bluuebunny/crossref_metadata_2025 huggingface dataset:
Data‐driven comparison of neurodegeneration patterns between autosomal dominant and sporadic late‐onset Alzheimer’s disease
Authors: Aksman Leon M. , Guzman Samuel , Ringman John M
Published: December 2023

Background

Autosomal dominant Alzheimer’s disease (ADAD) and sporadic late‐onset AD (LOAD) have similar biomarker profiles, supporting a shared pathophysiology. While both ADAD and LOAD are known to be heterogeneous, there are few studies that have compared the heterogeneity of neurodegeneration as indexed by volumetric MRI in LOAD to that of ADAD. Here we apply a data‐driven model of brain atrophy subtypes from LOAD to characterize atrophy within ADAD.

Method

We used cross‐sectional MRI from ADNI (LOAD) and the Estudio de la Enfermaded de Alzheimer en Jalisciences (EEAJ; ADAD). We used 13 cortical and subcortical Freesurfer‐based regions from 1,912 ADNI participants to train a Subtype and Stage Inference (SuStaIn) model of brain atrophy progression within LOAD. We built a three‐subtype model and applied it to subtype and stage 61 EEAJ participants: 47 carriers of the A431E mutation in PSEN1 and 14 carriers of the V717I mutation in APP. To harmonize the two datasets, we removed the effects of age, sex, education years, ICV and study (ADNI vs. EEAJ flag) from each regional volumetric biomarker prior to analysis. We retained 47 of the 61 EEAJ participants with an estimate SuStaIn stage greater than zero (in any subtype) for subsequent analyses.

Result

The progression patterns for each of the three data‐driven brain atrophy subtypes (typical, cortical, subcortical) are presented in Figures 1 A‐C. These are consistent with previous findings in LOAD. We found no difference in the percentage of participants in each subtype between LOAD, ADAD‐PSEN1 and ADAD‐APP groups (χ2 = 1.5, p = 0.84; Figure 1D). Within ADAD, those assigned the typical subtype had a slightly lower average stage of progression than those in the other two subtypes (t = ‐2.0, p = 0.049; Figure 2A). The triangle plot shows the probability of subtype membership is mostly clustered around the typical and cortical subtypes (Figure 2B), while the estimated stages increase dramatically after disease onset, as expected (Figure 2C).

Conclusion

We found a comparable distribution of LOAD‐based atrophy subtypes within both the PSEN1 and APP carriers groups in ADAD, showing that heterogeneous neurodegeneration is another commonality between ADAD and LOAD.
Baseline Cognitive Performance Is a Determinant of Prospective Health Resource Utilization Among Adults with Chronic Stroke: A Secondary Analysis
Authors: Davis Jennifer C , Adjetey Cassandra , Eng Janice J , Falck Ryan S , Dao Elizabeth , Best John R. , Tai Daria , Bennett Kimberly J , McGuire Katherine , Hsiung Ging‐Yuek Robin , Middleton Laura E , Hall Peter A , Liu‐Ambrose Teresa
Published: December 2023

Background

Cognitive impairment is a costly public health problem globally. Among older adults with chronic stroke, the literature is devoid of prospective data that identify factors responsible for driving health care resource utilization. This study aimed to ascertain key determinants of health resource utilization (HRU) at 6 and 12 months among older adults with chronic stroke.

Method

This study was a secondary prospective analysis of an economic evaluation conducted alongside the Vitality study, a 6‐month randomized controlled trial with a 6‐month follow‐up which included 120 community‐dwelling adults with chronic stroke, aged 55 years and older. Participants were randomized into 1) exercise (EX) or 2) cognitive and social enrichment activities (ENRICH), or 3) stretching and toning program (BAT) (i.e., control group/ comparator). The primary outcome measure of the randomized controlled trial was the Alzheimer’s Disease Assessment Scale‐Cognitive‐Plus (ADAS‐Cog‐Plus), a global measure of cognitive performance using multidimensional item response theory. We constructed two linear regression models with HRU at 6 and 12 months as the dependent variables for each model, respectively. Predictors relating to mobility, quality of life, global cognition and executive functions were examined. Age, sex, comorbidities, and group allocation (i.e., EX, ENRICH or BAT) were included regardless of statistical significance. Costs were reported in 2022 Canadian Dollars.

Result

The ADAS‐Cog Plus was a significant determinant of total HRU at 6 months (intervention cessation; p = 0.001) and 12‐months (6‐month followup; p = 0.004).

Conclusion

The ADAS‐Cog Plus, a measure of cognitive performance, was a significant determinant of HRU at 6 and 12 months among older adults with chronic stroke. This highlights the importance of interventions aimed at combating cognitive decline to minimize health care resource among individuals with chronic stroke.
Subtle cognitive difficulties increase risk of neurodegeneration, incident mild cognitive impairment, and dementia in older women.
Authors: Petkus Andrew J. , Wang Xinhui , Beavers Daniel P. , Espeland Mark A. , Resnick Susan M. , Salminen Lauren , Gatz Margaret , Rapp Stephen R. , Chen Jiu‐Chiuan
Published: December 2023

Background

Identifying individuals with preclinical Alzheimer’s disease and related disorders (ADRD) is important for prevention and eventual treatment. Here we aimed to integrate overall test performance with episodic memory process scores in a cohort of older women to identify those with subtle cognitive difficulties (SCD; e.g., individuals with the earliest declines in cognitive ability preceding a diagnosis of mild cognitive impairment (MCI) or dementia) and determine subsequent risk of MCI, dementia, and neuroimaging indices of neurodegeneration.

