bluuebunny/crossref_metadata_2025 huggingface dataset:
Race/ethnicity and the relationship between trust in researchers and hypothetical research participation
Authors: Bergren Stephanie , Ma Yiming , Merced Mariam , Guzman Jessica , Wang Su , Brogden Ruth , Castaneda Manuel J , Dong Xinqi , Hu William T.
Published: December 2022

Background

Research participation by minority individuals is critical to address health disparities, and lack of trust in research/researchers (TIR) is a significant barrier to participation. Few existing studies examine the relationship between level of TIR and hypothetical research participation in a sufficiently diverse sample.

Methods

The survey was conducted among White, Black, Hispanic, and Asian community‐dwelling adults in New Jersey (N = 293 between October 2020 and January 2022). A 12‐item TIR measure based on published scales was developed with input from community partners. Respondents were also asked if they would participate in different types of research (i.e. survey, blood draw, medication study). Exploratory and confirmatory factor analysis was conducted to identify the underlying structure of TIR. Cluster analysis on research participation was conducted to determine patterns. Regression‐based mediation analysis was done to determine relationship between race/ethnicity, TIR, and hypothetical research participation.

Results

Responses were collected from 293 adults, with 38% reporting ages of 55 years or older. Factor analysis revealed three main factors on 9‐items related to Researchers as Fiduciaries (lowest score in Chinese adults), Equity in Research (highest score in White adults), and Transparency in Research. Cluster analysis revealed two major clusters: one cluster only willing to participate in anonymous health‐related surveys, and the other highly willing to participate in studies involving blood tests and genetic analysis. Only Chinese race/ethnicity was associated with lower Researchers as Fiduciaries scores (B = ‐0.54, 95% CI‐0.85 to ‐0.23, p = 0.0007), with the mediation model (Sobel Z of ‐3.22, p<0.001, k2 = 0.13) showing a direct effect of ‐0.64 (95% CI ‐1.36 to 0.08, p = 0.08) and indirect effect of ‐0.69 (95% CI ‐1.06 to ‐0.32, p = 0.001) from Chinese race/ethnicity on participation willingness.

Conclusion

Chinese respondents showed low trust in researchers to serve as their fiduciaries, which mediated their low willingness to participate in research involving more than health‐related surveys. All non‐White groups also endorsed inequity in treatment by researchers, but Hispanic and Black adults were still likely to be interested in minimal risk (blood draw, genetic analysis) research participation. These findings call for community‐specific approaches to enhance biomedical research participation among non‐White adults.
Polygenic risk score association with cognitive decline in Parkinson’s Disease
Authors: Harvey Joshua , Reijnders Rick A , Shireby Gemma , Duits Annelien , Köhler Sebastian , Creese Byron , Lunnon Katie , Pishva Ehsan
Published: December 2022

Background

Cognitive impairment is a common and debilitating symptom in Parkinson’s disease (PD) with high variability in individual trajectory of decline. We sought to explore heterogeneity in the trajectory of individual cognitive change in a cohort of early stage PD patients and test association to cumulative genetic risk identified in large scale Genome Wide Association Studies (GWAS).

Method

Using longitudinal measures of the Montreal Cognitive Assessment (MoCA) we employed latent class mixed modelling (LCMM) to identify and investigate unknown populations in the Parkinson’s Progression Markers Inititative (PPMI) de‐novo PD cohort. Tranformed MoCA scores were modelled as a quadratic function of years from baseline, controlling for age, gender and motor symptom severity. Optimal group number was identified and determined using standardly advised model fit metrics. Polygenic risk scores (PRS) for five GWAS were calculated using PRSice‐2 applied to genotyping array data. Association of PRS with cognitive groups was tested using linear models and ANOVA tests.

Result

LCMM showed optimal fit statistics for three classes (lowest BIC, high entropy) and these groups were retained for further analysis The largest identified class (n = 240) on average, presented at baseline with higher MoCA scores and remained stable over time. The second class (n = 132) presented with lower MoCA scores and showed a slow declining trajectory whilst the smallest class (n = 13) presented with lower MoCA scores but declined at a rapid rate. Educational attainment and Alzheimer’s disease (AD) GWAS derived PRS were significantly associated with cognitive class and explained the highest amount of phenotypic variance. For PD case‐control status, only the PD PRS was significantly associated with Parkinson’s status and explained a similar level of phenotypic variation.

Conclusion

Latent class analysis may provide utility in subsetting longitudinal cognitive outcome groups for use in groupwise comparisons. Using this method we show evidence for association of educational attainment and AD cumulative genetic risk and worse cognitive outcomes in early PD.
Associations of erythrocyte omega‐3 fatty acids with cognition, brain imaging and biomarkers in the Alzheimer’s Disease Neuroimaging Initiative
Authors: Rouch Laure , Giudici Kelly V , Cantet Christelle , Guyonnet Sophie , Delrieu Julien , Legrand Philippe , Catheline Daniel , Andrieu Sandrine , Weiner Michael W. , Barreto Philipe de Souto , Vellas Bruno ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

Background

The association between ω‐3 polyunsaturated fatty acids and cognition, brain imaging and biomarkers is still not fully established. We aimed to analyze the cross‐sectional and retrospective longitudinal associations between erythrocyte ω‐3 index and cognition, brain imaging and biomarkers among older adults.

