bluuebunny/crossref_metadata_2025 huggingface dataset:
The X‐chromosome in Alzheimer’s disease genetics, stratified by APOE*4 and sex
Authors: Belloy Michael E. , Guen Yann Le , Napolioni Valerio , Greicius Michael D
Published: January 2025

Background

The X‐chromosome remains largely unexplored in Alzheimer’s disease (AD). We performed the first, stratified X‐wide association study (XWAS) of AD to chart the role of X‐chromosome genetic variation in AD sexual dimorphism and heterogeneity of APOE*4‐related AD risk.

Method

The study overview is shown in Figure 1A. SNP‐array AD XWAS datasets primarily composing the ADGC, together with whole‐genome sequencing (WGS) from ADSP (NG00067.v7), provided case‐control diagnoses for phase‐1. The UK Biobank provided subjects with ICD codes and family history of AD status for phase‐2. Subjects were of European ancestry. Linear mixed model regressions were performed (LMM‐BOLT v.2.3.4) on AD outcome measures, adjusting for sex, APOE*4/APOE*2 dosage, genetic principal components, and array/batch/center. XWAS hits (cf. Figure 1) were evaluated for interaction effects (meta‐regression for phase1+2 meta‐analyses) and assessed in functional follow‐up analyses, including colocalization with QTL datasets from the eQTL Catalogue.

Result

Stratified AD XWAS identified 17 loci (Figure 1B). These included KDM6A, which has previously been shown as an important risk gene for AD through rodent work. The MAP7D3 locus contains NHE6, which has also been implicated as a possibly important AD risk gene. The variant rs6629203, with a rare allele frequency of 0.3%, in the REPS2 locus reached genome‐wide significance (P<5e‐8) in APOE*4 negative individuals. At the NROB1 locus, the AD XWAS signal and eQTL signal on the EK gene, as expressed in monocytes, colocalized (PP4 = 0.77) (Figure 2). Other functional follow‐up results will be shared during the conference.

Conclusion

For the first time, we identified X‐chromosome loci/variants differentially associated with AD risk across APOE*4 and/or sex. Our findings contribute to our understanding of the genetic etiology of AD, which in turn contributes to advancing personalized genetic medicine. Additional follow‐up and replication work is in progress.
Quantitative effects of sleep‐disrupting medications on real‐world sleep metrics in older adults at risk for neurodegeneration
Authors: Chang Jun Ha , Scalzo Anthony J. , Shaffer Christopher L. , Rizzo Matthew
Published: January 2025

Background

This pilot study addresses unmet needs for empirical evidence on real‐world data (RWD) on sleep to inform pharmacological management in older adults at‐risk for neurodegenerative conditions. Polypharmacy is prevalent among older adults, with potential adverse effects on physiological functions, including sleep. Sleep disturbances are prevalent in aging, may signal onset of Alzheimer’s disease (AD), potentially contributing to the underlying pathology.

Methods

82 participants identified with cognitive decline (9 mild AD, 73 Mild Cognitive Impairment) (mean age = 76yrs; 47 male) and 56 age‐ and education‐matched controls (mean age = 75yrs; 19 male) (Table 1) self‐reported their prescribed medications. Only medications known to disrupt sleep (e.g., Cholinesterase inhibitors, ACE inhibitors) and administered orally daily were included in the analysis. Cognitive abilities were measured in all 138 participants at study induction using a battery of standard neuropsychological tests. Four weeks of nightly sleep data were collected using wrist‐worn actigraphy to estimate sleep duration and quality, including sleep efficiency [SE], wakefulness after sleep onset [WASO], and awakening count [AC]). Multivariate linear regressions examined the effects of the number of sleep‐disrupting medications and cognitive status on sleep variables, adjusting for age, gender, and education.

Results

45 participants did not take sleep‐disrupting medications, 46 took one, and 47 took two or more (Table 2). Greater numbers of the medications were linked to poorer SE (b = ‐0.26, p = 0.01), increased WASO (b = 0.27, p = 0.01), and greater variability in sleep duration (b = 0.23, p = 0.03), SE (b = 0.26, p = 0.02), WASO (b = 0.28, p = 0.009), and AC (b = 0.26, p = 0.01). Controls showed less variability in SE (b = ‐0.43, p = 0.01) and WASO (b = ‐0.37, p = 0.03) than those with cognitive decline.

Conclusion

Our results, using RWD of sleep and medications, underscore that polypharmacy in older adults is associated with disrupted sleep patterns, with a greater number of sleep‐disrupting medications exacerbating poor sleep outcomes. These findings highlight needs for careful medication management to preserve sleep and suggest that targeted pharmacological strategies can mitigate medication‐related sleep disturbances, thereby enhancing brain health, behavior, and overall health.
Examining Depression in Older Surgical Patients: An Observational Cohort Study
Authors: Alhamdah Yasmin , Yan Ellene , Butris Nina , Kapoor Paras , Lovblom Leif Erik , He David , Chung Frances
Published: January 2025

Background

Depression affects individuals across various ages but is of significance in the older surgical population due to its adverse impact on cognitive function, surgical recovery, and overall functional disability. This study aimed to determine the overall prevalence and trajectory of depression in older surgical patients preoperatively, and at 30‐, 90‐ and 180‐days postoperatively.