Method

Participants included 2,186 community‐dwelling older women without MCI or dementia (Mage = 73.4±3.8 years) who completed a comprehensive neuropsychological assessment as part of the Women’s Health Initiative Study of Cognitive Aging (WHISCA: 1999‐2000). Women were assessed annually for MCI and dementia until 2021, and 1,024 women underwent structural magnetic resonance imaging (sMRI) of the brain in 2005‐6. Women were classified as cognitively normal (CN), early SCD (e‐SCD; two episodic memory process scores 1 SD below normative means or one process score and one performance score 1 SD below normative means), or late SCD (l‐SCD; two overall performance scores 1 SD below normative means) at WHISCA baseline using validated criteria from the Alzheimer’s Disease Neuroimaging Cohort (Thomas et al., 2018 Journal of Alzheimer’s Disease). We used Cox proportional hazards to examine associations between SCD status and risk of developing MCI/dementia. Linear regressions were used to examine associations between SCD status and MRI indices of AD‐related neurodegeneration, global cerebrovascular damage, and brain volumes of structures that make up the medial temporal lobe. All associations were adjusted for sociodemographic, lifestyle, and clinical characteristics.

Result

Women with e‐SCD and l‐SCD were 1.58 (p<0.001) and 3.01 (p<0.001) times as likely to develop MCI/dementia compared to CN women, respectively (Figure 1). Women with l‐SCD (β = 0.20; p<0.001) had more AD‐related neurodegeneration compared to CN women (Table 1). Women with e‐SCD had marginally significantly greater AD‐related neurodegeneration (β = 0.14; p = 0.073) and had smaller volumes in the entorhinal cortex (β = ‐0.22; p = 0.009) compared to CN women.

Conclusion

Our study demonstrates the usefulness of the SCD criteria for the early identification of cognitively normal women who are at increased risk of MCI, dementia, and neurodegeneration.
CONCORDANCE BETWEEN VISUAL INTERPRETATION AND QUANTITATIVE ANALYSIS OF [18F]FLORTAUCIPIR PET IMAGES
Authors: Moscoso Alexis , Heeman Fiona , Raghavan Sheelakumari , Sparrman Kohl Johnson , Costoya‐Sánchez Alejandro , Camacho Valle , van Essen Martijn , Grothe Michel J. , Mainta Isminni , Ribaldi Federica , Devous Michael D , Pontecorvo Michael J. , Frisoni Giovanni B , Garibotto Valentina , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi , Schöll Michael
Published: December 2023

Background

Positron emission tomography (PET) imaging with [18F]flortaucipir allows for in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). The FDA‐approved label for [18F]flortaucipir PET provides a standardized, clinically applicable definition of tau‐PET positivity by visual interpretation. Here, we studied the concordance between this visual interpretation and quantitative approaches employed in research.

Method

We included 2692 participants (cognitively unimpaired [CU] and impaired [CI, MCI or AD dementia]) from four cohorts (Mayo Clinic Study of Aging and ADRC, ADNI, A4, and A05) with available [18F]flortaucipir PET (mean age: 70.2 y, 50.0% females). Three trained readers assessed each [18F]flortaucipir PET scan according to the FDA‐approved method. Visual reads were compared to an established approach for defining tau‐PET positivity based on SUVR values in a temporal meta‐ROI (Jack, et al. Alzheimers Dement. 2017). Previously defined “lenient” (SUVR = 1.22) and “conservative” (SUVR = 1.30) cut‐points were explored. In addition, visual reads were compared to tau‐PET positivity as defined by a scheme based on the expected spatial progression of tau pathology from the medial temporal lobe (MTL) to the temporal neocortex (NEO) (Ossenkoppele, et al. Nat Med. 2022; cut‐points: SUVRMTL = 1.30, SUVRNEO = 1.37).

Result

Concordance between visual and quantitative approaches was limited (Figure 1): the “lenient” and MTL‐NEO methods yielded high rates of quantitative‐positive, visual‐negative scans (73‐52% and 26‐18% for CU and CI, respectively), while the “conservative” cut‐point failed to detect 45% and 13% of the CU and CI visual‐positive scans, respectively. The prevalence of tau‐PET positivity in Aβ‐negative individuals was highest with the “lenient” cut‐point (∼24%) and lowest with visual interpretation (∼3%) (Figure 2). Visual‐positive, quantitative‐negative individuals were more frequently Aβ‐positive than visual‐negative, quantitative‐positive individuals (“lenient”: 86% vs 50%, p<0.001; “conservative”: 87% vs 58%, p<0.001; MTL‐NEO: 85% vs 70%, p = 0.005). Among visually‐positive participants, 164 (28%) showed a tau deposition pattern that deviated from the expected MTL to NEO progression (Figure 3).