Method

832 participants from the Alzheimer’s Disease Neuroimaging Initiative 3, mean (SD) age 74.0 (7.9) years, 50.8% female, 55.9% cognitively normal, 32.7% with mild cognitive impairment and 11.4% with Alzheimer’s disease (AD) were included. Low ω‐3 index (% eicosapentaenoic acid EPA + % docosahexaenoic acid DHA) was defined as the lowest quartile (≤3.70%). Cognitive tests (composite score; AD Assessment Scale cognitive (ADAS‐Cog) subscale; Wechsler Memory Scale (WMS); Trail Making Test A and B; Category fluency; Mini Mental State Examination; Montreal Cognitive Assessment; Clinical Dementia Rating) and brain variables (hippocampal volume, white matter hyperintensities (WMH), PET amyloid‐β and Tau) were considered as outcomes in regression models.

Result

Low ω‐3 index was not associated with cognition, hippocampal and WMH volume, brain Aβ and Tau after adjustment for age, education, ApoE ε4, cardiovascular disease, BMI and total intracranial volume in the cross‐sectional analysis. In the retrospective analysis, low ω‐3 index was associated with greater Aβ accumulation over time. The composite cognitive score did not differ between groups; however, low ω‐3 index was associated with greater cognitive decline on the WMS‐Delayed recall but unexpectedly lower cognitive decline on the total ADAS‐Cog. Low ω‐3 index was cross‐sectionally associated with lower performance on WMS tests and higher Tau accumulation among ApoE ε4 carriers.

Conclusion

Longitudinally, low ω‐3 index was associated with greater Aβ accumulation over time and cognitive decline on the WMS but unexpectedly with lower cognitive decline on the total ADAS‐Cog. Low ω‐3 index was associated with lower cognition on the WMS and higher Tau accumulation among ApoE ε4 carriers in the cross‐sectional analysis.
APOE ε4 and global cognitive functioning in individuals with autosomal dominant Alzheimer’s disease due to the PSEN1 E280A variant
Authors: Vasquez Daniel , Aguillon David , Chen Yinghua , Su Yi , Quintero Juan Felipe , Acosta‐Baena Natalia , Acosta‐Uribe Juliana , Baena Ana Y. , Garcia Gloria , Guzman Claudia F , Giraldo‐Chica Margarita , Tirado Victoria , Muñoz Claudia , Ríos‐Romenets Silvia , Oliveira Gabriel , Langella Stephanie , Yang Hyun‐Sik , Vila‐Castelar Clara , Pruzin Jeremy J. , Ghisays Valentina , Tariot Pierre N. , Arboleda‐Velasquez Joseph F , Kosik Kenneth S. , Reiman Eric M. , Lopera Francisco , Quiroz Yakeel T.
Published: December 2022

Background

APOE‐ε4 allele (APOE4) increases the risk for sporadic Alzheimer’s disease (AD) and is associated with an earlier onset of AD dementia. However, previous studies have shown conflicting results on the association of APOE4 with the age of dementia onset in individuals with autosomal dominant AD (ADAD). Here, we examined the impact of APOE4 genotype on the age‐related trajectory of global cognitive function in mutation carriers and non‐carriers from the Colombian ADAD kindred.

Method

Data were obtained from a retrospective cohort of individuals from the largest known early‐onset ADAD kindred, residing in Antioquia, Colombia. Analyses included 675 PSEN1 E280A carriers (ages 18 to 75; 141 with an APOE4 allele: APOE4+, and 534 without an APOE4 allele: APOE4‐) and 594 non‐carriers. The Mini‐Mental State Examination (MMSE) was used to assess global cognitive functioning. Age‐related trajectories were derived from cross‐sectional log‐transformed MMSE scores modeled using a restricted cubic spline model. Model parameters were estimated using a Hamiltonian Markov chain Monte Carlo method to compare APOE4+ versus APOE4‐ trajectories in the mutation carrier and non‐carrier groups and estimate the age at onset of differences in global cognitive functioning.

Result

Lower MMSE scores distinguished PSEN1 E280A mutation carriers from non‐carriers at age 31.4, approximately 14 years before the average age of mild cognitive impairment (MCI) onset in this cohort. Among PSEN1 E280A mutation carriers, lower scores in MMSE began to significantly differentiate APOE4+ from APOE4‐ at age 45, the estimated average age of MCI onset in this kindred (figure 1). MMSE scores did not differentiate APOE4+ from APOE4‐ in those without the PSEN1 E280A mutation.

Conclusion

Our findings suggest that age‐related changes in cognitive function, as measured by the MMSE, are accelerated in ADAD mutation carriers who are APOE4+, compared to those who are APOE4‐. Future longitudinal studies of PSEN1 mutation carriers are needed to further clarify the impact of APOE4 genotype on rates of cognitive decline, heterogeneity of clinical presentation, and clinical progression in the preclinical, MCI, and dementia stages.
Increased Sialylation in Alzheimer’s Disease Models
Authors: Fastenau Caitlyn , Solano Leigh , Wickline Jessica L , Smith Sabrina , Odfalk Kristian F , Bieniek Kevin F , Hopp Sarah C.
Published: December 2022

Background

Research shows evidence of increased sialylation localized to pathological protein aggregates in AD autopsied brains. Sialylation is a type of glycosylation with linkage bonds of sialic acid (SA) residues on glycoproteins and glycolipids. It is unclear how changes in SA distribution in AD contributes to disease. Microglia are partially regulated by sialylation. We hypothesize decreased removal of SA residues on microglia leads to increased sialylation near amyloid‐β (Aβ) plaques, reducing microglia mediated plaque clearance.

Method

A plant‐derived lectin was used to recognize α2‐6 SA bonds. Aβ plaques, microglia, and α2‐6 SA were histologically labelled in cortical brain tissue from human AD cases and 5XFAD mouse model of Aβ pathology. Stained hemibrains were imaged with confocal microscopy and quantified. To investigate the effects of reducing SA cleavage, we treated a subset of our 5XFAD and wild‐type (WT) mice with oseltamivir (Tamiflu), an inhibitor of desialylation, for five days. On day 3 and immediately following treatment, we measured cognitive and non‐cognitive behaviors using open field and novel object recognition tests.

