bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Alzheimer biomarkers in the 1946 British birth cohort: predicting conversion to amyloid PET positivity over a two‐year follow‐up period
Authors: Keshavan Ashvini , Camporesi Elena , Coath William , Cash David M , Fox Nick C , Karikari Thomas K , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Schott Jonathan M
Published: December 2023

Background

In the Insight 46 sub‐study of the 1946 British birth cohort we investigated concordance of baseline plasma biomarkers (age 71) with cerebral amyloid PET status at two time‐points (ages 71 and 73).

Method

Baseline plasma samples were tested using Simoa (Quanterix) commercial (NfL, GFAP, Aβ42, Aβ40, p‐tau181V2) and homebrew digital immunoassays (p‐tau181, p‐tau231: University of Gothenburg; NT1 tau: Harvard University). Logistic regression and ROC analysis were used to assess concordance of single biomarkers with cerebral amyloid PET status at each timepoint, defined as 18F‐florbetapir SUVR> = 1.071 normalized to whole cerebellum without partial volume correction (13 centiloids). Areas under the curve were compared to that from the base model (age, sex, APOE ε4 carrier status) using De Long tests. Combinations of the top five biomarkers that had singly significantly improved on the base model were compared using Akaike Information Criteria (AIC). Differences between biomarker values across the three amyloid PET groups (both scans negative, baseline negative and follow‐up positive, both positive) were assessed using Kruskal‐Wallis ANOVA and post hoc Dunn’s tests with Bonferroni correction.

Result

Baseline assessment of 502 individuals (mean age 70.7 years (s.d. 0.7), 51% male, 29.6% APOE ε4 carriers) yielded 432 individuals with plasma and amyloid PET available at the first timepoint (19.4% PET‐positive) and 336 at the second timepoint (25.3% PET‐positive). No single biomarker outperformed the base model in predicting amyloid PET status at either timepoint. However, each of Aβ40/42, all the p‐tau biomarkers, NT1 tau, and GFAP improved base model performance at both timepoints (Table 1). A model combining base model covariates with Aβ40/42, p‐tau181 homebrew and GFAP gave the best fit for follow‐up amyloid PET status, (AIC 292, compared with the base model AIC of 355 ‐ Table 2). Individuals who converted from PET‐negative to positive had higher median values of p‐tau181 (both assays) and p‐tau231 at baseline than those who remained amyloid PET‐negative (Figure 1).

Conclusion

Combining baseline plasma Aβ40/42, p‐tau181 and GFAP gave the best prediction of amyloid PET status over 2‐year follow‐up. Individuals who converted from amyloid PET‐negative to positive had higher values of p‐tau181 and p‐tau231 than those who remained PET‐negative.
X‐chromosome wide association study for Alzheimer’s disease
Authors: Borgne Julie Le , Gomez Lissette , Kunkle Brian W. , Bellenguez Céline ,   ADGC, CHARGE, DemGene, EADB, EADI, GERAD, GRA@CE/DEGESCO, IGAP
Published: December 2023

Background

Although the X‐chromosome represents about 5% of the genome, it has been excluded from the major genome‐wide association studies on Alzheimer’s Disease (AD) due to its genetic specificities. We performed an in‐depth X‐Chromosome‐Wide Association Study (XWAS) to better characterize the genetic landscape of AD.

Method

The XWAS is based on 49,333 clinically diagnosed cases and 68,882 controls (including 31,314 female cases and 39,407 female controls) of European ancestry from 29 studies from the International Genomics of Alzheimer’s Project (IGAP) and the European Alzheimer & Dementia Biobank (EADB) consortia. 45,993 samples were imputed with the 1000G reference panel and 72,220 samples were imputed with the TOPMed panel.

We considered three approaches to take into account the different inactivation scenarios on the X‐chromosome: 1) random X‐chromosome inactivation (r‐XCI) in females, equivalent to an additive genetic model with males coded as homozygous females; 2) skewed X‐chromosome inactivation in females, where a dominance effect was added to the r‐XCI model to capture the inactivation skewedness; 3) escape X‐chromosome inactivation in females, equivalent to an additive model with males coded as hemizygous. For each approach, we performed a single variant analysis with a meta‐analysis of the 29 studies, followed by a gene‐based analysis.

Result

We analyzed 404,688 variants, including 225,045 common variants (Minor Allele Frequency [MAF] > 1%). No genome‐wide significant signals were found in either approach, but three suggestive signals (p‐value < 1×10‐5) were identified in the r‐XCI approach. In one of these loci, we detected an X‐chromosome‐wide significant gene with the gene‐based analysis (p‐value = 5.45×10‐5). The top variant of this locus shows a similar effect in males and females (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.90–0.96, p‐value = 8.63 × 10−6, and MAF = 32%, with OR[CI] in females = 0.86[0.79‐0.94], and OR[CI] in males = 0.92 [0.87‐0.97]).

Conclusion

We identified promising genetic signals for AD on the X‐chromosome. To increase power, we are currently updating the imputation with TOPMed for all the studies and extending the analyses to large European biobanks.
Single‐cell Transcriptomes Reveal Cell‐type Specific Roles of VEGF Family Genes in the Pathogenesis of Alzheimer’s Disease
Authors: Wu Yiyang , Dumitrescu Logan C , De Jager Philip L , Menon Vilas , Schneider Julie A , Bennett David A. A , Petyuk Vladislav A , Hohman Timothy J.
Published: December 2023

Background

The role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer’s disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. Yet, cell‐specific alterations are not well characterized. To disentangle VEGFs’ cell‐specific effect on AD‐related traits, we performed association analyses of mRNA expression from 10 VEGF genes with cognitive performance and AD pathology in eight brain cell types using a large single nucleus RNA sequencing dataset from human brain.