Conclusion

Visual and quantitative methods for [18F]flortaucipir PET are non‐exchangeable. Tau‐PET positivity based on visual interpretation aligns better with Aβ‐pathology. A significant number of visually‐positive participants showed a pattern of tau accumulation that deviated from the expected stereotypical spatial progression and was not detected by standard quantitative methods.
Feasibility of implementing wearable technologies for in‐home assessment of behavioral and event‐related potential responses after sleep and wakefulness in Alzheimer disease
Authors: Hagan Brenna , DeCaro Renee , Dyer John , Schwartz Joel , Turk Katherine W , Murphy Brian , Waskow Emily , Lai Matteo , Mortera Andrea , Oglevee Catherine , Shinobu Leslie , Budson Andrew E
Published: December 2023

Background

Alzheimer’s disease (AD) is associated with impaired sleep that worsens over disease progression. To explore the circadian effects on memory consolidation and underlying neurophysiology in young versus old healthy volunteers versus patients with AD, we used two wearables in a repeated/longitudinal at‐home clinical paradigm that captured key behavioral and electrophysiologic responses after sleep and after daytime activity.

Method

A participant home‐administered, behavioral, and event‐related potential (ERP) through electroencephalogram (EEG) platform (Cumulus Neuroscience) is administered over a two‐week period to healthy younger adults, healthy older adults, and older adult patients with AD. Participants engaged in behavioral (image recognition) testing coupled with EEG/ERP recordings twice daily ‐ once in the morning following approx. 12 hrs of sleep/rest and once after at end of day before retiring activity. Two‐minutes of resting state EEG/ERPs began each session, for twenty‐two total sessions. Reports of sleep, together with smart watch actigraphy (Empatica, Inc), are used to estimate the duration and intensity of the rest/sleep period versus daytime activity. This novel protocol explores whether each wearable generates data that is sufficiently reproducible and sensitive to track and interpret changes in episodic memory consistent with known changes expected based on age and AD status.

Result

We report on feasibility of implementation of the experimental paradigm and whether the sensors employed reliably yield interpretable data. We share data on recruitment rates and subject feedback regarding tolerability of Cumulus Headset and Empatica watch.

Conclusion

The home‐based experimental paradigm is well‐tolerated with excellent adherence to the study design. Both sensors yielded experimental datasets of similar quality to those obtained in in‐house studies. Planned analyses focus on establishing whether this experimental paradigm yields data with sufficient sensitivity and reproducibility to confirm past observations regarding the effect of age and AD on memory consolidation.
The relationship between [18F]FDG‐PET signal and key‐players of brain glucose metabolism
Authors: Limberger Christian , Machado Luiza Santos , Ferrari‐Souza João Pedro , Povala Guilherme , Carello‐Collar Giovanna , Pascoal Tharick A. , Bouzier‐Sore Anne‐Karine , Pellerin Luc , de Souza Débora Guerini , Zimmer Eduardo R.
Published: December 2023

Background

Neuronal activity is supported by activity‐dependent lactate production from astrocytes, as postulated by the astrocyte–neuron lactate shuttle (ANLS) hypothesis. Indeed, astrocytic glutamate uptake is a main trigger for brain glucose consumption. [18F]fluorodeoxyglucose (FDG)‐PET showing a hypometabolic signature has been used as an index of neurodegeneration in Alzheimer’s disease (AD). In the early stages of the disease, soluble amyloid‐beta (Aβ) has been associated with neuronal hyperactivity due to decreased astrocytic glutamate uptake. It is hypothesized that this phenomenon occurs especially in regions with high ongoing baseline activity. Over time, neurodegeneration and hypometabolism in such regions may contribute to the progress of the AD continuum. Thus, we investigated whether the [18F]FDG‐PET signal in typical hypometabolic regions in AD is associated with the expression of ANLS transporters and enzymes in the healthy brain.

Method

Gene expression of GLUT1, GLUT3, MCT1, MCT2, MCT4, LDHA, and LDHB (ANLS genes) from postmortem brain tissue of healthy individuals were obtained from the Allen Human Brain Atlas. [18F]FDG‐PET data from cognitively unimpaired individuals were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Pearson correlations were performed between the mean gene expression and the mean [18F]FDG‐PET SUVr across typically hypometabolic brain regions in AD (precuneus, angular and temporal gyri, and parietal and cingulate regions) and non‐vulnerable regions (uncorrected p‐value < 0.05).

Results

The expression of ANLS genes had a stronger positive correlation with [18F]FDG‐PET SUVr across the AD hypometabolic regions than the non‐vulnerable regions (p < 0.05). Of note, the astrocytic glucose transporter GLUT1 presented a stronger correlation with [18F]FDG‐PET than the neuronal transporter GLUT3 in AD‐vulnerable regions. Figure 1 presents all correlations.

Conclusion

Our results show that the physiological expression of transporters and enzymes responsible for the brain glucose metabolism correlate more with the [18F]FDG‐PET signal in typical brain regions of the AD hypometabolic signature. This suggests these regions present a higher baseline activity and may be more susceptible to Aβ‐induced hyperactivation in early AD, which could lead to a bioenergetic collapse in later disease stages, as shown in the [18F]FDG‐PET of AD individuals.
Evaluation of Interpretable Speech Biomarkers for Monitoring Alzheimer’s Disease and Mild Cognitive Impairment Progression
Authors: Favaro Anna , Dehak Najim , Thebaud Thomas , Oh Esther S , Moro‐Velazquez Laureano
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Like for other dementias, biomarkers may help characterize distinct aspects of the underlying pathology, predict decline, and monitor disease progression. We extracted a composite array of 24 speech‐based biomarkers using machine learning and signal processing techniques. We then determined which of the given biomarkers was predictive of MCI and AD progression from baseline by conducting a correlation analysis.