Result

Qualitatively, α2‐6 SA levels displayed similar microglial‐like phenotype in 5XFAD and human AD cortical brain tissue. Two‐way ANOVA of histologically labeled hemibrains revealed 5XFAD mice had significantly increased α2‐6 SA levels compared to WT mice (p = 0.0007). High magnification image analysis supported a significant increase of α2‐6 SA area in 5XFAD mice versus WT (p<0.0001), yet there was no effect of oseltamivir treatment. Behavioral data similarly demonstrated no effect of treatment. Post‐hoc analysis of open field revealed 5XFAD mice exhibited greater velocity compared to WT (p = 0.03) and 5XFAD mice lacked habituation behavior with no decrease in velocity compared to WT (p = 0.02). Investigation of Aβ pathology indicated no oseltamivir effect.

Conclusion

We observed a significant increase in α2‐6 SA in 5XFAD mice similar to human AD, suggesting a plaque associated increase in sialylation. Next, we will closely examine localization of SA in the plaque microenvironment to understand the role of sialylation in microglial interactions with disease pathology. We postulate SA residues are localized to microglia interacting with Aβ plaques, potentially aggravating pathology.
Relationships between psychosocial stress, cerebrospinal fluid markers of Alzheimer’s disease, and cognitive function in middle‐aged and older adults
Authors: Zuelsdorff Megan , Van Hulle Carol A. , McLester‐Davis Lauren W. Y. , Chin Nathaniel A. , Livingston Sydnee , Logan Julianne , Carlsson Cynthia M. , Okonkwo Ozioma C. , Gleason Carey E. , Bendlin Barbara B. , Asthana Sanjay , Johnson Sterling C. , Betthauser Tobey J
Published: December 2022

Background

Exposure to psychosocial stress empirically associates with risk of cognitive impairment and dementia. Plausible mechanisms include (I) direct influence on AD pathology, and (II) indirect influence through cognitive reserve processes. Current evidence for modifiable determinants of amyloid and tau deposition is mixed, and stress has rarely been studied in this context. In richly characterized cognitive aging samples, we explored preliminary associations between (i) stress measures and amyloid (A), tau (T) and neurodegeneration (N) biomarkers in cerebrospinal fluid (CSF), and (ii) synergistic effects of stress and ATN in cognition.

Method

Participants were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) or Wisconsin Alzheimer’s Disease Research Center (ADRC), were cognitively intact, had stress and cognition data from at least one timepoint, and had available CSF data assayed using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd). Predictors included Perceived Stress T‐scores from the NIH Toolbox Emotion Battery, and self‐reported recent (past‐year) stressors. ATN outcomes included CSF measures of amyloid positivity, tau positivity, and neurofilament light protein (NfL). Cognitive outcomes included performance in domains of (a) processing speed and mental flexibility and (b) episodic memory. Multivariable regression models assessed cross‐sectional predictor‐outcome relationships.

Result

Characteristics of the predominantly white, middle‐aged and older samples are in Table 1. Stress scores associated with poorer performance on tests of speed and mental flexibility but not memory. There were no significant associations between measures of stress and any AD biomarker (Table 2). Estimate precision was limited by sample sizes, but there were observable interactions between stress measures and tau positivity and NfL, specifically in domains of speed and flexibility (Table 3; eg Figure 1); higher stress predicted poorer performance in the presence of accumulated pathology.

Conclusion

There was no evidence for direct relationships between stress exposure and ATN pathology. However, the presence of elevated AD biomarkers exacerbated cognitive detriment associated with psychosocial stress, particularly in a key domain of executive function. Our findings must be replicated in a larger and more diverse sample. However, this study provides preliminary evidence suggesting high stress may act on dementia risk indirectly, through reduced resilience to pathological changes in the brain.
Mouse Adapted SARS‐CoV‐2 induces ‘long‐COVID’ neuropathology in BALB/c mice
Authors: Gressett Timothy E , Ismael Saifudeen , Narayanappa Amruta , Biose Ifechukwude Joachim , Leist Sarah R , Baric Ralph S , Bix Gregory J
Published: December 2022

Background

COVID‐19 survivors develop neuro‐psychological symptoms as post‐COVID 19 syndromes, although the pathophysiology remains elusive. SARS‐CoV‐2 MA10 (MA10) is a model of mouse‐adapted SARS‐CoV‐2 that recapitulates acute respiratory distress syndrome observed in humans. However, the consequence of MA10 infection on brain pathology is not yet evaluated. The study aimed to evaluate the long‐term consequence of MA10 infection on blood‐brain barrier (BBB) integrity and neuroinflammation

Method

10‐week and 12‐months old female BALB/c/cAnNHsd mice were infected intranasally with 104 PFU and 103 PFU SARS‐CoV‐2 MA 10 respectively. The brain was isolated 60‐ and 120‐days post‐infection (60 and 120 dpi) and subjected to histological analysis and mRNA expression by qPCR array.

Result

Immunohistochemical analysis showed that MA 10 infection caused increased GFAP immunoreactivity in young mice. Histopathological analysis showed that MA10 infection induced significant neuropathology. Ongoing quantification on microglial activation and BBB integrity elucidated a possible correlation between infection and neuropathology.

