family history of AD, indicating that this subgroup of patients may require further study to determine how to best stratify their risk of AD.
In‐situ glial cell‐surface proteomics for normal brain aging
Authors: Burns Madeline P
Published: January 2025

Background

During aging, we observe several changes in the brain that render it more vulnerable to a variety of age‐related neurodegenerative diseases, including Alzheimer’s Disease. Glia‐neuron interactions mediate brain development and physiology via cell‐surface proteins at the cell‐surface interface, and dysregulation of these interactions is considered one of the hallmarks of brain aging. Due to the critical role glial cells play in neuroplasticity, immune function, and homeostasis, dysregulation of glial cell‐surface proteins is hypothesized to contribute to neurodegeneration. However, it remains technically difficult to profile glial cell‐surface proteomes from intact brains, which is necessary to preserve important neuron‐glia global dynamics.

Method

Recently, we employed a state‐of‐the‐art in‐situ cell‐surface proteomics technique to profile how glial cell‐surface proteomes change during normal brain aging in young and old flies.

Result

In total, we identified 872 glial cell‐surface proteins, and found that while most up‐regulated genes were associated with cell localization and transport, most down‐regulated genes were associated with neural development, circuit organization, and neuroplasticity. Based on our proteomic profiles, we selected 48 candidate genes for further screening (based on which were most up‐ or down‐regulated). Currently, we are conducting several gain‐of‐function/loss‐of‐function genetic screens to investigate the effects of each candidate gene on lifespan, using the repo‐GS/UAS binary system, and have selected two candidate genes of interest to investigate further.

Conclusion

We have found that some of the most differentially expressed genes were associated with neural development and wiring molecules not previously thought to be particularly active in glia.
The mTOR‐4E‐BP1 axis controls microglia inflammatory and neurodegenerative responses
Authors: Bermudez Sara , Choi Junghyun , Kim Sunghoon , Vogel Jacob W. , Mahmood Niaz , Zhu Vivian Yuchan , Yaqubi Moein L , Stratton Jo Anne , Hansson Oskar , Valles Argel Aguilar , Healy Luke M , Sonenberg Nahum
Published: January 2025

Background

Activation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022). mTOR complex 1 (mTORC1) inhibits the translation repressors, eukaryotic translation Initiation Factor 4E (eIF4E)‐Binding Proteins (4E‐BPs), via phosphorylation, which causes their release from eIF4E to promote mRNA translation (Hay and Sonenberg, 2004). mTORC1 promotes mitochondrial biogenesis via inhibition of 4E‐BPs, by preferentially stimulating the translation of mitochondria‐related mRNAs (Gandin et al., 2016; Morita et al., 2013). We investigated the mechanisms at the intersection of 4E‐BP‐dependent translational regulation and metabolism in microglial response to soluble Aβ.

Method

We carried out immunoblot analysis to investigate the phosphorylation status of 4E‐BP1, the isoform most abundant in microglia, following exposure to Ab. We manipulated the mTOR pathway by knocking out the downstream effectors, 4E‐BPs, to alleviate translation suppression in microglia in vitro and in vivo. We crossed the microglia‐specific 4E‐BPs knockout mouse with a RiboTag mouse to pull‐down ribosome‐bound mRNAs, providing a genome‐wide pool of actively translating mRNAs in the absence or presence of 4E‐BPs. Finally, we examined the relationship between 4E‐BP1 levels and neuroinflammation markers in cerebrospinal fluid (CSF) of AD patients.

Result

We showed that 4E‐BP1 is inhibited acutely upon exposure to soluble Ab, which is dependent on Spleen Tyrosine Kinase (SYK) activation upstream of mTORC1, but is reduced upon chronic exposure. Furthermore, 4E‐BP1 expression is induced during prolonged exposure to Ab. The deletion of 4E‐BPs in microglia in vitro leads to an increase in mitochondrial mass and reliance on oxidative phosphorylation while decreasing expression of pro‐inflammatory mediators and cell death upon exposure to Ab. We observed that increased levels of 4E‐BP1 in the CSF of patients with Aβ pathology are associated with higher neurodegeneration (Nfl) in the presence of microglial activation.

Conclusion

We demonstrate that mTORC1 signaling critically impacts microglia physiology and promotes neuroprotective functions via 4E‐BP1 inhibition. 4E‐BP1 activity in microglia engenders a dysfunctional or detrimental state that may lead to increased neurodegeneration. Therefore, 4E‐BP1 is an attractive target for microglia modulation in AD.
Targeting HDAC6 for chemotherapy‐induced neurotoxicity and Alzheimer’s disease
Authors: Ma Jiacheng , Goodwani Sunil , McReynolds Morgan , Huichalaf Claudia H , Buggia‐Prevot Virginie , Acton Paul , Kavelaars Annemieke , Heijnen Cobi J , Ray William J
Published: January 2025

Background

Chemotherapy‐induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. Connections between chemo‐treatment and increased risk of dementia have been reported. Mechanistically, chemotherapy treatment contributes to an accelerated aging phenotype in the brain through induction of pathogenic tau, disruption of neuronal integrity, reactive gliosis and neuroinflammation. Our work identified histone deacetylase 6 (HDAC6) as a potential therapeutic target against CICI. The primary substrates of HDAC6 include non‐histone cytoplasmic substrates, such as the microtubule protein α‐tubulin. Inhibition of HDAC6 has been shown to improve axonal transport of mitochondria and preserve axonal bioenergetics, the disruption of which are key factors contributing to cognitive impairment associated with chemotherapy and Alzheimer’s disease (AD). Therefore, inhibition of HDAC6 may provide benefits against chemotherapy‐induced neurotoxicity and Alzheimer’s disease.

