bluuebunny/crossref_metadata_2025_split huggingface dataset:
The gingipain inhibitor atuzaginstat and results of the GAIN trial
Authors: Sabbagh Marwan 
Published: December 2023

AbstractThe gingipain inhibitor atuzaginstat is a novel protease inhibitor that blocks a neurotoxic virulence factor known to trigger AD pathogenesis. Because the link between periodontal disease and AD is mechanistic and not incidental, it seems logical to develop drugs that target the virulence factors of P. gingivalis infection, such as gingipains. Atuzaginstat is appealing because it is orally bioavailable and blood–brain barrier penetrant. Clinical trials of atuzaginstat have been completed, with no evidence of amyloid‐related imaging abnormalities. However, a hepatotoxic signal has emerged that requires monitoring and could potentially influence further development of this potential treatment. Since the patients most likely to benefit from the results of the clinical trials underway are those with mild‐to‐moderate AD, more studies are being planned. Atuzaginstat can address the ongoing need for treatment for most patients for whom anti‐amyloids are not suitable.
Interplay Between Genes from Peroxisome Biogenesis and Integrated Stress Response Pathways is Significantly Associated with Alzheimer’s Disease
Authors: Yashin Anatoliy I , Wu Deqing , Arbeev Konstantin , Duan Hongzhe , Holmes Rachel , Bagley Olivia , Ukraintseva Svetlana 
Published: December 2023

AbstractBackgroundPeroxisomes are single‐membrane organelles involved among other things in ether‐phospholipids production that plays an important role in axon myelination in the central nervous system. Disruptions in cytosolic receptor PEX5L (involved in protein import into peroxisome matrix) may lead to peroxisome malfunctioning and disturbance of myelin homeostasis, which, in turn, may contribute to developing Alzheimer’s disease (AD). Experimental studies showed that peroxisome dysfunction is associated with activation of the integrative stress response (ISR). Recent studies provide evidence that the EIF2AK4 gene, a sensor of amino acid deprivation in ISR, is involved in the AD regulation. It is, however, unclear whether interplay between PEX5L and EIF2A4 is associated with AD.MethodTo test the association of the interplay between PEX5L and EIF2AK4 genes with the late‐onset‐AD, we analyzed the Health and Retirement Study (HRS) data using logistic regression model with the interaction term. Education, sex, smoking status, and first five principal components were included as observed covariates. The binary AD outcome was defined as “0” if AD onset was at any age, and as “1” if a person survived to age 85+ and did not get AD during the life. Linkage Disequilibrium test and SNP‐clumping procedure were used to reduce number of tests in SNPxSNP interaction analysis.ResultInteractions between SNPs in fifteen SNP pairs (one SNP in EIF2AK4 gene and another in PEX5L gene) were significantly associated with decreased odds of AD, with effect sizes (β coefficients before the interaction term) ranging between 0.62‐0.69, and p‐values between 1.64E‐04 ‐ 2.12E‐05, with Bonferroni correction threshold = 1.67E‐04. Six SNPs from PEX5L (rs1404271, rs11708154, rs59018122, rs9836757, rs76133869, rs6443674) and five SNPs from EIF2AK4 (rs3207297, rs2279579, rs2291625, rs12591842, rs117584784) participated in such interactions.ConclusionIn this study, interactions between SNPs in EIF2AK4 and PEX5L genes were significantly associated with lower odds of AD in HRS participants. Our findings support the idea that the interplay between genes involved in cellular stress response pathway and peroxisome biogenesis can play a protective role in AD. These results also demonstrate how the knowledge from experimental research can be translated to human applications population‐based studies of AD.
Structural and functional alterations in young adult presymptomatic frontotemporal lobar degeneration mutation carriers
Authors: Lombardi Jolina , Zhang Liwen , Flagan Taru M. , Vargas Andrea Gorham , Mandelli Maria Luisa , Brown Jesse A. , Häkkinen Suvi , Rosen Howard J. , Kantarci Kejal , Ramos Eliana Marisa , Miller Bruce L , Tempini Maria Luisa Gorno , Seeley William W. , Lee Suzee E. ,   the ALLFTD Consortium
Published: December 2023

