bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of plasma β‐synuclein levels in different stages of Alzheimer´s disease and relation to amyloid and tau‐PET
Authors: Oeckl Patrick , Janelidze Shorena , Halbgebauer Steffen , Stomrud Erik , Palmqvist Sebastian , Otto Markus , Hansson Oskar 
Published: December 2023

AbstractBackgroundSynaptic degeneration is a major hallmark of Alzheimer´s disease (AD). Easily accessible biomarkers are needed to study its role in AD pathogenesis and to detect positive effects on synaptic dysfunction in clinical drug trials. β‐Synuclein is an emerging synaptic blood biomarker for AD but changes of β‐synuclein levels in preclinical AD and its associations with amyloid and tau pathology have not yet been studied.MethodWe measured plasma β‐synuclein levels using immunoprecipitation‐mass spectrometry in the Swedish BioFINDER‐2 study (N = 230) including cognitively unimpaired individuals (CU) with positive Aβ‐PET (CU Aβ+
, i.e. preclinical AD, N = 48) or negative Aβ‐PET (CU Aβ−
, N = 61), Aβ‐positive patients with mild cognitive impairment (MCI Aβ+, N = 36) and Aβ‐positive AD dementia (N = 85). Amyloid (A) and tau (T) pathology were assessed by [18F]Flutemetamol and [18 F]RO948 PET, cortical thickness by MRI and cognitive performance using the Mini‐Mental State Examination (MMSE) and modified Preclinical Alzheimer’s Cognitive Composite (mPACC).ResultPlasma β‐synuclein levels were increased in CU Aβ+ (p = 0.033) and further increased in MCI Aβ+ (p = 0.007) and AD patients with dementia (p<0.001) compared with CU Aβ−. Furthermore, β‐synuclein levels were higher in AD dementia than in CU Aβ+ (p = 0.002) and MCI Aβ+ (p = 0.037). Stratification according to Aβ‐ and tau‐PET status revealed increased β‐synuclein levels in both A+T− (p = 0.014) and A+T+ (p<0.001) subjects compared with A−T− and further increased in the A+T+ group compared with A+T– group (p<0.001). Plasma β‐synuclein levels significantly correlated with Aβ‐PET SUVR (β = 0.279; p<0.001) and tau‐PET SUVR (β = 0.308; p<0.001) and were associated to temporal cortical thinning (β = ‐0.135; p = 0.044) and worse performance on MMSE (β = ‐0.252; p<0.001) and mPACC (β = ‐0.254; p<0.001).ConclusionOur data indicate that plasma β‐synuclein levels rise early in AD during the preclinical phase, preceding tau pathology, which supports that synaptic degeneration belongs to the very early events in sporadic AD. The results support plasma β‐synuclein as an easily accessible and scalable biomarker that can be used to detect positive effects of novel disease‐modifying therapies on synaptic dysfunction in AD and to further study synaptic degeneration in the pathophysiology of AD.
A novel drug‐free intervention to improve cognitive performance in unimpaired older participants: the power of affective touch
Authors: Frau Loredana , Cazzato Valentina , Macglone Francis , Bruno Davide 
Published: December 2023

AbstractBackgroundAffective and emotional symptoms (i.e., anxiety, depressions) are common neuropsychiatric symptoms in pre‐clinical dementia. Affective touch (AT),—a pleasant interoceptive stimulus which is signalled by the C‐Tactile system, has been shown to regulate stress responses, physical pain, and negative affect. However, to date, no study has examined if AT also may improve cognitive performance. Here,we investigated whether AT affected inhibitory control (IC; i.e., the ability to inhibit irrelevant information and select more appropriate behaviours)in unimpaired older adults.MethodThirty‐six unimpaired older adults (Mean age = 68.12, SD = 5.90) performed two computerised Stroop tasks (classic and emotional version). Before performing each task, participants in the experimental group received brush stroking on the forearm at CT‐optimalvelocity(3 cm/s) while participants in the control group did not receive any touch stimulation (No Touch). To estimate changes in the affective state we used a self‐rating questionnaire (PANAS) and physiological measures (Heart Rate variability‐HRV). To estimate cognitive performance we analysed response time and interference in both tasks. For analyses of HRVsignals, three‐time windows were examined: resting state pre‐task and, before each cognitive task. A repeated measure design was used at baseline and follow‐up.ResultParticipants in the AT group displayed improved response time in the Stroop tasks and greater physiological arousal (i.e., HRV) before performing both tasks compared to controls.ConclusionTo the best of our knowledge, this is the first study highlighting the role of the touch‐induced physiological arousal in inhibitory control. Beyond regulating emotion and arousal, gentle touch appears to enhance the cognitive processes underlying the suppression of goal‐irrelevant stimuli. Overall, current data seem to suggest that a multi‐modal affective‐cognitive intervention integrating AT may be a promising tool for delaying the natural effects of aging on cognition. Future research should extend this paradigm to individuals with impaired cognition and dementia.
Can escapees of familial AD help identify protective factors? A case report of an extremely resilient PSEN1 carrier
Authors: Smulders Michelle N.C.A. , Dijkstra Janna I.R. , Visser Denise , Vermunt Lisa , Giessen Elsmarieke , Pijnenburg Yolande A.L. , Holstege Henne , van der Flier Wiesje M. , Ossenkoppele Rik , van der Lee Sven J 
Published: December 2023