Method

This study is a prespecified sub‐study and analysis of the Postoperative Functional Disability in Unrecognized Cognitive Impairment Study. Participants ≥ 65 years undergoing elective non‐cardiac surgery were recruited. Participants completed the 15‐item Geriatric Depression Scale (GDS) through an online survey preoperatively and postoperatively at 30‐, 90‐ and 180‐days. A cut‐off of ≥ 5 was used to define depression. Participants also completed four cognitive screening tools: the Telephone Montreal Cognitive Assessment and Modified Telephone Interview for Cognitive Status over the telephone and the Ascertain Dementia Eight‐item Questionnaire and Center for Disease Control and Prevention cognitive question through survey. Cognitive impairment (CI) was defined as meeting the cut‐off on one of the cognitive screening tools. Linear mixed‐effects models were used for trajectory analysis.

Result

Among 307 participants (mean ± SD age: 72.9 ± 5.5; 56.0% female), 62 (20.2%) screened positive for preoperative depression. Forty‐five (14.7%) had mild depression (GDS score 5‐8), 11 (3.6%) had moderate depression (GDS score 9‐11), and 6 (2.0%) had severe depression (GDS score 12‐15). Those who were depressed had significantly lower mean GDS scores at 90‐ and 180‐days postoperatively vs. preoperatively (5.38 ± 0.37 and 5.41 ± 0.35 respectively vs. 7.52 ± 0.28, P≤0.05). While the value at 30‐days was lower than that preoperatively, it was not significant. Non‐depressed participants had significantly higher 30‐days postoperative mean GDS score vs. preoperatively (2.09 ± 0.16 vs. 1.42 ± 0.14, P≤0.05). The mean GDS scores decreased over time in both groups (P for time <0.0001) with significant difference in the trajectories (P for interaction <0.0001). Of those with preoperative depression, 63% screened positive for CI on ≥1 cognitive screening tool vs. 33% without depression.

Conclusion

Depression is prevalent in older surgical patients. Our novel study findings enable better understanding of depression in the older surgical population.
Prospective analysis of clinical, cognitive and functional impairments among older adults following a diagnosis of covid
Authors: Cintra Fabiana Carla Matos da Cunha , Cintra Marco Túlio , Vallle Estevão Alves , De Souza Henrique Dias Furtado , Almeida Daniella Cristina Brites , Fortini Iza de Faria , Viana Bernardo de Mattos , Bicalho Maria Aparecida Camargos
Published: January 2025

Background

Post‐Covid syndrome has been associated to enduring impairments in functionality, cognition, mood and physical capabilities among older adults.

Methods

The objective was to prospectively evaluate clinical, cognitive and functional impairments in elderly people at 3 and 12 months after the diagnosis of Covid‐19. Prospective cohort study of participants aged 60 years and over after a Covid‐19 diagnosis. The project was approved by the UFMG’s ethics committee. The assessment protocol included the scales Alzheimer’s Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL), Canadian Occupational Performance Measure (COPM), Clinical Frailty Scale (CFS), Mattis Dementia Rating Scale (DRS), Post‐Traumatic Stress Disorder Checklist – Civilian Version, Geriatric Depression Scale ‐ 15 items, Charlson Comorbidity Index, modified Medical Research Council for dyspnea and Fatigue Severity Scale. The statistical analysis included Paired Samples T Test for continuous variables, the Mcnemar Test for categorical variables and the Sign Test for ordinal variables.

Results

Twenty‐eight participants with a mean age of 69.46 ± 7.09 years and 8.04 ± 4.76 years of education were evaluated after 3 months (T1) and 12 months (T2). Women represented 56.6% and 82.1% of participants were hospitalized in the acute phase. There was an increase in frailty from 7.2% of frail people prior to covid diagnosis, to 39.3% at T1 (P = 0.004) and 32.2%, at T2 (p = 0.016) assessed by CFS. Functional recovery was not statistically significant (ADCS‐ADL ‐ P = 0.083), however, the subitem satisfaction and concerning functional performance assessed by COPM improved (P = 0.012). At (T1) 57.2% of the sample presented a diagnosis of MCI and 17.9% of dementia, while at (T2) 60.7% and 17.9%, respectively (P = 1.00). However, the DRS’s conceptualization domain showed statistical significance improvement [P = 0.011]. Dyspnea symptoms had a significant improvement: from 82.2% with grade II to IV dyspnea at (T1) to 50% at T2 (P = 0.031). No changes were observed in fatigue, depressive symptoms and post‐traumatic stress disorder.

Conclusion

This study showed that symptoms such as fatigue, cognitive and functional changes may persist in older adults with following the diagnosis of covid. However, there was a significant improvement in dyspnea, in the DRS’s conceptualization domain and satisfaction in relation to functional performance after 12 months of follow‐up.
Differential Pattern of Tau Deposition is Associated with Each Cognitive Score in Cognitively Unimpaired Elders
Authors: Nayak Siddharth , Hojjati Seyed Hani , Ozoria Sindy , Chernek Peter , Calimag Jenseric , Ghaderi Bardiya , Razlighi Qolamreza R
Published: January 2025

Background

Different subtypes of Alzheimer’s Disease (AD) are shown to have differential patterns of tau deposition on the cerebral cortex. However, for cognitively unimpaired elders the spatial specificity of tau deposition has not been fully investigated.

Objective

We aim to show that tau deposition in different brain regions is uniquely associated with performance in different cognitive domains. Furthermore, we investigate the influence of amyloid‐β (Aβ) in every tau‐cognition relationship.

