bluuebunny/crossref_metadata_2025 huggingface dataset:
Agora: An open‐access platform for the exploration of nascent targets for Alzheimer’s disease therapeutics
Authors: Britton Jessica S , Wiley Jesse C , Beck Jaclyn , Yi Lawrence , Bradic Ljubomir , Do Khai , Grosenbacher Nicholas , Simon Stockard , Hodgson Jay , Greenwood Anna K
Published: December 2023

Background

Agora (https://agora.adknowledgeportal.org) is an open resource developed to enable Alzheimer’s disease (AD) researchers access to target‐based evidence generated within the translational research portfolio of the National Institute on Aging (NIA). Agora aims to accelerate AD research and maximize therapeutic discovery by sharing information using interactive tools, data visualizations, and summarized evidence.

Method

Agora enables the sharing of information about potential AD therapeutic targets by surfacing data visualizations, summary evidence, and results from targeted validation studies. Agora users can browse a list of over 600 targets nominated by the NIA’s Accelerating Medicines Partnership in AD (AMP‐AD) consortium and Target Enablement to Accelerate Therapy Development for AD (TREAT‐AD) centers, and by the broader AD research community; see visualizations and summarized information based on harmonized genome‐wide analyses; use interactive visualizations designed to enable non‐bioinformaticians to evaluate and compare complex multi‐omic data; and access the data underlying these results and visualizations.

Result

Agora presents information and results about AD targets using approaches that make this information accessible to a broad spectrum of AD researchers. Recent updates to Agora include 1) presentation of TREAT‐AD target biodomain associations and target ranking scores and 2) a new exploration interface that enables the visual comparison of multi‐omic results across targets.

Conclusion

The advancement of promising new AD therapeutics requires efforts that span research groups and specialties across academia and industry. The Agora platform enables the AD research community to unite around target hypotheses to accelerate the investigation of promising new targets and mechanistic hypotheses.
The gingipain inhibitor atuzaginstat and results of the GAIN trial
Authors: Sabbagh Marwan
Published: December 2023

The 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

Background

Peroxisomes 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.

Method

To 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.

Result

Interactions 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.

Conclusion

In 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

Background

Presymptomatic 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.

Method

Leveraging 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).

Result

We 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.

Conclusion

Despite 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

Background

Cerebral 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).

Method

A 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.

Result

A 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).

Conclusion

The 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

Background

APOE4 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.

Method

Subjects 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.

Result

Among 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.

Conclusion

The 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

Background

Alzheimer’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.

Method

We 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.

Result

TAM 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.

Conclusion

Our 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

Background

To 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.

Methods

Individuals 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.

Results

After 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).

Conclusion

Our 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

Background

The 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.

Method

In 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.

Result

122 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.

Conclusion

This 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

Background

Among 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.

Method

Data 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.

Result

There 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).

Conclusion

Among 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

Background

Emerging 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.

Method

Baseline 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.

Result

In 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).

Conclusion

The 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.
Consequences of Pathogenic Tau Expression in Mouse Locus Coeruleus
Authors: Korukonda Anuradha , Marriott Alexia , Weinshenker David
Published: December 2023

Background

During the early stages of Alzheimer’s disease (AD), patients often suffer from prodromal symptoms such as anxiety, impulsivity, depression, agitation, and sleep disturbances prior to the onset of cognitive impairment. Incidentally, the brainstem noradrenergic locus coeruleus (LC) is the first structure to develop hyperphosphorylated ‘pretangle’ tau pathology in the human brain. Furthermore, norepinephrine (NE) influences several physiological processes such as sleep/wake cycle, arousal, stress, mood, and attention which have been implicated in the prodromal behavioral abnormalities. While clinical studies show significant correlations between LC dysfunction and neuropsychiatric symptoms, a causal relationship between early tau accumulation in the LC and the manifestations of prodromal behaviors remains to be resolved. To explore this, we developed a translationally‐relevant tau mouse model that recapitulates the ‘LC first’ phenomena commonly observed in humans.