Method

Spoken responses to a Cookie Theft Picture description task were recorded from 2 subjects with AD, 4 subjects with Mild Cognitive Impairment (MCI) due to AD (biomarker confirmed AD), and 4 subjects with MCI. We automatically extracted acoustic, linguistic, and cognitive biomarkers using speech recognition, acoustic, and language modeling techniques. We later computed Kendall’s tau‐b (τb
) correlation between the biomarker values and Montreal Cognitive Assessment (MoCA) scores. Recordings and MoCA scores were collected at baseline, at 6 months after baseline, and at 12 months for a subgroup of the subjects. To perform the correlation analysis, we used scipy.stats.kendalltau library in Python.

Result

With respect to the acoustic biomarkers, a strong negative correlation (τb= ‐0.50) was observed between the MoCA scores and features such as pause time, pause percentage, and pause speech ratio, while a moderate positive correlation (τb= 0.2) was found for rhythm standard deviation. With respect to the linguistic biomarkers a strong positive correlation(τb= 0.50) for the features of corrected type‐token ratio, average sentence length in words, and noun count was reported, while a moderate positive correlation (τb= 0.27) was found for the features of word type count, word token count, and moving average type‐token ratio. The other acoustic, linguistic, and cognitive biomarkers showed a very weak (τb= 0.00 ‐ 0.10) or weak correlation (τb= 0.10 ‐ 0.20).

Conclusion

Altogether, these results suggest that speech‐based interpretable biomarkers may help clinicians to diagnose AD at earlier stages and monitor disease progression. Our preliminary data suggest that AD patients encounter more problems delivering longer and linguistically elaborated narratives as the disease progresses.
Association of platelet aggregation to amyloid and tau PET in the Framingham Heart Study
Authors: Cejudo Jaime Ramos , Scott Matthew R , Beiser Alexa S. , Tanner Jeremy A. , Ghosh Saptaparni , Johnson Keith A. , Salinas Joel , Osorio Ricardo S , Wisniewski Thomas , Berger Jeffrey S , Johnson Andrew D , Seshadri Sudha
Published: December 2023

Background

Platelets are key mediators of inflammation and vascular dysfunction. Prior work highlighted a role of platelet function in Ab and tau dynamics, and dementia risk. We hypothesized that platelet aggregation may associate with amyloid and tau brain levels in middled age people at risk of cardiovascular disease.

Method

We examined cross sectional associations of platelet aggregation with brain amyloid and tau PET levels (11C‐labeled Pittsburgh Compound‐B (PiB) and tau (18F‐Flortaucipir (FTP)) in middle aged cognitively normal participants at the Framingham Heart Study (FHS) Gen3 Cohort. Platelet aggregation was measured by light transmission aggregometry. The response to 0.98uM ADP stimulation was primarily evaluated followed by additional agonists and stimulation doses for sensitivity analysis. The associations were explored in multivariate regression models adjusted for age, age squared, sex, the time from blood to PET examination, and PET camera used.

Result

The final study sample included 356 participants (median [Q1,Q3] age, 55 [49, 61]; 51% women) of which 82 (23%) were on preventive platelet modifying treatments (PPT) (Table 1). We found significant interaction between PPT and platelet aggregation in their association with amyloid and tau PET levels, motivating a stratified analysis by the use or not of PPT. The platelet aggregation response was not associated with PiB or FTP retention in non‐PPT users (n = 274) (Table 2). In PPT users, the platelet aggregation response was positively associated with amyloid levels in the precuneus (β±SE: 0.36±0.14, P<0.05), and tau levels in the rhinal (β±SE: 0.49±0.15, P<0.01) and temporal regions (β±SE: 0.39±0.17, P<0.05).

Conclusion

Our results indicate that platelet aggregation is not associated with amyloid and tau PET levels in the general population. In people who are on PPT for primary prevention of CVD, platelet aggregation associates with amyloid and tau PET in Alzheimer’s disease (AD) relevant brain regions. This result reinforces the need for further examining the mediator role of platelet aggregation in the association of cardiovascular risk and AD.
Adiposity and Insulin Resistance Moderate Brain Electrophysiology and Affect Regulation in Young Adults
Authors: Larsen Brittany A , Klinedinst Brandon S , Wolf Tovah , McLimans Kelsey E , Pollpeter Amy , Li Tianqi , Wang Qian , Barnett Neil , Fili Mohammad , Moody Shannin , Parvin Mohammadiarvejeh , Willette Sara A , Willette Auriel A
Published: December 2023

Background

Obesity and insulin resistance (IR) may negatively influence affect regulation in young adulthood. The paucity of studies that have investigated such associations have predominantly used functional magnetic resonance imaging. However, electroencephalography (EEG) can evaluate neural signatures in real‐time that may be complementary. Thus, this study investigated how adiposity and IR moderated brain activity and underlying affect regulation using EEG.