Methods

A total of 124 cognitively unimpaired older adults (68.62 ± 5.56 years) underwent 18F‐florbetaben (FBB) positron emission tomography (PET) scans to determine Aβ positivity and 18F‐MK‐6240 PET scans for measuring in vivo tau accumulation in addition to four cognitive domain assessments, and structural magnetic resonance imaging (MRI). Voxel‐wise multiple regression analysis is used with voxel‐wise tau uptake as the outcome and cognitive scores, Aβ status and their interaction as the predictor of interest controlling for age, sex, and head size.

Results

Memory and reasoning scores were associated with a unique pattern of tau deposition with negligible spatial overlap (less than 9% on Dice), as shown in Fig. 1, suggesting that each cognitive domain is affected by distinct patten of tau accumulation. Furthermore, as seen in Fig. 2, the presence of Aβ significantly modulates the effect of tau on memory in most regions shown in Fig. 1a in a way that only Aβ+ participants show significant tau‐memory relationships while Aβ‐ participants show no relationship. Strikingly, the tau‐cognitive relationship for other domains did not show strong interactions in the cortex. However, reasoning and speed showed a weak interaction with tau in the right entorhinal cortex and left hippocampus, respectively.

Conclusion

Our findings provide evidence for regional specificity of tau deposition in unimpaired elders, as it has been reported in AD patients. In addition, while the presence of Aβ strongly modulates the relationship between tau and memory, this modulation is significantly attenuated or completely missing from other cognitive domains.
Development and validation of a new measure Characterising Language Experience and Acculturation (CLEAr‐Q) to inform the cognitive assessment of culturally and linguistically diverse older adults
Authors: Page Zara A , Croot Karen , Lam Ben C. P. , Brodaty Henry , Kochan Nicole A.
Published: January 2025

Background

Language and cultural factors are known to influence cognitive performance on neuropsychological measures used to assess cognitive impairment and dementia. A new measure, the Characterising Language Experience and Acculturation Questionnaire (CLEAr‐Q) was developed to address the gap in access to a brief measure of these factors in the Australian context. The aim is to validate and further develop the CLEAr‐Q as a tool to capture linguistic and acculturation variables to improve measurement of cognition in older adults from Culturally and Linguistically Diverse (CALD) backgrounds.

Methods

The CLEAr‐Q was initially created as a paper questionnaire and completed by all older adults from CALD backgrounds in the CogSCAN Study. Items were drawn from the literature and adapted based on feedback from the CogSCAN group. An online version for validation with a larger sample was then developed with consultation from a CALD community working group via an adapted participatory research framework. The anonymous survey is completed online in English and data collection will conclude in February 2024. Preliminary analysis (e.g., Pearson correlation) will be conducted to check for redundant items and to select linguistic and acculturation variables (Table 1) to be included in an exploratory factor analysis; this will establish the factor structure and develop a streamlined, psychometrically validated version of the CLEAr‐Q.

Results

The CogSCAN sample included 75 participants aged 60‐95 who reported speaking and/or reading a language other than English (LOTE). The validation sample to date consists of 244 participants aged 60‐90 who reported speaking and/or reading a LOTE at a functional level, were born in over 50 overseas countries (Figure 1) and speak on average more than two languages (Table 2). Data analysis is in progress.

Conclusions

Results will contribute to validating the CLEAr‐Q and demonstrating its utility to characterise known diversity in CALD samples. Future directions include examining the relative importance of linguistic and acculturation variables from the CLEAr‐Q in predicting cognitive performance, which is expected to improve diagnostic accuracy of current neuropsychological measures for assessment of cognitive impairment and dementia in older adults from CALD backgrounds.
Navigating Dyslexia Diagnosis in Primary Progressive Aphasia within Transparent Languages: A Study in a Spanish‐Speaking Community
Authors: Garcia Florentina Morello , Calandri Ismael Luis , Hernández Micaela A , Crivelli Lucia , Difalcis Micaela , Leiva Samanta , Ferreres Aldo , Allegri Ricardo
Published: January 2025

Background

Surface dyslexia serves as a complementary feature in the classification of the semantic variant of Primary Progressive Aphasia (PPA), while reading deficits have also been reported in the other two PPA variants. In opaque languages, tasks involving regular and irregular words and non‐words are useful tools for dyslexia diagnosis. However, in transparent languages like Spanish, where most words are regular for reading, different approaches are needed. This study aims to: 1) present an alternative approach for detecting reading deficits in Spanish‐speaking PPA patients, and 2) identify brain FDG‐hypometabolism patterns in PPA subjects with dyslexia.

Method

We assessed 17 PPA patients and 61 age‐sex‐education‐matched healthy subjects with tasks of word and non‐word reading, foreign word reading (FWRead), and visual lexical decision with pseudohomophones (VLDPsh). Employing a single‐case series methodology with a case‐control design, we conducted comparisons against controls and intra‐subject analyses. To assess hypometabolism, we performed 18F‐FDG PET scans on all subjects, and we analyzed the images using SPM. We adjusted a prediction model of 18F‐FDG signal in control subjects to determine the w‐score for each patient. A region was defined as abnormal if it fell below a w‐score of ‐1.5.

Result

We detected dyslexia in 94% of all PPA subjects. Specific patterns were identified: 5 cases of surface dyslexia (characterized by impairments in the lexical reading mechanism), 2 of phonological dyslexia (impairments in the phonological mechanism), 3 of mixed dyslexia (impairments in both reading mechanisms), and 6 unspecified. The FDG‐PET results revealed left ventral occipitotemporal, left ventral inferior parietal, and left superior temporal cortex hypometabolism (see Figure 1).