Method

CICI was established in mice with two cycles of cisplatin treatment. A brain‐penetrant HDAC6 inhibitor was then administered for two weeks. Behavioral testing, immunohistochemistry and biochemical approaches were taken to determine the effect of HDAC6 inhibition on cognitive function, synaptic mitochondrial function, synaptic integrity and tau pathology. To determine the therapeutic potential of targeting HDAC6 for AD, we crossed the Tg4510 tauopathy mouse model with HDAC6 knockout mice and evaluated behavioral changes and markers of neurodegeneration including NeuN staining and plasma neurofilament‐light.

Result

HDAC6 inhibition normalizes cisplatin‐induced cognitive impairments, restores microtubule stability and reverses tau phosphorylation, leading to normalization of synaptic mitochondrial function and synaptic integrity in CICI. These data suggest that short‐term treatment with a brain‐penetrant HDAC6 inhibitor is sufficient to achieve prolonged reversal of functional deficits induced by chemotherapeutics. In the context of AD, short‐term treatment with the HDAC6 inhibitor did not provide benefits in the Tg4510 tauopathy mouse model. However, knockout of HDAC6 in Tg4510 mice reverses the hyperactive behavioral phenotype, preserves neuronal integrity and reduces plasma neurofilament‐light level up to 6‐month of age.

Conclusion

HDAC6 inhibition has great therapeutic potential for both chemotherapy‐induced neurotoxicity and AD.
Microbiota‐Microglia Interactions Modulate Beta‐Amyloid Levels
Authors: Cox Laura M
Published: January 2025

Background

The gut microbiota and microglia play critical roles in Alzheimer’s disease (AD), and more information is needed on how specific bacteria affect brain immunity in AD. We found that Bacteroides increased in aging Tg2576 mice and correlated with amyloid‐beta (Aβ) plaques and hypothesized that Bacteroides worsens AD pathology by modulating microglia. Bacteroides is also elevated in AD patients and correlates with cerebrospinal fluid levels of Aβ and tau.

Method

To test the effect of B. fragilis on Aβ plaques and microglia, we administered Bacteroides fragilis to APP/PS1‐21 mice, assessed plaques by immunohistochemistry, and investigated microglial transcriptional responses on FAC sorted microglia by RNAseq. To determine whether B. fragilis suppressed microglial uptake, we also administered B. fragilis to aged WT mice for two months, then injected fluorescently labeled human Aβ1‐42 peptides to the brain and measured FITC‐Aβ by flow cytometry.

Result

We found that B. fragilis increased Aβ plaques in female mice, modulated cortical gene expression involved in amyloid processing, and down regulated expression of microglial genes involved in phagocytosis and protein degradation. To investigate microglial phagocytic function, we administered B. fragilis to aged WT female and male mice for 2 months, injected fluorescently labeled human Aβ1‐42 peptides to the brain, and found that B. fragilis suppressed uptake of Aβ in both male and female mice. Depleting murine Bacteroidota with metronidazole decreased amyloid load in aged 5xFAD mice, and activated microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation.

Conclusion

Taken together, these data suggest that bacteria in the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, leading to impaired Aβ clearance and accumulation of plaques.
NCRAD: Academic Biorepository to Support Standardization and Efficacy of Clinical Research Biospecimens for the Advancement of AD/ADRD Research
Authors: Snoddy Casey , Faber Kelley M. , Lacy Kaci , Jackson Jacqueline M , Foroud Tatiana M.
Published: January 2025

Background

NCRAD is a National Institute on Aging (NIA) cooperative grant, awarded to Indiana University since 1990, whose purpose is to serve as a biorepository for AD/ADRD researchers. With 74 participating across 150 unique institutions, NCRAD links specimens to clinical research data. NCRAD maintains over 2 million aliquots from more than 126,000 research participants spanning a wide range of AD/ADRD related phenotypes as well as healthy controls.

Method

To ensure standardization and uniformity, NCRAD develops a manual of procedures specific to each study protocol that includes detailed pictures, schematics, and flow charts for each sample type collected. NCRAD conducts web‐based training for site staff and provides supplemental training videos to ensure

Researchers receiving samples from NCRAD agree to share the data generated from the samples. Since its inception, NCRAD has distributed over 410,000 samples to more than 200 researchers. NCRAD biospecimens and data have been reported in more than 850 publications.

Result

NCRAD’s mission is to maintain uniformity in collection and processing of samples sites involved in each study. Centralized biobanking and broad sharing of biospecimens has accelerated research discovery.