Conclusion

Our data shows the first time that MA10 infection induces neuropathological outcomes several weeks after infection. These observations can help to develop novel therapeutic strategies to ameliorate neuroinflammation and restore brain function
Evaluating the Utility of Existing Plasma Biomarkers in a Clinical Patient Cohort
Authors: Dubois Kelly N. , Grabinski Tessa , Morgan Dave , Kanaan Nicholas M
Published: December 2022

Background

Biomarker assessments will become an instrumental component of effective clinical management and trial coordination for Alzheimer’s Disease (AD) and related dementias and will enable precision medicine approaches to diagnosis and treatment. Plasma offers an inexpensive non‐invasive peripheral biofluid for biomarker assessments that can easily be collected longitudinally. The development of ultrasensitive single molecule array (SIMOA) assays has enabled plasma measurements for AD‐related blood biomarkers. Indeed, several plasma biomarkers were recently identified as potentially useful for AD and related dementias. However, their utility in additional clinical cohorts requires further investigation.

Methods

Plasma samples were collected from participants clinically diagnosed as cognitively unimpaired (CU; n=30), mild cognitive impairment (MCI; n=60) or probable AD (AD; n=34) from the Michigan ADRC. Levels of total Tau, phospho‐tau 181 (pT181), amyloid β40 (Aβ40), and amyloid β42 (Aβ42) were measured using SIMOA. Ongoing studies will include additional samples and measure plasma neurofilament light chain, glial fibrillary acidic protein, placental growth factor, vascular endothelial growth factor, and phospho‐tau 231. Biomarker levels were compared across diagnostic groups and correlated with cognitive and demographic variables.

Results

Among the biomarkers assessed, interim results indicated significantly elevated pTau181 in AD compared to CU and receiver operating characteristic (ROC) analysis showed an AUC of 0.81 for CU versus AD. This analyte correlated significantly with CDR sum of boxes (p=0.01). There was a nonsignificant reduction (8%) in the Aβ42:Aβ40 ratio and an AUC of 0.65 for CU versus AD. Aβ40 and the Aβ42:Aβ40 ratio were significantly correlated with age. No sex differences were detected. Except for pTau181, no significant correlations with CDR sum of boxes or CDR global were found. Biomarker levels showed no correlation with body mass index (BMI) within diagnostic groups.

Conclusions

Generally, our results align fairly well with other studies using clinical patient cohorts with extensive additional biomarkers (e.g. PET tracer measurements and CSF biomarkers). The AD‐associated increase in plasma pT181 levels support the potential utility of this form of phospho‐tau as a useful plasma biomarker. The lack of significant effects with the other biomarkers used here suggests additional novel biomarkers are necessary.
early noninvasive diagnosis of neurodegeneration
Authors: Sidenkova Alena Petrovna
Published: December 2022

Background

Alzheimer's disease (AD) is a neurodegenerative pathology that develops mainly in elderly and senile people. The aim of the study was a comparative analysis of the results of neuropsychological tests with the indicators of the study of oral fluid and buccal epithelium cytograms in patients with Alzheimer's disease.

Method

laboratory, neuropsychological

Result

In the main group of 12 patients with Alzheimer's disease, m=76.25±4.89. There were 12 cognitively healthy people in the control group. The average MMSE score among the observations of the main group was 13.42±3.63. The ADAS‐COG scale was used to detail the impaired cognitive functions. The concomitant pathology is compensated. The content of BDNF, TNF‐α, IL1RA, IL‐6, and IL‐8 was determined in the oral fluid and in the blood serum. The concentration of salivary and serum biomarkers was determined by multiparametric fluorescence analysis with magnetic microspheres. Micronuclei, karyopycnosis, karyorexis, and karyolysis were determined in the cellular structures of the buccal epithelium. The material for cytological examination was collected from the inner surface of the cheek.

When analyzing buccal cytograms, attention was drawn to a pronounced increase in the number of cells with micronuclei in patients with AD to 1.8%; in the control group, the median was 0.1% (p<0.05). A direct correlation was established between the number of binuclear cells and the level of BDNF in the blood serum (r=0.646; p=0.03) in patients with AD. It is also important to note that the level of serum BDNF had a significant direct correlation with immediate memory, and the concentration of salivary BDNF correlates with the parameter of naming objects.

Conclusion

Correlations between amnesia, speech disorders, praxis, gnosis and pathology of the oral fluid and buccal epithelium, especially with the severity of karyopycnosis and karyorexis, have been established, indicating a direct correlation between the neurodegenerative process pathogenetically associated with Alzheimer's disease and the processes of systemic inflammation and degeneration of the buccal epithelium.
The effect of COVID‐19 restrictions on sleep in individuals with cognitive impairment and their carers
Authors: Blackman Jonathan , Carrigan Neil , Wearn Alfie , Desai Bhavisha , Meky Saba , Selwood James , Piggins Hugh , Turner Nicholas , Greenwood Rosemary , Coulthard Elizabeth
Published: December 2022

Background

COVID‐19 restrictions have been associated with apathy, anxiety and depression in individuals with cognitive impairment1‐3 and increased stress in caregivers4. But despite links between these restrictions and sleep impairment in the general population5, effects on sleep in this cohort are not widely reported. Here we determine overall sleep quality in these populations during the first UK lockdown, how this changed over time and explanatory factors associated with longitudinal change.

Method

Cognitively impaired group (CIG), carer group (CG) and older healthy participants completed online self‐reported validated questionnaires (PSQI, GAD‐7, PHQ‐8 and DBAS) alongside bespoke questions comprising the ‘SleepQuest’ study at two comparable stringent lockdown periods within the UK [t1 – (29/4/20‐13/5/20) and t2 – (5/11/20‐2/12/20)]. Analysis utilised paired t‐tests with Bonferroni correction with 95% confidence intervals. Multivariable linear regression evaluated predictive factors.

