bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type 2 diabetes and dementia in the Health and Retirement Study: A Mendelian randomization approach
Authors: Ware Erin B , Bustamante Ana Cristina Morataya , Fu Mingzhou , Bakulski Kelly M 
Published: December 2020

AbstractBackgroundType 2 diabetes mellitus (T2DM) and dementia are leading causes of mortality and disability in the US. T2DM has been associated with dementia; however, causality has not been established. The aim of this study is to test for an association between T2DM and dementia status using a Mendelian randomization approach.MethodParticipants from the 2010 wave of the longitudinal Health and Retirement Study, a nationally representative survey of US adults over the age of 50, and who were of European or African genetic ancestry were included in the study (n=10,571). History of T2DM was self‐reported. Cognitive status was defined from clinically validated cognitive assessments as dementia, cognitively impaired non‐dementia, or normal cognition. Cumulative genetic risk for T2DM and dementia was determined using polygenic risk scores. Multivariable logistic regression was used to test the association between cumulative genetic risk for T2DM and cognitive status adjusting for age, sex, education, APOE‐ε4 carrier status, and genetic principal components. The inverse variance method was used to test inferred causality using Mendelian randomization.ResultAmong included participants, 20.75% had T2DM and 21.8% had dementia or cognitive impairment. Among European ancestry participants, T2DM was associated with 1.28 times odds of cognitive impairment non‐dementia (95% confidence interval: 1.09‐1.50) relative to normal cognition. A one standard deviation increase in cumulative genetic risk for T2DM was associated with 1.43 times higher odds of T2DM (95% confidence interval: 1.33‐1.54). Cumulative genetic risk for T2DM was not associated with dementia status or cognitive‐impairment non‐dementia in either ancestry (P>0.05); lack of association here is an important assumption of Mendelian randomization. Using Mendelian randomization, we did not observe evidence for an inferred causal association between T2DM and cognitive impairment (odds ratio: 1.08; 95% confidence interval: 0.86‐1.37).ConclusionConsistent with prior research, T2DM was associated with cognitive status. In the current study; however, evidence for inferred causality was not observed. Prevention of T2DM and cognitive decline are critical for public health.
Mendelian randomization of smoking behavior on cognitive status among older Americans
Authors: Bakulski Kelly M , Fu Mingzhou , Faul Jessica D , Jin Yuan , Ware Erin B 
Published: December 2020

AbstractBackgroundSmoking is associated with dementia status, and smoking behavior has a genetic component. In this study, we jointly test the associations between cumulative genetic risk for smoking, smoking behavior, and cognitive status.MethodWe conducted a cross‐sectional study using the 2010 wave of the Health and Retirement Study. First, we used logistic regression to test the relationship between cumulative genetic risk for smoking and current smoking behavior. Second, we tested the association between smoking behavior and cognitive status. Third, we checked the assumption that cumulative genetic risk for smoking was not associated with cognitive status. All analyses were adjusted for age, sex, years of education, rural/urban residence and five ancestry‐specific genetic principal components. Analyses were stratified by ancestry. Finally, a Mendelian randomization framework was used to test inferred causal relationships between smoking behavior and cognitive status via genetic instruments.ResultAmong European ancestry participants (n = 8,735), one standard deviation increase in smoking polygenic score was associated with 1.28 times odds of current smoking behavior (95% confidence interval: 1.18, 1.38) relative to never smoking. Current smoking was associated with 1.62 times odds of cognitive impairment (95% confidence interval: 1.29, 2.01) relative to never smokers and those with normal cognition. No association was observed between smoking polygenic score and cognitive status, an important assumption of the Mendelian randomization framework. Using the smoking genetic instrument, a significant inferred causal relationship was observed between current smoking and cognitive impairment (P=0.02, 1.53 odds ratio, 95% confidence interval: 1.07, 2.18).ConclusionThese findings demonstrate current smoking is likely causally related to cognitive impairment. Promotion of smoking cessation is important for public health and brain health specifically. Studies on dose and duration of smoking on cognition are critically needed, as well as in research non‐European ancestries.
Association of metabolic syndrome and cognitive function in a population‐based cross‐sectional study of adults aged 60 years or older
Authors: Karanth Shama D. , Katsumata Yuriko , Nelson Peter T. , Kryscio Richard J. , Schmitt Frederick A , Slade Emily , Vsevolozhskaya Olga , Fardo David W. , Abner Erin L. 