AbstractBackgroundPresymptomatic frontotemporal lobar degeneration (FTLD) mutation carriers as young as their thirties display gray matter (GM) deficits and alterations in the specific neural networks targeted during the symptomatic phase (Lee et al. NeuroImage Clin 2017; Bertrand et al. JAMA Neurol 2018). These studies raise the question of a potential neurodevelopmental role of pathogenic mutations in FTLD, yet sufficient research in young adults is lacking.MethodLeveraging 3T MRI brain scans from UCSF and the ALLFTD Consortia, we studied structural and functional connectivity alterations in 31 presymptomatic mutation carriers [PreSxAll; 12 C9orf72,13 MAPT, 6 GRN, mean age: 25.2±3.9, range 18‐30 years] and 28 demographically‐matched healthy controls [HC; mean age: 26.5±3.1, range 18‐30 years]. We performed voxel‐based morphometry (VBM) to compare GM volume between HC and PreSxAll, and HC and each mutation carrier subgroup using ANCOVA (SPM12). VBM statistical results were thresholded at a height of p<0.001 uncorrected or p<0.05 familywise error corrected. We used seed‐based task‐free functional MRI (tf‐fMRI) analysis to examine salience network (SN) and default mode network (DMN) connectivity. Single‐subject connectivity maps were analyzed using ANCOVA in SPM for group comparisons and masked to the relevant network. Tf‐fMRI results were thresholded at a height of p<0.05 and extent of p<0.05. For all analyses, nuisance covariates included age, sex, education, handedness, scanner and TIV (GM only).ResultWe found no significant GM differences between groups. PreSxAll showed regions of SN hyperconnectivity compared with HC, specifically in the bilateral insula, right superior frontal gyrus, bilateral midcingulate cortex, and the left cerebellum. Compared to controls, each mutation carrier subgroup featured SN hyperconnectivity within key network hubs, such as the insula and anterior cingulate cortex. The DMN showed no significant alterations for PreSxAll vs. HC. Scattered small clusters of DMN alterations were noted in subcortical regions and the cerebellum in presymptomatic C9orf72 and GRN.ConclusionDespite the absence of GM deficits in young adult FTLD mutation carriers, tf‐fMRI detected SN alterations in these carriers compared with healthy controls. Future studies focused on other neuroimaging measures will further explore differences in young adult FTLD mutation carriers.
Prevalence of cerebral microbleeds in Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease dementia: a systematic review and meta‐analysis
Authors: Chin Kai Sin , Holper Sarah , Loveland Paula M , Churilov Leonid , Yassi Nawaf , Watson Rosie 
Published: December 2023

AbstractBackgroundCerebral microbleeds (CMB) are often associated with vascular risk factors and/or cerebral amyloid angiopathy and are frequently identified in people with dementia. This study aimed to estimate the pooled prevalence of CMB across the three most common late‐onset dementia diagnoses, Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).MethodA systematic search with pre‐defined search terms was performed on Medline, EMBASE and PubMed, from inception to 19th October 2022. Identified articles were manually screed for titles and abstracts by independent reviewers. Relevant MRI studies that reported raw prevalence data of CMB in AD, DLB or PDD were included. Studies which investigated Parkinson’s disease without dementia or people with mild cognitive impairment were excluded. Prevalence data were manually extracted, and study quality was assessed using the Joanna Briggs Institute Checklist for Prevalence Studies. Data were pooled using random‐effect models. The predefined primary outcome was prevalence of CMB in AD, DLB and PDD. Secondary outcomes were associations between CMB and vascular risk factors as well as amyloid‐β burden.ResultA total of 65 studies met the inclusion criteria for data extraction. CMB, predominantly lobar, were present in 32% of AD (n = 5409; 95% CI 29‐35%), 36% of DLB (n = 348; 95% 26‐45%) and 31% of PDD participants (n = 236; 95% CI 23‐40%). The prevalence estimates of CMB in AD and DLB increased with higher field strength and the use of susceptibility‐weighted imaging. CMB in AD were associated with a history of hypertension (odds ratio [OR] 1.74, 95% CI 1.33‐2.28) and amyloid‐β burden (standardised mean difference [SMD] 0.41; 95% CI 0.25‐0.57). CMB in DLB were associated with hypertension (OR 1.95; 95% CI 1.00‐3.83), but not amyloid‐β burden (SMD 0.05; 95% CI ‐0.32‐0.42).ConclusionThe prevalence of CMB was similar across AD, DLB and PDD (31‐36%). The underlying pathophysiology of CMB in DLB might differ from that of AD. More studies evaluating CMB in DLB and PDD are needed.
Effects of apolipoprotein E2 and E4 on brain microstructure in cognitively intact and mildly impaired older adults: Modification by sex and age
Authors: Reas Emilie T. , Triebswetter Curtis , Banks Sarah J , McEvoy Linda K. 
Published: December 2023