Method

Real‐time EEG was recorded in 28 lean and obese young adults with and without IR (18‐39 years, 46.4% female). Two event‐related potential (ERP) components of affect regulation, early posterior negativity (EPN) and late positive potential (LPP), were quantified from EEG data. Participants completed the Interactional Picture Affective System task to measure affect regulation, from which mean valence ratings and stimulus‐to‐response‐onset reaction times were calculated. ERP components and affect regulation parameters were then contrasted in three conditions, as follows: 1) Negative – Neutral; 2) Positive – Neutral; and 3) Negative – Positive. Height, weight, body fat percentage (%BF), and serum proteomics were collected. Fasting glucose and insulin readings were obtained to quantify Homeostatic Model Assessment for Insulin Resistance (HOMA‐IR). Hierarchical moderated regression analysis was utilized to test the interrelationships between adiposity, IR, neural activity, and affect regulation.

Result

Across all contrasted conditions, HOMA‐IR and %BF were found to moderate the relationships between frontal and parietal LPP amplitudes during the late latency window and affect regulation. Specifically, higher late frontal LPP amplitudes were associated with less negative and more positive valence ratings to unpleasant and pleasant stimuli, respectively, among participants with low, but not high, IR and %BF levels. In the Negative – Neutral and Negative – Positive conditions, lower late parietal LPP amplitudes were also associated with less negative overall valence ratings in response to unpleasant stimuli, but only in lean, insulin sensitive participants. These results overall suggest that modulation of negative and positive affectivity only occurs in lean young adults without IR.

Conclusion

Young adults with greater adiposity and IR showed worse affect regulation than those without obesity and IR. Furthermore, AD‐associated characteristics may start early in life, and EEG signatures may be a useful neuroimaging approach for tracking such events.
Correlational analysis of plasma metabolome and brain imaging in a humanized APOE mouse model
Authors: Bhattrai Avnish , McLean John W. , Simmons Hannah , Raikes Adam C. , Wiegand Jean‐Paul L. , Kaddurah‐Daouk Rima F. , Brinton Roberta Diaz
Published: December 2023

Background

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for the development of late‐onset Alzheimer’s disease (LOAD). Additionally, females have a 2x greater risk of developing LOAD than males. LOAD patients show brain glucose hypometabolism and severe reduction in hippocampal volume. Hippocampal atrophy has also been linked with plasma ceramide and phosphotidylcholine (PC) levels in these patients. This study explores the effects of sex and genotype on the plasma metabolome and potential correlations to brain imaging metrics in an aged humanized APOE (hAPOE) mouse model.

Method

Plasma samples from 23–25‐month‐old hAPOE mice (37M/32F) expressing ε3/3, ε3/4 or ε4/4 genotypes were analyzed via mass spectrometry using the Biocrates MxP® Quant 500 platform. In a subset of these animals (24M/20F), in‐vivo FDG‐PET and high‐resolution ex‐vivo MRI were obtained. Cerebral FDG‐PET standardized uptake values were normalized to cerebellum (SUVr). Cerebral SUVr and regional volumes were correlated with detected metabolites and metabolic indicators using Pearson correlations. Two‐way ANOVAs were used to identify sex and genotype effects with post‐hoc t‐tests to determine statistical significance.

Result

hAPOE ε3/3 mice had significantly greater cholesteryl ester (54%; p < 0.026) and lysophosphotidylcholine (lysoPC; 27%; p < 0.031) levels compared to ε4/4 mice. Females had lower levels of PCs (93%; p < 0.007), lysoPCs (82%; p < 0.018), triglycerides (62%; p < 0.045), and 1‐Met‐His (p = 5.84E‐25) than males. Significant positive correlations were observed between cerebral SUVr and PCs (45%; p < 0.049) as well as lysoPCs (82%; p <0.017). Total brain volume was negatively correlated with plasma 3‐Met‐His:creatinine ratio, indicative of muscle protein degradation (r = ‐0.44; p = 0.003) and positively correlated with (LysoPC+ arachidonic acid): PC ratio, indicative of phospholipase A2 activity (r = 0.42; p = 0.004). Right hippocampal volume percentage was significantly positively correlated with PCs (64%; p < 0.045) and 1‐Met‐His (p = 0.00067).

Conclusion

At a comparable human age of ∼ 70 years, within the humanized APOE mouse, sex was the major contributing factor to metabolic differences in peripheral blood plasma. Levels of peripheral metabolites correlated with brain volumetrics and glucose metabolism, highlighting potential therapeutic targets for interventions designed to preserve neuronal health in AD.
Urban but not rural patterns of ambient air pollution exposure is associated with an accelerated rate of late life memory decline in the Wisconsin Longitudinal Study
Authors: Williams Victoria J. , Sicinski Kamil , Herd Pamela , Asthana Sanjay
Published: December 2023

Background

Exposure to ambient air pollution is an emerging risk factor for dementia, yet air pollution levels are found to vary by neighborhood affluence and across rural/urban settings. In this study, we leverage data from the Wisconsin Longitudinal Study (WLS) to evaluate the effects of ambient air pollution exposure on the rate of memory decline in late life, while accounting for both local (neighborhood) and regional (urbanization) residency characteristics.