Method

Adult male and female tyrosine hydroxylase (TH)‐Cre mice aged 4 months underwent intra‐LC infusions with a Cre‐dependent adeno‐associated virus (AAV) expressing mCherry, wild‐type (WT) human tau or P301S mutant human tau (n = 3/group). 3 months post‐infusion, mice underwent a panel of behavioral tests to assess sleep latency, locomotor activity, compulsivity, stress‐induced anxiety‐like behavior, association memory deficits, impulsivity, and attentional impairments. Following behavioral tests, brain sections comprising the LC, hippocampus and prefrontal cortex (PFC) were immunostained with TH to assess for LC integrity, AT8 to detect pretangle tau, NE transporter (NET) to evaluate NE fiber intensity in projection regions, and GFAP and IBA1 to identify neuroinflammatory markers. Immunoreactivity (IR) will be calculated as a measure of fluorescence via ImageJ.

Result

It has been proposed that tau accumulation in the LC may provoke mild to moderate damage in LC neurons, triggering compensatory mechanisms such as LC hyperactivity. It is hypothesized that at 3 months, LC‐specific tau pathology will result in hyperarousal, compulsivity, anxiety‐like behavior, and impulsivity. In tandem, human tau‐expressing mice are expected to display increased TH, reflecting LC hyperactivity, neuroinflammatory markers and reductions in NE fibers in LC‐projecting regions. These findings will be presented in July 2023.

Conclusion

This research will elucidate the role of LC in governing prodromal symptoms. Further studies will be needed to assess molecular mechanisms underlying tau‐mediated LC dysfunction in early AD.
Thalamic Contributions to Functional Circuitry in Preclinical Alzheimer’s Disease
Authors: Li Joyce S , Tun Samantha M , Lacadie Cheryl , Fredricks Carolyn
Published: December 2023

Background

Thalamic nuclei are heterogeneously impacted by Alzheimer’s disease (AD) pathology. The anterior thalamus shows tau deposition early on in AD, while other nuclei, such as the mediodorsal (MD) thalamus are spared by tau until much later in the disease process (Braak and Braak, 1991). Furthermore, anterior and MD thalamus have dissociable roles in memory performance – the anterior has a greater role in recollective memory, while the MD plays a role in familiarity. Additionally, the anterior thalamus has direct anatomical links to brain regions implicated in poor short‐term memory performance in AD, while MD thalamus connectivity is primarily to regions spared of AD pathology until late. We sought to identify differences in functional connectivity between the anterior and MD thalamus in amyloid negative and positive individuals.

Method

We examined resting‐state functional MRI data from the A4 study (n = 569), including 254 healthy controls and 315 individuals with preclinical AD based on amyloid SUVR>1.14 (Table 1). We assessed functional connectivity of anterior and MD thalamus to the whole brain using 2mm radius spherical seeds at the center of mass of Morel atlas nuclei. All results were covaried for age, sex, handedness, and years of education.

Results

Anterior thalamic activity was positively correlated with parahippocampal gyrus, fusiform, and insula, and negatively with the striatum and thalamus. MD thalamic activity was positively correlated with the amygdala, ventral striatum, and anterior cingulate, and negatively correlated to the superior temporal gyrus and regions of the parieto‐occipital lobe. In preclinical AD, compared with HCs, the positive correlations in either thalamic nuclei were lost.

Conclusion

The thalamic functional connectivity observed agrees with preexisting literature dissociating structures related to the anterior and MD thalamus. Our results provide a basis for further exploration of thalamic nuclei to AD‐involved functional networks, as well as future analysis of the observed connectivity measures to cognition.
Association of individual and multiple comorbid neuropathologies with cognitive decline in the oldest‐old: Results from The 90+ Study
Authors: Biswas Roshni , Jiang Luohua , Kawas Claudia H. , Sajjadi S. Ahmad , Montine Thomas J. , Bukhari Syed A. , Corrada María M. M.
Published: December 2023

Background

Age‐related neuropathologies are common in the oldest‐old and associated with cognitive decline. In this study, we examined the associations of individual and multiple comorbid neuropathologies with cognitive decline in participants who had normal cognition in at least one in‐person visit during their time in The 90+ Study.

