bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic risk score for Alzheimer’s disease and APOE ε4 status in relation to cognitive decline: a population‐based study of individuals followed over 16 years.
Authors: Najar Jenna , Thorvaldsson Valgeir , Skoog Johan , Kern Silke , Waern Margda , Zetterberg Henrik , Blennow Kaj , Skoog Ingmar , Zettergren Anna 
Published: December 2022

AbstractBackgroundPolygenic risk scores for Alzheimer’s disease (AD‐PRS) have been associated with incident AD and dementia. However, few long‐term studies have examined the effect of AD‐PRSs, and the interaction with APOE ε4 status, on cognitive performance over time in the general population.MethodA population‐based sample of 855 participants born 1930 were examined at age 70, 75, 79, and 85 years. AD‐PRSs that surpassed four P value thresholds (P<5e‐8, P<1e‐5, P<1e‐3, P<1e‐1) were generated based on information from recent genome‐wide association studies. Cognitive performance was measured at all examinations using a composite global cognitive score based on five psychometric tests (Thurstone’s Picture Memory, immediate recall of 10 words, Block Design, PSIF [perceptual speed], and Mini‐Mental State Examination score). Linear mixed effect models with random intercepts and slopes were used to analyze the effect of AD‐PRSs and APOE ε4 status on cognitive performance. The models included sex*age, AD‐PRS*age, APOE ε4 status*age, and 10 principal components to correct for population stratification. Analyses were repeated in samples without prevalent and incident dementia.ResultThe interaction‐term 5e‐8 AD‐PRS*age (β=‐0.2, P=.03) and APOE ε4 status*age (β=‐0.2, P=.02) were associated with cognitive decline. The results remained in those without prevalent and incident dementia (the 5e‐8 AD‐PRS*age: β=‐0.2, P=.02, APOE ε4 status*age: β=‐0.2, P=.007). No association was observed between AD‐PRSs that surpassed P value thresholds >5e‐8 and cognitive performance over time (1e‐5 AD‐PRS*age: β=‐0.06, P=.08, 1e‐3 AD‐PRS*age: β=‐0.03, P=.3, and 1e‐1AD‐PRS*age: β=‐0.02, P=.6). Further, neither APOE ε4 status nor AD‐PRSs were associated with cognitive performance at baseline (APOE ε4 status: β=‐0.9, P=.3, the 5e‐8 AD‐PRS: β=0.6, P=.5, 1e‐5AD‐PRS: β=0.5, P=.2, 1e‐3 AD‐PRS: β=0.5, P=.1, and 1e‐1 AD‐PRS: β=0.2, P=.6).ConclusionWe found an effect of a 5e‐8 AD‐PRS and APOE ε4 status on cognitive decline in individuals from the general population followed over 16 years, regardless of dementia diagnosis. These results contribute with additional knowledge to identify individuals at increased risk of cognitive decline, which may be important to implement personalized prevention as early as possible.
Elucidating the molecular basis of altered Presenilin 2 expression on Alzheimer’s disease pathology
Authors: Perdok Anika , Sannerud Ragna , Vegh Zsuzsanna , Serneels Lutgarde , Annaert Wim 
Published: December 2022

AbstractBackgroundγ‐Secretase is an intramembrane protease which plays a pivotal role in the onset and progression of Alzheimer’s disease (AD). Presenilin provides the catalytic activity of which two homologues exist, Presenilin‐1 and Presenilin‐2 (Psen1/2). Psen2/γ‐secretase complexes are restricted in their localization to the late endosomes and lysosomes, as opposed to the broader distribution of PSEN1/ γ‐secretase, making it the main generator of intracellular abeta (Aβ). Although the focus has been on the extracellular pool, this toxic intracellular pool has been shown to precede plaque and tangle formation and correlates well with synaptic dysfunction highlighting its importance. This project aims to unravel the effects of altered Psen2 expression and this intracellular pool on AD pathogenesis.MethodsWe generated novel mouse models by crossing the well characterized APP NL‐G‐F model with a Psen2 knock out (KO) mouse and an in‐house generated Psen2 knock in (KI) model carrying the familial AD‐linked N141I mutation (FAD‐Psen2).ResultsCuriously, opposed to expectations, we found an identical accelerated plaque pathology coinciding with the presence of dystrophic neurites and amyloid precursor protein c‐terminal fragment (APP‐CTF) accumulation in both genotypes. These alterations in pathology equally translated to an earlier deficit in working memory for both APPxPsen2KO and APPxFADPsen2. In contrast, gliosis was markedly different with increased and earlier microglia recruitment in the case of APPxPsen2KO whereas APPxFAD‐Psen2 displayed a delayed recruitment.ConclusionThese surprising differential effects on distinct pathological features suggest both a protective role for Psen2 as well as specific, yet unexplored, roles in neurons as well as glial cells. We are currently examining primary neurons and microglia from the different genotypes to explore underlying molecular mechanisms.