AbstractBackgroundCarriers of mutations in PSEN1, PSEN2 or APP develop early‐onset Alzheimer’s dementia around a certain age depending on the specific mutation. However, some individuals “escape their fate”, meaning they remain asymptomatic far beyond their expected age at onset (EAO). We call these individuals “escapees”. A well‐known example is the resilient PSEN1 carrier that led to the identification of the protective APOEε3‐Christchurch mutation (Arboleda‐Velasquez et al., 2019). Here we present an extremely resilient PSEN1‐P264L mutation carrier where the cause of resilience has not yet been identified.MethodCarriers of PSEN1‐P264L have an EAO of 47 (SD = 4.3 years; Ryman et al., 2014). Our patient remains asymptomatic at age 58, which less than 0.6% of mutation carriers are expected to reach unaffected. We characterized this individual over the course of eight years with neuropsychological tests (n = 9), MRI scans (n = 5), amyloid (n = 3, [18F]florbetapir) and tau (n = 3, [18F]flortaucipir) PET scans and cerebrospinal fluid (CSF; n = 1). Genetic analysis of APOE and polygenic risk score (PRS) is described.ResultNeuropsychological test scores were within normal range at baseline and no significant cognitive decline was observed from age 50 to 58. On five consecutive MRI scans, no abnormalities or evidence of neurodegeneration was observed with visual read. At age 50, the patient was amyloid‐positive and tau‐positive in CSF (table 1). The patient was also amyloid‐positive on their first PET at age 51 (fig. 1). Widespread amyloid‐PET binding was observed, which increased over time. On tau‐PET, the patient was negative at age 51 and 53 (fig. 1), but positive at age 56, with an atypical binding pattern that shows high occipital load with relative sparing of the temporal and parietal cortex. This tau pattern and progression are remarkably similar to that seen in the escapee with the APOEε3‐Christchurch mutation. The APOE status of the patient is APOE ε3ε3 and the patient had an average PRS (+0.2SD from population average). Whole genome sequencing is ongoing.ConclusionWe describe an “escapee” of a PSEN1 mutation in which we have not yet identified the protective factor(s). Escapees represent rare but potent resilience phenotypes that should be studied systematically.
Mid‐life APOE4 to APOE2 ‘Switching’ Alters the Cerebral Transcriptome and Lipidome in a Transgenic Mouse Model
Authors: Golden Lesley R , MacLean Steven M , Smith Cathryn T , Lee Sangderk , L'Italien Nicholas , Whitus Callie M , Goulding Danielle S. , Chen Jing , Zhu Haining , Pandya Kumar , Gordon Scott , Morganti Josh M. , Johnson Lance A 
Published: December 2023