Conclusion

Using standardized biospecimen collection, processing, shipping, storage, and distribution procedures established at NCRAD, in conjunction with attention to detail, strict compliance with regulations, and oversight from the NIA, has resulted in a biorepository with highest quality samples available to researchers investigating the etiology, early detection and therapeutic development for AD/ADRD.
Analysis of neurovascular unit after voluntary physical exercise in a transgenic mouse of Alzheimer’s disease
Authors: Andrade José de Jesús , Orta‐Salazar Erika , Díaz‐Cintra Sofia , Soto‐Rojas Luis Oskar
Published: January 2025

Background

Alzheimer’s disease (AD) stands out as the most prevalent neurodegenerative condition globally, marked by a progressive cognitive decline. Its distinctive histopathological features include neurofibrillary tangles composed of Tau protein aggregates and amyloid beta (Aβ) aggregates forming neuritic plaques in the parenchyma and cerebral amyloid angiopathy (CAA) in blood vessels. Intriguingly, it has been hypothesized that CAA induces alterations in the cells comprising the neurovascular unit (NVU), exacerbating the disease’s symptoms. Currently, effective treatments for AD remain elusive. The triple transgenic mouse model for AD (3xTg‐AD), harboring three mutations associated with familial AD (PS1M146V, APPSWE, and tauP301L), is widely employed to investigate molecular mechanisms and assess therapeutic strategies. One promising non‐pharmacological approach is physical exercise, a planned, repetitive, and regulated physical activity. However, its impact on the cerebrovascular system remains unclear. This study aims to analyze the effect of physical exercise on the NVU in the 3xTg‐AD model.

Method

A total of 40 ten‐month‐old female mice, including 3xTg‐AD (n = 20) and non‐Tg (n = 20), were equally divided into exercise and sedentary groups. A voluntary physical exercise intervention spanning three months, with a frequency of five times a week, was implemented. Subsequently, we evaluated cognitive functions, CAA, and NVU morphostructure through histological assays

Result

Our results demonstrate that 3xTg‐AD mice develop vascular amyloid deposits, correlating with NVU alterations and cognitive deficits. Intriguingly, voluntary physical exercise reduces CAA and amyloid plaques, coinciding with improvements in cognitive abilities and NVU component integrity.

Conclusion

The intervention with voluntary physical exercise holds promise for enhancing vascular system stability and reducing CAA in symptomatic stages of AD, presenting a potential therapeutic avenue for individuals affected by the disease.
Functional impairment in a dementia‐free sample associated with a higher risk of Mild Behavioral Impairment
Authors: Mortby Moyra E , Ismail Zahinoor , Anstey Kaarin J.
Published: January 2025

Background

Mild Behavioral Impairment (MBI) and functional ability are two non‐cognitive markers of dementia. To date, little is known about the impact of functional ability on the clinical manifestation of MBI. Using data from the Australian population‐based PATH Through Life Study we examined the impact of functional ability on MBI. We hypothesized that poorer functional ability in a dementia‐free sample (with at most Mild Cognitive Impairment; MCI) would be associated with a higher likelihood of MBI.

Method

1377 dementia‐free participants (52% male; aged 72‐79; 847 cognitively healthy, 397 cognitively normal, but‐at‐risk (i.e., subjective cognitive decline), 133 MCI) were included. Functional ability was assessed using the Bayer Activities of Daily Living scale (B‐ADL), which comprises 25 items assessed by an informant. Items are scored 1‐10 with higher scores indicating poorer functional ability. Presence and absence of MBI and its five domains (decreased motivation, affect dysregulation, impulse dyscontrol, social inappropriateness, abnormal perception/thought content) were approximated using a previously published transformation algorithm, which utilizes items from the Neuropsychiatric Inventory assessed at a single study visit. Binomial logistic regression analyses were conducted to examine risk of MBI associated with functional impairment. Models controlled for Mini Mental State Exam scores (MMSE) and self‐reported gender (male/female).

Result

Adjusted logistic regression (MMSE and gender) showed that a one‐unit increase on the B‐ADL was associated with a 2.27‐fold greater risk of MBI (95% CI 1.962‐2.624; p<.001). Similarly, for all 5 MBI domains, a one‐unit increase of B‐ADL was associated with greater risk of all domains: decreased motivation (B = 2.26; 95% CI 1.898‐2.684; p<.001), affect dysregulation (B = 2.02; 95% CI 1.763‐2.306; p<.001), impulse dyscontrol (B = 2.01; 95% CI 1.756‐2.301; p<.001), social inappropriateness (B = 2.01; 95% CI 1.707‐2.378; p<.001), and abnormal perception/thought content (B = 1.82; 95% CI 1.417‐2.335; p<.001).

Conclusion

This study is amongst the first to identify a higher risk of MBI associated with functional ability in dementia‐free older adults. These findings highlight the importance of early monitoring of changes in functional ability and behaviour, even prior to the onset of cognitive symptomatology. They also provide further evidence of the clinical utility of functional ability and MBI as early markers of dementia.