Method

This project utilized recently published single‐cell transcriptomes derived from dorsolateral prefrontal cortex tissues of 424 donors collected at Rush Alzheimer’s Disease Center. Processed single cell RNA sequencing data were acquired from AD Knowledge Portal (syn2580853). Mean age at death was 89 years, 68% were females, and 37% were AD cases. Negative binomial lognormal mixed models implemented in the NEBULA R package were used to detect differential expression between AD cases and cognitively normal controls, and to analyze the associations with immunohistochemical amyloid and tangles, and finally to assess cross‐sectional and longitudinal global cognitive scores. Correction for multiple comparisons was completed using the false discovery rate procedure (Pfdr<0.05).

Result

Prefrontal cortical FLT1 expression was upregulated in AD participants compared to cognitively normal controls in both endothelial (endo) and microglial (micro) cells. Higher micro‐FLT1, endo‐FLT4, and oligodendrocyte (oligo) VEGFB expression was associated with greater β‐amyloid burden in AD samples, whereas higher VEGFB expression in inhibitory neurons was associated with lower β‐amyloid burden. Higher expression of micro‐FLT1 and oligo‐VEGFB associated with worse cognitive trajectories. Higher micro‐ and endo‐ expression of FLT1 associated with lower cognition scores at the last clinic visit before death. Lastly, higher astrocyte‐expressed NRP1 was associated with lower tangle burden.

Conclusion

Consistent with our previously reported bulk tissue results, prefrontal cortical expression of FLT1 and FLT4 were associated with global cognition, longitudinal cognitive trajectories, and AD neuropathology, and these associations appear to be limited to endothelial and microglial cells. In contrast, VEGFB expression seems to have opposite effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD physiopathology.
Examining Environmental Predictors of Behavioral Symptoms of Dementia Using Dynamic Structural Equation Modelling
Authors: Petrovsky Darina , Pickering Carolyn E , Yildiz Mustafa
Published: December 2023

Background

Most persons with Alzheimer’s disease and related dementias (ADRD) experience behavioral symptoms as a result of exposure to stressors in the environment. Daily diaries can capture fluctuations in behavioral symptoms in response to environmental stressors. The purpose of this multi‐time series longitudinal study was to determine whether potential protective factors, caregiver reciprocity and a shared activity were associated with the number of behavioral symptoms person with ADRD.

Method

A community‐dwelling sample of 453 caregivers for persons with ADRD (age 18+) completed 21 days of once‐a‐day diary surveys. Caregiver perceived reciprocity was assessed using a question asking, “How satisfied were you with amount of affection or appreciation your relative with dementia showed towards you?” Responses were coded using a Likert scale with 1‐Not at all and 5‐Very much. Caregivers were asked whether they did a pleasant non‐care activity with their relative and about a presence of eight different behavioral symptoms in persons with ADRD. We used a two‐level dynamic structural equation model to examine the relationship between the number of different behavioral symptoms, caregiver reciprocity and a shared activity on a given day, and the following day.

Result

Caregivers completed 7,783 diaries. Caregivers were mostly female (87.4%), non‐Hispanic white (51.4%) with a mean age of 53 years (SD = 14) caring for a parent/parent‐in‐law/stepparent (61.5%) with a mean age of 79 years (SD = 9). Caregiver perceived reciprocity had a significant direct effect on the number of behavioral symptoms experienced the same day and the next day. While no significant main or cross‐lagged effects were found between shared activity and behavioral symptoms, estimates suggest the impact was negligible (0.7% increase).

Conclusion

We found that caregiver perceived reciprocity may reduce the number of behavioral symptoms a person with ADRD has that day and the following day. These findings support the growing body of theoretical and empirical work suggesting caregivers are an important feature of the environment and influence behavioral symptom presentation.
Prazosin for Agitation in Alzheimer’s Disease: PEACE‐AD
Authors: Peskind Elaine R
Published: December 2023

Background

Disruptive agitation is a major source of distress to patients/caregivers and is a common precipitant of long‐term care placement. High CNS noradrenergic signaling at the alpha‐1 adrenoreceptor (AR) in AD appears contributes to disruptive agitation. Prazosin, a CNS active alpha‐1 AR antagonist, was effective for reducing disruptive agitation and was well tolerated in our previous pilot study. The objective of this study was to evaluate efficacy and safety of prazosin for disruptive agitation in AD participants residing at home or in long‐term care in a multicenter RCT conducted by the NIA‐funded Alzheimer’s Disease Cooperative Study.

Method

In this multi‐site RCT recruitment was substantially handicapped by COVID‐19. Participants were randomized to prazosin or placebo 2:1 for 12 weeks. Prazosin was titrated over 4 weeks to a maximum possible dose of 4 mg mid‐morning and 6 mg at bedtime based on tolerability and persistent agitation. Adverse events and orthostatic blood pressure and heart rate were monitored. Primary outcome: ADCS‐Clinical Global Impression of Change‐Agitation (CGIC‐A) targeting disruptive agitation. Secondary outcomes: 17‐item Neuropsychiatric Inventory (NPI), Cohen Mansfield Agitation Inventory (CMAI), and total # study days completed. An exploratory outcome was the NPI 5‐item subscale reflecting agitation. Methods were adapted to allow for remote consent, participant screening, and outcome and safety assessments.