AbstractBackgroundCompared to the ‘neutral’ E3, the E4 allele of Apolipoprotein E (APOE) confers up to a 15‐fold increase in Alzheimer’s Disease (AD) risk. Conversely, the neuroprotective E2 allele decreases AD risk by a similar degree. APOE’s strong risk profile and multitude of effects make it a promising therapeutic target. Here, we aimed to assess the therapeutic potential of allelic ‘switching’ by investigating the physiological changes associated with an inducible, in vivo APOE4 to APOE2 transition in a novel transgenic mouse model.MethodThe APOE “switch mouse” (APOE4s2) uses the Cre‐loxP system to allow for inducible APOE allele switching from APOE4 to APOE2. These mice express a floxed human APOE4 coding region followed by the human APOE2 coding region. To study the effects of full body APOE switching, APOE4s2 mice were crossed to ubiquitous ROSA26‐CreERT1
mice. Gene expression and proteomic analyses were used to validate that the model worked as expected. Untargeted lipidomics and single‐cell RNAseq were used to measure physiological changes following the APOE4 to APOE2 allele switch.ResultmRNA and protein analyses confirm that APOE4s2 mice synthesize full‐length human APOE4/ApoE4 pre‐switch and that the inducible switch results in successful and efficient recombination and expression of human APOE2/ApoE2. Single‐cell RNAseq shows that global, genetic replacement of APOE4 with APOE2 results in distinct alterations to glial cell transcriptomes affecting pathways involved with lipid and mitochondrial metabolism, inflammation, blood‐brain barrier integrity, and amyloid beta. Excitingly, differentially expressed genes associated with an E4 to E2 ‘switch’ included several AD GWAS, and both aging‐ and AD‐associated pathways. Additionally, nontargeted lipidomics reveals changes to several lipid classes in the brain, in particular glycerophospholipids.ConclusionTogether, these data suggest that a successful transition from APOE4 to APOE2 has broad impact on the cerebral transcriptome as well as peripheral and cerebral metabolism. Ongoing studies aim to determine whether cell‐specific replacement of APOE4 with APOE2 will rescue E4‐associated metabolic dysfunction, disease‐associated gene signatures, and AD pathology.
Reduced pace of biological aging explains the association of diet with dementia: results from the Framingham Offspring Study
Authors: Thomas Aline , Belsky Daniel W , Gu Yian 
Published: December 2023

AbstractBackgroundSubstantial evidence supports the benefice of healthy diet for brain aging; however, the underlying pathways remain largely unknown. Leveraging a unique cohort design with assessment of long‐term dietary habits, DNA methylation data, and 10‐year follow‐up for dementia, we evaluated the mediating role of pace of biological aging on the relationship of diet with dementia. We investigated the specificity of this pathway for brain aging, as compared to overall aging, by investigating the same mediation for the risk of all‐cause mortality.MethodWe included 1,644 participants (≥60 years‐old) from the Framingham Offspring Cohort, who were free of dementia at baseline examination (exam 8 [2005‐2008]). We evaluated long‐term adherence to a Mediterranean diet (MeDi) by averaging dietary scores across four assessments (validated food frequency questionnaire at exams 5 [1991‐1995], 6 [1995‐1998], 7 [1998‐2001], and 8). Using DNA methylation data collected at baseline, we measured the pace of biological aging through the DunedinPACE epigenetic clock, which was the DNA methylation measure the most strongly associated with dementia in prior studies. Incidence of dementia and mortality was adjudicated from baseline until 2018 by expert committees. We performed mediation analyses to estimate the role of pace of biological aging on the relationship between diet and dementia or all‐cause mortality.ResultOver the follow‐up (maximum, 13.8 years), 140 (8.5%) participants developed dementia, and 471 (28.6%) died. Participants with a higher adherence to MeDi had a slower pace of biological aging, and lower risks of dementia and of all‐cause mortality (Figure). A faster pace of aging was associated with increased risks of dementia and mortality. Biological aging mediated 13% [95% CI, 0.06; 0.43] of the association between diet and dementia, and 43% [0.23; 1.08] of the association of diet with mortality.ConclusionPart of the association of healthier diet with lower risk of dementia is mediated by a slowing of global processes of biological aging. However, this pathway does not fully explain the association of diet and dementia and the proportion mediated was three times smaller than what was observed for mortality, suggesting that other mechanisms, especially brain‐specific mechanisms, need to be further described.
Associations between Distinct Trajectories of Cardiometabolic Risk Factors (Hypertension, Hypercholesterolemia, and Diabetes) over 15 Years Preceding Dementia and Incidence of Dementia
Authors: Ren Dianxu , Lopez Oscar L. , Lingler Jennifer H , Conley Yvette 
Published: December 2023