AbstractBackgroundAPOE4 is the strongest single genetic risk factor for sporadic Alzheimer’s disease (AD), whereas APOE2 confers protection against AD. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations differ from those presenting with mild cognitive impairments, are unclear. Furthermore, few studies have evaluated whether effects of APOE on early neurodegenerative changes are modified by other AD risk factors including age and sex.MethodSubjects included older adult participants (77±7 years; 57% women) of the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer’s Disease Research Center, including 192 cognitively normal (CN) individuals and 33 with mild cognitive impairment (CI). Participants completed a multi‐shell diffusion MRI scan and restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4‐carriers (33%), APOE2‐carriers (10%), and APOE3 homozygotes (57%). Linear regressions, adjusting for age, sex, and scanner, were conducted among CN to assess associations between APOE and RSI measures, as well as interactions of APOE with sex, and with linear or squared age. Regressions across all subjects examined interactions between APOE4 and cognitive status.ResultAmong CN participants, entorhinal cortex neurite density was lower for APOE4‐carriers than non‐carriers, whereas entorhinal restricted isotropic diffusion decreased with age among APOE4 non‐carriers but not among carriers. Entorhinal cortex hindered diffusion was lower for APOE2‐carriers than non‐carriers among women only. Age more strongly correlated with white matter and subcortical microstructure among APOE2 non‐carriers than among APOE2 carriers. Across the full sample, associations between cognitive status and microstructure were modified by APOE4, with greater differences between CN and CI for APOE4‐carriers in medial temporal regions, but stronger differences for APOE4 non‐carriers in the striatum.ConclusionThe entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 preceding cognitive decline, whereas APOE2 may protect against entorhinal microstructural injury, particularly among women. APOE modifies patterns of microstructural abnormalities associated with aging and cognitive impairment, which may support the development of biomarkers differentially indicative of cytoarchitectural changes occurring with normal brain aging, APOE‐dependent pathways, and non‐AD etiologies.
Inpp5d deficiency exacerbates tau pathology and cognitive deficits in MAPTP301S mouse
Authors: Castranio Emilie L , Wang Minghui , Zhang Bin , Gandy Samuel E. , Ehrlich Michelle E. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia and is characterized by the cerebral accumulation of amyloid plaques and tauopathy. The gene inositol polyphosphate‐5‐phosphatase D (INPP5D), which encodes Src homology 2‐containing‐inositol‐phosphatase‐1 (SHIP1), has been highlighted by multiple approaches as a gene that modulates the risk for AD. SHIP1 expression in brain is restricted to inflammatory cells called microglia that have been shown to play significant roles in the induction and spread of tauopathy. Therefore, the goal of the current study was to examine the effect of microglial Inpp5d/SHIP1 knockdown on a mouse model of tauopathy.MethodWe generated a mouse model of conditional Inpp5d knockdown in microglia to assess the impact on pathology in the MAPTP301S mouse model of tauopathy, using Inpp5dflox mice crossed with an inducible Cx3cr1CreER/+. To induce recombination, 3‐month‐old (mo) Inpp5dfl/fl/Cx3cr1CreER/+ mice, with and without the MAPTP301S transgene, were injected for 5 consecutive days with either tamoxifen (TAM) or corn oil (CO). At 8.5 mo, we assessed learning behavior using the Barnes Maze test and Novel Object Recognition test. Finally, we performed immunohistochemistry, immunoblotting, and quantitative real‐time PCR to assess neuroinflammation and tau pathology.ResultTAM treatment of Inpp5dfl/fl/Cx3cr1CreER/+ mice and MAPTP301S /Inpp5dfl/fl/Cx3cr1CreER/+ mice was used to induce microglial Inpp5d deficiency in both lines. Microglial Inpp5d deficiency in MAPTP301S mice was associated with increased levels of AT8+ hyperphosphorylated tau, yet the numbers of IBA1+ microglia and GFAP+ astrocytes were similar to MAPTP301S expressing normal levels of Inpp5d.ConclusionOur findings suggest that, in our mouse model, Inpp5d deficiency plays an important role in the pathogenesis of tauopathy, but fails to induce an obvious increase in the numbers of either IBA1+ microglia or GFAP+ astrocytes. Our results provide evidence for further evaluation of INPP5D/SHIP1 as a potential target for treating and/or preventing AD.
Bumetanide Exposure Association with Alzheimer’s Disease Risk
Authors: Graber‐Naidich Anna , Lee Justin , Younes Kyan , Greicius Michael D , Guen Yann Le , He Zihuai 
Published: December 2023