Published: December 2020

AbstractBackgroundMetabolic syndrome (MetS) is defined by the presence of five cardiovascular risk factors: diabetes, hypertension, high body weight, and hypercholesterolemia. Each factor has been reported to associate with cognition, but the association of MetS with cognitive function is not well understood. The current study explored the association of MetS with cognition in a nationally representative sample of elderly adults in the United States.MethodCross‐sectional data from the National Health and Nutrition Examination Survey (NHANES 2011‐2014) were obtained for participants age ≥60 years. MetS was defined per American Heart Association criteria (≥ 3/5 factors). Cognitive performance was based on components of the Consortium to Establish a Registry in Alzheimer’s disease (CERAD) neurocognitive battery. A composite z‐score was calculated for each CERAD component; z‐scores were then averaged to estimate global cognition (Figure 1). Memory complaint was based on self‐report. Linear regression models were fit to evaluate the association between global cognition and MetS, and logistic regression was used to evaluate the association of memory complaint with MetS; we used survey statistics to account for the complex NHANES sampling design.ResultIncluded participants (n=2593) were mean 69.4 years old; 54.8% (n=1318) were female. MetS was present in 60.9% (n=1633) of participants. After adjustment for age, sex, race/ethnicity, education, alcohol use, poverty, marital status, and memory complain, MetS was associated with almost 1/3 standard deviation lower mean global cognition compared to participants with no MetS factors (β= ‐0.28; 95%CI ‐0.46,‐0.10), while participants with 1‐2 MetS conditions had similarly lower cognitive scores relative to participants with none (β= ‐0.23; 95%CI ‐0.42,‐0.04) (Table 1). After adjustment for age, sex, race/ethnicity, education, alcohol use, poverty, marital status, and z‐score, MetS was not significantly associated with memory complaint (OR=0.90; 95%CI 0.33, 2.45).ConclusionOur findings suggest that MetS was associated with lower cognitive performance in older adults, but this association may be modified by participant characteristics. Participants who did not meet criteria for MetS but had 1‐2 risk factors showed similar cognitive performance to those with MetS, so focusing on dichotomous MetS classifications may obscure cognitive risks for those individuals who don’t fully meet the MetS criteria.
Trends in sex/gender differences across whites, blacks, and Hispanics
Authors: Avila Justina F , Rentería Miguel Arce , Vonk Jet MJ , Manly Jennifer J 
Published: December 2020

AbstractBackgroundWe determined if later birth year is associated with an increased verbal memory advantage for women and examined whether childhood socio‐economic status (CSES) and adult socio‐economic status (ASES) explain secular trends similarly across Whites, Blacks, and Hispanics.MethodParticipants were 5,258 non‐Hispanic White (White), non‐Hispanic Black (Black), and Hispanic men and women in the Washington/Hamilton Heights Inwood Columbia Aging Project (WHICAP) who were administered neuropsychological tests of memory at 18 to 24 month intervals for up to 25 years. Multiple‐group latent growth curve modeling examined trajectories across birth cohorts (before 1925 vs 1925 and later) within sex/gender by race/ethnicity subgroups after adjusting for immigration status (yes/no). Factor scores for CSES (parental education, occupation, and sibship size) and ASES (educational attainment, income, and occupational status) were examined as potential mediators.ResultOverall, people born after 1925 and women had higher initial memory performance than people in the earlier birth cohort and men, respectively. However, the benefit of later birth year was restricted to White men and women and Black women, and there was no benefit among Black men or Hispanic men and women. White and Black women demonstrated a similar memory advantage over White and Black men, respectively. This advantage widened for Black women in the later born cohort, but remained similar for later born White women. Hispanic men and women obtained similar memory scores across birth cohorts. While earlier birth year was associated with more rapid rate of decline across racial/ethnic groups, men and women within each birth cohort declined at the same rate. The influence of birth cohort on memory was fully mediated by CSES for White men and mediated by ASES among White and Black women.ConclusionThe verbal memory advantage of women varies across and within birth cohorts and racial/ethnic groups. Later birth year was associated with an increased memory advantage for Black women over Black men. Secular trends were differentially explained by childhood and adult SES for White men and White and Black women.