AbstractBackgroundCardiometabolic Risk Factors (Hypertension, Hypercholesterolemia, and Diabetes) have been reported inconsistently to associate with dementia, with both increased and decreased risks. The purpose of this study was to examine longitudinal distinct trajectories of cardiometabolic risk factors over 15 years preceding dementia with incident dementia using the large national dataset from National Alzheimer’s Coordinating Center (NACC).MethodWe used NACC dataset from 2005 to December 2020 and performed a nested case‐control study (up to 1 to 5 match). The sample included 720 cases of all‐causes dementia with at least 5–years follow‐up time preceding dementia diagnosis, and 2526 non‐dementia controls matched on age, sex, race, education and baseline cognitive status. Group‐based trajectory models were applied to identify longitudinal distinct trajectory groups of binary status measures (absent/inactive vs. recent/active) of hypertension, hypercholesterolemia and diabetes among this sample. Conditional logistic regression models were used to evaluate the effect of distinct trajectories of each cardiometabolic risk factor, APOE genotype and the interaction between them with incident dementia.ResultFor the case group (n = 720), mean age at enrollment was 75.5 years and average education in years was 15.6, participants were more female (58.7%), non‐Hispanic white (87.1%) and healthy cognitive status at initial visit (61.9%). All three binary outcome trajectory models identified similar three trajectory groups over 15 years preceding dementia: “low‐flat,” “low‐to‐high,” and “high‐flat”. Conditional logistic regression model revealed no significant main effects of hypercholesterolemia and hypertension as well as no interaction between them and APOE genotype on the incidence of dementia. However, there is borderline significant effect of diabetes trajectory group on the incidence of dementia. Comparing to “low‐flat” diabetes trajectory group, “high‐flat” group were more likely to develop dementia [OR = 1.32, 95% CI (0.99‐1.76), P = 0.056] after controlling APOE genotype.ConclusionOur findings suggest the existence of distinct trajectories of cardiometabolic risk factors preceding incident dementia. Active diabetes status may play an important role for developing dementia especially those who are with long‐term diabetes are with greater risk for the incidence of dementia.
Mitochondrial Localized Amyloid Precursor Protein Alters Mitochondrial Function and Mitophagy
Authors: Wilkins Heather M 
Published: December 2023

AbstractBackgroundMitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer’s disease (AD). Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), from which Aβ is generated, is found in mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. How these interactions contribute to AD pathology and progression are unknown. Here we interrogated the association of full‐length APP with mitochondria, mitochondrial function, and AD pathological hallmarks.MethodND (n = 5, without DS) and DS with dementia (DSD, n = 5) postmortem brain tissue was obtained from the University of California Irvine. A human iPSC line underwent Crispr/Cas9 genome editing to mutate three amino acids in APP and generate a 3M APP model, with reduced mitochondrial APP localization. We also leveraged a human iPSC line with triplication of the APP gene. iPSC models were differentiated into neurons using StemCell Technologies reagents and protocols. We examined mitochondrial function using a Seahorse XF analyzer. We measured full‐length APP protein levels in whole cell extracts and mitochondrial fractions via Western Blotting. We measured Aβ levels with ELISA kits from ThermoFisher. Mitophagy and mitochondrial mass/biogenesis was measured using MitoTimer and EGFP‐Cox8 adenoviral constructs.ResultiPSC derived neurons showed alterations to Aβ production. 3M APP models had reduced Aβ production while APP triplication models had increased production. 3M APP models had reduced mitochondrial APP levels and APP triplication models had increased mitochondrial APP levels. 3M APP models had reduced mitophagy, increased mitochondrial biogenesis, and increased mitochondrial mass. APP triplication models had increased mitophagy and reduced mitochondrial mass. Mitochondrial respiratory function was reduced in both 3M APP and APP triplication models. DSD postmortem brain tissue had reduced mitochondrial function in females. Full‐length APP levels were significantly higher in mitochondrial fractions in DSD brain tissue. Full‐length APP levels in mitochondrial fractions correlated with mitochondrial function. Higher mitochondrial APP (full‐length) levels associated with lower mitochondrial function.ConclusionWe describe a relationship between mitochondrial APP accumulation, mitochondrial function, and Aβ. These data support a centralized role for mitochondrial function in APP physiology and APP may play a role in modulating mitophagy.
Assessment of Research Community Characteristics in Engagement and Recruitment to Dementia Research
Authors: Bergey Abigail E , Gabela Nicole Taikeff , Jackson Jonathan D. , DeSousa Elma , Reynolds Marissa L. , Bennett Erin E 
Published: December 2023