Result

35 participants were randomized. MMRM analysis revealed: no significant differences in CGIC‐A or total NPI scores; 7 of 18 prazosin participants were moderately‐markedly improved on the CGIC‐A compared to 1 of 4 placebo participants (NS); change from BL in the CMAI significantly favored prazosin (p = 0.04) and the 5‐item NPI Agitation subscale numerically favored prazosin (NS); 63% of prazosin participants completing compared to 38% of placebo participants (NS). Adverse events were as anticipated for prazosin. Remote consent and assessments allowed continuation of the study without the necessity of in‐person clinic visits.

Conclusion

Assessments were limited by the small # of participants. There was some benefit with prazosin with the expected safety profile. Feasibility of performing an RCT for disruptive agitation in AD using remote technology was demonstrated. A larger study of prazosin for moderate‐severe disruptive agitation in AD is necessary.
Plasma glial fibrillary acidic protein mediated the association of midlife pulmonary function and cognition in later‐life: A causal mediation analysis in a longitudinal population‐based cohort
Authors: Hu Yi‐Han , Gudnason Vilmundur , Seshadri Sudha , Tracy Russell P. , Launer Lenore J J.
Published: December 2023

Background

Epidemiological evidence indicates that poorer pulmonary function (PF) may be linked to faster cognitive decline and a greater risk of dementia. Inflammation is one possible mediator between poor PF and cognitive decline. Plasma glial fibrillary acidic protein (GFAP,) as a marker of neurodegeneration and inflammation, may mediate the association of poor PF to poor cognitive function. The APOE ε4 is a marker of Alzheimer’s disease (AD) genetic susceptibility and may modify the PF‐cognition association with mediating factors. We aimed to prospectively examine whether GFAP mediates the association of mid‐life PF with cognition and whether the mediation effects differ by APOE ε4 carriership.

Method

We studied 1,001 participants (average midlife age of 50.5 years, 45% men) in the Age, Gene/Environment Susceptibility‐Reykjavik Study with midlife PF measures [forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC)] and blood draw and cognition measured on average 23 years later. Plasma GFAP levels were assayed using a Simoa HD‐1 analyzer. A general cognition score was created by principle component analysis using multiple cognitive tests. Causal mediation regression models were constructed to estimate GFAP’s mediation effect on the association between mid‐life PF and cognitive function in later life. Analyses were stratified by APOE ε4 status (yes/no). Models were adjusted for age, sex, education, smoking, BMI, and estimated glomerular filtration rate.

Result

Low midlife FEV1 and FVC were related to poor general cognition in later life [β = 0.44 (95% CI = 0.28, 0.62) and β = 0.38 (95% CI = 0.22, 0.54), respectively]. Higher PF was associated with lower plasma GFAP levels. The proportion of the association between FEV1 on cognition mediated by plasma GFAP was 4.4% (95% CI = 1.0%–10.0%), and between FVC and cognition was 4.9% (95% CI = 0.8%–14.6%). The mediation effect was greater in the APOE‐ε4 allele carriers [14.4% (95% CI = 0.04%–60.9%) and 14.6% (95% CI = 1.0%–54.5%) for FEV1 and FVC, respectively].

Conclusion

Low PF in midlife may increase the risk for later cognitive problems. This study suggests poor PF may contribute to neuroinflammation (as measured by GFAP) over the long term, especially in individuals at genetic risk of AD.
Do Subjects Not Meeting Screening Inclusion Criteria at Baseline Differ in Screening Performance in Diagnostic Tests in Early Dementia Clinical Trails?
Authors: Miller David S. , Wang Xingmei , Kott Alan
Published: December 2023

Background

The success of any clinical trial begins with ensuring that participants entering the trial meet the inclusion criteria and disease severity. Score manipulation to meet eligibility criteria may contribute to loss of signal in clinical trials. Based on our prior analyses of early Alzheimer’s disease (AD) clinical trials, over 10% of randomized participants likely had inflated MMSE scores at inclusion determination. In addition to ‘traditional’ instruments such as the MMSE or CDR, other ‘diagnostic’ instruments such as the RBANS, FCSRT and Wechsler Memory Scale are often used to select the study population. In the current analysis we explore the relationship between the performance on the diagnostic tests and the likely inflation in MMSE.

Method

Baseline MMSE scores and Screening diagnostic tests results were pooled from 6,387 subjects from multiple clinical trials in early AD. Within each trial, participants’ performance on the diagnostic tests was broken into quartiles – best performers, second best, second worst and worst performers. Participants were also classified by their Baseline MMSE score as either meeting or being below the Screening MMSE inclusion criteria. A logistic regression was used to explore the association of the diagnostic test performance quartiles and Baseline MMSE score categories correcting for Screening MMSE score.

Result

1223 (19.2%) participants comprised the best performing quartile on the diagnostic tests. Comparatively, with each subsequent quartile, the odds of not meeting the Screening inclusion criteria at Baseline increased significantly ‐ by 1.4x in the 1666 participants (26.1%) in the second best, by 2.0x in the 1696 (26.6%) in the second worst, and by 2.4x in the 1800 (28.2%) in the worst quartile.