Conclusion

This research provides valuable insights into the presence and types of dyslexia shown by Spanish‐speaking PPA patients and emphasizes the importance of studying reading, as it has been observed to be affected in 94% of our sample. Our findings underscore the need to employ tasks such as FWRead and VLDPsh to assess lexical reading mechanisms in Spanish‐speaking contexts. Moreover, the identification of hypometabolism in brain regions contributes additional insights into the metabolic deficits observed in PPA patients and is consistent with reported data about regions linked to reading.
Using Ambulatory Assessment to Explore Links between Daily Activities and Daily life Cognitive Functioning among Older Adults
Authors: Weinstein Andrea M. , Rothenberger Scott , Moore Raeanne C , Snitz Beth E. , Cohen Ann D , Butters Meryl A
Published: January 2025

Background

Characterizing dementia risk is difficult with traditional neuropsychological testing. Ecological Momentary Cognitive Testing (EMCT) uses ecological momentary assessment (EMA) methods to sample daily life cognition. The current study examined how daily activities were related to EMCT performance and explored whether associations remained when stratifying by amyloid‐beta (Aβ) status.

Method

Older adults without dementia underwent Pib‐PET imaging and a 10‐day EMA and EMCT protocol using the NeuroUX platform. EMCT measures included verbal memory (12‐item Memory List accuracy), spatial memory (Memory Matrix accuracy), inhibitory control (Color Trick reaction time [RT]), and visual search/processing speed (Matching Pair RT). We examined EMCT in relation to concurrent and previous day activities reported by EMA: 1) work/volunteer activities and 2) physical leisure activities (e.g., exercising or gardening). EMCT task performance was calculated by intraindividual mean and variability, assuming higher mean accuracy and lower variability indicated better cognition. We jointly modeled the mean function and log transformed intraindividual variability for each EMCT task in relation to concurrent and previous day activity, controlling for age, education, and protocol day. We then explored associations stratified by Aβ status.

Result

Forty participants (age = 73.6 years [67‐91]; education = 15 years [10‐19]; 21 female; 77% white; 7 Aβ+) completed the protocol. For instance, concurrent physical leisure (β = ‐.15, p = .011) or work activities (β = ‐.15, p = .012) was associated with lower Color Trick RT variability and this association held in Aβ+ individuals (β = ‐.69, p<.01; β = ‐.39, p = .01). Concurrent physical activities were associated with higher Memory List mean accuracy (β = .67, p = .05) and concurrent work activities was associated with lower Memory List variability (b = ‐.15, p = .04). Conversely, concurrent physical leisure activities were associated with higher Matching Pair RT variability (β = .15, p = .02) but only in Aβ‐ individuals. When looking at previous day activities, physical leisure (β = ‐.13, p = .05) and work (β = ‐.16, p = .02) activities were associated with less next‐day Memory Matrix variability, in both Aβ+ and Aβ‐ individuals.

Conclusion

Daily cognitive performance (i.e., EMCT) is sensitive to daily activities, with possible differences by Aβ status. Ongoing work is further examining these patterns (K23AG076663).
The role of the RUDAS can facilitate in differentiating dementia with Lewy bodies from Alzheimer’s disease in an urban Peruvian population
Authors: Custodio Nilton , Menendez Carlos E.E. Araujo , Custodio Belen , Malaga Diego Marco , Montesinos Rosa , Chambergo‐Michilot Diego , Bustamante‐Paytan Diego , Aguero Katherine , Verastegui Graciet , Tosto Giuseppe
Published: January 2025

Background

Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) differ in their cognitive characteristics. Subscales of the Rowland Universal Dementia Assessment Scale (RUDAS) provide an opportunity to test these cognitive domains across the two conditions. Multiple brief cognitive screening tools have been evaluated to differentiate specific types of dementia, but there are no reports regarding RUDAS yet.

Methods

One hundred and twenty‐one [DLB (n = 46) and AD (n = 75)] patients enrolled in the Instituto Peruano de Neurociencias (IPN). AD cases were derived from the GAPP study (NIA grant #alz090494AG069118). Independent group t‐tests and chi‐square tests were used to examine differences in key demographic variables and in RUDAS sub‐scores (Orientation, praxis, construction, judgment, memory, and language) between groups.

Results

On average, AD patients were older and had a lower total RUDAS score. AD and DLB patients performed significantly differently (p < 0.05) on all RUDAS cognitive domains (table 1). The RUDAS memory sub‐score was particularly effective in fully differentiating patients with AD from ones with DLB (AD: mean = 1.7, range = 0‐2; DLB: mean = 5, range = 4‐8; Figure 1).

Conclusion

Our results provide preliminary evidence of the utility of RUDAS to differentiate between cases diagnosed with AD and DLB in urban Peruvian populations. Future work will focus on confirming if the RUDAS memory sub‐score can aid in differentiating DLB from AD in larger, community‐dwelling populations in Peru.
Passively collected data from smartphones improves detection of frontotemporal dementia compared to the MoCA
Authors: Paolillo Emily W. , Casaletto Kaitlin B. , Taylor Jack C. , Heuer Hilary W. , Wise Amy B. , Dhanam Sreya , Sanderson‐Cimino Mark E. , Palacios Brandon R. , Young J. Clayton , Bui Mai Anh , Saloner Rowan , Dutt Shubir , VandeBunte Anna M. , Cadwallader Claire J. , Kramer Joel H. , Kremers Walter K. , Forsberg Leah K. , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. , Staffaroni Adam M. ,   the ALLFTD Consortium
Published: January 2025

Background

Frontotemporal dementia (FTD) is a common young‐onset dementia. Challenges to in‐person FTD evaluations (e.g., behavioral symptoms, disease rarity), highlight the need to develop remote, low‐burden assessment techniques. A growing literature supports passive digital phenotyping for monitoring neurobehavioral change. Thus, we examined the utility of passively collected data from smartphones to detect prodromal or symptomatic FTD compared to that of the Montreal Cognitive Assessment (MoCA), a common cognitive screener.