AbstractBackgroundResearch studies and clinical trials in Alzheimer’s disease and related dementias (ADRD) attract only socio‐demographically advantaged populations, despite a higher risk of ADRD in historically marginalized and minoritized populations (HMM). Advancements in participant recruitment, retention, and engagement (RER), and clinical research design are urgently needed to address ADRD disparities and inequities. In light of these critical shortfalls in diverse and representative RER, this mixed‐methods study assesses RER strategies as well as the context in which these strategies are practiced within the ADRD Centers Program.MethodsSemi‐structured interviews and focus groups were conducted across four ADRD research centers and their respective surrounding communities. Interviews were conducted with research and non‐research faculty, research staff, faith and civic leaders, patients, care providers, and community members. Geospatial mapping tools were used to better define where current RER practices were being focused relative to where HMM and high‐risk populations resided.ResultsExtracted themes demonstrated that current diversity, equity, and inclusion efforts (DEI) from sites inefficiently connected HMM communities with ADRD research institutions. Instability in collaborative culture and a lack of grounded, fully embraced DEI efforts were cited in driving the divide between HMM and research communities. Inequitable burden of funding and sustaining DEI efforts, as well as the diffused impact in HMM communities further limited RER activities targeting HMM and high‐risk populations. Geospatial analysis additionally revealed that RER activities tended to occur proximal to advantaged populations, rather than in spaces accessible to HMM and high‐risk communities.ConclusionThe current study sought to assess RER strategies as well as the context in which these strategies are practiced to better understand motivations and barriers within NIA’s ADRD Centers Program. This sharper degree of information and clarity regarding RER activities may yield precision RER strategies and resources.
Genetic context controls microglia‐induced neuronal damage in Alzheimer’s disease
Authors: Heuer Sarah E , Keezer Kelly J , Hewes Amanda , Onos Kristen D , Bloss Erik B , Howell Gareth R 
Published: December 2023

AbstractBackgroundThe activation of microglia and the loss of synapses have emerged as key events in Alzheimer’s disease (AD) progression, yet the relationship between these processes is not clear. Previous studies suggest genetic variation controls microglial activation in AD mouse models, so we evaluated how the elimination of brain microglia influenced synapses on hippocampal pyramidal cells across two genetically distinct AD mouse models.MethodUsing a viral approach, we labeled hippocampal neurons that project to the frontal cortex by expressing GFP in young (3m) inbred C57BL/6J and genetically distinct PWK/PhJ female mice with or without a transgenic (APP/PS1) allele that drives amyloid pathology. At 4m we placed half of the mice on diet formulated with CSF1R inhibitor PLX5622 to deplete brain microglia. At 8m, a time when plaque pathology is present in transgenic mice, we examined cognition using the delayed spatial task. We then analyzed the density and morphology of spines across multiple dendritic domains, as well as amyloid plaques and markers of disease‐associated (DAM) and interferon responding (IRM) states of IBA1+ microglia.ResultWhile spatial cognition was unaffected by PLX5622, we identified B6.APP/PS1 as susceptible and PWK.APP/PS1 as resilient to cognitive deficits at 8m. Across both strains, PLX5622 depleted hippocampal microglia but did not affect amyloid plaques. In contrast, we observed strain differences in spine synapse density and morphology. Compared to spine stability across PWK wild‐type (WT) and APP/PS1 mice, we measured increased density of small spines in B6.APP/PS1 mice (compared to WT). B6.APP/PS1 mice showed reduced spine density with PLX5622, whereas PWK.APP/PS1 mice remained unaltered. These changes in spine density corresponded to DAM being resistant to depletion with PLX5622 in APP/PS1 mice (especially B6), whereas IRM were susceptible, suggesting a neuroprotective role for IRM.ConclusionWe show here that genetic context determines how synapses on CA1 projection neurons respond to the depletion of brain microglia and AD transgenes. Since PWK.APP/PS1 are resistant to hippocampal neuronal damage with robust microglia activation, this strain can be leveraged to further study mechanisms of resilience to AD cognitive deficits and neuropathological damage that can be harnessed for better AD therapeutic treatments.