Conclusion

This post‐hoc analysis identified increasingly significant odds of not meeting Screening MMSE related inclusion criteria at Baseline for each progressive quartile of worsening diagnostic test performance, when correcting for the Screening MMSE score. We suggest that despite the limitations of this post‐hoc analysis, outlying poor performance on the diagnostic tests should be considered a risk marker for possible score inflation and assessed in the whole context of the available data. Further work is necessary.
Mayo Clinic Alzheimer’s Disease Research Center Approach
Authors: Petersen Ronald C. , Kantarci Kejal
Published: December 2023

Mayo Clinic Alzheimer’s Disease Research Center (ADRC) has been operational since 1990 supported by the US National Institutes of Health. In addition, in the aging and Alzheimer’s disease (AD) spectrum research, Mayo Clinic has been active in since 1986 with the Mayo Alzheimer’s Disease Patient Registry that evolved to the Mayo Clinic Study of Aging (MCSA) to become a population‐based study of aging and cognitive impairment in 2004.

The overall goal of Mayo Clinic ADRC is to provide a structured environment that supports innovative research and enable translation aimed at accelerating the development of effective treatment and prevention for AD and related dementias at all stages of the disease. Our comprehensive ADRC is located in Rochester, Minnesota (MCR), and Jacksonville, Florida (MCF), and shares its operations in all of the Cores between the two geographic sites. ADRC core activities include the Administrative Core, Clinical Core, Data Management and Statistics Core, Neuropathology Core, Neuroimaging Core, Biomarker Core, the Outreach and Education Core (ORE Core), and the Research Education Component. ADRC Cores also interact directly with the MCSA.

The theme of the center during the current cycle is “Similarities and Differences Among Neurodegenerative Disorders”. Therefore, in addition to focusing on the recruitment of participants along the AD spectrum, we continue to focus on the recruitment of persons on the frontotemporal lobar degeneration (FTLD) and the Lewy body disorders (LBD) spectra, including the prodromal stages of the neurodegenerative dementias.This focus expands on previous accomplishments of the ADRC across the neurodegenerative disease spectra. The acquisition and development of new biomarkers for the neurodegenerative diseases is a major focus of the Center, and the recruitment of research participants in all three disorders enhance randomized controlled trial studies.

The Mayo ADRC interacts with other ADRCs on various collaborative efforts and supports Developmental Projects that utilize ADRC resources with the goal of attracting early‐stage and established investigators into the AD research field.
Mass spectrometry on cerebrospinal fluid uncovers association of novel glycolysis biomarkers with Alzheimer’s disease in a complex clinical cohort
Authors: de Geus Matthijs B , Leslie Shannon N , Wang Weiwei , Lam TuKiet , Broekman Marike , Neefjes Sjaak , Nairn Angus C , Carlyle Becky C. , Arnold Steven E.
Published: December 2023

Background

Diagnosis of Alzheimer’s disease (AD) primarily relies on cognitive assessments supported by imaging and cerebrospinal fluid (CSF) biomarkers of amyloid and tau proteins. These limited biomarkers correlate poorly with disease progression or treatment response. Broader, more comprehensive biomarker sets together with traditional ATN biomarkers could improve the diagnosis and prognosis of AD, identify contributing pathophysiologies and comorbidities, and prove useful in measuring treatment efficacy. In this study we leverage mass‐spectrometry to simultaneously quantify hundreds of proteins in CSF from a large‐scale neurology clinic cohort, all of whom had clinical indication for diagnostic lumbar puncture. We aim to define markers that can stratify and diagnose AD in this “real‐life” clinically complex cohort.

Method

CSF samples from 408 patients were collected from the Massachusetts General Hospital Neurology Service following written informed consent for research biobanking and analysis of excess CSF. The patient cohort consisted of ATN‐verified cognitively‐unimpaired (n = 81), mild‐cognitive impairment from AD (n = 116), mild‐cognitive impairment from other non‐AD causes (n = 78), dementia from AD (n = 65) and dementia from other non‐AD causes (n = 31). Samples were analyzed on an Orbitrap Fusion using a Data Independent Acquisition method and raw files were searched using Scaffold‐DIA.

Result

1761 unique peptide sequences belonging to 516 proteins were robustly quantified by DIA in CSF. Linear regression analyses found 572 peptides to be significantly differentially abundant across all diagnoses compared to AD (padj < 0.05). Ontological analysis of these peptides indicated enrichment of glycolysis in AD, potentially indicating a shift in brain metabolism in AD. 4 peptides belonging to 2 glycolysis proteins (PKM, ALDOA) were elevated in AD compared to all non‐AD diagnoses, suggesting specificity for AD. Differential abundance of these proteins was verified through immunoassay.

Conclusion

Here, unbiased mass‐spectrometry on CSF highlighted novel AD specific biomarkers ALDOA and PKM, potentially indicating a metabolic shift in the brain. Further mechanistic studies should investigate dysregulation of these markers in AD and correlation with FDG‐PET.
Electrophysiological correlates of objective memory impairments in community‐dwelling older adults at risk of dementia
Authors: Gonzalez‐Montealegre Rodrigo A , Gonzalez‐Hernandez Alfredis , Bonilla‐Santos Jasmin , Parra‐Rodriguez Mario A
Published: December 2023

Background

The electrophysiological correlates of Short‐Term Memory Binding (STMB) have been previously investigated in older adults at risk of dementia (i.e., Mild Cognitive Impairment ‐MCI). Pietto et al. (2016) reported reduced early electrophysiological activity (100‐250 ms) over fronto‐central (FC) and parieto‐occipital (PO) regions in MCI patients recruited from clinic. We investigated if such an electrophysiological pattern is also observed in a larger sample of community‐dwelling older adults with MCI who had not sought medical advice.