AbstractBackgroundTo investigate whether exposure history to two common loop diuretics affects the risk of developing Alzheimer’s disease (AD) after accounting for socioeconomic status and congestive heart failure.MethodsIndividuals exposed to bumetanide or furosemide were identified in the Stanford University electronic health record using the deidentified Observational Medical Outcomes Partnership platform. We matched the AD case‐cohort to a control cohort (1:20 case:control) on gender, race, ethnicity, hypertension and controlled for variables that could potentially be collinear with bumetanide exposure and/or AD diagnosis. Among individuals older than 65 years, 5,839 AD cases and 116,103 matched controls were included. A total of 1,759 patients (54 cases, 1,705 controls) were exposed to bumetanide.ResultsAfter adjusting for socioeconomic status and other confounders, bumetanide and furosemide exposure were significantly associated with reduced AD risk (respectively, bumetanide odds ratio [OR] = 0.23; 95% confidence interval [CI], 0.15‐0.36; p = 4.0×10−11; furosemide OR = 0.42; 95% CI, 0.38‐0.47; p < 2.0×10−16).ConclusionOur study replicates in an independent sample that a history of bumetanide exposure is associated with reduced AD risk, while also highlighting an association of the most common loop diuretic (furosemide) with reduced AD risk. These associations need to be additionally replicated and the mechanism of action remains to be investigated.
Performance of complex daily tasks and cerebrospinal fluid biomarkers of Alzheimer disease
Authors: Keleman Audrey A. , Bollinger Rebecca M. , Wisch Julie K. , Schindler Suzanne E. , Morris John C , Ances Beau , Stark Susan L. 
Published: December 2023

AbstractBackgroundThe preclinical stage of Alzheimer disease (AD) is a clinically silent period that is detectable through neuroimaging and biofluid biomarkers of amyloid, tau, and neurodegeneration. We evaluated whether performance on cognitively‐focused complex daily tasks is associated with cerebrospinal fluid (CSF) biomarkers of brain amyloidosis or tau pathology in cognitively normal (CN) older adults.MethodIn this cross‐sectional analysis of an ongoing longitudinal cohort study, CN older adults performed three cognitively‐focused complex tasks of daily living (shopping, checkbook balancing, and medication management) from the Performance Assessment of Self‐Care Skills (PASS) in their home. PASS tasks were scored for independence (cues required to complete task) and adequacy of performance (quality and process, efficiency, redundant actions). Participants also had a CSF sample obtained within two years of completing the PASS. CSF amyloid (Aβ42, Aβ40) and CSF tau phosphorylated at position 181 (p‐tau181) were measured with Lumipulse immunoassays. Nonparametric partial correlations were used to examine the associations between task performance and biomarkers of AD (CSF Aβ42/Aβ40 and CSF p‐tau181), controlling for age, gender, and level of education.Result122 CN participants (mean age 74.4 years, 53% female, 88% white) were included. After controlling for age, gender, and years of education, worse performance on complex daily tasks was associated with lower CSF Aβ42/Aβ40 (more cues required: Spearman rho = ‐0.213, p = 0.03), and there was a trend towards lower adequacy (rho = 0.161, p = 0.08). There were no significant associations with CSF p‐tau181.ConclusionThis study suggests that worse performance on complex daily tasks in CN older adults may be associated with greater amyloid burden. These findings could lead to a better understanding of functional changes that may be associated with amyloidosis prior to the onset of noticeable memory symptoms in AD or related dementias.
Sensitivity of NIH Toolbox‐Cognition Battery task performance to amyloid positivity status in cognitively normal older adults
Authors: Maher Amanda Cook , Persad Carol C , Brush David M. , Perrin Cameron K , Bross Jordan R , Fisher Jordan , Murphy Yi Lu , Koeppe Robert A. , Giordani Bruno 
Published: December 2023