Sex differences in neurodegeneration and memory performance in preclinical autosomal dominant Alzheimer’s disease: Baseline findings from the API ADAD trial
Authors: Vila‐Castelar Clara , Tariot Pierre N , Sink Kaycee M , Clayton David , Langbaum Jessica B , Thomas Ronald G , Chen Yinghua , Su Yi , Hu Nan , Giraldo‐Chica Margarita , Tobon Carlos , Acosta‐Baena Natalia , Luna‐Maldonado Ernesto , Londoño Marisol , Ospina Paula , Tirado Victoria , Muñoz Claudia , Henao Eliana , Bocanegra Yamile , Alvarez Sergio , Rios‐Romenets Silvia , Ghisays Valentina , Goradia Dhruman D , Lee Wendy , Luo Ji , Malek‐Ahmadi Michael H , Protas Hillary D , Lopera Francisco , Reiman Eric M , Quiroz Yakeel T ,   API ADAD Colombia Trial Group
Published: December 2020

AbstractBackgroundGrowing evidence suggests that females have greater biological risk for Alzheimer’s disease (AD). As levels of AD pathology increase, females show greater tau accumulation, faster hippocampal volume loss, and faster cognitive decline than males. We sought to investigate sex differences in individuals with preclinical autosomal dominant AD (ADAD), who are destined to develop early‐onset dementia and have minimal age‐related confounds known to vary by sex (e.g., mortality, cardiovascular disease, or menopause). We plan to examine the role of sex in the associations among markers of pathology, neurodegeneration, and cognition leveraging baseline data from the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial.MethodsWe analyzed baseline data from 242 cognitively unimpaired 30‐53 year‐old prevention trial participants, including 167 PSEN1 E280A mutation carriers and 75 non‐carrier family members. Clinical ratings, CERAD word list delayed recall, hippocampal grey matter volume, florbetapir cortical‐to‐pontine standard‐uptake value ratios (SUVR), and precuneus 18F‐fludeoxyglucose (FDG) positron emission tomography were included in the analyses. T‐tests and multiple regressions models controlling for age, PSEN1 mutation status and amyloid burden were conducted.ResultsAcross groups, females had greater hippocampal volumes (p=.05) and better delayed recall (p=.005) than males. Female carriers were younger than male carriers (p=.04). Females continued to have better delayed recall after adjusting for glucose metabolism in the precuneus (Sex: β=.562, p=.023), and showed a trend towards significance after adjusting for hippocampal volumes (Sex: β=.462, p=.059). In carriers only, as age increased, males had lower hippocampal volumes than females (Slope difference: p ≤ .05), while no differences were found in amyloid levels or metabolism. There was no sex difference in the relationship between amyloid accumulation, hippocampal volumes (Sex: β=.000, p=.094), and metabolism (Sex: β=‐.004, p=.815).ConclusionFindings suggest that cognitively unimpaired female mutation carriers may have greater cognitive resilience to AD‐related neurodegeneration compared to male mutation carriers. Further investigation of sex‐specific differences in AD‐related clinical and pathological markers is key to inform AD detection, prevention, and development of treatments.
Without a lifeline: Improving outcomes for patients diagnosed with dementia who do not have caregivers or family involvement in care
Authors: Sitarz Claire 
Published: December 2020

AbstractBackgroundHealthcare providers have long depended on caregivers or family members of persons with dementia to manage care after an appointment is over. Whether it is completing follow‐up, managing medications, or ensuring testing is completed, caregivers are typically the lifeline to medical compliance and successful treatment planning. However, not all patients have the support of a caregiver or family member; how do healthcare providers ensure adequate care for persons with dementia living independently in the community? This poster presentation will include a literature review examining best practices for persons living independently, as well as case studies providing real life examples of interventions used in our Neurology practice in Philadelphia, Pennsylvania, USA. Through use of social services, care coordination, and communication among providers, patients are connected to resources and supports that allow them to remain independent in the community and build a network of care they would not otherwise have access to. The literature review synthesizes evidence based research that shows the scope of the problem, while case studies details successful interventions used, as well as difficulties and road blocks encountered in this population. Suggestions for best practices, as well as maintaining a focus on patient‐centered care are examined.
