bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s Disease‐Related Polygenic Risk Score Profiles and Brain Proteinopathies
Authors: Katsumata Yuriko , Abner Erin L , Kryscio Richard J , Schmitt Frederick A , Fardo David W. , Nelson Peter T 
Published: December 2022

AbstractBackgroundGenome‐wide association studies (GWAS) have identified more than 70 genetic loci significantly associated with Alzheimer’s disease (AD). AD‐associated genetic variants have been mapped to biological pathways including endocytosis, oxidative stress, immune response, synaptic plasticity, lipid metabolic, apoptotic process, and amyloid‐beta formation. These diverse biological pathways may be differentially responsible for brain pathologies and combinations of proteinopathies. Pathway‐specific polygenic risk scores (PRSs) are useful to estimate an individual’s genetic liability according to well‐characterized biologic pathways. In this study, we investigated differences in AD‐PRSs calculated by biological pathways in different brain proteinopathies.MethodParticipant data comprised autopsied volunteers from the National Alzheimer’s Coordinating Center (NACC) database linked to Alzheimer’s Disease Genetics Consortium (ADGC) genotype data. We obtained Gene Ontology (GO) terms listed for Homo sapiens and mapped genes to each of the GO terms. Of 18,826 GO terms, 7,300 biological processes were extracted among those constructed of 3 or more genes. We also obtained AD‐related GWAS summary statistics from Kunkle et al. (2019; PMID 30820047). We then extracted single nucleotide polymorphisms (SNPs) with p<0.5 that were not located near the APOE loci. We examined the associations between biological pathway‐specific PRSs and proteinopathies using the Kruskal Wallis non‐parametric test.ResultADGC genotype data were available for 1,610 NACC participants. There were 4,866 biological processes that had GWAS summary statistics from at least five SNPs. The distributions of “negative regulation of amyloid‐beta formation” PRSs were significantly different between A scores (Thal phase ratings for Aβ distribution: A0 = Phase 0, A1 = Phase 1 or 2, A2 = Phase 3, and A3 = Phase 4 or 5). The top three biological processes for B score (Braak NFT stage: B0 = Stage 0, B1 = Stage I or II, B2 = Stage III or IV, and B3 = Stage V or VI) were “cell differentiation”, “signal transduction”, and “protein transport”. There was no significant biological pathway associated with TDP‐43 or Lewy body pathologies.ConclusionDistinct brain proteinopatholies are likely caused by disruption of unique, albeit correlated, biological pathways. Further studies that integrate genetic information with PRSs may elucidate the mechanisms underlying brain proteinopathies.
Impaired glucose tolerance in Mild Cognitive Impairment is associated with lower brain amyloid on PET
Authors: Lockhart Samuel N. , Rundle Melissa M. , Okonmah‐Obazee Stephanie E. , Sai Kiran K. Solingapuram , Whitlow Christopher T. , Williams Benjamin J. , Bateman James R. , Hughes Tim M. , Craft Suzanne 
Published: December 2022

AbstractBackgroundAmong community‐dwelling older adults with mild cognitive impairment (MCI), there exists little knowledge regarding how metabolic function impacts brain amyloid pathology (measured using PET) and cognitive status.MethodThis study explored, in participants diagnosed with MCI enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core, markers of baseline metabolic risk (Oral Glucose Tolerance Testing of blood glucose 120‐minute post challenge; OGTT‐2h), amyloid deposition by global PiB PET SUVr and disease subtype (MCI with and without amnestic symptoms) at a subsequent visit, as well as genetic (APOE‐ε4 carrier status) and demographic variables (age, sex, education). Consensus diagnosis of MCI was adjudicated by a panel of experts close in time to PET. OGTT‐2h>140 mg/dL indicates impaired glucose tolerance (IGT).Result59 MCI participants underwent OGTT at initial visit (39 normoglycemic, 20 IGT), and amyloid PET at a later visit (mean delay=362days). N=55 also had APOE genotype determined. PiB SUVR was not statistically different (p=.15) between MCI‐NG (1.51) and MCI‐IGT (1.33). However, in models controlling for age, sex, years education, and time between OGTT and PET, glycemic status was significantly associated (p=.007) with amyloid, such that MCI‐IGT had lower SUVR. APOE‐ε4 status did not attenuate this effect (glycemic status p=.011). A similar significant association was present for continuous OGTT‐2h values before (p=.006) and after (p=.02) controlling for APOE‐ε4 status, with higher OGTT‐2h associated with lower SUVR. Scatterplots of the negative association between OGTT‐2h and PiB SUVR are presented in Figure 1 (before [a] and after stratifying by APOE‐ε4 status [b]). Associations between glycemic status and PiB SUVR were similar when restricting to participants with amnestic symptoms (i.e., MCI‐A or MCI‐MDA; n=52), before (p=.008) and after controlling for APOE‐ε4 status (p=.012). In none of these analyses was an interaction term of APOE‐ε4 status and the glycemic variable significant (p’s>.23).ConclusionAmong community‐dwelling participants with MCI, elevated OGTT‐2h and IGT are associated with lower PiB SUVR. Participants with IGT, at the same level of cognition (MCI), have lower brain amyloid. In these MCI‐IGT participants, factors other than amyloid may be driving MCI status.
CSF biomarkers for Alzheimer Disease are associated with spatial cognition in cognitively normal older adults
Authors: Coughlan Gillian T , DeSouza Brennan , Zhukovsky Peter , Hornberger Michael , Grady Cheryl , Buckley Rachel F. 
Published: December 2022