Methods

A sample of 215 community‐dwelling older adults were recruited into the study. They were assessed with a battery of cognitive tests including CERAD (Aguirre‐Acevedo et al., 2016), the Addenbrooke’s Cognitive Examination (ACE‐R), the STMB Task, clinical, and functional scales. The STMB task assesses the ability to detect changes between two consecutive visual arrays of coloured shapes. Changes consisted of shapes swapping colours (the binding condition). Time‐locked EEG signals were collected while participants performed the STMB task. Monte Carlo tests and non‐parametric bootstrapping running 1000 permutations revealed electrodes and time windows of relevance.

Results

A group of 108 participants met classical criteria for MCI (Petersen, 2004; Winblad et al., 2004). They showed impaired STMB abilities. ERP analyses revealed significant Group x Time Windows interactions (p<0.01). Early ERP showed reduced neural recruitment (MCI<HC) on the left PO and right centro‐parietal (CP) (300‐500ms) regions during shape‐colour encoding, and on PO bilaterally and left FC during retrieval (150‐450ms). Late ERP showed increased neural recruitment (MCI>HC) on right fronto‐central (FC) regions (900‐1200ms) during shape‐colour encoding, and on left FC and PO regions (872‐1200ms) during retrieval.

Conclusion

Altered spatio‐temporal dynamics underpinning STMB deficits in MCI patients followed a pattern similar to that described by Pietto et al. (2016). Of note, we observed hyper‐recruitment for late ERP linked to encoding and retrieval over anterior and posterior regions of the STMB network. Such hyper‐recruitment may reflect compensatory changes in the early stages of MCI. These results confirm the usefulness of EEG‐based cognitive biomarkers to screen community‐dwelling older adults at risk of dementia.

Aguirre‐Acevedo et al. (2016). Int. Psychogeriatr, 28(3), 503‐510.

Pietto et al. (2016). Journal of Alzheimer’s Disease, 53(4), 1325‐1340.
Differential effects of neuronal Cdkn2a over‐expression in mouse brain
Authors: Finneran Dylan , Desjarlais Taylor , Morgan Dave , Gordon Marcia N.
Published: December 2023

Background

Aging is the primary risk factor for Alzheimer’s disease (AD). With aging, senescent cells accumulate in the body and the brain. Cells that become senescent cease contributing to homeostasis but do not typically undergo apoptosis. Prior studies have identified a broad association between increased cellular senescence and AD‐like pathology and have identified senescent cells in AD patient brain and mouse models of AD‐like pathology. However, contributions of senescent cells to disease progression remains uncertain.

Method

The two gene products of the senescence regulator Cdkn2a (p16‐Ink4a and p19‐Arf) were overexpressed using intracranial delivery of adeno‐associated viral vectors (AAV). Mice were injected with 2 µL of 1×1013, 5×1012, or 1×1012 vg/mL of AAV‐Arf and tissue was collected two months post‐injection. Control mice were injected with AAV empty capsid. Brain weights, NeuN IHC, and p19‐Arf mRNA were assessed. A second cohort of mice was injected with AAV‐Ink, AAV‐Arf, AAV‐Ink & AAV‐Arf (co‐injection), or AAV‐GFP and followed for four months post‐injection. We assessed body mass, brain mass, NeuN IHC, and expression of senescence‐induced genes by PCR‐array and qRT‐PCR. A third experiment over‐expressing p19‐Arf in PS19 mice is ongoing.

Result

We observed that animals over‐expressing p19‐Arf failed to gain body mass up to four months post‐injection. Post‐mortem, we found that over‐expression of p19‐Arf is toxic to neurons, reducing gross brain mass and NeuN area staining. Furthermore, a greater number of differentially regulated genes were observed in mice over‐expressing p19‐Arf than in mice over‐expressing p16‐Ink4a. We confirmed increased expression of the senescence‐regulator p21 in mice over‐expressing p19‐Arf, but not p16‐Ink4a, by qPCR. In a separate experiment, we replicated the finding of neurotoxicity induced by over‐expression of p19‐Arf at only two months post‐injection and determined the optimal viral titer to administer that induces significant over‐expression with minimal neurotoxicity for use in future studies.

Conclusion

As observed in cultured cells, over‐expression of Cdkn2a seems to increase markers of senescence. Effects on tau pathology will be examined in the PS19 mouse model of tauopathy. Cell type‐specific expression in neurons, astroglia, and microglia will be used to elucidate cell type specific contributions to senescence‐induced disease progression.
Neuropsychiatric symptoms are Predictors of Disturbed Sleep in Mexican American Caregivers
Authors: Cantu Phillip A , Milani Sadaf Arefi , Mroz Emily , Pan Yulu , Miner Brienne , Sheehan Connor , Jody Sharninghausen
Published: December 2023

Background

Caregivers of people living with dementia are more likely to experience disturbed sleep compared to non‐caregivers. Mexican‐Americans may be especially at risk due to low rates of nursing home use even in advanced dementia, when behavioral symptoms are most apparent. Few studies have evaluated predictors of disturbed sleep in this high‐risk group.

