bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction between APOE4 and lifestyle on neuroimaging biomarkers and cognition in cognitively unimpaired older adults
Authors: Felisatti Francesca , Chauveau Léa , de Flores Robin , Marchant Natalie L , Collette Fabienne , Demnitz‐King Harriet , Whitfield Tim , Requier Florence , Palix Cassandre , Haudry Sacha , Delarue Marion , la Sayette Vincent De , Vivien Denis , Poisnel Géraldine , Chetelat Gael , Gonneaud Julie 
Published: December 2022

AbstractBackgroundAPOE4 is the main genetic risk factor for Alzheimer’s disease (AD). Recent findings suggest that lifestyle factors could modulate the association between APOE4 and cognitive impairment and/or dementia risk. However, a comprehensive assessment of the interactions between lifestyle and APOE4 status on neuroimaging and cognitive markers of aging and AD is still missing. Our objective is to assess this question in cognitively normal elderly.MethodBaseline data of 134 cognitively unimpaired older adults (mean age: 69) from the Age‐Well study were analysed. They underwent lifestyle questionnaires (physical and cognitive activity, and diet), neuropsychological assessment (global cognition, memory, attention and executive functions) and multimodal neuroimaging (structural MRI, FDG‐ and Florbetapir‐PET). Interactions between lifestyle and APOE4 status on neuroimaging and cognition were assessed for each lifestyle factor separately.ResultThere was an interaction between APOE4 status and cognitive activity on neuroimaging measures (p‐values<.04), such that higher cognitive engagement was associated with lower grey matter volume in the parahippocampal cortex and lower brain perfusion in the entorhinal and perirhinal cortices in APOE4 carriers only (Figure 1A). However, greater cognitive engagement was associated with increased cognitive performance (global cognition, executive function and attention, all p‐values<.005), and this irrespective of APOE4 status (i.e., no cognitive activity x APOE4 status interaction; Figure 1B). For diet, interactions were evidenced (p‐values <.04) such that higher adherence to the Mediterranean diet was associated with i) higher brain glucose metabolism in the medial temporal lobe (Figure 2A) and ii) higher performance on attention tests (Figure 2B) in APOE4 carriers only. No interactions were found for physical activity.ConclusionOur results indicate that APOE4 carriers with higher cognitive activity had lower brain outcomes but preserved cognition, suggesting that enriched cognitive engagement promotes cognitive resilience in this population. On the other hand, APOE4 carriers with higher adherence to the Mediterranean diet had greater cerebral metabolism and greater attention capacities. Overall, this suggests that distinct lifestyle factors differentially help APOE4 carriers to resist or cope with brain alteration and postpone cognitive decline. ClinicalTrials.gov Identifier: NCT02977819.
Phonemic restoration in Alzheimer’s disease and semantic dementia
Authors: Jiang Jessica , Johnson Jeremy , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Sivasathiaseelan Harri , Volkmer Anna , Crutch Sebastian J , Hardy Chris JD , Warren Jason D 
Published: December 2022

AbstractBackgroundIn daily life, spoken messages are often interrupted by extraneous sounds. However, we generally perceive such messages as continuous: our brains automatically and efficiently ‘repair’ interrupted speech signals by phonemic restoration, a fundamental physiological process whereby speech sounds that are obscured by noise are ‘filled‐in’ perceptually to reconstitute the underlying signal. As a dynamic, integrative process, phonemic restoration is potentially affected by neurodegenerative pathologies but this has not been clarified.MethodHere we studied this phenomenon in patients with typical Alzheimer’s disease and semantic dementia, relative to healthy age‐matched controls. Participants heard isolated sounds, spoken real words and pseudowords in which noise bursts either overlaid a consonant or replaced it; a tendency to hear replaced (missing) speech sounds as present signified phonemic restoration.ResultAll groups perceived isolated noises normally and showed phonemic restoration of real words, most marked in the Alzheimer’s disease group. For pseudowords, healthy controls showed no phonemic restoration, patients with Alzheimer’s disease showed a marked suppression of phonemic restoration and patients with semantic dementia showed phonemic restoration comparable to real words.ConclusionOur findings provide the first evidence that phonemic restoration is preserved or even enhanced in neurodegenerative diseases, with distinct syndromic profiles that may reflect the relative integrity of bottom‐up phonological representation and top‐down lexical disambiguation mechanisms in different diseases. This work has theoretical implications for predictive coding models of language and neurodegenerative disease, and for understanding cognitive ‘repair’ processes in dementia.
Mitochondrial DNA drives AD Phenotypes in Cell Models
Authors: Troutwine Benjamin R , Weidling Ian , John Casey S. , Green Zachary D. , Kueck Paul J. , Swerdlow Russell H , Wilkins Heather M , Morris Jill K. 
Published: December 2022