AbstractBackgroundSpatial cognition has emerged as a promising cognitive fingerprint for the detection of Alzheimer’s disease (AD). Despite evidence that spatial cognition is highly sensitive to AD dementia and is apparent even in adults at‐genetic‐risk of AD, the association between spatial cognition and AD biomarkers in cognitively normal adults is unknown.MethodThis study leverages data from the European Prevention of Alzheimer’s Dementia Consortium, a multinational observational study of clinically normal adults initiated in 2016 that includes two digital spatial paradigms: The Supermarket Task (SMT)and the Four Mountains Task (4MT;Fig1). Using a mixed model approach with random intercepts, we investigated cross‐sectional associations between cerebrospinal fluid (CSF) β‐amyloid1‐42 (Aβ1‐42) and phosphorylated tau (p‐tau181) with task performance (N = 1672; mean age = 68.08[SD = 6.96]).ResultFive hundred and forty‐nine (32.8%) participants had abnormal levels of CSF Aβ1‐42 and p‐tau181. Across the whole sample, higher p‐tau181 concentrations were associated with greater spatial disorientation from the starting location on the SMT (r = ‐0.449, p = <0.001). There was a small association with CSF Aβ1‐42(r = 1.984, p = 0.003; Fig2A‐B). Higher levels of CSF p‐tau181 were associated with more 4MT feature memory errors (r = ‐0.570, p<0.001). There was also a main effect of Aβ1‐42 on 4MT performance (r = 0.301, p = <0.001; Fig2C‐D). Entorhinal cortex and hippocampal volumes both predicted better performance on both tasks (r’s = 0.37‐0.57; Fig3). Post hoc analyses revealed a significant interaction between sex and hippocampal volume, indicating that the association between hippocampal volume and recall of environmental features was stronger in males than females. Finally, volume of the entorhinal cortex, but not the hippocampus, mediated the relationship between p‐tau181 and performance on both spatial tasks (Fig4).ConclusionOur results suggest that spatial tasks are sensitive to CSF p‐tau181 and to a lesser extent Aβ1‐42 in preclinical AD. Given the well‐validated digital platform that these tasks are founded on, these tools provide access to racially and ethnically diverse individuals for preclinical AD trial registries via unsupervised assessment.
Associations Between Plasma, Imaging, Cerebrospinal Fluid Biomarkers and Naturalistic Driving Behaviors, Cognitive Tests Among Cognitively Normal Persons
Authors: Roe Catherine M , Bayat Sayeh , Murphy Samantha , Doherty Jason , Walker Alexis , Pina Yasmin , Babulal Ganesh M 
Published: December 2022