Result

Within the CIG, baseline n = 79 [MCI, n = 33; AD, n = 19; Other, n = 27], mean age 68.7±9.7, with follow‐up data for n = 37. Within the CG, baseline n = 183, mean age 59.4±11.1, follow‐up n = 116. Overall sleep quality by PSQI Total was impaired at baseline (CIG = 7.8±4.3; CG = 7.9±4.0) compared to 6.6±3.6 for older healthy participants (n = 2354). There was a trend towards sleep quality deterioration from t1‐t2 in both groups (CIG ‐ Mean diff = 0.84, CI[‐0.20,1.84], p = 0.111; CG ‐ Mean diff = 0.51, CI[‐0.01,1.02], p = 0.053). PSQI subcomponent analysis revealed increasing sleep medication use in both groups (CIG – Mean diff = 0.83, CI[0.36,1.32], pcorr = 0.007; CG – Mean diff = 0.99, CI[0.81,1.17], pcorr<0.001). However, levels of daytime dysfunction improved in both groups (CIG – Mean diff = ‐0.54, CI[‐0.87,‐0.21], pcorr = 0.014; CG – Mean diff = ‐0.46, CI[‐0.61,‐0.30], pcorr<0.001). Within the CIG, affective and behavioural factors at t1 did not predict sleep at t2. Within carers, increased anxiety (total GAD‐7) at t1 predicted worse sleep at t2 (Est[normalised PSQI total] = 0.22, SE = 0.10, p = 0.041).

Conclusion

Overall sleep quality for individuals with cognitive impairment and their carers was poor at baseline and trended towards further deterioration, although daytime function improved. Within this cohort, potential compensatory strategies included increased use of sleep medication (associated with adverse outcomes). Given impaired sleep may accelerate progression of dementia neuropathology6,7, it is important to understand and ameliorate the impact of prolonged socio‐political stressors on people with dementia and their carers.
Associations between ALOX5 and ALOX5AP Genetic Polymorphisms and Cognitive Performance in Patients with Alzheimer’s Dementia and Mild Cognitive Impairment
Authors: Noor Shiropa , Xiong Lisa Y. , Wong Yuen Yan , Wu Che‐Yuan , Swardfager Walter ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

Background

Leukotriene activity may contribute to cognitive deficits in Alzheimer’s disease (AD). Leukotrienes are synthesized by 5‐lipoxygenase (5‐LOX) and its activating protein (FLAP), encoded by ALOX5 and ALOX5AP, respectively. This cross‐sectional study investigated the associations of ALOX5 and ALOX5AP single nucleotide polymorphisms (SNPs) with cognitive performance in patients with AD or mild cognitive impairment (MCI).

Method

ALOX5 SNP rs2029253 and ALOX5AP SNPs rs10507391, rs12429692, rs4147064, rs9551963, rs9579646 were selected based on previous associations to ischemic stroke. Participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) diagnosed with AD or MCI at baseline were separated by genotype for each SNP. Rey Auditory Verbal Learning Test (RAVLT), Mini Mental State Exam (MMSE), and Trail Making Part B (TRAB) tests were selected to measure memory, overall cognitive status, and executive function, respectively. Associations between SNPs and white matter hyperintensities (WMH) were also explored. Additive, dominant, and recessive models were tested for each SNP and outcome pair. Linear regressions were used to assess associations between genotypes and outcomes controlling for age, sex, and education.

Result

rs12429692 TT homozygotes (MAF = 25.3%) had lower RAVLT learning (i.e. Trial 5 minus Trial 1) scores (F1,508 = 7.19, p = 0.008, n = 513, recessive model). rs4147064 TC heterozygotes (MAF = 46.5%) had higher MMSE scores than TT homozygotes (F2,508 = 3.34, p = 0.036, n = 514, additive model). rs9551963 CC homozygotes (MAF = 49.1%) had higher TRAB times (F1,481 = 6.06,
p = 0.014, n = 486, recessive model). Split by sex, rs12429692 was associated with TRAB times in males (F1,277 = 5.52,
p = 0.020, n = 281, dominant model) and rs9551963 was associated with RAVLT % forgetting scores in females (F1,212 = 4.98,
p = 0.027, n = 216, recessive model). The rs12429692 A/T SNP (MAF = 25.4%) trended towards an association with WMH (F1,507 = 3.33,
p = 0.069, n = 512, recessive model).

Conclusion

Three ALOX5AP SNPs were associated with aspects of cognitive performance. This preliminary clinical evidence suggests a possible effect of leukotriene synthesis on cognition in patients with AD or MCI.
Conserved cell‐type specific signature of resilience to Alzheimer’s disease nominates role for excitatory cortical neurons
Authors: Telpoukhovskaia Maria , Hadad Niran , Gurdon Brianna , Dai Miko , Ouellette Andrew R , Neuner Sarah , Dunn Amy R , Hansen Shania L , Wu Yiyang , Dumitrescu Logan , O'Connell Kristen MS , Dammer Eric B , Seyfried Nicholas T. , Muzumdar Sukalp , Gillis Jesse , Robson Paul , Zhang Jigang , Hohman Timothy J. , Philip Vivek M. , Menon Vilas , Kaczorowski Catherine C.
Published: December 2022

Background

Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease‐modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD.

Method

In this study, we use single‐nuclear transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid.

Result

Our cross‐species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GABRB1, PTK2, and ROCK2. Nominated resilience genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Additionally, we identified several potential mechanisms of resilience, including regulation of membrane potential, axonal and dendritic growth, and general increase of protein cycle, potentially of membrane proteins.

