bluuebunny/crossref_metadata_2025_split huggingface dataset:
Collaborating with Australian Indigenous communities: A protocol to address the high rates of dementia found in aboriginal and Torres Strait Islander people
Authors: Russell Sarah G , Quigley Rachel , Sagigi Betty , Miller Gavin , Strivens Edward 
Published: December 2020

AbstractBackgroundIn Australia, Indigenous people aged 45 and over have three to five times higher risk of dementia than the wider community. Research shows that up to a third of dementia cases may be delayed by modifying lifestyle risk factors. Specific risk and protective factors contributing to the increased dementia risk in Indigenous communities require clarification as the first step towards developing culturally appropriate interventions. The aim of this paper is to outline a study protocol investigating whether potential protective factors identified in the wider population as supporting cognitive function in later life confer protection to Indigenous populations.MethodThis project will use a Participatory Action Research approach to enable communities to identify and prioritise dementia risk reduction strategies/potential risk and protective factors. Using a Continuous Quality Improvement Framework, primary health care centres will address modifiable dementia risk factors identified to change practice and systems through the development of culturally appropriate interventions.ResultsResulting interventions will identify and address barriers and enablers unique to Aboriginal and Torres Strait Islander communities.ConclusionThe outcome will be a culturally appropriate framework that incorporates evidence‐based best‐practice guidelines for delivering community specific interventions for risk reduction and prevention of dementia.
Vascular risk factors and amyloid pathology: Additive or interactive associations?
Authors: Schott Jonathan M , Lane Christopher A , Barnes Jo , Keuss Sarah E , James Sarah‐Naomi , Lu Kirsty , Sudre Carole H , Cash David M , Parker Thomas D , Malone Ian B , Keshavan Ashvini , Murray‐Smith Heidi , Wong Andrew , Buchanan Sarah M , Gordon Elizabeth , Coath William , Barnes Anna , Dickson John , Modat Marc , Thomas David L , Chaturvedi Nishi , Hughes Alun , Crutch Sebastian J , Richards Marcus , Fox Nick C 
Published: December 2020

AbstractBackgroundThe two commonest contributors to late‐life cognitive impairment are Alzheimer’s (AD) and cerebrovascular disease; these two conditions almost invariably overlap. Understanding the determinants of the pathologies that underpin these conditions and how they interact to influence late‐life brain health is vital for rational risk prevention and for clinical trials.MethodData from the Insight 46 cohort will be presented, comprising individuals from the MRC 1946 British Birth Cohort all born in mainland Britain in one week in 1946. These individuals have been followed prospectively including serial measures of cognition from age 8, cardiovascular risk since the mid‐30s, and a range of cardiac and vascular outcomes in their 60s. At age 69‐71 they had detailed cognitive testing, 3T‐MRI including determination of white matter hyperintensity volume (WMHV) and 18F‐Florbetapir (β‐amyloid) PET. All individuals are being seen for a second visit, two‐years after the first.ResultsA total of 502 participants were assessed cross‐sectionally; data from up to 465 participants (51.0% male, mean age=70.7±0.7, 18.2% β‐amyloid positive) are available. Results of cross‐sectional analyses investigating the relationships between life course cardiovascular risk factors genetics, β‐amyloid and WMHV will be presented, alongside analyses of the associations of these pathologies with cross‐sectional cognitive function and MRI metrics. Investigations exploring mechanistic relationships e.g. between cardiac and vascular outcomes including pulse wave velocity and echocardiography, β‐amyloid and WMHV and cognition will be presented. Interim results of analyses exploring relationships between baseline β‐amyloid and WMHV and rates of cognitive decline and brain atrophy will be described in n=250 (47.6% female, age=72.5±0.33, 18.1% β‐amyloid positive) of the cohort. These results will be compared and contrasted with those from other cohort studies including the Atherosclerosis Risk in Communities (ARIC) study, and Mayo Clinic Study of Ageing.ConclusionCombining life course data, contemporaneous measurement of PET‐amyloid status, WMHV and cognition, vascular metrics and longitudinal measures of brain atrophy and cognitive change provides a powerful opportunity to explore how and when vascular and β‐amyloid pathology influence brain health in later‐life. Emerging evidence from several studies suggest that vascular risk influences the development of cognitive impairment and dementia principally via non‐amyloidogenic pathways.
Patterns of default mode network co‐activation in young APOE ε4‐carriers: An HCP replication study
Authors: Mentink Lara J. , Guimarães João P.O.F.T. , Sprooten Emma , Rikkert Marcel G.M. Olde , Haak Koen V. , Beckmann Christian F. 
Published: December 2020