AbstractBackgroundPrevious work indicates that imaging and cerebrospinal fluid (CSF) amyloid and tau biomarkers are associated with driving behaviors, and that driving behaviors can be used to identify preclinical Alzheimer’s disease (AD). Along with traditional biomarkers, we examined the extent to which newer plasma and CSF biomarker are related to driving and cognitive metrics among cognitively normal older drivers.MethodMean driving and cognitive metrics were computed for all available time points in cognitively normal (Clinical Dementia Rating ® = 0) participants (N=167, mean age=73.3±4.9). Participants had a data logger installed in their personal vehicles and drove at their discretion for at least 6 months (mean follow‐up 2.2y±0.9y, range=0.6y‐4.7y) between 6/2/2015 and 2/29/2020 (pre‐COVID data) and took part in cognitive testing yearly. Participants took part in biomarker testing including, imaging (positron emission tomography [PET] amyloid, PET tau, normalized hippocampal volume [nHV]), CSF (Aβ42, Aβ40, tau, ptau181, neurofilament light chain [NfL]), and/or plasma (Aβ42, Aβ40, Aβ42/Aβ40, NfL) within 2 years of data logger installation. Fisher’s Z transformation was used to examine the correlations between the biomarker variables and the driving and cognitive measures.Results(Figure attached) Individual biomarkers were differentially related to different driving behaviors (e.g., number of trips was associated with PET amyloid [p<0.035], plasma Aβ42 [p<0.012] and Aβ40 [p<0.004], but not the other imaging, CSF, and plasma biomarkers [p>0.275]); and to different cognitive scores (e.g., Montreal Cognitive Assessment [MoCA] total scores were associated with amyloid imaging [p<.026], nHV [p<0.033], and plasma Aβ42/Aβ40 [p<0.035] but to no other biomarkers [p>0.080]). Some biomarkers were associated with driving behaviors but not cognitive scores (e.g., CSF Aβ40, tau, NfL; plasma Aβ42 and Aβ40 considered separately) whereas others were related to cognitive scores but not to any of the individual driving metrics (e.g., CSF Aβ42/Aβ40 ratio).ConclusionsDifferent biomarkers are associated with different aspects of driving and cognitive functioning. These distinct relationships may help in understanding how different biological changes that occur during the preclinical stage of AD impact various sensorimotor and cognitive processes.
White Matter Fractional Anisotropy in a Nonhuman Primate Model of Early Alzheimer’s Disease‐like Neuropathology: Relationships with Social Status and Physiologic Measures of Stress Responses
Authors: Frye Brett M. , Craft Suzanne , Register Thomas C. , Kim Jeongchul , Whitlow Christopher T. , Barcus Richard A. , Lockhart Samuel N. , Sai Kiran K. Solingapuram , Shively Carol A. 
Published: December 2022

AbstractBackgroundPsychosocial stress is associated with micro‐ and macrostructural brain changes that may increase risk of Alzheimer’s disease (AD). White matter (WM) appears particularly vulnerable, and changes in white matter integrity are an early sign of AD pathogenesis. Cynomolgus macaques (Macaca fascicularis) have complex central nervous systems and naturally develop early AD‐like neuropathology with age. Female macaques form social status hierarchies in which subordinates exhibit behavioral and physiological signs of stress, and increased stress‐related pathologies similar to humans. Nonhuman primate studies provide a useful platform in which to assess relationships between stress and brain health is a well‐controlled environment with limited outside influences. Thus, these nonhuman primates are useful translational models for studying relationships of psychosocial stress with early AD‐like neuropathology.MethodUsing diffusion tensor imaging, we examined the relationship between psychosocial stress and fractional anisotropy (index of WM microstructural integrity (FA)) in 38 middle‐aged female cynomolgus macaques living in small social groups. Subjects were classified as either dominant or subordinate based upon the outcomes of agonistic interactions. FA in several regions of interest (ROIs): splenium, body, and genu of the corpus callosum (CC), frontal, temporal, occipital, and total cerebral and cerebellar white matter was assessed in relation to social status and several contemporaneous measures of stress physiology (blood pressure, resting cortisol, and heart rate variability (HRV)).ResultRepeated measures ANOVA using left and right ROIs as a repeated measure showed that dominants had significantly higher FA than subordinates in the genu and splenium of the CC, and the occipital and frontal cortices (all p<0.05). Dominants also had higher FA, on average, in the body of CC (p=0.07) and cerebrum (p=0.10), although these differences were not significant. Dominants and subordinates did not differ in temporal or cerebellar FA (both p>0.7). FA was inversely correlated with blood pressure, directly correlated with HRV (p’s<0.05), but not correlated with serum cortisol.ConclusionPsychosocial stress of subordination, as well as physiologic indices of stress responses, was associated with diminished WM integrity in several brain regions. These studies lay the groundwork for investigations of interventions on psychosocial stress to reduce AD risk later in life.
Comparison of degu (Octodon degus), Naked Mole Rat, Mouse and Human genomes identified common hallmarks of aging and Alzheimer's Disease
Authors: Cogram Patricia , Urra Claudio , Travisany Dante , Yañez Cristian , Hurley Michael J 
Published: December 2022