Method

Our study included 251 individuals from The 90+ Study‐ a longitudinal study on aging, who had at least 2 in‐person visits, had normal cognition in at least one of them and had autopsy data. We used longitudinal Mini Mental State Examination (MMSE) scores to assess cognitive trajectories. For the first part of our analysis, we examined individual neuropathologies that were evaluated as: Alzheimer’s Disease neuropathologic change (ADNC) (intermediate/high), presence of Cerebral amyloid angiopathy (CAA), Microinfarcts (2+), atherosclerosis, arteriolosclerosis, Lewy body disease (LBD), Hippocampal sclerosis (HS), Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), and Age‐related tau astrogliopathy (ARTAG). For the second part of our analysis, we examined multiple comorbid neuropathologies. For this analysis we recoded each neuropathology as: 0 for absent/negligible levels, 0.4 for intermediate, or 1 for severe. These recoded scores were added to create four summary indices: all pathology index (total of all individual neuropathologies), vascular index (CAA, Microinfarcts, atherosclerosis, and arteriolosclerosis), neurodegenerative index (ADNC, LB, HS, and LATE‐NC) and non‐AD neurodegenerative index (LB, HS, and LATE‐NC). We used linear mixed effects models to examine the associations of individual neuropathologies and the pathology indices with cognitive decline.

Result

At baseline, participants had a mean age of 93 years and a mean MMSE score of 27.6. Mean follow up time was 5.1 years (Table1). Presence of LBD (ß = ‐0.20; p = 0.07), and HS (ß = ‐0.24; p = 0.06) trends toward to an association with faster cognitive decline (Table2). All pathology index (ß = ‐0.10; p = 0.01), neurodegenerative index (ß = ‐0.17; p = 0.003) and non‐AD neurodegenerative index (ß = ‐0.16; p = 0.02) were significantly associated with faster cognitive decline (Table3).

Conclusion

In individuals who maintain normal cognition until age 90+ and then start declining, the rate of cognitive decline is related to the burden of neuropathologies, particularly neurodegenerative neuropathologies. Therefore, multiple comorbid neuropathologies need to be targeted for preventing cognitive decline in the oldest‐old.
Validation of the Ten‐word Test for Immediate Memory in Middle‐Aged and Older Population with Subjective Cognitive Decline and Mild Cognitive Impairment
Authors: Wang Ziqi , Xu Lisi , Wang Yu , Li Hongyi
Published: December 2023

Background

To validate the ten‐word test for immediate memory from the Alzheimer’s Disease Assessment Scale‐Cognitive section (ADAS‐Cog) in detecting subjective cognitive decline (SCD) and mild cognitive impairment (MCI).

Method

79 people aged 38∼80 years old participated in the study and they were classified as SCD (n = 55) or MCI (n = 24).

Result

The the Mann‐Whitney U test showed that the ten‐word test score was significantly different in SCD compared to MCI (p = 0.001, Figure 1). In particular, a cut‐off score of 4.15 points had an 63% sensitivity and 87% specificity for discriminating MCI from SCD (AUC = 0.73, p = 0.001), while a cut‐off score of 4.15 also had a sensitivity of 79% and a specificity of 83% for discriminating MCI from SCD in age > 60 years old adults (AUC = 0.82, p = 0.001), and a cut‐off score of 4.35 points had a sensitivity of 90% and a specificity of 95% for discriminating MCI from SCD in those age > 60 years old adults with education level > 9 years (AUC = 0.93, p < 0.001) (Figure 2‐3). Convergent validity was found between the ten‐word test and ADAS‐cog total scores (r = 0.56, p < 0.001), and the Mini‐Mental State Examination (MMSE) (r = ‐0.28, p = 0.013) and the Montreal Cognitive Assessment‐Basic (MOCA‐B) (r = –0.20, p = 0.078).

Conclusion

The ten‐word test for immediate memory from the ADAS‐Cog is a good to fair screening tool with adequate discriminant validity for administration in people with SCD and MCI.
AD Biomarkers in Chronic Kidney Disease and Kidney Transplant
Authors: Gupta Aditi , Morris Jill K , Kueck Paul J. , Blankenship Anneka , Mahnken Jonathan D , Young Kate
Published: December 2023

Background

Blood biomarkers of Alzheimer’s disease (AD) are elevated in chronic kidney disease (CKD). Whether this is due to deceased kidney clearance or increased production, and how they change with kidney transplant (KT), is unclear.