AbstractBackgroundFilippini et al. reported an increased default mode network (DMN) co‐activation during rest in young APOE ε4‐carriers [1]. This work has been of substantial importance, often used to illustrate the trajectory of DMN alterations in APOE ε4‐carriers from young adults and normal aging to mild cognitive impairment and AD. However, this study only assessed a small sample. Here, we aimed to replicate their finding in a substantially larger sample from the Human Connectome Project (HCP).MethodWe included participants from the HCP S1200 dataset. We followed the methods of [1] for structural MRI and resting‐state fMRI data, with the following deviations: instead of using voxel‐based morphometry to assess gray matter density, we assessed gray matter volume with FreeSurfer. To test for differences in DMN co‐activation and gray matter volume between APOE ε4‐carriers and non‐carriers, we used Permutation Analysis of Linear Models (PALM). PALM controls for biases induced by the family structure of the HCP sample. Results were family‐wise error rate corrected at p < 0.05.ResultWe included 167 APOE ε4‐carriers and 419 non‐carriers for the DMN analysis. In contrast to [1], we did not find significant differences in DMN co‐activation between carriers and non‐carriers. For the morphometric analyses, 243 carriers and 544 non‐carriers were included. No differences in brain volume were found between carriers and non‐carriers. For both analyses, including covariates (different combinations of age, sex, education level, head motion) did not alter the results.ConclusionWe could not replicate the early findings of [1] in a large sample. Our results suggest that solely APOE ε4‐carriership does not influence brain function at a young age. Future work will focus on the use of polygenic risk scores to study whether any genetic predisposition for AD influences brain function in young adults. Still, genetic predisposition for AD might not have any measurable effect decades before clinical expression of AD. Therefore, repeating the analysis in a healthy, middle‐aged cohort could inform us whether the influence of genetic predisposition for AD increases over time. Altogether, our replication study is an important step forward in unravelling AD development. Resource: (1) Filippini et al., PNAS, 2009.
Quantifying dementia prevention potential in the FINGER randomized controlled trial using the LIBRA prevention index
Authors: Deckers Kay , Koehler Sebastian , Ngandu Tiia , Verhey Frans RJ , Kivipelto Miia , Solomon Alina 
Published: December 2020

AbstractBackgroundIndividuals in early dementia prevention trials may differ in how much they benefit from the interventions depending on their initial level of dementia risk. Using a composite risk score comprising health‐ and lifestyle factors (i.e., modifiable dementia risk) might be useful to better target future interventions and to monitor intervention effects during study execution. The present study examines whether the effects of a multi‐domain lifestyle intervention on cognition differ across baseline modifiable dementia risk, and to investigate the potential use of a modifiable dementia risk score as an outcome measure in intervention studies.MethodThe 2‐year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) randomized controlled trial recruited 1260 people aged 60‐77 and at‐risk of dementia from the general Finnish population. Participants were randomized 1:1 to a multi‐domain intervention group (diet, exercise, cognition, and vascular risk management) or control group (general health advice). Modifiable dementia risk was ascertained with the ‘LIfestyle for BRAin health’ (LIBRA) score. LIBRA consists of 12 risk and protective factors for cognitive decline and dementia, with higher scores indicating greater dementia risk (i.e. a more unhealthy lifestyle; range: –5.9 to +12.7). Primary outcome was change in cognition (baseline, 1‐ and 2‐year) measured with a comprehensive neuropsychological test battery (NTB) total score, and other outcomes include executive functioning, processing speed, memory and abbreviated memory.ResultHigher LIBRA scores at baseline were associated with lower cognitive test scores and predicted more decline on the NTB total score and in the memory and abbreviated memory domain over the 2‐year study period, but treatment outcomes did not differ across LIBRA scores/tertiles. LIBRA scores declines both at one and two year follow‐up. There was more decline in the LIBRA score in the intervention group compared to the control group (B = ‐0.184, 95% CI ‐0.328 to ‐0.040; p = 0.012).ConclusionThe FINGER intervention was evenly effective in those at low, medium or high lifestyle‐based risk. LIBRA may be useful as a surrogate/intermediate endpoint and surveillance tool to monitor intervention success during trial execution.
Association of early life BMI with dementia risk: Findings from a pooled cohort analysis
Authors: Hazzouri Adina Zeki Al , Vittinghoff Eric , Hoang Tina D , Golden Sherita H , Fitzpatrick Annette L , Zhang Adina , Yaffe Kristine 
Published: December 2020