AbstractBackgroundTo provide new insight into the mechanisms of Alzheimer’s disease (AD) pathogenesis and aid the discovery of new therapies in humans it is important to expand and complement research using mouse models by developing, characterizing, and validating suitable new or unconventional mammalian, non‐murine models of AD. Our goal was to create genome assemblies at the chromosome level associated with AD‐like pathogenesis using two long‐lived animal models. The degu (Octodon degus) which naturally exhibits AD neuropathology and the naked mole rat (H. glaber) best known for its resistance to cancer and aging. To understand evolutionary paths to longevity and associated diseases like AD we characterized their genome features and identified common substitutions in long‐lived rodents that support enhanced tolerance to DNA damage.MethodSynteny maps among M. musculus, H. glaber, H. sapiens and O. degus were created using SyMAP 5.0.6. To evaluate disease‐related mutations in humans a pairwise comparison of protein sequences was performed using the HGMD.ResultWe identified several synteny blocks that were part of the putative rodent ancestor genome. 78% genome was covered in H. glaber and 75% coverage in O. degus. In addition, 58 of the 426 synteny blocks were longer than 10 Mbp in M. musculus and 62 in O. degus. The identification of substitutions in orthologs at disease‐causing sites revealed that DNA damage and repair genes are under selection in long‐lived species. Our comparative genomic analyses identified that the top disease categories enriched in degu and naked mole rat were associated with lipid metabolism, DNA repair, stress and IGF‐1.ConclusionOur comparative genome analysis revealed changes in genes and pathways associated with adaptations to acquired longevity. Substitutions at AD causing sites may contribute to long‐term survival pathways affected by natural selection in long‐lived models. When compared to short‐lived mouse models, pathways associated with lipid metabolism, oxidative stress and DNA repair were identified. This data is particularly valuable for providing a within family (Rodentia) comparison for mouse AD model genomics to develop a comprehensive analysis to determine conserved genetic alterations between the unconventional animal models and to bridge our existing databases of mouse models and humans.
Multidisciplinary medication therapy management and participant responses to recommendations: Results from the INCREASE trial
Authors: Smith Noah I , Huffmyer Mark , Eckmann Lynne , George Rosmy , Abner Erin L , Jicha Gregory A , Moga Daniela C 
Published: December 2022

AbstractBackgroundMedication use, especially in the context of polypharmacy and inappropriate medications, may be a modifiable risk factor for cognitive impairment and dementia. Medication therapy management (MTM) interventions, which seek to optimize patient‐specific medication regimens, may restore cognitive function and delay onset of cognitive decline. Here, we describe an MTM protocol, delivering patient‐centered recommendations through joint decision‐making among the study participant, pharmacy specialist, and non‐pharmacist clinician (e.g., study physician) directed at delaying the symptomatic onset and progression of AD.MethodCommunity dwelling adults age 65 and older, without dementia, using at least one potentially inappropriate medication (PIM) were enrolled in a clinical trial to evaluate the effect of the MTM on improving medication appropriateness and cognition (INCREASE; NCT08245639). In a three‐step process, study pharmacists first identified potential mediation‐related problems (MRPs) and made initial recommendations for prescribed and over‐the‐counter medications, vitamins, and supplements. Second, study team clinicians and pharmacists reviewed all initial recommendations together with the participants, allowing for revisions to make a final recommendation. Third, participant responses to final recommendations were recorded. Here, we evaluated participant responses in relation to medication class and type of final recommendation.ResultAmong the 90 randomized participants, a mean 6.7±3.6 MRPs per participant were reported. A total of 259 initial MTM recommendations were made for the treatment group participants, with 40% percent undergoing revision in the second step (Table 1). Participants reported willingness to adopt 46% of final recommendations and need for additional primary care input in response to 38% of final recommendations. Willingness to adopt final recommendations was highest when therapeutic switches were offered and/or with anticholinergic medications (Table 1).ConclusionAs integration of healthcare disciplines and specialized services become an increasingly important part of collaborative healthcare practices, this study demonstrated that initial MTM recommendations often change through group discussion, and multidisciplinary decision‐making that incorporated the preferences of patients themselves often led to positive participant responses. Further studies are needed to assess whether participants adhere to MTM recommendations long‐term, and to evaluate the health and economic impact of MTM on chronic disease prevention and maintenance, such as with AD and related dementias.
Associations among plasma ptau181, tau PET, and amyloid PET in a community‐based study during midlife
Authors: Lao Patrick J. , Simoes Sabrina , Banjoko Michael B. , Benavides Andrea , Lippert Rafael , Berroa Joncarlos , Igwe Kay C , Schupf Nicole , Mayeux Richard , Manly Jennifer J , Brickman Adam M. 
Published: December 2022