Method

199 adults enrolled in the ALLFTD Mobile App study (mean age = 53.4 [SD = 15.2]; 58% women) completed up to 6 months of passive smartphone monitoring via the ALLFTD Mobile App. 55% were unimpaired [CDR®+NACC FTLD = 0], 22% had prodromal FTD [CDR®+NACC FTLD = 0.5], and 23% had symptomatic FTD [CDR®+NACC FTLD≥1] with a variety of syndromic presentations. Battery percentage was collected frequently (median interval = 45 min), and total daily battery usage was calculated as a proxy for smartphone use (higher battery usage = more smartphone use). Daily step counts were also passively collected. Logistic regression classified prodromal or symptomatic FTD vs. unimpaired as a function of: MoCA score [Model 1]; 7 passive features characterizing average, inter‐day variability, and changes over time in smartphone use and movement [Model 2]; or passive smartphone features and MoCA [Model 3]. Analyses were repeated excluding participants with symptomatic FTD to detect prodromal FTD vs. unimpaired.

Result

The area under the curves (AUCs) for detecting prodromal or symptomatic FTD (vs. unimpaired) from the MoCA alone [Model 1] and passive smartphone features alone [Model 2] were 0.77 (95%CI: 0.70‐0.85) and 0.77 (95%CI: 0.70‐0.84), respectively. Their combination [Model 3] resulted in a significantly improved AUC of 0.86 (95%CI: 0.80‐0.92) compared to Model 1 (p = 0.001). Significant Model 3 predictors included average daily battery usage (p = 0.02), slopes of change in step count (p = 0.04), and MoCA score (p<0.01). When distinguishing prodromal FTD from unimpaired, passive smartphone features alone (AUC = 0.75) were significantly better than the MoCA alone (AUC = 0.66; p<0.01), and their combination had the largest AUC (0.80).

Conclusion

Results support the utility of novel passively collected information from smartphones for detecting and monitoring FTD without contributing to assessment burden. With continued validation, passive digital monitoring methodologies have potential to increase access to dementia care.
Deciphering how ApoE shapes neurodevelopment
Authors: Sud Reeteka
Published: January 2025

Background

What does neurodevelopment look like when neurodegeneration is the outcome – this is overarching theme of investigations currently ongoing in our lab. The E4 isoform of ApoE protein is the most consistently replicated risk factor in Alzheimer’s Disease (AD). And yet, much remains unknown about the biological pathways that connect APOE4 genotype with the development of pathology that eventually leads to AD, nor do we know how early in life these cellular alterations begin.

Method

We derived neural precursor cells (NPCs) from induced pluripotent stem cells (IPSCs) that were CRISPR‐edited at the APOE locus. As these cells give rise to neurons and glia in the developing fetal brain, elucidating how ApoE affects these cells can highlight its possible effects on neurodevelopment. Proteomic analysis was performed to characterize the protein expression landscape in the NPCs subsequent to targeted deletion of E4 from a parent IPSC line of APOE3/4 genotype. Differentially expressed proteins (DEPs) following mass spectrometric analysis were determined from the protein abundance fold change values obtained for each protein. Proteins which showed >1.5‐fold difference with FDR adjusted P‐value < 0.05 were considered differentially expressed.

Result

CRISPR‐editing of E4 from the parent line revealed 98 differential expressed proteins. Of these, 54 were upregulated, and 44 were downregulated. Further analysis of the DEPs via STRING database showed that these changes primarily affect pathways linked to RNA processing, plasma membrane repair, and cytoskeleton organization.

Conclusion

It is crucial to understand the developmental roles of ApoE and the isoform‐specific differences in its functions to better understand its function and dysfunction. Indeed, we find the effects of E4 extend beyond proteins considered central to AD pathology. Our results add to the growing body of literature on altered course of neurodevelopment from genetic risk factors in AD.
Lysosomal defects in Grn loss of function modulate microglial cell state and immune responses
Authors: Tejwani Leon , Paolo Gilbert Di
Published: January 2025

Background

Macrophages and microglia are myeloid cells that play critical roles in the surveillance of the local environment of the tissues in which they reside. The ability of these phagocytes to perform key functions is contingent on their capacity to sense extracellular cues and mount responses that involve chemotaxis, proliferation, cytokine secretion, and phagocytosis of various cargos for lysosomal clearance. Our overarching hypothesis is that lysosomal degradation of phagocytic cargoes is critical for the resolution of cellular/tissue damage, as well as of inflammation, and that failure to accomplish this step affects myeloid cell states and immune responses.

Method

To test this hypothesis, we examined the consequences of disrupting lysosomal function on myeloid cell state, using GRN deficiency as a model of primary lysosomal dysfunction.