Tau accumulation and degeneration differ across functional networks in atypical Alzheimer's disease phenotypes
Authors: Phillips Jeffrey S , Burke Sarah E , Cousins Katheryn A Q , Arezoumandan Sanaz , Ohm Daniel T , Chen Min , Cook Philip , Dubroff Jacob G. , Nasrallah Ilya M. , McMillan Corey T , Grossman Murray , Wolk David A. , Irwin David J. 
Published: December 2022

AbstractBackgroundRecent models of Alzheimer's disease (AD) posit that pathogenic tau propagates through interconnected structural networks, suggesting amnestic and non‐amnestic AD (aAD & naAD) phenotypes could reflect differential involvement of functional networks. We tested this hypothesis by contrasting longitudinal grey matter (GM) atrophy and tau accumulation across AD clinical phenotypes in 7 canonical functional networks.MethodsWe analyzed longitudinal 3‐Tesla T1‐weighted MRI from 122 patients [aAD=49; logopenic primary progressive aphasia (lvPPA)=31; posterior cortical atrophy (PCA)=23; behavioral/dysexecutive AD (bvAD)=6; corticobasal syndrome (CBS)=6; mixed naAD=4] with autopsy or CSF evidence of AD pathology and 91 cognitively normal controls (Table 1). Thirty‐one patients (aAD=9; lvPPA=7; PCA=9; bvAD=2; CBS=3; naAD=1) had longitudinal flortaucipir PET (FTP‐PET) data. We computed baseline values and annualized change for GM volume and FTP‐PET standardized uptake value ratios (SUVRs) in the 100‐label, 7‐network parcellation of Schaefer et al. (2018). Linear mixed effects models (α=0.05, corrected) adjusting for MMSE assessed group differences in atrophy and tau accumulation.ResultsAll groups exhibited significant baseline and longitudinal atrophy vs. controls in multiple networks (Figs. 1‐2). Differences in longitudinal atrophy rate (Fig. 2) were observed in the dorsal attention network [PCA>lvPPA, t(371)=3.1, p<0.04], salience network [PCA>aAD, t(371)=3.1, p<0.04], and limbic network [CBS>aAD, t(371)=3.3, p<0.02; CBS>bvAD, t(371)=3.7, p<0.006]. PCA patients exhibited FTP‐PET SUVR increases in all networks (all p<0.02), while aAD patients displayed increases in all networks except visual and limbic (all others p<0.0001). LvPPA patients exhibited net SUVR increases only in the somatomotor network [t(97)=3.5, p<0.001]. At baseline, lvPPA patients had left > right atrophy in all networks [all t>3.7, p<0.0002]; right > left atrophy was observed in the visual network for PCA and CBS; the salience network for PCA and bvAD; and in the dorsal attention, frontoparietal control, and default mode networks for bvAD [all t>3.0, p<0.03]. In longitudinal analyses, no hemispheric differences were found in rates of GM volume loss or FTP‐PET change.ConclusionAD clinical variants exhibited GM atrophy and tau accumulation in partially overlapping networks. Investigating early‐stage disease will be crucial for assessing whether disease spread through canonical functional networks can explain anatomic differences in aAD and naAD phenotypes.
The PIONEER Study: A Multi‐center, Randomized, Double‐blind, Placebo‐controlled Phase 2 Trial of the Effects of T3D‐959 on Safety, Cognition, Function and Plasma Biomarkers in Mild to Moderate Alzheimer’s Disease Subjects: Study Update.