AbstractBackgroundThe evidence about the timing and influence of some key cardiovascular risk factors, such as Body Mass Index (BMI), on the risk of Alzheimer disease and other dementias remains debatable. Studies have shown that high midlife BMI increases the risk of dementia, while high late life BMI may be protective; however, relatively little is known about the role of early life BMI on the risk of Alzheimer Disease and other dementias.MethodWe studied 5,104 older adults from two studies, the Cardiovascular Health Study (CHS, n=2,909) and the Health, Aging and Body Composition study (Health ABC, n=2,195) study. For CHS‐Health ABC older adults, we imputed early and midlife BMI, beginning at age 18, using linear mixed models applied to a pooled cohort which also included young and middle‐aged adults from CARDIA and MESA. BMI was then summarized by time‐weighted averages in early (ages 20‐49), mid (ages 50‐69), and late life (ages 70‐89). In CHS, dementia was adjudicated by an expert committee following a detailed neuropsychological test battery and neurological examination. In Health ABC, dementia diagnosis was determined based on hospitalization ICD codes, dementia‐related drugs and decline on the Modified Mini Mental State Examination. All analyses were sex stratified.ResultCHS‐Health ABC participants had a mean age of 72.6 years (SD=4.2) at enrollment, 18% were black and 56% were women. For women, dementia risk increased with higher early life BMI: it was 1.8 times higher among those who were overweight (OR=1.8; 95% CI=1.31‐2.54) and 2.5 times higher among those who were obese (OR=2.45; 95% CI=1.47‐4.06), from pooled logistic regression models adjusted for midlife and late life BMI. For men, dementia risk increased with higher early life (Obese OR=2.47; 95% CI=1.46‐4.19) and mid life BMI (Overweight OR=1.51; 95% CI=1.11‐2.05 and Obese OR=2.00; 95% CI=1.16‐3.42), in models also adjusted for late life BMI. For both women and men, dementia risk decreased with higher late life BMI.ConclusionOur study is the first to report heightened dementia risk with higher early life BMI, for both women and men. Accounting for early life BMI, we found no effect for midlife BMI on dementia risk among women.
Novel homozygous nonsense mutation in SORL1 gene presenting as dementia and cerebral amyloid angiopathy
Authors: Palmero Víctor Antonio Blanco , Velasco Sara Llamas , Mora María Isabel Álvarez , Martínez David Andrés Pérez , Carro Eva , Martín Alejandro Octavio Herrero San , Sánchez Marta González , Martín Verónica Puertas , Bartolome Fernando , Muñoz Almudena López Rufián , Martínez Alba García , Galende Alberto Villarejo 
Published: December 2020

AbstractBackgroundThe SORL1 gene encodes a type‐I transmembrane protein termed sortilin‐related receptor (SorLA). SorLA regulates the intracellular transport and processing of the amyloid precursor protein in neurons, and therefore, it has been implicated in the pathogenesis of Alzheimer’s disease (AD). Several SORL1 mutations have been described as a risk factor for AD, especially rare missense and non‐coding variants. To date, there are no reports of nonsense SORL1 mutations in homozygosis. Also, the relationship between cerebral amyloid angiopathy (CAA) and SORL1 mutations is not well established.MethodCase report.ResultsA 62‐year‐old man was referred to our department complaining of a 3‐year history of apathy, memory complaints and spatial difficulties. His family history was remarkable for early onset dementia in his father and behavioural problems in his mother starting at the age of 80. Neuropsychological testing showed moderate episodic memory impairment, mild ideomotor apraxia and mild dysexecutive symptoms. The MRI showed marked global atrophy, superficial siderosis and multiple cortico‐subcortical microhemorrhages, fulfilling Boston criteria for probable CAA. Genetic testing using whole exome revealed the variant c.364C>T (p.R122*) in SORL1 gene (NM_003105.5) in homozygosis. In addition, APOE genotype was 3/3.Conclusionwe describe a novel SORL1 mutation associated with AD. This is the first human report of a SORL1 nonsense mutation in homozygosis. SORL1 could play a role in the development of CAA.
Transcriptome‐based analyses of EADB reveal new insights into Alzheimer's disease
Authors: Küçükali Fahri ,   EADB
Published: December 2020