Result

GRN is highly expressed in these cells and encodes progranulin, a frontotemporal dementia‐linked protein critical for the regulation of lysosomal degradative processes. We first performed single‐nucleus RNA‐sequencing of purified microglia from aged wild‐type and Grn knockout (KO) mice, defining the diverse subpopulations that emerge with disease in this context. Next, we characterized primary microglia and macrophages from Grn KO mice cultured in the absence of other cell types, which revealed robust cell autonomous transcriptional and functional alterations resulting from Grn deficiency. To further examine how specific forms of lysosomal dysfunction impact myeloid cell state, we induced pharmacological and genetic perturbations of various lysosomal properties, which uncovered a robust response of myeloid cells to lysosomal deacidification that largely overlaps with that observed in Grn KO myeloid cells. Finally, we identified putative transcription factors that mediate the transcriptional remodeling of myeloid cells in response to lysosomal stress.

Conclusion

Overall, these data reveal a novel link between lysosomal health and myeloid cell transcriptional and functional states.
Factors influencing adults' willingness to be screened for dementia risk
Authors: Reed Alexandra M , Hooyman Andrew , Lee Nicole M , Fauth Elizabeth B. , Love Jill W , Schaefer Sydney Y
Published: January 2025

Background

The Alzheimer’s Association recommends early screening of Alzheimer’s disease and related dementias(ADRD), urging the development of biomarkers and other tools for early risk/detection. However, the general public’s willingness to be tested for early ADRD must be considered, particularly among minoritized populations. For example, Black older adults within the United States (U.S.) are twice as likely to develop ADRD compared to White non‐Hispanic older adults, but have lower rates of engagement/trust in the medical system.

Method

This study used Amazon MTurk to survey 572 U.S. adults on their willingness to take a (hypothetical) test for short‐term dementia risk. Mean participant age was 41.9±11.9. The sample was 47% Female, 77% non‐White, and 92% non‐Hispanic/Latino, with 37% having less than a bachelor’s degree. We also calculated an aggregated Area Deprivation Index (ADI) based on 5‐digit zip code to quantify a location’s relative advantage or disadvantage on a scale of 1‐100 compared to state and national percentiles, where lower ADI values represent greater area deprivation (mean±SE ADI = 47.65±24.51). All participants were non‐demented based on the Functional Assessment Questionnaire (score<9).

Result

Although White and non‐White participants were both willing to test (∼77%), non‐White participants were approximately four times more likely to test only if their results were not shared with their medical provider/insurer. The desire to test outside of medical environments is further supported by the fact that the most common reason for taking the test was peace of mind (78%) rather than facilitating treatment plans, and that a positive test result would be most shared with family (62%) rather than with doctors right away. Older age was also associated with increased willingness to test, while ethnicity and socioeconomic status were not.

Conclusion

Historical contexts and marginalization of minoritized groups may also impact willingness to screen for early ADRD risk/detection, which needs to be explored further. Building medical trust may take decades for some populations, thus supporting the need to develop options now for biomarkers or other ADRD‐risk screeners that are accessible and appropriate for culturally diverse groups, both within and outside of a medical context.
Atrophy Network Mapping of Anxiety in Cognitively Unimpaired Older Adults in Preclinical AD
Authors: Lee Soyoung , Palm Stephan T , Drew William J , Zide Benjamin S , Donovan Nancy , Fox Michael D , Siddiqi Shan
Published: January 2025

Background

Anxiety is prevalent among cognitively unimpaired older adults and is associated with accelerated amyloid‐β‐related cognitive decline and incident cognitive impairment. Investigating these mechanisms is challenging due to low pathologic burden, high individual variability, and subsyndromal level of symptoms. Recently, brain networks involved in AD were successfully localized by mapping the brain connectivity of atrophy patterns associated with memory impairment and delusions. In this study, we investigated anxiety symptoms in older adults with elevated amyloid‐β using the novel method of atrophy network mapping.

Method

We utilized baseline data from ∼1800 cognitively unimpaired older adults, aged 65‐85, from the Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) trial, including clinical assessment of anxiety measured by the 6‐item State‐Trait Anxiety Inventory as well as structural brain MRI and amyloid‐β (18F‐florbetapir) PET acquisitions. We generated a vertex‐wise general linear model of cortical thickness to create individualized atrophy maps for each participant with elevated amyloid‐β deposition, using data from older adults with low amyloid‐β deposition as a control group. Then, we used a normative human connectome (n = 1000) to estimate the functional connectivity of each participant’s unique atrophy pattern. From the network connectivity maps, we identified atrophy‐based brain networks associated with higher anxiety. To validate this brain network, we performed a spatial correlation with a pre‐established anxiosomatic network derived from focal brain stimulation sites that selectively modify anxiety and assessed significance using permutation testing. We hypothesized that atrophy patterns associated with greater anxiety would correspond to this anxiosomatic network.

Result

Anxiety symptoms localized to a distinct brain network based on individuals' atrophy patterns. The identified brain network was correlated to the anxiosomatic network (r = 0.65), and the correlation was stronger when controlled for depressive symptoms (r = 0.67). The network was more similar to the anxiosomatic network than expected by chance (p<0.05).

Conclusion

We identified a brain network associated with anxiety symptoms in cognitively unimpaired older adults with elevated amyloid‐β. These findings help elucidate a neuropathophysiology of anxiety in preclinical AD and, possibly, its role in disease progression. The brain network identified in this project could yield new neurostimulation targets for anxiety in older adults across the AD continuum.
House dust mite‐induced asthma alters BBB integrity, increases amyloid beta accumulation, and alters brain cytokine levels in AppNL‐G‐F mice
Authors: Sahu Bijayani , Nookala Suba , Floden Angela M , Ambhore Nilesh , Venkatachalem Sathish , Combs Colin K
Published: January 2025

Background

Alzheimer’s disease (AD) is an age‐related neurodegenerative disorder affecting nearly 50 million individuals worldwide. Besides aging, various comorbidities can increase the risk of AD, such as asthma. However, the molecular mechanism(s) underlying this asthma‐associated AD exacerbation is unknown. This study was designed to explore the effects of house dust mite‐induced asthma on AD‐related brain changes using the AppNL‐G‐F transgenic mouse model.