Method

Annualized rate of change for both immediate and delayed recall trials of a 10‐item word list were calculated between 2010‐1 (baseline) and 2021‐2 (follow‐up) data collection waves. Yearly averages of geocoded regional air pollution data were obtained for 5 pollutants at baseline: particulate matter > 2.5um (PM2.5), ozone (O3), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO). Principal component analysis was performed to reduce multicollinearity among the 5 pollutants in subsequent analyses. Annualized rate of change in memory measures were regressed on resultant pollutant factor scores, additionally controlling for baseline age, adolescent IQ, education, health conditions (heart disease, stroke, hypertension, diabetes), neighborhood‐level deprivation, ApolipoproteinE‐4 (ApoE‐4) status, and sex.

Result

3,601 WLS participants were included in analyses, with a mean age of 70.4±3.4 years at baseline and 80.1±3.4 years at follow‐up. PCA yielded a 2‐factor solution classifying air pollutants into distinct urban (PM2.5, NO2, and CO2) versus rural (SO2 and O3) composites. Linear regression analysis revealed that greater annualized decline in delayed recall was predicted by higher exposure to urban air pollutants (but not rural), adolescent IQ, older age at baseline, and a history of heart disease. Air pollution exposure did not predict annualized change in immediate recall.

Conclusion

Using longitudinal data from the WLS cohort, we find that higher levels of urban ambient air pollutant exposure predicted a more precipitous decline in delayed memory across late life. This finding remained significant after controlling for relevant confounders including neighborhood disadvantage, adolescent IQ, and ApoE‐4 status. Although the effect size of pollution exposure on the rate of memory decline was small, it remains a modifiable risk factor and stands to inform public policies to optimize late life cognition.
Building a normative sample for smartphone‐based measures of cognition and motor functioning: Study design and initial feasibility findings
Authors: Dhanam Sreya , Staffaroni Adam M. , Taylor Jack C , Sanderson‐Cimino Mark E. , Wise Amy B. , Clark Annie L , Heuer Hilary W. , Kwang Winnie , Kramer Joel H. , Boeve Brad F. , Rosen Howard J. , Weiner Michael S. W. , Nosheny Rachel L , Boxer Adam L.
Published: December 2023

Background

Smartphone‐based cognitive and motor tests enable frequent remote assessments in observational research studies and clinical trials, limiting travel burden and increasing access to research for underrepresented groups. One such smartphone tool is the ALLFTD Mobile App, which was designed to capture the clinical features of neurodegenerative diseases via a battery of cognitive, speech, and motor tasks. In this study, we focus on recruiting a demographically diverse normative sample. We have partnered with the UCSF Brain Health Registry (BHR) to recruit 1,000 cognitively healthy participants across the lifespan. Here we describe the study design and initial feasibility results.

Methods

We designed an automated workflow in which participants never interact with the study team except for troubleshooting. BHR participants without reported cognitive impairment were contacted by email to participate in this study (n = 668). Interested participants downloaded the app onto their smartphone and completed in‐app electronic consent. They were asked to complete three ∼30‐minute sessions of cognitive, motor and speech measures over two weeks. Adherence was determined by evaluating the completion rate of app tasks. In a subset who completed a user experience questionnaire (n = 116), responses were quantified using descriptive statistics.

Results

The current enrollment rate is 23.20% (155/668) of contacted participants. Average age is 62 (SD = 8.2, range = 25‐84). Average adherence is 76%. Participants reported a range of perceived task difficulty: 38% indicated tasks were “very easy” or “somewhat easy”, 26% indicated they were “neutral,” 36% found the tasks “somewhat difficult,” and none reported them to be “very difficult.” The time commitment was reported to be acceptable by 97% of participants, and 20% were willing to complete additional tasks. Over half (59%) of participants indicated that they preferred using a smartphone to complete cognitive assessments over traditional pen‐and‐paper measures.

Conclusions

Our preliminary results demonstrate the feasibility and acceptability of recruiting participants, including older adults, through a registry and conducting remote smartphone testing via a fully automated workflow that is highly scalable. Future analysis will study the effects of demographic factors on feasibility and investigate the reliability and validity of the app measures in this sample.
Multimorbidity and competing risks for incident dementia and dementia‐free death in an ADRC cohort
Authors: Choate Radmila , Kucharska‐Newton Anna M. , Jicha Gregory A , Abner Erin L
Published: December 2023

Background

Older adults are often affected by more than one coexisting chronic disease, a condition referred to as multimorbidity. Multimorbidity associates with poor physical and mental health outcomes, cognitive decline, and higher mortality. This study aims to assess the association between the number of self‐reported chronic conditions (CC) and risks for dementia and dementia‐free death in a cohort of older adults.

Method

We examined data from the University of Kentucky Alzheimer’s Disease Research Center cohort, a convenience sample of community‐based older adults followed longitudinally until death. Adults ≥50 years with normal cognition at baseline and data available on 11 measured CC and mental and physical components of SF‐36 (health‐related quality of life measure) were included in this study. The cohort was stratified at baseline based on self‐reported CC into 3 groups: 0, 1, and ≥2. A competing risk analysis using Fine‐Gray subdistribution hazard models was performed to estimate associations between the number of comorbidities and incident dementia or dementia‐free death.