The trajectory of cognitive decline and neuropathological features among APOEɛ2 carriers
Authors: Gauthreaux Kathryn , Teylan Merilee , Culhane Jessica E. , Miller Zachary , Schwabe‐Fry Kristen , Chen Yen‐Chi , Chan Kwun Chuen Gary , Mock Charles , Kukull Walter A. 
Published: December 2020

AbstractBackgroundResearch on the APOEɛ2 allele and its role in neurodegenerative disease is sparse compared to APOEɛ4. Studies have indicated that ɛ2ɛ2 homozygosity is protective against developing Alzheimer’s disease neuropathology (ADNP). Our goal was to explore cognitive trajectories and neuropathological features among APOEɛ2 carriers versus an ɛ3ɛ3 reference group.MethodData were obtained from the National Alzheimer’s Coordinating Center. Participants were included if they had neuropathology data available within 2 years of their most recent clinic visit. Due to sample size, we combined the ɛ2ɛ2 and ɛ2ɛ3 genotypes into one group for our analyses. Linear regression models with generalized estimating equations were run comparing the trajectory of CDR® Dementia Staging Instrument sum of boxes (CDR‐SB) over time between participants with ɛ2ɛ2/ɛ2ɛ3 or ɛ2ɛ4 to those with ɛ3ɛ3. Logistic regressions were run comparing the odds of having various neuropathological features in these groups. All models were stratified by baseline CDR global score (CDR) and adjusted for education, sex, race/ethnicity, smoking status, and hypercholesterolemia. Linear models additionally adjusted for age at baseline and accounted for repeated measures by individual, while logistic models examining neuropathological features adjusted for age at death.ResultWe identified 356 ɛ2ɛ2/ɛ2ɛ3, 105 ɛ2ɛ4, and 1937 ɛ3ɛ3 participants with a mean follow‐up of 3.8, 4.1 and 3.7 years, respectively. Both ɛ2 carrier groups showed significant cognitive decline in CDR‐SB regardless of baseline CDR, although the slopes were not significantly different from the ɛ3ɛ3 group. When comparing the neuropathological features present in these groups, ɛ2ɛ2/ɛ2ɛ3 participants who were mildly impaired (i.e., CDR = 0.5) at baseline had significantly higher odds of FTLD‐tau pathology (p < 0.01) and lower odds of ADNP (p < 0.01) compared to ɛ3ɛ3 participants.ConclusionIn our sample, we found that ɛ2ɛ2/ɛ2ɛ3 participants displayed more FTLD‐tau at autopsy, but less ADNP compared to ɛ3ɛ3 participants. Our finding that ɛ2ɛ2/ɛ2ɛ3 participants had less ADNP supports the notion that ɛ2 is protective against ADNP, although when the ɛ4 allele is present it overrides the ɛ2 protective effects against ADNP. Despite this protective effect of the ɛ2ɛ2/ɛ2ɛ3 genotype against ADNP we found that the ɛ2ɛ2/ɛ2ɛ3 genotype did not prevent cognitive decline when compared to the ɛ3ɛ3 group.