AbstractBackgroundAmong cognitively normal older adults, high brain amyloid burden may signal the presence of early Alzheimer’s disease processes. While research has shown subtle neuropsychological performance differences among cognitively intact older adults with and without elevated brain amyloid, early investigation has not found similar between‐group differences on the NIH Toolbox‐Cognition Battery (NIHTB‐CB; Snitz et al., 2020). Here, we utilize data from a longitudinal observational driving study to evaluate potential differences in NIHTB‐CB task performance among older adults determined to be cognitively normal via clinical research consensus, based on brain amyloid status.MethodData from cognitively normal adults age 65+ who completed an amyloid Positron Emission Tomography scan, NIHTB‐CB tasks, and additional neuropsychological testing through the Michigan Alzheimer’s Disease Research Center were analyzed. Amyloid positivity was determined based on a centiloid scale (≤10 indicating amyloid negativity; ≥20 amyloid positivity). Thirty participants were amyloid negative and 17 were amyloid positive. Nine individuals with intermediate amyloid values were excluded. Group differences in NIHTB‐CB performance were analyzed via independent sample t‐tests. Linear regressions were used to assess demographic and NIHTB‐CB task/neuropsychological performance predictors of amyloid positivity.ResultThere were no demographic differences between the groups. Overall, amyloid negative participants outperformed their amyloid positive peers on NIHTB‐CB List Sorting and backward Digit Span tasks (p’s<0.05), both of which are measures of working memory. There were no other group differences in cognitive performance, including episodic memory. The final NIHTB‐CB regression model only included NIHTB List Sorting, which accounted for 16.2% of the variance in amyloid status (F = 8.69, p = 0.005). Digit Span backward similarly accounted for 16.6% of the variance in amyloid status (F = 6.39, p = 0.017).ConclusionAmong cognitively normal older adults with known amyloid status, working memory performance, but not episodic memory performance, differentiated amyloid positive and negative groups. This is consistent with research demonstrating an association between elevated amyloid and executive dysfunction, but not memory impairment, in cognitively normal adults (Tideman et al., 2022). NIHTB‐CB’s List Sorting Working Memory is a complex, challenging sequencing task that appears sensitive to amyloid positivity in older adults and task performance may serve as a marker for early prediction of Alzheimer’s disease.
Association between social networking and cognition among middle aged and older adults in rural India
Authors: Rai Pooja , Sundarakumar Jonas S. , Stezin Albert , Issac Thomas Gregor ,   SANSCOG study team
Published: December 2023

AbstractBackgroundEmerging evidence suggests that better social networking is associated with better cognitive performance among older adults. However, most of the prior studies have used global cognitive measures to study the above relationship. In this study, we aim to investigate the role of social networking on distinct cognitive domains, among dementia‐free middle‐aged and older‐age adults from a rural Indian population.MethodBaseline assessment data of 2403 participants (≥45 years), who are part of an ongoing, prospective, aging cohort study in rural India (Srinivaspura Aging, NeuroSenescence, and COGnition, SANSCOG) and having a Clinical Dementia Rating (CDR) of ‘0’ who are cognitively healthy was utilized for this study. Social networking was assessed using Cohen’s Social Network Index (SNI), wherein three dimensions were examined – network diversity, number of people in social network and number of embedded networks. Cognitive functions were assessed using episodic memory, geometric figure spatial recognition, verbal fluency, semantic association, word comprehension, reading comprehension and visuospatial span subtests of a culturally validated, computerized, neurocognitive test battery. Linear regression models, adjusted with age and gender were used for statistical analysis.ResultIn the linear regression model, adjusted for age and gender, higher network diversity was significantly associated with better cognitive performance in episodic memory (β = 0.16, p = 0.001), attention function (β = 0.07, p = 0.004), geometric figure spatial recognition (β = 0.13, p = 0.001), verbal fluency phonemic cue (β = 0.11, p = 0.001), reading comprehension (β = 0.09, p = 0.001) and semantic language association function (β = 0.08, p = 0.001). Further, higher dimension of number of people in social network was significantly associated with better cognitive performances in semantic language association function (β = 0.002, p = 0.04). Furthermore, in the third dimension of SNI, higher dimension of number of embedded networks was significantly associated with better cognitive performances in visuospatial span (β = 0.05, p = 0.046) and verbal fluency phonemic cue (β = 0.103, p = 0.001).ConclusionThe findings suggest that better social networking in all three dimensions was associated with better cognitive functions in multiple distinct cognitive domains. It is important to follow‐up these participants longitudinally with serial cognitive monitoring to understand if social networking can potentially delay cognitive decline and thereby, serve as a protective factor for dementia.