Result

Among 772 adults (mean age 73.1±6.7 years, 66.6% female, 89.0% white), a majority (64.4%) reported ≥2 of the measured 11 CC at baseline; 22.8% had one, and 12.8% had none (Figure 1). These groups did not significantly differ in main demographic characteristics (Table 1). Individuals with multimorbidity had lower physical component scores of SF‐36 indicating worse self‐perceived physical health than other groups. Almost half (45.9%) of the overall cohort reported a history of smoking, which was most common in the ≥2 CC group. Unadjusted and adjusted Fine‐Gray models did not show an association between the number of CC at baseline and incident dementia, accounting for competing risk of death during mean 6.8±3.9 annual follow‐up visits. There was a significant association between the number of CC at baseline and dementia‐free death, accounting for competing event dementia, in unadjusted analyses; this association did not remain significant in the adjusted analyses(Table 2).

Conclusion

Multimorbidity is prevalent in this cohort of older adults. When accounting for competing risks of death, the number of CC was not associated with incident dementia. Further studies are needed to examine associations with mild cognitive impairment and cognitive decline.
Dementia vs Alzheimer’s Disease – Perceptions from Latine individuals and its implications for health communications
Authors: Pinzon Maria C Mora , Benito Melanie Nicole , Kurasz Andrea , Li Zhanhai , Carlsson Cynthia M
Published: December 2023

Background

Health communication best practices include the development, testing and refinement of messages as a way to increase the reach of information and to promote engagement of target audiences. In the field of Alzheimer’s Disease (AD) and Related dementias there are multiple terminologies and misunderstanding that we need to account for at the time of developing new messages. The present study seeks to describe how Latine individuals interpret different terms.

Method

This is a mixed‐methods concurrent study, in which qualitative data was collected from structured interviews with Latine adults .A card‐sorting technique was used to explore perceptions about ADRD. Quantitative data was also collected by a mail‐in survey in English and Spanish that was distributed in metropolitan areas of WI with high proportion of Latine individuals during fall 2021. We used inductive content analysis to analyze the data qualitatively. Descriptive analytics are provided, and Chi‐square test was used to assess statistical significance for categorical variables. All p‐values were considered significant if <0.05. All analyses were done by Statistical Analysis System (SAS) version 9.4, NC, Cary.

Result

Qualitative data from 23 interviews (ages 50 – 87 years old, 65% Women) showed that Latine individuals perceived that cognitive conditions are a spectrum of different conditions where “memory problems” are the initial stage, which then progresses to dementia, and then develops into AD. Even among those with family members diagnosed with AD, there was a perception that AD was a different condition from dementia. The mail‐in survey was completed by 117 individuals (79% female, 47% Hispanic, Median age 56) provided similar information: 44% of respondents considered AD a mental illness, 60% considered that dementia was different from AD, and 45% considered that AD is more severe than dementia. Table 1 shows survey responses and how responses varied by gender, ethnicity, and age group. Table 2 shows some quotes that elaborate how individuals explained their perceptions.

Conclusion

Latine individuals perceived dementia and AD as separate entities, which indicates that healthcare providers and public health agencies need to adjust their communication strategies to promote conversations about ADRD risks and prevention.
The effects of ApoE e4 genotype on plasma p‐tau181 concentrations on clinically diagnosed Alzheimer’s disease (AD) compared to controls
Authors: Hsiung Ging‐Yuek Robin , Kumar Pankaj , Mousavi Ali , Encarnacion Mary , Frykman Hans
Published: December 2023

Background

The association between ApoE e4, a powerful genetic risk factor for AD, and beta‐amyloid (Aβ) pathology has been reported, but the evidence for the correlation with tau pathology is not as clear. The current study examined the relationship between ApoE e4 allele and plasma concentrations of p‐tau181 in patients with clinically diagnosed AD compared with an age‐matched controls with normal cognitive function.

Method

We examined 302 EDTA plasma samples of patients assessed at the UBC Hospital Clinic for Alzheimer’s disease. The cohort was clinically characterized as controls (n = 59) if no significant cognitive impairment was found, and AD (n = 243) if they fulfilled the NIA‐AA criteria (McKhann 2011). The plasma ptau‐181 levels were measured using an ADx‐developed p‐tau181‐specific Simoa assay. ApoE genotyping was performed on extracted DNA from blood samples. We examined the association of presence of ApoE e4 allele and plasma p‐tau181 concentrations using two‐by‐two ANOVA using SPSS 29.

Result

The plasma concentrations of p‐tau181 in AD who are ApoE e4 carriers (75.4 pg/ml) were slightly higher than but not significantly different from in AD non‐ ApoE4 carriers (70.1 pg/ml) (p = 0.64). The plasma levels of ptau‐181 in control cases with and without the ApoE allele were 24.8 and 24 pg/ml respectively (p = 1.000). There was no statistical significant interaction between the effects of AD and ApoE e4 carrier status on plasma p‐tau181 (F (1, 298) = 0.21, p = 0.65, ηp2 = 0.001).