Amyloid‐β oligomer‐induced, tau‐dependent dysregulation of mitochondrial DNA replication is mediated by SOD1
Authors: Norambuena Andrés , Sun Xuehan , Shivange Nutan , Bloom George S. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized by accumulation of amyloid‐β (Aβ), Tau phosphorylation, insulin resistance and mitochondrial dysfunction, but molecular mechanisms interconnecting these phenomena remain poorly understood. We recently discovered nutrient‐induced mitochondrial activity (NiMA), an inter‐organelle signaling pathway whereby activation of mTORC1, on lysosomes (lysomTORC1) by insulin or amino acids (nutrients) triggers mitochondrial oxidative metabolism (MitoOXPHOS) in cultured cells, including primary neurons, and in live mouse brain. Intriguingly, Tau was found to regulate mitochondrial DNA (mtDNA) replication in neurons through the NiMA pathway. Aβ oligomers (AβOs), which activate mTORC1 at the plasma membrane (PM), but not at lysosomes, by a Tau‐dependent mechanism (Alzheimer's & Dementia 13: 152‐167), were found to counteract nutrient effects on both MitoOXPHOS and mtDNA replication (EMBO J 37: e100241). We now report details of a mechanism by which Tau and mTORC1 regulate mtDNA replication.MethodEdU incorporation in live neurons was used to image mtDNA replication in wild type (WT) and Tau knockout (KO) mouse cortical neuron cultures. In‐gel enzyme assays were used to evaluate Copper and Zinc superoxide dismutase (SOD1) activity.ResultNutrient‐induced activation of lysomTORC1 suppressed mtDNA replication in WT, but not Tau KO neurons, unless the latter expressed WT human Tau (hTau). Interestingly, expression of WT, or a 14‐site phospho‐mimetic or phospho‐null (Neuron 68:1067‐81), but not P301L hTau mutant in Tau KO neurons inhibited mtDNA replication in the absence of nutrient stimulation. Mechanistically, we found that Tau upregulates lysomTORC1, which in turn inhibits SOD1 (Mol Cell 70:502‐515). Pharmacological inhibition of SOD1 in WT neurons inhibited mtDNA synthesis, mimicking the effects of nutrients, and of WT, phospho‐mimetic or phospho‐null hTau re‐expression in Tau KO neurons. In contrast, AβO‐mediated activation of mTORC1 at the PM in WT neurons increased SOD1 activity.ConclusionThe Tau‐mTORC1‐SOD1 signaling pathway enables nutrients to suppress mtDNA replication under non‐pathological conditions, and is required for the failure of nutrients to block mtDNA replication in the presence of AβOs. Thus, Tau is part of a nutrient‐sensing machinery that functionally couples nutrient availability to mtDNA replication under normal conditions and mechanistically links mitochondrial dysfunction to AD, independently of Tau phosphorylation at 14 sites.
Degeneration of vascular architecture associated with disease pathology in the 5XFAD mouse model of Alzheimer’s disease
Authors: Moore Shannon J. , Stevenson Tamara K. , Gyan Araba , Carrasquillo‐Morales Karina , Murphy Geoffrey G. 
Published: December 2020

AbstractBackgroundBeta‐amyloid (Aβ) plaques have long been considered a defining hallmark of Alzheimer’s disease (AD), though the pathogenic mechanism and therapeutic efficacy of targeting plaques remain unclear. Accumulating evidence suggests that cerebrovascular abnormalities are also associated with cognitive decline and neurodegeneration in AD patients. We examined the relationship between Aβ plaque deposition and vascular architecture in different brain regions in the 5xFAD mouse model of Alzheimer’s disease.MethodsSeparate cohorts of male and female wild‐type (WT) and 5xFAD mice (C57BL/6 background) were evaluated at different time points during the progression of AD pathogenesis. First, learning and memory were assessed using a contextual fear conditioning paradigm to evaluate cognitive function. Then, blood vessels were labeled using DyLight 594 tomato‐lectin (tail‐vein injection) and a TRITC‐Dextran gelatin solution (cardiac perfusion); Aβ plaques were labeled ex‐vivo with 6‐OH‐BTA‐1 (an intervening derivative of Pittsburgh compound B). Confocal images of optically cleared (SeeDeepBrain method) sagittal sections (450 µm) were collected from four distinct regions (subiculum, dentate gyrus, cortex, and cerebellum) to analyze Aβ plaque deposition and vascular architecture.ResultsAt 4 months old, 5xFAD and WT mice performed equally well in contextual fear conditioning, but by 8 months of age, 5xFAD mice exhibited lower freezing 24 hours after conditioning compared to their WT littermates. In 5xFAD mice, total Aβ plaque burden substantially increased from 4 to 8 months, but regions exhibited differential vulnerability, with the subiculum accumulating the most plaques while the cerebellum had none. Blood vessel health appeared to be more compromised in 8 compared to 4 month‐old 5xFAD mice, while it remained largely unchanged with age in WT mice. Interestingly, the regions displaying the greatest Aβ plaque burden in 5xFAD mice also had the largest reduction in the intensity of intact vascular labeling.ConclusionsThese experiments demonstrate that by 8 months of age, 5xFAD mice on a C57BL/6 background exhibit significant learning and memory impairments, increased Aβ plaque burden, and deterioration of the cerebrovasculature. They further suggest that vascular degeneration may be related to regionally specific Aβ plaque deposition and that this is an important pathological feature of disease progression.