AbstractBackgroundMitochondrial DNA (mtDNA) inheritance influences Alzheimer’s Disease (AD) risk. Adult children of mother’s afflicted with AD show decreased cognition and increased AD biomarkers (both peripheral and brain) at earlier ages than adult children with father’s afflicted with AD. These human derived data paired with prior in vitro work support a maternal inheritance association of AD risk. However, the exact mechanism linking mtDNA inheritance patterns and AD is not understood.MethodsCytoplasmic hybrid (cybrid) cells were derived by fusing platelet mitochondria with SH‐SY5Y cells devoid of mtDNA. Cybrid cells have the same nuclear DNA background with varying mtDNA sequences derived from human subjects. We examined mitochondrial function parameters in cybrids derived from 8 cognitively healthy (CH), 7 AD, and 5 mild cognitive impairment (MCI) subjects. Mitochondrial electron transport chain (ETC) function was measured using Seahorse XF technology. Mitochondrial membrane potential, mitochondrial superoxide, and mitochondrial calcium were measured using fluorescent assays (TMRE, MitoSox, and Rhod2AM). Mitophagy and mitochondrial biogenesis/mass were measured using adenoviral constructs (EGFP‐Cox8 and MitoTimer).ResultsCybrids derived from AD subjects had elevated mitochondrial superoxide production when compared to CH cybrid cells. MCI cybrids did not show changes to mitochondrial superoxide production. Mitochondrial membrane potential and mitochondrial calcium were not changed in MCI or AD cybrids compared to CH. AD cybrids, but not MCI cybrids, showed reduced flux through all ETC components, including complex I, II, III, and IV. Finally, AD cybrids showed increased mitophagy levels but no change in mitochondrial biogenesis. MCI cybrids did not reflect these changes. Data do indicate AD cybrids might have increased mitochondrial mass, but further assays are needed to verify these findings.ConclusionsTransfer of mtDNA from AD patients to cells harboring consistent nuclear DNA recapitulates mitochondrial phenotypes observed in AD. We are currently measuring AD biomarkers in these models and working to examine their correlation with clinical data from this cohort of research subjects.
A large‐scale genome‐wide association study of early‐onset Alzheimer disease
Authors: Neupane Achal , da Fonseca Eder Lucio , Kurup Jiji Thulaseedhara , Pericak‐Vance Margaret A. , Martin Eden R. , Schellenberg Gerard D. , Reitz Christiane , Beecham Gary W. , Cruchaga Carlos , Fernandez Victoria 
Published: December 2022

AbstractBackgroundEarly‐onset (≤65 years old) Alzheimer Disease (EOAD), which accounts for approximately 10% of all AD cases, is sometimes equated with dominantly inherited forms of AD (i.e., caused by known mutations in APP, PSEN1 or PSEN2). However, 90% of EOAD cases remain unexplained by these variants. This project aims to identify novel EOAD‐associated variants through a large‐scale, multi‐ethnic genome‐wide association (GWA) study.MethodWe have leveraged the Alzheimer Disease Genetics Consortium (ADGC) GWAS dataset that is aligned to GRCh38 and imputed with the TOPMed imputation server. This includes 39 studies from non‐Hispanic Whites (NHW; CA = 3,202; CO = 5,782), 17 from African American (CA = 139; CO = 253), six from Asian (CA = 133; CO = 474), and seven from Hispanic (CA = 199; CO = 59) cohorts. Only the younger (≤65yo) and older participants (>80yo) were included for analysis as cases and controls, respectively. The genetic background was confirmed using PCA. We are performing single‐variant analysis to identify variants that confer a higher risk for EOAD.ResultOur preliminary single‐variant association analysis (using sex, PC1‐PC10 as covariates) emerging from the largest NHW cohort (CA = 3,202; CO = 5,782) have revealed nine different loci that were associated with EOAD at a suggestive P‐value<1×10−6. The strongest signal from our analysis was in the APOE region. Additionally, we identified three novel genome‐wide significant (P‐value <5×10−8) loci of interest at HLA‐DRB9 (rs9268852, P‐value = 2.9×10−9, OR = 1.22); FAM86B3P (rs73199790, P‐value = 3×10−11, OR = 1.32); and MSMB (rs2075895, P‐value = 2.83×10−16, OR = 1.26); while also confirming the previously identified loci at MS4A4A (rs7108663, P‐value = 1.13×10−10, OR = 0.80) and CR1 (rs6656401, P‐value = 2.54×10−12, OR = 1.32). We will perform qualitative associations on the other three ethnicities to confirm the transferability of these signals.ConclusionOur single‐variant analysis has identified three novel loci associated with EOAD. This study is the largest genetic screening for risk and protective variants in EOAD and will be instrumental to identifying novel variants and pathways implicated in unexplained EOAD. Our future analysis includes gene‐based association and pathway analyses per ethnicity to identify variants that confer a higher risk for EOAD, followed by transethnic analysis to validate the comprehensive nature of these risk factors. Additionally, we have also generated GWAS data from the Knight‐ADRC participants, which will be merged with the ADGC datasets for our future analysis.
The effect of microglial DMT1 inhibition on neuroinflammation in male and female mice
Authors: Volk Katrina M. , Harrison Fiona E. , Hasty Alyssa H. 
Published: December 2022