Conclusion

While the plasma p‐tau181 concentrations were significantly higher in AD groups compared to controls (p<0.001) it was no significant effect of ApoE e4 genotype on the levels of plasma p‐tau181 in the control or AD groups (p = 0.94, p = 0.21). This suggests that the ApoE e4 carrier status does not affect plasma p‐tau181 concentrations significantly, independent of the AD clinical status.
Network changes and compensation mechanisms of wake‐promoting neurons across AD continuum
Authors: Grinberg Lea T.
Published: December 2023

Background

Sleep is a complex process regulated by various neural mechanisms, including those promoting wakefulness, those promoting sleep, and those regulating the circadian clock. Recent research has revealed that wake‐promoting neurons, specifically those found in the noradrenergic locus ceruleus (LC), the orexinergic (ORX) neurons in the lateral hypothalamic area (LHA), and the histaminergic neurons in the hypothalamic tuberomammillary nucleus (TMN), are particularly vulnerable to the AD‐tau pathology found in the early stages of Alzheimer’s disease (AD). These studies have uncovered how these neurons accumulate AD‐tau, the extent to which they die in AD, and specific correlations with polysomnographic readings. Notably, a complex pattern of neuronal dysregulation within and among these wake‐promoting neurons has been observed, suggesting the existence of robust compensatory mechanisms in an attempt to overcome dysfunction. Thus, understanding the vulnerability of these nuclei to AD requires network‐based studies. These studies are crucial for informing disease‐specific treatment for sleep disturbance and identifying factors underlying the vulnerability of these neurons.

Methods

Results from several ongoing experiments in the Grinberg Lab, including methods such as quantitative pathology, molecular profiling and clinicopathological correlation

Results

For example, the hypocretin (orexin) receptor 1 (HCRTR1) shows upregulation in orexin neurons from early AD stages, while no changes are observed in the LC or TMN. Additionally, while the LC shows an early pattern of upregulation of genes associated with neuroinflammation, early dysregulation in the ORX is related to synapse‐related genes. Furthermore, circadian genes such as CRY1 and CRY2 show upregulation in the ORX but downregulation in the TMN during AD progression.

Conclusion

This talk will focus on current knowledge, including unpublished data, based on studies in humans, on the vulnerability of wake‐promoting neurons in AD, with a particular emphasis on similarities and contrasts in the patterns of dysregulation among these nuclei during AD progression, in conjunction with changes in the suprachiasmatic nucleus, the circadian clock, and regional expression of circadian genes.
Neural responses to peripheral infection in Alzheimer’s disease model mice
Authors: Fitz Nicholas F , Lu Yi , Saibro‐Girardi Carolina , Lefterov Iliya , Koldamova Radosveta
Published: December 2023

Background

Clinical and animal studies have suggested that peripheral inflammation affects the central nervous system (CNS) and may be a major factor in the pathophysiology of neurodegenerative diseases like AD. Furthermore, a variety of signaling factors originating in the periphery, such as inflammatory mediators, have been associated with the regulation of brain barrier functions. Here, we hypothesized that the presence of peripheral inflammation dysregulates brain barriers’ integrity and induces neuroinflammation with consequences on amyloid pathology.

Method

In this study, we employed an AD mouse model nasally infected with Staphylococcus aureus to assess the impact of chronic or acute peripheral inflammation on brain transcriptome and amyloid pathology. We utilized both single cell and Spatial Transcriptomics to better determine transcriptional response to peripheral inflammation.

Result

The chronic exposure increased the diffuse and compact amyloid plaques and blood cytokine levels. Following a short‐term exposure, single‐cell and spatial transcriptomics uncovered cell type‐ and spatial‐specific transcriptional changes indicating a dysregulation of the brain barriers, including the blood‐brain and the blood‐cerebrospinal fluid barriers. Brain macrophages exhibited increased Apoe expression and macrophage‐specific genes were upregulated at ventricular areas of infected mice. In addition, we report an increase of disease associated microglia genes around the Ab plaques, together with disbalances in neuronal expression in response to peripheral inflammation.

Conclusion

We observed that low‐grade peripheral infection triggers transcriptional responses linked to brain barriers and brain infiltrated/resident macrophages indicate a fundamental importance of them in the mechanisms linking peripheral inflammation and AD pathogenesis. Finally, we showed that bacterial infection caused molecular changes restricted to specific cell types and/or brain spatial microenvironments, which highlights the relevance of studying brain molecular responses with high resolution in order to have new insights on AD etiology.
Integrated AD trial data from multiple sources and stakeholders
Authors: Maruyama Tetsuyuki
Published: December 2023

There is every reason to cheer recent advances is treatments and diagnostics for Alzheimer’s and other dementias, but enormous need remains, and progress is still too slow. An important way to accelerate new discoveries is through sharing of the vast amounts of relevant data, especially the data collect from human research participants. There is consensus among many researchers, clinicians, patients, and governments that data sharing accelerates science by increasing the utility of data. This allows for new analysis, meta‐analysis, and replication, inspiring new ideas and approaches.

There are, however, challenges to data sharing. These include accessible and affordable infrastructure, tools, and resources to support data curation, sharing, and analysis. There also needs to be more incentives – to move away from siloed efforts and towards global collaboration.

The Alzheimer’s Disease Data Initiative (ADDI) is dedicated to data sharing by advancing solutions to these challenges. The AD Workbench provides researchers with the infrastructure to share data and to discover data within a secure, cloud‐based environment.

For data contributors, supports and resources are available to assist with harmonization and curation of data. There are also options available regarding permissioned access, whether the data is simply accessed on the AD Workbench or through federated sharing. For researchers, the AD Workbench offers compute resources, data analysis tools, and other resources to help advance their work.

To both support work on the AD Workbench and to foster community and collaboration, AD Connect offers resource libraries, discussion forums, and other helpful information. We know that meaningful ADRD advances will not be made by any one person or organization. Bringing researchers together, to engage, interact, and inspire each other will help us move closer to fundamentally transforming ADRD research.