AbstractBackgroundFor the majority of Alzheimer’s disease (AD) genetic risk loci, the mechanism of action of variants or genes in AD pathophysiology remains unidentified. One way to approach this is to investigate the downstream effects of AD‐associated variants on molecular phenotypes such as expression and splicing. By integrating EADB and AD‐relevant brain expression and splicing data we performed the largest transcriptomic investigation of AD GWAS to date.MethodWe generated both eQTL and sQTL catalogues on six AD‐relevant brain regions by integrating whole‐genome sequencing (WGS) genotypes of a total of 1067 individuals with 1552 brain RNA‐Seq samples after quality control, available at AMP‐AD Knowledge Portal. We quantified expression and splicing using GTEx and Leafcutter pipelines, and used enhanced FastQTL to perform linear regression of WGS genotypes against normalized molecular phenotypes with adjustment for sex, genetic and transcriptomic principal components. We investigated the overlap between AD‐associated EADB GWAS variants and e/sQTL variants. We then generated expression and splicing weight panels using these catalogues and conducted expression and splicing TWAS for AD on summary statistics of the EADB GWAS including 100,000 Europeans. Long‐read nanopore sequencing was performed using 60 lymphoblastoid cell lines, 18 frontal cortex BA10 and 16 hippocampal cDNA samples on a MinION platform to further study complex splicing events.ResultWe identified 1225 genome‐wide significant variants that overlap with a significant eQTL (associated with 175 genes) and 525 genome‐wide significant variants that overlap with a significant sQTL (associated with 260 splice junctions) in at least one of the six catalogues created. Expression and splicing TWAS confirmed known AD‐associated genes and highlighted new genes in novel loci, including a gene on chromosome 10 located within one of the most significant novel loci of EADB GWAS, whose TWAS‐associated splice junctions (P = 7.24 × 10−10 and 7.33 × 10−10 in MayoRNASeq TCX and ROSMAP DLPFC TWAS) are hinting at novel cryptic exons, which we confirmed by Nanopore sequencing, within its functional domain.ConclusionOur results indicate that in addition to eQTLs, part of AD GWAS loci can be explained by sQTLs that are understudied in the field; and together these catalogues provide a valuable resource for understanding the genes involved in AD.
Better cardiovascular fitness is associated with better structural brain integrity in midlife: A population‐representative birth cohort study
Authors: d'Arbeloff Tracy , Cooke Megan , Knodt Annchen , Sison Maria , Ramrakha Sandhya , Keenan Ross , Poulton Richie , Hariri Ahmad R. , Caspi Avshalom , Moffitt Terrie E. 
Published: December 2020

AbstractBackgroundImproving cardiovascular fitness has been promoted as a promising nonpharmacological strategy for buffering against age‐related cognitive decline and mitigating risk for Alzheimer’s disease and related dementia (ADRD). These beneficial effects may be related to the capacity for improved cardiovascular fitness to stave off age‐related brain atrophy. However, there is evidence that some neurological benefits associated with adult cardiovascular fitness may be better explained by early childhood factors—referred to as neuroselection—rather than any active neuroprotective effects of fitness on the brain.MethodData from 875 participants from the population‐representative Dunedin Study were utilized to investigate associations between cardiovascular fitness (VO2Max) at age 45, changes in cardiovascular fitness across adulthood, and structural brain integrity (cortical thickness, surface area, and subcortical grey matter volume) at age 45. Critically, the potential confounding effects of childhood IQ on any observed associations in midlife were evaluated in order to disentangle potential neuroselective from neuroprotective effects.ResultBetter VO2Max at age 45 was associated with thicker cortex in frontal and temporal lobes (βs:0.14 to 0.25, Figure 1b) and smaller hippocampal fissure volumes at age 45 (β=‐0.18). Higher rates of decline in VO2max were associated with lower total (β=‐0.11) and distributed regional (βs:‐0.11 to ‐0.19, Figure 2b) surface area at age 45. These associations were unaffected by the inclusion of childhood IQ in the analyses.ConclusionBetter midlife cardiovascular fitness may offer neuroprotective effects on brain structure, which may in turn mitigate ADRD risk and buffer against cognitive decline.
Frailty, neuropathological burden and clinical severity: A cross‐sectional analysis of data from the National Alzheimer’s Coordinating Center
Authors: Ward David D , Wallace Lindsay MK , Rockwood Kenneth 
Published: December 2020