AbstractBackgroundNeuroinflammation and microglial activation are critical components of Alzheimer’s Disease neuropathology as observed in patients and animal models. Microglia have multiple functions in addition to their inflammatory phenotype that can contribute to disease. Specifically, iron accumulates in AD‐associated brain regions, and we and others have shown enhanced iron load in activated microglia surrounding amyloid‐beta (Aβ) plaques. Furthermore, we and others have shown a distinct upregulation in the microglial iron importer, divalent metal transporter 1 (DMT1) in response to Aβ. Our aim is to further elucidate the role of microglial iron‐handling in age and AD‐associated inflammation.MethodWe measured DMT1 gene expression to assess changes in iron‐handling in response to age and inflammation. Microglia isolated from aged mice were treated with an inflammatory Aβ stimulus before measuring DMT1 expression and immunohistochemical markers of iron load. To determine the role of microglial DMT1 during inflammatory pathology in vivo, we targeted DMT1 expression utilizing a microglial‐specific tamoxifen‐inducible genetic mouse model in males and females. Transgenic mice were given intraperitoneal lipopolysaccharide (LPS) as a widely‐used model of neuroinflammation. We isolated microglia 24hr after LPS administration and measured DMT1 expression via qRT‐PCR for knockdown confirmation. Sickness behavior and markers of inflammatory state were also assessed.ResultMicroglia from 2‐year‐old aged mice display an augmented increase in Aβ‐induced DMT1 expression compared to young controls. Our in vivo studies also suggest a sex‐dependent increase in microglial DMT1 expression following systemic LPS. In our genetic mouse model, we obtained a 79% and 89% knockdown of microglial DMT1 gene expression in males and females, respectively. Male knockdown animals exhibited a trending decrease in Il‐1β expression in response to LPS, indicating an intimate link between pro‐inflammatory signaling and microglial iron‐handling.ConclusionThese studies link changes in microglial iron‐handling and the neuroinflammatory response. Additional in vivo work is further being analyzed to comprehensively determine the effects of DMT1 inhibition on the neuroinflammatory response. Considering the prominence of iron‐loaded microglia and chronic neuroinflammation in late‐stage AD, early intervention aimed at a specific aspect of microglial iron‐handling could be a target to decrease inflammation and AD‐related pathology.
Carbonic anhydrase inhibitors: a novel pharmacological strategy to rescue Aβ‐induced neurovascular pathology and gliosis in vivo
Authors: Canepa Elisa , Vazquez‐Torres Rafael , Guzman‐Hernandez Roberto , Debure Ludovic , Angiulli Federica , Parodi‐Rullan Rebecca M , Lemon Nicole L , Fossati Silvia 
Published: December 2022