AbstractBackgroundThe amyloid‐tau‐neurodegeneration (AT(N)) research framework uses a biomarker definition of Alzheimer’s disease (AD); neuroimaging has been the in vivo gold standard, but plasma‐based measures are becoming more widely available yet need to be characterized earlier in the life course and AD continuum, as well as in representative samples. Our objective was to understand how plasma measures of ptau181 correspond with PET‐derived measures of amyloid and tau in middle age.MethodsIn the ongoing Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease, participants (n=61; 61±6, 52‐79 years old, 67% women, 14±4 years of education, 10% Non‐Latinx White/25% Non‐Latinx Black/65% Latinx) underwent measures of amyloid (weighted average Florbetaben SUVR in Thaal phase regions) and tau (average MK‐6240 SUVR in Braak stage I; SIMOA‐based plasma ptau181). Amyloid‐positivity was determined at >1.25 SUVR and tau‐positivity was determined at >2 SD above the mean SUVR in an independent sample of cognitively unimpaired individuals. General linear models tested associations among plasma ptau181, tau PET, and amyloid PET.ResultsFifteen percent were amyloid‐positive while five percent were tau‐positive. Ptau181 was not associated with PET‐based tau burden (R=‐0.18, p=0.17). Amyloid burden increased with age (R=0.37, p=0.003). PET‐based tau burden increased with amyloid (R=0.29, p=0.02), but not with age (R=0.16, p=0.22). Conversely, ptau181 increased with amyloid (R=0.26, p=0.04) and with age (R=0.25, p=0.05).ConclusionsA temporal discrepancy between plasma and PET‐based tau, particularly in a sample of mostly amyloid‐ and tau‐negative middle‐aged adults, may explain the lack of association between ptau181 and tau PET. However, both plasma and PET‐based tau were associated with elevated amyloid burden, which is thought to be necessary for the spreading of pathological tau in AD. Prior studies suggest that associations between plasma ptau181 and tau PET are stronger and shift from early Braak stage regions to late Braak stage regions further along the AD continuum. Therefore, it is important to understand the utility of plasma ptau181 in the context of age and disease stage.
Announcing the Vietnamese Insights into Aging Program (VIP)‐ The First Cohort Study of Cognitive Aging in Vietnamese Americans
Authors: Meyer Oanh L. , Farias Sarah Tomaszewski , Whitmer Rachel A. , Kanaya Alka , Hinton Ladson , Harvey Danielle J. , Tiet Quyen Q , Vuong Quyen , Park Van Ta 
Published: December 2022

AbstractBackgroundAsian Americans are the fastest growing racial population in the U.S; yet very little is known about their cognitive aging and Alzheimer’s disease and related dementias (ADRD) risk. Vietnamese Americans are the largest Southeast Asian group and are at high risk for health disparities. Unlike other large Asian subgroups, due to their sociopolitical history and experiences as refugees, Vietnamese Americans have faced a significant amount of adversity and trauma. As Vietnamese Americans age and their susceptibility to ADRD increases, their context may provide unique understanding in terms of within‐group heterogeneity and reveal key factors in ADRD and cognitive aging. The Vietnamese Insights into Aging Program (VIP) is the first longitudinal study of older Vietnamese Americans and addresses the dearth of ADRD research in this high‐disparity population. The goal is to obtain estimates of cognitive impairment and dementia in the community and identify ADRD risk (e.g., early life trauma) and protective (e.g., social support) factors in this understudied population.MethodWe will enroll 540 Vietnamese (age ≥65 years) across two sites in Northern California. Participants will be seen annually over 3 years to assess cognitive change over time. The following data will be collected: 1) a full neuropsychological battery; 2) an extensive interview about early life history and trauma as well as psychological and sociocultural factors, and 3) cardiovascular risk factors (hypertension, diabetes, smoking, etc.). Assessments will be conducted in Vietnamese and take place at a community partner site. In collaboration with local community partners, extensive community outreach and education were conducted prior to study recruitment.ResultVIP has developed a protocol for the bilingual Vietnamese assessments which has been further refined by scientists, staff, and VIP’s community advisory board, many of whom are bicultural and bilingual Vietnamese American. VIP currently has a waitlist of over 250 participants as of January 2022. We aim to complete Time 1 assessments of all 540 participants by Spring 2023.ConclusionInnovative research with older Vietnamese Americans provides a unique opportunity to refine research methodology and more fully delineate the factors that contribute to ADRD disparities in underserved populations.