Conclusion

Because our discovery of resilience‐associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre‐clinical studies in our human‐relevant AD‐BXD mouse panel.
Tau and memory performance in women: Advantages of visuospatial over standard verbal memory tests
Authors: Shepherd Alyx L , Wang Xin , Bernier Rachel A , Lui Kitty K , Deters Kacie D , Chowdhury Tasnuva , Edland Steven D. , Sundermann Erin E. , Banks Sarah J
Published: December 2022

Background

The accumulation of pathological tau in the medial temporal lobe is a hallmark of early Alzheimer’s disease (AD) that leads to memory decline. The majority of studies in AD use exclusively verbal memory tests to detect this memory loss, which is problematic because women have a lifelong advantage in verbal memory such that these tests may be less responsive to early AD. In our Women: Inflammation and Tau Study (WITS), we used both verbal and nonverbal memory tests, with the hypothesis that the nonverbal test would more accurately reflect tau in women.

Method

WITS is a study of older women (aged 65+) with high risk for AD by way of the AD polygenic hazard score and mild cognitive deficits. Data are from 16 participants thus far. Tau PET imaging was completed using the MK6240 ligand. Two volume‐weighted composite of Braak III&IV regions and metatemporal regions were our regions of interest (ROIs). Memory tests were the Rey Auditory Verbal Learning Test (RAVLT) and Brief Visuospatial Memory Test‐Revised (BVMT). Both tests have multiple learning trials in addition to delayed recall. A series of linear regression models separately examined RAVLT and BVMT scores in relation to tau burden in each ROI. We used Akaike Information Criterion (AIC) to compare model fits.

Result

Poorer performance in both RAVLT and BVMT delayed recall was significantly related to greater tau in each ROI (ps<.01); however, relationships were stronger with the BVMT. For the metatemporal ROI, RAVLT explained 14.6% of the variance in tau, while BVMT explained 44.6% (Figure 1). For the Braak III&IV ROI, RAVLT explained 10.1% of the variance and BVMT explained 29.8%. The AIC implied superiority of the models with BVMT over the models with RAVLT.

Conclusion

Our preliminary results show that tau burden in women is better reflected by visual memory performance than verbal memory. Reliance on verbal memory may not be ideal in studies of AD involving women. Upon replication, our results suggest that visual memory performance may be a more accurate clinical marker of early AD with better prognostic value in women that can lead to improved effect sizes and more efficient clinical trials.
The role of human microglia and microglial LRRK2 in tau pathogenesis
Authors: Karabova Maria Kreger , Cowley Sally A. , James William S.
Published: December 2022

Background

The G2019S mutation in leucine‐rich repeat kinase 2 (LRRK2) is the most common genetic determinant of Parkinson’s disease (PD), reported in both familial and sporadic PD cases. Even though tau‐positive pathology features prominently in the G2019S PD patients, the role of LRRK2 in tau pathogenesis remains poorly understood. Human microglia – the chief brain‐resident phagocytes of the innate immune system ‐ become one of the highest LRR2K expressing cells upon IFN‐y stimulation. Moreover, microglia have been recently implicated in increasing pathological tau transmission by secreting exosome‐bound, seeding‐competent tau into the extracellular space. Using human iPS‐macrophages, a simple but physiologically relevant and genetically tractable model of human microglia, we set out to define the role of microglial LRRK2 in uptake, degradation, and secretion of disease‐associated tau protein.

Method

We have developed a quantitative phagolysosomal proteolysis assay based on dequenching of DQ‐BSA fluorogenic substrate attached to silica microspheres, allowing us to investigate cell‐autonomous phagocytic and degradative capacity of G2019S, LRRK2 KO and isogenic control iPS‐macrophages. In parallel, we have optimised purification and in vitro aggregation of endotoxin‐free, human recombinant 2N4R tau to study tau‐induced phagolysosomal proteolysis deficits in the said iPS‐macrophages.

Result

We have found that human iPS‐macrophages readily internalize extracellular tau monomer and fibrils, and LRRK2 is required for macrophage uptake of tau monomer. Degradation of internalized tau is concentration and incubation‐length dependent regardless of genotype. However, G2019S macrophages show deficits in degradation of internalized tau fibrils. Moreover, non‐degraded tau fibrils present within G2019S cell‐ lysates 24h post incubation retain seeding competency and induce aggregation of naïve tau monomer in K11 tau RT‐QuIC assay, unlike tau fibrils internalized by LRRK2 KO macrophages.

Conclusion

LRRK2 expressed by iPS‐macrophages is important for monomeric tau entry, degradation, and seeding capacity of internalized tau fibrils. Future studies will focus on elucidating the molecular mechanisms behind the LRRK2 and tau interaction.
Application of the Preclinical Alzheimer’s Cognitive Composite for tracking progression in cognitively unimpaired older adults with known Amyloid status: A 24‐month Interim Analysis of the Chariot‐Pro cohort
Authors: Novak Gerald P , Udeh‐Momoh Chinedu T. , Price Geraint J , Baker Susan , de Jager Celeste A , Giannakopoulou Parthenia , Middleton Lefkos T
Published: December 2022

Background

The ongoing CHARIOT‐PRO Substudy aims to estimate the rate of cognitive change in the early Alzheimer’s pathological continuum, comparing individuals with and without baseline biomarker evidence of amyloid deposition, over a 4.5yr follow up. We previously reported subtle cognitive differences between the two groups at baseline. Here we extend follow‐up to 24m.