Method

Using data from the 2015 wave of the Hispanic Established Population for Epidemiologic Study of the Elderly, a representative sample of older Mexican‐Americans and their caregivers in the southwestern United States (n = 460), we examined the association of care recipient neuropsychiatric symptoms with disturbed sleep in caregivers. Care recipients’ behavioral symptoms of cognitive decline were assessed using the caregiver‐reported Neuropsychiatric Inventory. We examined caregivers’ depressive symptoms as an additional stressor. Potential “buffers” against sleep disturbances included communal support (neighbor, church, social services) and respite care. Caregivers were classified as having “highly disturbed sleep” if they reported disturbed sleep three or more days a week, and were compared to caregivers with “non‐highly disturbed sleep” (reported disturbed sleep less than three days a week). We used multivariable logistic regression to examine the association between behavioral symptoms and highly disturbed sleep, controlling for demographic factors and care buffers.

Result

Caregivers in the sample were predominantly spouses or adult children of their care recipients. They had a mean age of 59.7 and7 8% were women. Care recipients were a mean age of 90 and 65% were women. Caregivers with disturbed sleep (12% of the sample) reported significantly more care recipient NPI symptoms, distress from symptoms, and more depressive symptoms. In the regression model accounting for all predictors, the number of NPI symptoms and depressive symptoms were associated with higher odds of disturbed sleep, while communal support was associated with lower odds of disturbed sleep. Use of respite care did not show associations.

Conclusion

Behavioral symptoms of cognitive impairment are associated with sleep disturbance in Mexican American caregivers. Though respite has been described as a crucial resource for caregiver sleep health, communal supports were more significantly associated with sleep l. These results should inform the development of culturally‐competent resources for Mexican‐Americans.
Evaluation of the Causal Effects of COVID‐19 on Alzheimer’s Disease: LD Score Regression Analysis and Mendelian Randomization Study
Authors: Chen Jingchun , Cummings Melika J. , Zhang Mark L. , Lu Yimei , Cammann Davis B , Do Jenifer , Zheng Jennifer J.
Published: December 2023

Background

COVID‐19 is an acute respiratory infection that is frequently followed by short‐ or long‐term neurological abnormalities, and may increase the risk of developing Alzheimer’s disease (AD). However, the genetic and biological mechanisms underlying this risk are poorly understood. Utilizing publicly available large genome‐wide association studies (GWAS), we explored the possible causal effects of three different COVID‐19 phenotypes on AD.

Method

COVID‐19 GWAS data from European cohorts were obtained from the Host Genetics Initiative website in its most recent release (HGI7‐EUR) with three phenotypes: 1) critically ill COVID‐19 (case/ctrl: 13,769/1,072,442); 2) hospitalized COVID‐19 (case/ctrl: 32,519/2,062,805); 3) regular COVID‐19 infection (case/ctrl: 2,475,240/12,597,856). European AD GWAS data were retrieved from Jansen et al.’s study (case/ctrl: 71,880/ 383,378). The linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) methods were used to analyze the genetic correlation and possible causal effects among the three COVID‐19 phenotypes and AD.

Result

LDSC indicated that AD had significant positive correlations with the critically ill COVID‐19 (FDR = 0.021, z = 2.45, rg = 0.224) and hospitalized COVID‐19 (FDR = 0.020, z = 2.71, rg = 0.241) phenotypes, but not regular COVID‐19 infection (FDR = 0.133). On the other hand, MR with the fixed‐effects inverse variance weighted method indicated that regular COVID‐19 had some causal effect on AD (P = 0.019, beta = 0.032). Marginal causal effects on AD were also found from critical COVID‐19 (P = 0.072, beta = 0.008) and hospitalized COVID‐19 (P = 0.082, beta = 0.013). In addition, MR with weighed mode method showed significant effects on AD from three COVID‐19 phenotypes (P = 0.040‐0.003), while MR‐Egger method did not show any significance between the two diseases.

Conclusion

Using LDSC and MR approaches, our preliminary data identified a genetic correlation between hospitalized and critically ill COVID‐19 phenotypes and AD, and possible causal effects on AD through genetic variants shared with standard COVID‐19 infection. With the continuing COVID‐19 epidemic and the high comorbidity and mortality of AD from COVID‐19 infection, our observations emphasize the urgency of understanding the overlapping genetic risk for the two diseases. Further studies might shed light on the long‐term neurological influence of COVID‐19 and further provide strategies for disease intervention against COVID‐19 and AD.
In vivo characterization of tau accumulation in patients with frontotemporal dementia: A PET study with 18F‐florzolotau
Authors: Kubota Manabu , Endo Hironobu , Takahata Keisuke , Tagai Kenji , Suzuki Hisaomi , Onaya Mitsumoto , Sano Yasunori , Yamamoto Yasuharu , Kurose Shin , Matsuoka Kiwamu , Seki Chie , Shinotoh Hitoshi , Kawamura Kazunori , Zhang Ming‐Rong , Takado Yuhei , Shimada Hitoshi , Higuchi Makoto
Published: December 2023

Background

Frontotemporal dementia (FTD) is a group of neurodegenerative disorders with diverse clinical and neuropathological features. However, in vivo neuropathological assessments of FTD at an individual level have not hitherto been successful. Here, we aimed to classify patients with FTD based on topologies of tau protein aggregates captured by positron emission tomography (PET) with 18F‐florzolotau, which allows high‐contrast imaging of diverse tau fibrils in Alzheimer’s disease (AD) and non‐AD tauopathies.