AbstractBackgroundWithin the National Alzheimer’s Coordinating Center (NACC) dataset, we quantified the associations of frailty and global neuropathological burden with clinical dementia severity, and explored whether frailty influences the expression of dementia at a given level of neuropathology.MethodThe sample included 2,621 individuals who had available clinical data and had undergone autopsy within 24 months of their last study visit. A 32‐item frailty index (FI) was calculated retrospectively using the deficit accumulation approach, and a measure of global neuropathological burden (NP) was calculated using a similar index approach from 12 markers of brain disease (e.g. neurofibrillary tangle Braak stage, density of neocortical neuritic plaques, severity of cerebral amyloid angiopathy, presence of microinfarcts). Linear models were used to model the change in the 18‐point Clinical Dementia Rating Scale sum of boxes score (CDR‐SB) per 10% increase in either the FI score or NP score, after adjusting for age, sex, education level, primary language, time from clinical assessment to autopsy, and APOE ε4 allelic status.ResultThe analytical sample was 80.8 years old (SD = 9.4 years, range = 60 – 100 years), on average. Each 10% increase in either measure was associated with a significantly higher CDR‐SB (FI: 2.41 points [95% CI = 2.27, 2.56]; NP: 0.87 points [95% CI = 0.73, 1.01]). A significant interaction indicated that the relationship between NP and CDR‐SB became weaker for each 10% increase in FI (P = .001). The largest increase in CDR‐SB due to a 10% increase in NP was observed among the least frail individuals (FI < 0.3; 1.15 points [95% CI = 0.91, 1.39]), with smaller and similar increases in CDR‐SB observed in both medium (FI ≥ 0.3; 0.77 points [95% CI = 0.47, 1.07]) and high frailty (FI ≥ 0.5, 0.73 points [95% CI = 0.39, 1.07]) groups.ConclusionAn increasing degree of frailty and neuropathology are each independently associated with more severe impairment. Among the least frail individuals, neuropathological burden is closely related to clinical function, whereas clinical impairment may occur even at a low level of neuropathology in those who are more frail.
Longitudinal data in peripheral blood confirms PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicates its dynamic role in disease progression
Authors: Wang Qi , Chen Yinghua , Readhead Benjamin , Chen Kewei , Su Yi , Reiman Eric M. , Dudley Joel 
Published: December 2020

AbstractBackgroundGenome wide genetic/epigenetic studies are revealing more risk loci associated with the Alzheimer’s disease (AD). One recent analysis of human epigenome‐wide association studies (EWAS) reports an association between variations in the gene PM20D1 and AD, showing hypermethylation in the brain tissues in patients with advanced‐stage AD.MethodsWe used whole genome DNA methylation data collected from peripheral blood mononuclear cells (PBMCs) in a cohort (n = 649) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among different diagnosis groups. We also leveraged the longitudinal data up to 4 years, sampled at approximately 1 year intervals to model the alterations in the methylation levels detected at the differentially methylated regions (DMRs) to delineate the methylation change course over aging and disease progression. The dynamic pattern of DNA methylation level with disease progression at the PM20D1 locus in brain tissues were also modeled from the data in The Religious Orders Study and Memory and Aging Project (ROSMAP) Study cohort (n = 740).ResultsWhen compared with controls, patients with mild cognitive impairment (MCI) consistently displayed promoter hypomethylation at reported methylation QTL gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in brain tissues in patients with advanced‐stage AD. By leveraging longitudinal DNA methylation data, linear mixed‐effects (LME) modeling for the unchanged diagnosis groups and U‐shape testing for those with changed diagnosis (converters) indicate that, we observe initial promoter hypomethylation of PM20D1 during MCI and early stage AD, which reverses to eventual promoter hypermethylation in the transition to late stage AD. We also confirm this observation in ROSMAP cohort as neuropathology deteriorates. Correlation of DNA methylation between blood and brain tissues at PM20D1 promoter region also demonstrates the pattern is consistent across tissues.ConclusionsOur results confirm that PM20D1 is an mQTL for AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in‐depth study is thus warranted to fully decipher its role in the evolution of AD, and potentially explore its utility as a blood‐based biomarker for AD.