AbstractBackgroundCerebrovascular dysfunction (CVD) and neuroinflammation are associated and contribute to Alzheimer's disease (AD) progression. Most AD cases also present cerebral amyloid angiopathy (CAA), characterized by amyloid beta (Aβ) deposits at the brain vasculature, which trigger CVD and dysregulated brain clearance. In addition, CVD and altered clearance worsen vascular Aβ deposition, inducing cellular stress, neuroinflammation, metabolic waste accumulation, vascular permeability, infiltration of blood‐borne cells, and eventually leading to neurodegenerative processes and cognitive impairment. Endothelial cells (ECs) and glial cells are major players in mediating vascular fitness and brain clearance, promoting the removal of toxic material from the brain, including Aβ. Our previous findings demonstrated that Aβ elicits mitochondrial dysregulation and caspase‐mediated apoptosis in ECs and glial cells. Moreover, we showed that acetazolamide (ATZ) and methazolamide (MTZ), FDA‐approved carbonic anhydrase inhibitors (CAIs), employed in non‐AD related conditions, hinder these pathological events.MethodsTgSwDI mice, expressing human Amyloid‐β Precursor Protein, APP, carrying the Swedish, Dutch and Iowa mutations, were employed as AD/CAA model. Tg mice, which develop, starting at 6 months, fibrillar Aβ burden, primarily in the cerebral microvasculature, and gliosis, were fed a CAI‐diet (from 8 to 16 months of age), following which we tested cognitive function, and harvested the brains for biochemical and immunohistochemical analyses.ResultsATZ‐ and MTZ‐diet improve behavioral performances, and decrease total brain Aβ burden and caspase‐3 activation. Specifically, CAIs reduce Aβ accumulation in ECs, astrocytes and microglia, and the cell‐specific Aβ‐initiated caspase activity, promoting vascular health, glial anti‐inflammatory/pro‐healing phenotype and perivascular Aβ phagocytosis, which may underlie cerebral Aβ reduction.ConclusionsOur results show that CAIs foster endothelial and glial proper function, improving Aβ clearance, and ultimately providing neuroprotection, and indicate CAIs as a novel pharmacological strategy to rescue Aβ‐induced neurovascular pathology and gliosis in AD/CAA pathology.
Proteomics reveals associations between inflammation and chronic depression in a prospective study of post‐stroke cognition
Authors: Zera Kristy A , Bidoki Neda , Nassar Huda , Drag Lauren , Mlynash Michael , Osborn Elizabeth , Musabbir Muhith , Kim Da Eun , Mendez Maria , Lansberg Maarten , Aghaeepour Nima , Buckwalter Marion S 
Published: December 2022

AbstractBackgroundDepression affects approximately 40% of people with dementia, and is critical to quality of life. Here we examined the relationship between chronic depression and cognition in people with ischemic stroke and used plasma proteomics to get at potential mechanisms and identify novel therapeutic targets.MethodWe recruited subjects 5 months to 9 years after ischemia, age >40, who completed a 60 minute battery of cognitive tests. Composite scores of memory, processing speed, working memory, spatial functioning, and a global cognition score (the average of all cognitive tests) were created based on age‐normed performance. Mood was assessed with the Stroke Impact Scale (SIS3), transformed to a 100‐point scale. Linear regression models analyzed the relationship between depression and cognitive scores in 99 subjects. Plasma was analyzed by O‐link proteomics for 1011 proteins in 85 subjects. Additional regression models were constructed to estimate SIS3 using proteomics. Models were subject to bootstrapping for robustness, and cross‐validation to ensure results were reported on subjects blinded during model training. Pearson correlation identified linear associations between individual proteins and mood. We also investigated differences in proteins with subjects dichotomized into non‐depressed (SIS3>63) or depressed (SIS3≤63) groups.ResultMood was significantly associated with global cognitive score (R=0.368; p<0.001), visuospatial score (R=0.255; p=0.014), and processing speed (R=0.430; p<0.001), but not memory (p=0.441) or working memory (p=0.166). Proteomics alone predicted SIS3 in multivariable models. A total of 180 proteins correlated significantly with SIS3. Plasma levels of IL‐6 (p=0.0325), and TRIM5 (p=0.0011) were significantly elevated in subjects with depression, while HPGDS was significantly reduced (p<0.001). There was no difference in plasma levels of candidate proteins IL‐1ß (p= 0.0830) or TNF (p=0.5287) between depressed and non‐depressed subjects.ConclusionWe report that depression is associated with cognitive outcomes in a population with ischemia, and that machine learning models can predict mood from comprehensive plasma proteomics. We also identified proteins of interest including HPGDS (produces Prostaglandin D) and TRIM5 (upstream of NFkB) that point to an immune association with ischemia‐triggered depression. Future studies are needed to replicate these findings, and preclinical models may help uncover mechanistic relationships that could lead to new therapies.
Plasma pTau181/Aβ42 identifies cognitive change earlier than CSF pTau181/Ab42
Authors: Fowler Christopher , Stoops Erik , Rainey‐Smith Stephanie , Vanmechelen Eugeen , Vanbrabant Jeroen , Dewit Nele , Mauroo Kimberley , Rowe Christopher , Fripp Jurgen , Li Qiao‐Xin , Bourgeat Pierrick , Collins Steven , Martins Ralph N , Masters Colin L , Maruff Paul , Doecke James D 
Published: December 2022