Method

We examined serum AD biomarkers from CKD patients pre‐ to post‐KT and compared findings with controls without CKD or AD. Analyses were performed on a Simoa HD‐X, using pTau181 and Neuro 4 Plex E assays.

Age was used for covariate adjustment in linear mixed models (LMM) analyzing phosphorylated tau 181 (ptau181), neurofilament light (NfL), amyloid beta (AB42, AB40, 42/40), and glial fibrillary acidic protein (GFAP). Change in p‐tau181 was our primary outcome. LMM included age and levels for control, pre‐KT, or 12‐weeks or 1‐year post‐KT. Based on residual patterns, the natural log (In) of each measure was used for final analyses. Linear contrasts were used to generate estimated differences between group/time points from age‐adjusted models. These included averaged pre‐KT, post‐KT, and control comparisons. Two degree‐of‐freedom tests compared the post‐KT measures to pre‐KT and controls.

Result

The 59 CKD patients were 52±12 years old and 13 controls were 51±8 years old. Pre‐KT, ln(p‐tau181) was higher than controls (p<0.0001) and post‐KT (p<0.0001) (Figure). Post‐KT p‐tau181 greatly decreased but remained higher than controls (p = 0.0004). There was no difference between 12 weeks and 1 year post‐KT levels (p = 0.70). ln(pTau) increased with age (p = 0.06). ln(NfL) followed a similar pattern; pre‐KT levels were higher than controls (p<0.0001) and post‐KT (p<0.0001). Post‐KT levels decreased but remained higher than controls (p<0.0001). 12‐week and 1‐year post‐KT levels did not differ (p = 0.57). Levels increased with age (p<0.0001). Pre‐KT AB42 was higher than controls (p<0.0001) and post‐KT (p<0.0001). Post‐KT, levels decreased but remained higher than controls (p = 0.005) and continued declining 1‐year post‐transplant (p = 0.01). In(AB40) and In(GFAP) showed the same pattern. The AB42/AB40 was not different pre‐KT vs controls (p = 0.58) and did not change following KT. Cognitive function improved post‐KT. Patients with residual kidney function had lower baseline levels of AD blood biomarkers.

Conclusion

In severe CKD, blood biomarkers of AD are dependent on kidney function and caution should be used in interpreting them.
Association between retinal layer thickness and cerebral white matter hyperintensities in older adults
Authors: Han Ji Won , Kim Hyeong Min , Kwon Min Jeong , Park Jieun , Kim Jun Sung , Woo Se Joon , Kim Ki Woong
Published: December 2023

Background

The brain and retina may share pathophysiological mechanisms in various central nervous system disorders, suggesting the potential associations between retinal layer thickness and cerebral white matter hyperintensities (WMH).

Method

A total of 149 participants without dementia aged over 65 years (mean age: 75.4, SD: 5.4, range: 65‐91; male: 90 [60.4%]) from the randomly sampled community‐dwelling prospective cohort were included in the analysis. Using spectral‐domain optical coherence tomography, we assessed the thickness of 6 retinal layers in the macular region, the peripapillary retinal nerve fiber layers, and the subfoveal choroid. We classified WMH into 3 groups using the distance from the ventricle surface: juxtaventricular (JVWMH, < 4mm), periventricular (PVWMH, >4mm, <14mm), and deep WMH (DWMH > = 14mm). The associations between retinal layer thickness and WMH volume were examined using linear regression models adjusting age, sex, comorbid hypertension, and diabetes.

Result

The thicknesses of superior outer, inferior outer ganglion cell layers (GCL) and superior outer, inferior outer, total outer inner plexiform layers (IPL) were negatively associated with the total WMH, PVWMH, and DWMH volumes. Reduced thicknesses of total outer GCL and temporal outer inner nuclear layer (INL) were associated with higher total WMH and PVWMH volumes. Center GCL thickness was positively associated with JVWMH volume, and nasal outer GCL thickness was negatively associated with DWMH volume.