Method

Cognitively unimpaired individuals aged 60–85 years, in good general health and with global Clinical Dementia Rating (CDR) scale = 0, underwent amyloid assessment via PET or lumbar puncture; approximately equal numbers of amyloid positive (A+) and amyloid negative (A‐) individuals were enrolled. This report focuses on the preclinical Alzheimer’s cognitive composite (PACC) total score and the CDR, performed at baseline and at M12 and M24. Subtle deficit at baseline was defined as PACC scores below the 15th percentile of A‐ individuals. The A+ and A‐ groups were compared on rate of progression to CDR > 0 and annualized change from baseline in PACC. Individuals with and without progression at any point in the CDR were compared with respect to PACC baseline and change scores.

Result

A+ participants had lower PACC scores at baseline (‐0.39 (2.56) vs 0.40 (2.71), p = 0.001). There was a trend for less improvement at M24 (0.29 (2.1) vs 0.62 (1.76), p = 0.068). More A+ than A‐ participants progressed to CDR = 0.5 (Figure 1; Kaplan‐Meier survival 84.6% vs 93.1%, respectively, p = 0.004). Those with subtle deficit at baseline were more likely to progress to CDR = 0.5 (14.1% vs 5.9%, OR = 2.63, p = 0.008). Participants with progression to CDR = 0.5 at any time had lower PACC scores at baseline (‐1.30 (2.72) vs 0.24 (2.59), p < 0.0005) and greater decline at M24 (‐0.30 (2.20) vs 0.55 (1.88), p = 0.014).

Conclusion

In A+ individuals, a greater decline in mean PACC scores trended towards significance at 24m, a larger proportion had change in CDR, and CDR progression was associated with declining PACC. In addition, low baseline PACC predicted subsequent increase from CDR = 0. These findings provide further evidence that the PACC has sufficient sensitivity to measure subtle cognitive deficits and serve as an indicator of progression on the early Alzheimer’s pathological continuum.
Modeled Impact of APOE4 Genotype on ARIA‐E Incidence in Patients Treated With Lecanemab
Authors: Reyderman Larisa , Hayato Seiichi , Reddy Harsha , Takenaka Osamu , Yasuda Sanae , Swanson Chad J , Willis Brian A , Hussein Ziad
Published: December 2022

Background

Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species with activity at insoluble fibrils. A multicenter, double‐blind, placebo‐controlled phase 2 study (Study 201 Core) was conducted in 856 patients with early Alzheimer’s disease (EAD). Patients could optionally participate in an open label extension (OLE) study at a dose of 10 mg/kg bi‐weekly (Q2W). Amyloid related imaging abnormalities — edema/effusion (ARIA‐E) was a main adverse event of special interest. Incidence of ARIA‐E was lecanemab dose‐dependent and greater in APOE4 carriers. A previously presented logistic model found steady‐state Cmax was a predictor of ARIA‐E incidence and more likely in APOE4 carriers (Hussein, 2019).

Methods

This work expands upon the previously developed logistic model by exploring the effect of APOE4 genotype (noncarrier, heterozygous carrier, homozygous carrier) on ARIA‐E incidence. Modeling was conducted using NONMEM 7.4.3 with data from Study 201 Core. Model predictions were compared to the observed incidence in the OLE study among patients newly treated with lecanemab (ie, placebo‐treated in the Core study).

Results

Inclusion of APOE4 genotype as a covariate in the model with three categories (noncarrier, heterozygous carrier, homozygous carrier) led to a statistically significant decrease in model objective function (p <0.001). A model utilizing only 2 categories (homozygous carrier, others) was not significantly different from the model with 3 categories (p = 0.5297). Model‐predicted ARIA‐E rates for APOE4 homozygous carriers treated with lecanemab 10 mg/kg Q2W were 22.5% (versus 6.8% in heterozygous or 5.4% in noncarriers) and comparable to the observed 25% incidence in newly‐treated homozygous carriers (1/4) in the OLE study, and less than the 50% incidence in homozygous carriers (5/10) in the Core.

Conclusions

The incidence of ARIA‐E in subjects treated with lecanemab appears highest in APOE4 homozygous subjects. No statistically significant difference in ARIA‐E incidence was found between non‐carriers and heterozygous carriers. Data from the larger CLARITY‐AD study will be needed to confirm these findings.

Reference: Hussein, et al., Population Pharmacokinetic (PK) and Exposure‐Response (ER) Analyses for Efficacy and Safety of BAN2401 in Patients with Early Alzheimer’s Disease (AD), International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD), 2019.
Risk of violent crime may be associated with hippocampal‐dependent cognitive function in older African Americans
Authors: Tan Genesis , Gimenez‐Santana Alejandro , Fausto Bernadette A. , Esiaka Darlingtina , Gluck Mark A.
Published: December 2022

Background

Research on Area Deprivation Index (ADI) suggests that the social environment and neighborhood stressors (e.g., violent crime risk) play a role in later‐life cognitive function. However, most of the research linking ADI and cognitive function has been conducted on non‐Hispanic white American samples. Further, while the ADI is useful in facilitating efficient integration of social determinants of health (SDOH) into models of cognitive aging, it does not take into account micro‐level measures of neighborhood stressors which may also affect cognitive function. Therefore, the purpose of the current study is to determine whether violent crime risk contributes to later‐life cognitive function above and beyond ADI in older African Americans.

Methods

Participants are part of an ongoing study at Rutgers University‐Newark called the Pathways to Healthy Aging in African Americans, a university‐community collaboration fostered over 16 years (2006‐2022) of community engagement, health education, and public service. Analyses included 149 older African Americans aged 60 and above (Mage = 68.68, SD = 7.25; Medu = 13.99, SD = 2.43; n = 149). Cognitive function was assessed via the acquired equivalence task, a measure of one’s ability to generalize past learning to novel task demands. Violent crime risk was calculated using the Risk Terrain Modeling technique, a geospatial risk assessment that evaluates the influence of the built environment on the distribution of crime.