Method

Male and female C57BL/6 wild type and AppNL‐G‐F mice (8‐9 months old) were exposed to either saline or house dust mite (dose: 833µg/kg in saline) every alternate day for 16 weeks. Mice were sacrificed at the end of the experiment and broncho‐alveolar lavage fluid (BALF), lungs, blood, and brains were collected. BALF was analyzed for immune cell markers, inflammatory mediators, and LDH activity. Lung sections were stained with Alcian blue and Masson’s Trichrome to examine mucus and collagen production, respectively. The serum was analyzed for cytokine levels. Brain sections were immunostained for Aβ, GFAP, and collagen‐4. Finally, frozen hippocampi and cortices were used to perform Aβ ELISAs and cytokine arrays, respectively.

Result

Dust‐mite exposure increased inflammatory cells, cytokine levels, and LDH activity in the BALF and increased the mucus and collagen production in the lungs from both sexes and genotypes, suggesting induction of a severe asthma‐like condition. This correlated with increased levels of serum cytokines in all dust‐mite‐exposed groups. In agreement with this peripheral change, hippocampi from asthma‐induced male and female AppNL‐G‐F mice demonstrated elevated Aβ plaque load and increased soluble Aβ 1‐40/42 and insoluble Aβ 1‐40 levels. Dust‐mite exposure also increased astrogliosis in both sexes of AppNL‐G‐F mice, as indicated by GFAP immunoreactivity. Additionally, dust‐mite exposure‐induced asthma elevated cortical levels of several cytokines in both sexes and genotypes. Finally, dust‐mite exposed groups also showed a disturbed BBB integrity in the hippocampus of AppNL‐G‐F mice, as indicated by decreased collagen‐4 immunoreactivity.

Conclusion

Dust‐mite exposure induced a severe asthma‐like condition that exacerbated Aβ pathology, astrogliosis, cytokine changes, and disturbed BBB integrity in the brains of male and female AppNL‐G‐F mice. Defining the mechanisms of secondary effects of asthma on the brain may provide a novel therapeutic approach for both asthma and AD.
Frailty and Cognition: Unravelling the Intricate Nexus
Authors: Partha Ajith , S Monisha , Stezin Albert , L Abhishek M , Mallikarjun Divya N , M Amitha C , HS Deva Kumar , Narayanasamy Rajitha , Menon Meenakshi , R Meghana , Vishwanath Vindhya , Velavarajan Goutham , Malo Palash K , Arvind Prathima , Hameed Shafeeq K Shahul , HS Sunitha , Singh Sadhana , Mondal Banashree , Agrawal Deepashri , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: January 2025

Background

Frailty, synonymous with physical vulnerability and decline, may exert nuanced effects on cognitive functions.(Borges, Canevelli, Cesari, & Aprahamian, 2019) This study assesses possible association between frailty and cognitive performance with the aim of identifying vulnerable cognitive domains.

Method

We analysed the baseline data from Tata Longitudinal Study of Ageing (TLSA)(Sundarakumar et al., 2020), an ongoing longitudinal study, based in urban Bangalore, India. Frailty was evaluated using clinical markers such as Timed Up and Go test (TUG), Hand Grip Strength right and left (HGSRt and HGSLt respectively), and Chair Stand test (CST). Cognitive function was evaluated using Addenbrooke’s Cognitive Examination III (ACE III), and Clinical Dementia Rating (CDR) scores. Generalized linear models/ Binary logistic regression were used to evaluate the relationship between frailty parameters and cognition.

Result

In a cohort of 1484 participants (51% males, 49% females; mean age 62.3 ± 9.6, mean education 15.2±3.8 years), significant positive correlation was found between HGS and ACE scores and significant negative correlation was found between TUG and ACE scores. Notably, no significant association was found between the Chair Stand Test (CST) and ACE scores (Table 1&2). Individuals with higher HGSRt (Odds Ratio [OR] = 0.967, 0.939‐0.996, p value 0.026), and CST (OR = 0.903, 0.839‐0.972, p value 0.006) exhibited a lower likelihood of Mild Cognitive Impairment (MCI). Additionally, those with MCI took longer duration in TUG test (OR = 1.209, 1.122‐1.304, p value <0.001) compared to normal participants. There was no significant association between MCI and HGSLt (OR = 0.973, 0.945‐1.002, p value <0.069).

Conclusion

The study reveals a significant association between frailty parameters and cognitive functions. These findings demonstrate the impact of physical resilience on cognitive well‐being, emphasizing the importance of addressing frailty as a modifiable factor in promoting cognitive health among aging individuals.
Robust Symptomatic Subtypes of Typical Alzheimer’s Disease Characterized by Differential Neuropathological Patterns and Functional Decline
Authors: Zalzale Hussein , Ferreira Pamela C.L. , Lemaire Peter , Madeiros Marina Scop , Soares Carolina , Bellaver Bruna , Bauer‐Negrini Guilherme , Lussier Firoza Z , Povala Guilherme , Ferrari‐Souza João Pedro , Abbas Sarah , Aguzzoli Cristiano Schaffer , Rodrigues Matheus Scarpatto , Rohden Francieli , Amaral Livia , Leffa Douglas Teixeira , Oliveira Markley , Tudorascu Dana , Tissot Cécile , Rahmouni Nesrine , Ashton Nicholas J. , Blennow Kaj , Hong Chang Hyung , Son Sang Joon , Rosa‐Neto Pedro , Cohen Ann D , Lopez Oscar L. , Villemagne Victor L , Pascoal Tharick A.
Published: January 2025

Background

Alzheimer’s disease (AD) is classically viewed as a predominantly amnestic syndrome, with other cognitive and neuropsychiatric symptoms (NPS) being non‐integral associations. Emerging Evidence suggests that within typical AD, these symptoms are core features from the onset.