Conclusion

Outer GCL and IPL thicknesses may be associated with WMH volume in older adults. This study may also suggest differential associations based on etiology between retinal layer subfields and WMH subgroups.
Joint Exposure‐Response Analysis of PET Amyloid Plaque Data from the BACE1 Inhibitor Verubecestat and Amyloid mAbs Trials in Prodromal to Moderate Alzheimer’s Disease
Authors: van Maanen Eline , Stone Julie A , Bennacef Idriss , Duffull Stephen , Robey Seth
Published: December 2023

Background

Positron‐emission tomography (PET) with amyloid radiotracers allows the quantification of pathological amyloid deposition in brain tissues. An exposure‐response (E‐R) analysis of individual study data of the β‐secretase‐1 inhibitor verubecestat and summary level data of four amyloid mAbs in patients with Alzheimer’s disease (AD) was conducted, to quantify the drug effects and plaque turnover rates and facilitate prediction of unstudied regimens.

Method

Individual (n = 188) verubecestat amyloid‐PET plaque data and exposures from APECS [Egan et.al, 2019] were pooled with summary. amyloid‐PET data and serum exposures from literature for aducanumab [Sevigny J, et al. 2016], donanemab [Lowe SL, et al. 2021, Lily ADPD, 2021], gantenerumab [Klein G, et al. 2019, Portron A, et al. 2020] and lecanemab [Swanson CJ, et al. 2021]. Amyloid plaque levels in SUVR units were converted to Centiloid [Klunk WE, et al. 2015]. All data were fit simultaneously in a joint model by nonlinear mixed‐effects modeling

Result

An indirect response (turnover) model with verubecestat inhibiting plaque formation, and amyloid mAbs stimulating plaque removal well represented the available data (Figure 1). All plaque time course data from natural progression (control arms), β‐secretase‐1 inhibition and amyloid mAb treatment arms were well described by a joint model. The plaque turnover was estimated to be 0.00028 per day, corresponding to a half‐life of plaque of ∼ 6.8 years. Verubecestat AUC50 was estimated as 0.313 uM*h, commensurate to a 93.5% reduction in plaque formation at the typical 40 mg exposure and consistent with the >60% reductions in CSF Aβ40 and 42 observed in APECS. Aducanumab 10 mpk Q4W, donanemab 1400 mg Q4W, lencanemab 10 mpk Q2W, and gantenerumab 1200 mg SC Q4W were estimated to results in 13.5‐, 16.4‐, 16.6‐, and 12.6‐fold increases in plaque removal rate, respectively.

Conclusion

The joint turnover model, linking drug exposure with amyloid plaque load, was adequate to describe natural progression and treatment response, and allows for estimation of the underlying turnover rate. This approach improves cross‐study comparisons and prediction of alternative regimens and therapeutic approaches by accounting for differences in baseline plaque load, dosing and titration regimens, and mechanism of action.
Baseline cognitive dispersion is related to increases in white matter hyperintensities in cognitively preserved older individuals
Authors: Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Solé‐Padullés Cristina , Cabello‐Toscano María , Abellaneda‐Pérez Kilian , Perellón‐Alfonso Ruben , Perera‐Cruz Oriol , Bargalló Núria , Bartrés‐Faz David
Published: December 2023

Background

Cognitive dispersion (CD), understood as intra‐individual variability in performance, is considered a sensitive marker of prodromal stages of Alzheimer’s Disease (AD; Halliday et al. J. Intell 2018;6(1):12), and it is thought to complement cognitive performance (CP) in predicting age‐related changes (Costa et al. ClinicNeuropsychol 2019;33(2)). Moreover, white matter hyperintensities (WMH) are a common age‐associated finding that especially impacts processing speed (Boutzoukas et al. Front in AgingNeurosci 2021;13) and executive function (Papp et al. NeuropsycholDev 2014;21(2)). Therefore, we aimed to investigate (i) associations between CD, CP, and WMH, and (ii) whether WMH age‐related changes can be better predicted by baseline CD or CP in a cognitively normal aging sample.