Method

Twenty‐six patients with FTD, consisting of 15 patients with behavioral variant FTD (bvFTD) and 11 patients with other FTD phenotypes, and 20 age‐ and gender‐matched healthy controls were studied. They underwent PET imaging of amyloid and tau depositions with 11C‐PiB and 18F‐florzolotau, respectively.

Result

By combining visual and semiquantitative analyses of PET images, the bvFTD patients were classified into the following subgroups: 1) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three‐repeat tauopathies (n = 3); 2) predominant tau accumulations in subcortical structures accompanied by various degrees of neocortical accumulations resembling four‐repeat tauopathies (n = 4); 3) amyloid and tau accumulations consistent with AD (n = 4); and 4) no overt amyloid and tau pathologies (n = 4). Despite these distinctions, clinical symptoms and localization of brain atrophy were not significantly different among the identified bvFTD subgroups. Patients with other FTD phenotypes were also classified into similar subgroups.

Conclusion

To conclude, PET with 18F‐florzolotau potentially enables the characterization of each individual with FTD on a biological basis, thereby possibly contributing to diagnostic and therapeutic approaches to this illness.
Center of Alzheimer’s Disease in Beijing, China
Authors: Jia Jianping , Quan Meina
Published: December 2023

Innovation Center of Neurological Disorders (ICND) at Xuanwu Hospital, Capital Medical University in Beijing was found in 2015 by Prof. Jianping Jia. The center follows the integrated research paradigm, called “cognitive unit”, which includes memory clinics, laboratories, and research wards. This unit facilitates the comprehensive diagnosis and treatment of cognitive disorders, and helps improve the quality of dementia research. There are 82 researchers, lab technicians and clinicians in the center, plus ∼20 graduate students and over 40 visiting/trainee doctors. We carry out research focusing on mechanisms, drug development and peripheral biomarkers of Alzheimer’s disease (AD) and related dementias. Our center leads several large national multicenter cohort studies, including the Chinese familial Alzheimer’s Network (CFAN), the China Cognition and Aging Study (China COAST), the Study on Biomarkers for Early Diagnosis of Alzheimer’s Disease (Bio‐AD), and the Dementia Cohort Project of “China Brain Initiative 2030”. Prof. Jia, the director of the center, is the PI of nearly 30 national and international multicenter clinical trials on drug development, and the 2021 recipient of the Zaven Khachaturian Award.

The Center promotes multidisciplinary research on AD and related dementias. We collect extensive clinical data and biological samples, standardize the inclusion/exclusion criteria, establish large‐sample dataset and biobanks, provide advanced training for AD specialists, generate national guidelines on dementia management, train exchanging students and visiting scholars, and organize national and international dementia and Alzheimer’s conferences. Research findings from the center have impact on national health strategies, and help policymakers to establish public health strategies, and develop individualized and precision interventions. As an example, Prof. Jia established the large national Alzheimer patients cohorts to examine the genetic, biofluid, imaging and domain‐specific cognitive markers, and underling mechanisms. The Center encourages data sharing, exchanging ideas, and discussing possible solutions based on the mutual scientific questions and clinical problems, as well as the existing differences from each country.

International Alzheimer’s Research Centers can collaborate on global initiatives for establishing international AD cohorts, screening tools and techniques to evaluate the diagnostic utility of biomarkers, and to initiate global multicenter clinical trials.
The contribution of school quality to stroke and cardiovascular disease risk in the U.S. Stroke Belt
Authors: Lybbert Emily , Muller Chandra , Grodsky Eric , Warren John Robert
Published: December 2023

Background

Stroke and cardiovascular disease (CVD) are important risk factors for later life dementia. In the United States the geographical distribution of high stroke risk, known as the U.S. Stroke Belt, is an important contributor to race and SES‐based gradients in not only CVD but dementia as well 1. In this study we examine the impact that schools have on stroke risk and CVD. We hypothesize that school characteristics will mitigate the effects of attending high school in a Stroke Belt state.

Method

We use the High School and Beyond study, a longitudinal dataset of individuals who were in high school in 1980. The most recent wave of data collection occurred in 2020/2021. We perform competing risk regressions to predict the hazard of dying from stroke and CVD controlling for going to high school in a Stroke Belt state, background characteristics, school quality, and individual education characteristics. We also predict the odds that surviving respondents had coronary heart disease or a stroke by 2021. Missing information on an individual level was multiply imputed and survey weights were used in all analyses.

Result

High schools in the Stroke Belt had significantly lower average SES and students had lower achievement scores on average. Going to high school in a Stroke Belt state was associated with a higher hazard of early mortality due to cardio‐and cerebrovascular causes. Stroke Belt origin was also associated with higher odds of stroke diagnosis in midlife. These associations were partially accounted for by variation in background characteristics, especially parental education. Measures of school academic press were associated with cardio‐and cerebrovascular disease mortality and heart disease diagnosis, net of covariates.

Conclusion

The findings of this study indicate that going to high school in the Stroke Belt is associated with higher risks of CVD and stroke. School quality seems to additionally affect individual risk, not explain the Stroke Belt risk.