Authors: Stanek Jessica , Swearingen Blake , Gabriel Hoda , Strittmatter Warren , Chamberlain Stan , Didsbury John 
Published: December 2022

AbstractBackgroundT3D‐959 is a novel (non‐amyloid/non‐tau‐directed) new chemical entity aimed at improving dysfunctional brain glucose energy and lipid metabolism in Alzheimer’s disease (AD). Dysfunctional brain metabolism in AD results from increasing resistance to insulin. Insulin resistance contributes to amyloid plaque formation, tau tangle formation and inflammation. T3D‐959, a brain‐penetrant, small molecule dual nuclear receptor agonist, acts as an insulin sensitizer to overcome insulin resistance to restore and maintain metabolic homeostasis.MethodPIONEER is a randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients (MMSE = 14‐26) dosed orally once‐a‐day for 24‐weeks in 4 parallel arms (T3D‐959 15mg, 30mg, 45mg and placebo QD in a 1:1:1:1 ratio). Co‐primary outcome measures include the ADAS‐cog11 cognition and global function ADCS‐CGIC measures. Secondary outcome measures include DSCT and plasma Aβ 42/40 ratio. Exploratory outcome measures include plasma NfL tau, ptau217 and ptau181, apathy as measured by the NPI, expressive language function as measured by CFT, physical activity as measured by RAPA, plasma metabolomic and proteomic biomarkers and change in absolute regional, and whole brain, cerebral metabolic rate for glucose (CMRgl) as assayed by FDG‐PET.ResultPIONEER commenced in March 2021. The study is two‐thirds enrolled and ongoing [See ClinicalTrials.gov identifier NCT04251182]. Blinded, grouped, summary cognitive and functional endpoint data, as well safety data will be presented and discussed.ConclusionPIONEER is designed to evaluate the efficacy and safety of multiple dose strengths of T3D‐959 in patients with mild to moderate severity AD. Topline results are expected in 2023.
Identification and Treatment of Agitation in Nursing Home Settings: Applying the IPA Algorithm
Authors: Lanctôt Krista L. , Wang Janet Hui Jue 
Published: December 2022

AbstractBackgroundWith an estimated prevalence of 55%, agitation is particularly common among nursing home residents. The recent International Psychogeriatric Association (IPA) agitation treatment algorithm describes steps for the identification and treatment of agitation across multiple care settings.MethodThis abstract describes the application of the IPA algorithm to the long‐term care (LTC) setting.ResultIn the IPA algorithm, nonpharmacologic care is considered first and continued for both treatment and prevention. In LTC residents, nonpharmacologic interventions are a key first step. For agitation in nursing home residents with dementia, the current evidence suggests that group activity based interventions (e.g., recreation therapy), resident interventions (e.g., massage and touch therapy, and music therapy) and multidisciplinary training and care (e.g., person‐centred care) are the most consistently effective nonpharmacologic treatments. There are several caveats that may impact efficacy of interventions. Feasibility and scalability considerations may impact implementation of nonpharmacologic interventions in long‐term care settings. Most interventions require training, implementation, or supervision by external specialized staff. Feasibility of interventions may also be limited by the capabilities of individuals with dementia; sensory impairments and physical disabilities may preclude some residents from participating in interventions such as music therapy or exercise. As such, interventions must be personalized. Data also show that nonpharmacologic interventions that modify the environment or stimulate the senses may be effective for different aspects of agitation in LTC residents with dementia. Pharmacologic care is personalized and guided by the major features of the agitation including when it occurs, severity and whether it represents a danger to self or others. Importantly, recent efforts have evaluated multi‐modal interventions in LTC. Taken in toto, literature to date provides evidence for use of the above mentioned nonpharmacological interventions for mild agitation in long‐term care facilities. Implementing these interventions requires assessment of medical and environmental causes for agitation, ongoing nonpharmacologic intervention and then pharmacologic interventions as necessary.ConclusionFuture studies should continue to investigate the long‐term effects of multi‐modal nonpharmacological interventions, alone and in combination with pharmacologic interventions in participants with severe agitation.