Method

One hundred and three healthy elders (age: 68.61±3.01 years; 72 females) underwent a neuropsychological assessment and a magnetic resonance image acquisition and repeated them after 2 years. Based on processing speed and executive function scores, we computed a baseline CD (i.e., CD‐tp1; using the intraindividual standard deviation method, Costa et al. Clinic Neuropsychol 2019;33(2)) and a CP (calculated with principal component analysis) at both time‐points (i.e., CP‐tp1, CP‐tp2). 3D‐FLAIR sequence was used to estimate WMH volumes (i.e., WMH‐tp1, WMH‐tp2) using the SPM12 Lesion Segmentation Toolbox (Schmidt et al. Neuroimage 2012;59(4)). The baseline volumes were subtracted from the follow‐up ones to obtain the difference (i.e., CP‐diff, WMH‐diff). Statistical analyses were linear regressions adjusted by age, sex, years of education, and intracranial volume for WMH analyses. Paired t‐tests were used for the longitudinal approach.

Result

There was a negative cross‐sectional relationship between CD‐tp1 and CP‐tp1 (B = ‐.240, t = ‐3.034, p = .004; Fig1), while those cognitive measures were unrelated to WMH‐tp1 volumes. Longitudinally, we detected a significant increase in WMH (t = 7.244, p<.001), while CP remained stable and there were no significant associations between CP‐diff and WMH‐diff. The main finding was the significant relationship found between WMH volume increases (i.e., WMH‐diff) and CD‐tp1 (B = ‐.320, t = ‐3.060, p = .003; Fig2), but not with CP‐tp1.

Conclusion

The results show that in healthy elderly individuals who evidenced cognitive stability in processing speed and executive function, the CD is a sensitive marker to predict significant age‐related increases in WMH, which would be beneficial in the AD‐continuum.
Dementia Risk Estimation: Individual Needs and Preferences– Preliminary Data of the PreTAD‐Study
Authors: Gerards Michelle , Baumeister Annika , Hübner Constanze , Ribaldi Federica , Marquié Marta , Cantero‐Fortiz Yahveth , Schmitz‐Luhn Björn , Wittrock Julia , Schwegler Carolin , Boada Mercè , Frisoni Giovanni B , Woopen Christiane , Jessen Frank , Rostamzadeh Ayda
Published: December 2023

Background

Due to new, more reliable and accessible technologies, a paradigm shift from curative to predictive and preventive medicine is emerging. Despite progress in the field of Alzheimer’s dementia risk estimation, little is known about the individual perspectives in this regard. The tri‐national PreTAD (The Predictive Turn in Alzheimer’s Disease: Ethical, Clinical, Linguistic and Legal Aspects) project aims to study the perspectives of individuals from the general population, first‐degree relatives of persons with Alzheimer’s dementia, APOE4 allele carriers, and of individuals with subjective cognitive decline (SCD) on individual risk factor assessment and dementia risk estimation. In a quantitative and qualitative longitudinal study, needs, preferences and decision‐making parameters will be conducted.

Method

For the quantitative study, hypothetical scenarios on predictive AD diagnosis for an individual person were developed. Based on these scenarios, instruments to measure psychological distress, subjective well‐being, quality of life, willingness to make lifestyle changes, and to take preventive measures were applied. The qualitative approach uses individual interviews to obtain complementary in‐depth information on personal preferences. Results of the pilot study with 10 cognitively unimpaired healthy participants and 10 participants with SCD are reported.

Result

The participants of the pilot study wanted to know their estimated personal risk of developing Alzheimer’s dementia. Higher test accuracy was more important than low invasiveness. In the pilot data, age and the possibility of influencing the risk by lifestyle changes, but also the attitude of relatives, influenced the decision for risk estimation. Willingness to assess dementia risk seems to be independent of the absence of causal treatment options.

Conclusion

The PreTAD project will provide a deeper comprehension of needs and preferences regarding the individual dementia risk estimation. From an individual point of view, there seems to be an interest in risk assessment and prediction, which is influenced by a variety of factors. The findings of the PreTAD project will help to incorporate the perspectives of potential users risk estimation in the development of guidance for counseling and clinical management in predictive and preventive approaches in the field of dementia.