1. Glymour MM, Kosheleva A, Wadley VG, Weiss C, Manly JJ. Geographic Distribution of Dementia Mortality: Elevated Mortality Rates for Black and White Americans by Place of Birth. Alzheimer Disease & Associated Disorders. 2011;25:196‐202.
3D Bioprinted differentiated murine neurospheres as a neurogenesis model
Authors: Salles Geisa Rodrigues , Dall'Agnol Ferreira Natalia , Ferreira Clara Pompeu , Pacheco‐Soares Cristina , Porcionatto Marimelia Aparecida
Published: December 2023

Background

Adult neurogenesis, the generation of neurons by neural stem cells (NSCs), occurs mainly in neurogenic niches, located in the dentate gyrus of the hippocampus and in the subventricular zone (SVZ) of the lateral ventricles. However, in Alzheimer’s disease (AD), proliferative activity of NSCs and the generation of new neurons is deregulated. Although there are animal models of AD, developing an in vitro three‐dimensional (3D) model of the disease may certainly enhance the approach of a multidinamic microenvironment able to evaluate specific areas of pathogenesis. The aim of this study was to produce 3D constructs targeting their application as an in vitro model of neurogenesis.

Method

Neurosphere (clusters of NSCs and neural progenitor cells) cultures were developed from isolated cells from the SVZ of 6 weeks old C57bl/6 mice. Cells were cultivated in poly‐HEMA coated flasks for 7 days, then, formed neurospheres (∼100µm) were dissociated and bioprinted in an alginate:gelatin solution (6%:4%, respectively). The bioink was 3D printed, crosslinked with 2% CaCl2, and the constructs were maintained for 2 days in culture medium to allow neurosphere expansion. From days 3‐7, the constructs were cultivated in growth or differentiation medium, to stimulate neuronal differentiation. Morphological organization of cells within the neurospheres was evaluated.

Result

The produced 3D constructs are cytocompatible and allow neurosphere formation and growth under growth condition (Fig. 1A). As the growth medium was substituted by the neuronal differentiation medium, processes outgrowth was observed spreading outside the spheres (Fig. 1B).

Conclusion

A biocompatible construct loaded with neurospheres was produced by 3D bioprinting. The outgrowth of cellular processes outside the spheres suggest that neuronal differentiation occurs, showing that the biomaterial consists in an excellent model to investigate neurogenesis and neurogenic niches dynamics, two impaired elements in AD pathogenesis. Further steps of this study include the improvement of the 3D constructs, creating a microenvironment suitable to better simulate the potential of cellular differentiation under AD pathological conditions.

Acknowledgments: This study was supported by São Paulo Research Foundation (FAPESP, grants 2022/08664‐4 and 2018/45605‐8), and by the Brazilian National Council for Scientific and Technological Development (CNPq, grant 406258/2022‐8).
Metabolites correlate with plasma biomarkers and clinical diagnosis of Alzheimer’s Disease
Authors: Kalia Vrinda , Reyes‐Dumeyer Dolly , Dubey Saurabh , Nandakumar Renu , Lee Annie J , Lantigua Rafael A. , Medrano Martin , Mejia Diones Rivera , Recio Patricia , Honig Lawrence S. , Mayeux Richard , Miller Gary W , Vardarajan Badri N
Published: December 2023

Background

Energy, amino acid, and lipid metabolism are dysregulated in Alzheimer’s Disease. We investigated circulating plasma metabolites to capture systemic biochemical changes associated with Alzheimer’s disease (AD) using the clinical diagnosis and followed by the addition of plasma‐based biomarkers.

Method

Exogenous and endogenous metabolites in plasma were measured in 300 individuals with a clinical diagnosis of AD and 430 healthy individuals without dementia of Caribbean Hispanic ancestry using untargeted liquid‐chromatography, performed on HILIC (+ ionization) and C18 (‐ ionization) columns, coupled to a Thermo Orbitrap HF‐X mass spectrometer. Genome‐wide SNP data and plasma biomarkers including pTau181, Aβ40, Aβ42, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were obtained on all participants. Metabolite association with the clinical diagnosis of AD and for the AD biomarker, pTau‐181, levels were assessed after adjustment for age and sex.

Result

More than 6000 metabolic features were measured with high accuracy in the sample. 270 metabolic features were associated with pTau‐181 levels and 66 metabolic features were associated with clinical AD status, after correction for multiple testing. Valyl‐Serine (p = 1.1e‐7) and creatinine (p = 9.6e‐7) were strongly associated pTau‐181 levels. When using a diagnostic cutoff of pTau181 levels for AD as the outcome (biological AD), we also observed significant associations with a lysophospholipid (p = 9.5e‐5). Malic acid (p = 4.2e‐4) and tryptophan (p = 3.9e‐4) were significantly associated with clinical AD status. Metabolites associated with pTau‐181 levels were enriched in glycan biosynthesis, energy, amino acid, urea cycle/amino group and carbohydrate metabolism pathways. Patients with both clinical and biological AD showed altered tyrosine and tryptophan metabolism.

Conclusion

Metabolites, specifically amino acids and lipids, were associated with AD status and pTau181 levels. Metabolite profiling can identify perturbed pathways in clinical and pre‐clinical AD and integration with genome‐wide SNP data will identify mechanisms underlying genetic association with disease.