Aggregation‐prone human tau accelerates lifespan and motility decline in a Caenorhabditis elegans model of tau polymerization
Authors: Nunez Wendy C Aquino , Ackley Brian D 
Published: December 2022

AbstractBackgroundTau aggregates is a key molecular hallmark of Alzheimer’s disease and other Alzheimer’s Disease‐Related Disorders. In these neurodegenerative disorders tau is aggregated in areas of the brain that exhibit high levels of synaptic and neuronal degeneration. Most animal models focus on neuronal death as is an apparent phenotype; however, we lack an in vivo model to observe the events that occur early in pathology compared to the endpoint (neuronal death). Thus, we want to build a model using C. elegans to understand the factors that initiate tau polymerization and toxicity.MethodTo this end, we have generated a transgenic C. elegans model expressing different variants of the longest human tau isoform (hTau40) tagged to GFP. We used a pan‐neuronal promoter to express wild‐type hTau40 and several aggregation‐prone hTau40 variants. We also used mutated alleles to test the conditions under which wild‐type tau is induced to aggregate or can exacerbate the phenotype observed under the aggregation‐prone tau variants. We used confocal microscopy to assess the accumulation of tau‐GFP within neurons in an age‐dependent manner. In addition, we used a combination of lifespan, behavior and biochemical assays to evaluate the role of tau‐GFP intensity/location with the overall healthspan of the nematode.ResultWe observed differences in the accumulation and presentation of tau variants can be measured in vivo using GFP. Wild‐type tau‐GFP appears smooth and filamentous and localized to axons and cell bodies. On the contrary, the aggregation‐prone 3PO‐tau is punctate in axons with extensive inclusions of GFP in cell bodies which increases in an age‐dependent manner. The expression of aggregation‐prone tau variants appears to correlate with the decreased lifespan and decreased motility, which is an indication that tau aggregation within the cell bodies is toxic.ConclusionThese results suggests that we can use our model to identify factors that can regulate tau aggregation in vivo. Additionally, the further development of this C. elegans model can be use to question early physiological changes that occur early vs. late in the disease while identifying or validating possible risks factors.
Reference Intervals for Plasma Biomarkers of Alzheimer’s Disease
Authors: Cooper Jennifer G , Stukas Sophie K , Ghodsi Mohammad , Ahmed Nyra , Holmes Daniel , Wellington Cheryl L 
Published: December 2022

AbstractBackgroundSeveral blood‐based biomarkers are emerging as potential screening, diagnostic, and prognostic tools for Alzheimer’s disease (AD), including: the ratio of amyloid beta 42 over 40 (Aβ42/40), reflecting the pathology of amyloid plaques; phosphorylated tau‐181 (p‐tau‐181), reflecting the formation of neurofibrillary tangles; neurofilament light (NF‐L), reflecting axonal damage observed in neurodegeneration; and glial fibrillary acidic protein (GFAP), reflecting neuroinflammation through astrocyte activation. A critical step in the translation of these biomarkers from research to clinical implementation is establishment of reference intervals derived from an appropriate population.Methods900 plasma samples from male and female participants aged 3‐79 years old were analyzed for Aβ42/40, p‐tau‐181, NF‐L and GFAP to create reference intervals (RI). Samples are obtained from the Canadian Health Measures Survey (CHMS), a national study that collects demographics, health questionnaires, clinical data and biospecimens from participants. Analysis was preformed on the Quanterix Simoa HD‐X analyzer using the Neurology 4‐plex E and p‐tau‐181 assay. Discrete and continuous RIs were produced for each biomarker. Discrete RIs are produced according to the Clinical Laboratory Standards Institute guidelines (EP20‐A3c). Continuous RIs are created using quantile regression.ResultsParticipant samples were selected from the following age bins designated by the CHMS biobank: 3 to 5 years (N=56), 6 to 11 years (N=58), 12 to 19 years (N=58), 20 to 39 years (102), 40 to 59 years (N= 102), 60 to 79 years (N=140). After analysis, age partitions for discrete RI were created, resulting in two to five age‐bins per biomarker which reference intervals were generated for. Continuous RIs produced smooth centile curves across all ages, from which point estimates for any age can be calculated.ConclusionsBoth discrete and continuous RIs for plasma Aβ42/40, p‐tau‐181, NF‐L and GFAP may help refine normative cut offs for each biomarker across the lifespan.