Methods

We employed K‐modes clustering on 2483 cognitively impaired (CI) individuals (CDR ≥ 0.5), excluding participants diagnosed with atypical AD, non‐amnestic MCI, or CI due to non‐AD dementias from five cohorts: TRIAD, ADNI, BICWALZS, OASIS‐III, and Pittsburgh. Cluster‐specific clinical and pathological profiles were established through comparison with 2670 cognitively unimpaired (CU) participants across plasma biomarkers (Ptau‐181, Ptau‐217, GFAP, Nfl, AB42/40 ratio) and neuroimaging (amyloid and tau PET, white matter hyperintensity, MRI‐derived degeneration maps). The rate of functional decline, modeled by increase in CDR‐SB, was assessed using a Cox‐proportional hazards model and a linear mixed‐effect model.

Results

We identified five distinct clinical phenotypes within typical AD: ‘Pure Amnestic’ (30.2%), ‘Linguistic‐Hyperactive’ (14.7%), ‘Visuospatial‐Affective’ (14.7%), ‘Frontal’ (27.6%), and ‘Global’ (19.3%) (Figure 1, Figure 3). These phenotypes demonstrated consistency regardless of amyloid status or cohort. Each phenotype exhibited a unique neuropathological signature and a distinct pattern of neurodegeneration (Figure 2). A critical aspect of our findings is the differential rate of functional decline across these phenotypes. The ‘Pure Amnestic’ group showed the slowest decline, followed by ‘Linguistic‐Hyperactive’ (HR = 1.39; B = 0.2), ‘Visuospatial‐Affective’ (HR = 2.13; B = 1), ‘Frontal’ (HR = 2.23; B = 1.53), and the ‘Global’ phenotype showing the fastest decline (HR = 3.52; B = 2.66) (Figure 2, Figure 3).

Conclusion

Our results challenge the concept of “typical” AD by uncovering five robust clinical phenotypes with divergent neuropathological profiles and clinical characteristics. These results mark an important advancement toward personalized medicine in the landscape of emerging AD treatments.
Physical performance, frailty and BPSD in patients with dementia: a retrospective study
Authors: Bianco Maria Giovanna , Rogani Sara , Pullia Rosanna , Bianchi Elena , Carlo Ludovica Di , Bufi Gianluca , Carmassi Francesca , Silvestri Rosa , Calsolaro Valeria , Virdis Agostino
Published: January 2025

Background

Behavioral and psychological symptoms of dementia (BPSD) can lead to loss of independence, increased risk of hospitalization and early institutionalization. This work aims to evaluate the relationship between physical performance and BPSD in older patients with dementia.

Method

In this observational single‐center study, patients with dementia underwent a Comprehensive Geriatric Assessment (ADL, IADL, CIRS, CFS) and cognitive and neuropsychiatric evaluation (MMSE, NPI). Through K‐means cluster analysis for frailty, disability and burden of comorbidities, we split the population in three clusters, according. BPSD were classified in three groups: “mood/apathy” (depression, apathy, appetite and sleep disturbances), “psychosis” (delusions, hallucinations, anxiety) and “hyperactivity” (agitation, euphoria, aberrant motor activity, irritability, disinhibition).

Result

263 patients aged > 65 years (mean age 83.6±5) were enrolled; 111 patients underwent a 12‐month follow‐up. The global population had low comorbidity burden (CIRS 1.33±1.4), mild frailty (CFS 5.4 ± 1.2, BADL 5±3, IADL 3±4) and moderate cognitive decline (MMSE 18.9±5). Based on physical performance and comorbidities (ADL, IADL, CIRS, CFS) three clusters were identified: cluster 1 (47 patients) showed higher comorbidity burden, cluster 2 (106 patients) mild frailty and younger patients, cluster 3 (110 patients) higher ADL/IADL disability. The three group significantly differed in cognitive performance (MMSE1 19.2 ± 5.3; MMSE2 20.8 ± 4.6; MMSE3 16.9 ± 4.5, respectively), particularly between clusters 1 and 3 (p = 0.01) and between clusters 2 and 3 (p<0.01). At baseline, there was no difference in the distribution of mood/apathy and psychosis symptoms, while the prevalence of hyperactivity symptoms was higher in cluster 3 (p <0.001). At 12‐month re‐evaluation, the prevalence of psychosis symptoms in clusters 2 and 3 was significantly higher (p = 0.008). A correlation was also highlighted between hyperactivity symptoms and IADL‐impairment at baseline. In addition, in all the three clusters a significant worsening in physical and functional performance was highlighted over 12‐months.

Conclusion

In dementia patients with BPSD, cognitive and physical performance worsen over time. The presence of positive psychiatric symptoms was higher in clusters with a higher degree of frailty and disability, but we ignore the causality to one another. Larger studies are needed to assess the relation between BPSD and frailty.