Results

A multiple linear regression was run to examine the relationship between violent crime risk and cognitive function. Violent crime risk was significantly associated with acquired equivalence task performance, F(6, 142) = 5.948, p = .024, adj. R2
= .167, even after controlling for ADI, age, education, and depression. The results showed that individuals living in areas with higher risk of violent crime had poorer ability to generalize past learning to novel task demands.

Conclusion

Our findings suggest that for African Americans in an urban setting, hyper‐local violent crime risk appears to be supplemental with ADI at capturing the impact of neighborhood disadvantage on cognitive function and Alzheimer’s disease risk. Thus, for African American individuals’ later‐life cognitive health, it is important to consider micro‐level measures of neighborhood stressors such as violent crime risk.
Parenchymal CSF Fraction and DTI‐ALPS in Brain Aging
Authors: Zhou Liangdong , Nguyen Thanh D , Li Yi
Published: December 2022

Background

The perivascular space (PVS) functions as part of a brain clearance system that drains interstitial fluid and solutes including Aβ and tau from brain parenchyma and is associated with the development of AD. Recent developed imaging tools of cerebral parenchymal CSF fraction (CSFF)1 and diffusion tensor imaging along perivascular spaces index (DTI‐ALPS)2 provide an insight of the perivascular CSF flow and early PVS pathology in the cerebral cortex. We applied CSFF and DTI‐ALPS in an elderly cognitive normal cohort to investigate its value in brain aging.

Method

A total of 27 cognitive normal subjects in this study are within age 57 and 82 years (mean=67.7, std=6.4). We conducted MR FASTT2 scan for CSFF, T1W, T2W for PVS burden, and DTI for DTI_ALPS index. CSFF was fitted using three compartment model with 6 TEs = 0, 7.5, 17.5, 67.5, 147.5, 307.5 ms. PVS burden was calculated by using imaging processing based PVS segmentation on enhance PVS image (T2W/T1W). DTI_ALPS was calculated by mean(D𝑥_𝑝𝑟𝑜𝑗,D𝑥_𝑎𝑠𝑠𝑜𝑐)/mean (D𝑦_𝑝𝑟𝑜𝑗, D𝑧_𝑎𝑠𝑠𝑜𝑐), where Dx, Dy and Dz are the diffusivity along x‐, y‐ and x‐axis, and the projection, association regions. Multi‐variate linear model Age∼1+DTI_ALPS+CSFF was compared with Age∼1+DTI_ALPS+PVS_burden.

Result

Figure 1 (a) and (b) show the PVS mask on T2W and CSFF map. Figure 2 shows the scattered plot of linear model between age and PVS burden+DTI_ALPS, which is not significant (p=0.06, R2=0.14). Figure 3 is the plot of the model between age and CSFF+DTI_ALPS, which is significant (p<0.01, R2=0.34).

Conclusion

The preliminary results showed CSFF and DTI‐ALPS can better predict brain aging. The conventional PVS burden only measures the MRI visible PVS in brain white matter while CSFF can assess micro‐scale PVS along small arteriole and capillary in the cerebral cortex, which is closely related to glymphatic system and may reflect the PVS function alert at early stage. CSFF and DTI‐ALPS could be a potential marker for detecting early stage of dysfunction of glymphatic clearance.

Reference: 1. Liangdong Zhou, BioRvix:2021.02.01.429067, 2021. 2. Toshiaki Taoka, Jpn.J.Radiol. 2022;40:147–58.3.
Investigating the role of tau loss‐of‐function in Alzheimer’s Disease pathogenesis
Authors: Schwarze‐Taufiq Tiara A. , Frankowski Harald , Lemieux Madeline , Link Christopher D. , Young Jessica E.
Published: December 2022

Background

One hallmark of Alzheimer’s Disease (AD) pathology is hyperphosphorylation of tau protein, which leads to loss of its normal function and promotes aggregation into neurotoxic fibrillary tangles. While tau gain‐of‐toxic function is well‐documented, the exact role of tau loss‐of‐function in AD pathogenesis remains uncharacterized. We hypothesize that tau loss‐of‐function contributes to AD pathogenesis by activating the cellular stress response in neurons and astrocytes, characterized by cytoplasmic double‐stranded RNA (dsRNA) release, stress granule formation, and inflammation.

Method

We generated human induced pluripotent stem cell (hiPSC)‐derived mixed cortical cultures and primary human fetal astrocyte cultures, allowing us to model the earliest stages of AD pathogenesis in a uniquely human system. In these cultures, we depleted tau through lentiviral transduction and CRISPR‐Cas9 to model acute and chronic loss‐of‐function, respectively. We utilized quantitative real‐time polymerase chain reactions, enzyme‐linked immunosorbent assays, and immunocytochemistry to investigate the expression of genes and proteins implicated in stress and inflammation.

Result

Preliminary results indicate upregulation of genes and proteins associated with inflammation and stress granule formation in tau‐depleted neurons and astrocytes. Tau‐depleted cortical cultures exhibit increased secretion of chemoattractant cytokines, and tau‐depleted astrocytes demonstrate increased glial fibrillary acidic protein expression suggestive of non‐cell autonomous pro‐inflammatory cytokine induction. Further, tau‐depleted neurons show increased levels of stress chaperones and cytoplasmic dsRNA known to induce stress granules.

Conclusion

Tau loss‐of‐function may contribute to AD pathogenesis through promoting the release of double‐stranded RNA into the cytoplasm, stress granule formation, and inflammation.