Understanding comorbid metabolic dysfunctions in Alzheimer’s disease using the AD‐BXDs
Authors: Dai Miko , Dunn Amy R , Hadad Niran , Cousineau Cody , Bridges Dave , Kaczorowski Catherine C. , O'Connell Kristen MS 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a neurogenerative disease characterized by cognitive deficits. Cognitive decline in AD is often accompanied and preceded by non‐cognitive comorbidities, including metabolic dysfunctions such as weight loss. Therefore, understanding how comorbid metabolic dysfunctions contribute to AD disease progression can provide useful insights into early disease risk detection and intervention.MethodWe investigated how genetics, diet, and sex interact to modify metabolic symptoms of AD using 39 mouse strains from the AD‐BXD panel (Neuner et al., 2019, Neuron) at 4, 6 and 14 months of age. Mice were fed normal chow diet, or 45% high‐fat diet (HFD) starting at ∼2.5 months of age. We monitored food/water intake as well as the activity of mice over a period of five days, and measured metabolic phenotypes via indirect calorimetry, nuclear magnetic resonance, and glucose tolerance test. Plasma samples were collected and assayed for lipid panel, cytokines, and metabolism‐related hormones to investigate molecular changes in the periphery. Heritability of metabolic traits were calculated, and heritable traits were mapped using GEMMA with appropriate covariates (Zhou and Stephens, 2012, Nature Genetics) to identify associated genetic variants.ResultWe observed a wide range of variations across the AD‐BXD population in metabolic and cognitive responses to aging and diet. Overall, the presence of the 5XFAD transgene reduced lean and fat mass across the population. Aging exacerbated the loss of lean mass due to the 5XFAD transgene but does not have such interactive effect on percent fat mass. Genetic background significantly modifies the effect of the transgene on multiple phenotypes including body weight, sleep, and glucose tolerance. Responses to a HFD also differed by sex and AD genotype and are substantially modulated by gene‐by‐environment interactions across phenotypic domains. Both cognitive and metabolic phenotypes have moderate to high heritability, allowing us to identify genetic loci associated with these traits.ConclusionOur data characterizing metabolic and cognitive phenotypes from the genetically diverse AD‐BXDs are important resources to study the role and origin of comorbidities in AD. Future studies on mechanism of the observed metabolic disruptions may lead to discovery of therapeutic targets to delay, prevent, or treat AD.
Worse Performance of Complex Daily Activities is associated with Plasma Neurofilament Light
Authors: Keleman Audrey A. , Wisch Julie K. , Bollinger Rebecca M. , Schindler Suzanne E. , Morris John C. , Ances Beau M , Stark Susan L. 
Published: December 2022

AbstractBackgroundThe preclinical stage of Alzheimer disease (AD) is a clinically silent period that is detectable through neuroimaging and biofluid biomarkers of amyloid, tau, and neurodegeneration. We evaluated whether performance of cognitively‐focused complex daily activities is associated with plasma biomarkers of brain amyloidosis or neuroaxonal injury in cognitively normal (CN) older adults.MethodIn this cross‐sectional analysis of an ongoing longitudinal cohort study, CN older adults performed three cognitively‐focused complex daily activtites (shopping, checkbook balancing, and medication management) from the Performance Assessment of Self‐Care Skills (PASS) in their home. PASS tasks were scored for independence of performance, with more assistance required indicating worse performance. Participants also had a plasma sample obtained within two years of completing the PASS. Plasma amyloid (Aβ42 and Aβ40) were evaluated by high precision immunoprecipitation mass spectrometry assays and neurofilament light (NfL), a marker of neuroaxonal injury, was measured with single molecule array (Simoa) assays. Amyloid Probability Score (APS) was calculated from a combination of plasma Aβ42/Aβ40, APOE status, and age and reflects the likelihood that an individual will be amyloid positive on an amyloid positron emission tomography (PET) scan. Nonparametric partial correlations were used to examine the associations between PASS performance and biomarkers of AD (plasma Aβ42/Aβ40, APS, and plasma NfL), controlling for age and sex.Result105 CN participants (mean age 74.7 years, 55% female, 88% white) were included. After controlling for age and sex, worse performance of complex daily tasks (more assistance required) was associated with increased plasma NfL (Spearman’s ρ: 0.234, p = 0.04) but not plasma Aβ42/Aβ40 or APS.ConclusionThis study suggests that worse performance of complex daily activities in CN older adults may be associated with increased plasma NfL, a marker of neuroaxonal injury, but not with other plasma biomarkers of brain amyloidosis (plasma Aβ42/Aβ40 or APS). These findings could lead to a better understanding of functional changes that may associate with neuroaxonal injury prior to the onset of noticeable memory symptoms in AD or related dementias.