AbstractBackgroundPlasma biomarkers now show an accuracy in detecting Amyloid Beta (Aβ) similar to AD biomarkers derived from cerebral spinal fluid (CSF). However, the ability of plasma AD biomarkers, alone or in combination, to predict cognitive decline has not yet been compared to that of CSF AD biomarkers.MethodPlasma biomarker data from 233 participants’ first visit in the Australian Imaging, Biomarkers and Lifestyle study (AIBL) was submitted to linear mixed effects models (LME) to quantify the relationship with change in cognition (measured using the AIBL PACC) and in clinical disease stage (CDR SoB) in both PET Aβ‐ (Centiloid value <20CL) and Aβ+ (Centiloid value ≥20CL) participant subgroups. Separate models were used to assess CSF (Elecsys) and plasma (ADx NeuroSciences) data for Aβ42, pTau181 and the pTau181/Aβ42 ratio. Biomarker values were classified into low vs high levels based on ROC‐derived thresholds optimizing separation of PET Aβ status (low vs high at 20 CL). Changes in cognitive and clinical symptoms were then compared between the low/high plasma biomarker groups.ResultIn Aβ‐ participants, no significant interactions between binary biomarker classification and time were observed for AIBL PACC or CDR SoB, for either CSF or plasma biomarkers. In the Aβ+ participants, interactions between the binary plasma biomarker classification and change in cognition were greater in magnitude that those detected for CSF biomarker classification. For plasma, abnormally high values of both pTau181 and the pTau181/Aβ42 ratio predicted a significant increase over time in CDR SoB (Figure 1H & 1L) and a significant decrease over time in the AIBL PACC score (Figure 1F & 1J), compared the group with low values on the same biomarkers. In cognitively unimpaired Aβ‐ participants, the AIBL PACC score declined in those with abnormally high values of the pTau181 and the pTau181/Aβ42 ratio (Figure 1F & 1J).ConclusionAssays to measure pTau181 and Aβ42 in the plasma possess an accuracy equivalent to those derived from CSF. In particular, abnormally high levels of plasma pTau181 or the ratio of pTau181 to Aβ42 ratio provide a strong prediction of early cognitive changes, even in those with normal PET Aβ status.
Social Networks and Incident Alzheimer’s Disease: the Kuakini Honolulu‐Asia Aging Study
Authors: Kallianpur Kalpana J , Masaki Kamal H , Chen Randi , Willcox Bradley J , Allsopp Richard C , Dodge Hiroko H 
Published: December 2022

AbstractBackgroundWe assessed the longitudinal association between social networks in late life and the incidence of all‐cause dementia (DEM), Alzheimer’s disease (AD) and vascular dementia (VaD) over a 10‐year follow‐up period in a community‐based cohort of older Japanese‐American men.MethodThis prospective study analyzed data from cognitively intact participants of the Kuakini Honolulu‐Asia Aging Study (K‐HAAS). The K‐HAAS began with the Kuakini Honolulu Heart Program’s fourth examination in 1991‐1993, which served as our baseline timepoint. We followed 2,636 Japanese‐American men through the seventh exam (1999‐2000). Participants were dementia‐free at baseline and during the first 3 years of follow‐up. Social network strength was assessed by the Lubben Social Network Scale (LSNS). Weak and strong social network groups were defined by a median split of LSNS scores. Global cognitive functioning was evaluated by the Cognitive Abilities Screening Instrument (CASI), and depressive symptoms by the Center for Epidemiologic Studies Depression (CES‐D) 11‐item Scale. Dementia was diagnosed and classified by consensus of neurologists and geriatricians using standard criteria. Associations between baseline LSNS scores and the risks of DEM, AD and VaD were evaluated by multivariable Cox regression and Kaplan‐Meier estimators using age as the time scale.ResultStudy participants had a median (range) baseline age of 77 (71‐93) years. The age‐adjusted incidence of DEM was significantly higher among men who had weak (LSNS score ≤29) vs. strong (>29) social networks (12.6 vs. 8.7 per 1,000 person‐years of follow‐up; p = 0.014). Kaplan‐Meier survival curves showed that the men with strong social networks were less likely to develop DEM (p<0.0001) and AD (p = 0.0006); the probability of DEM‐free survival at almost 10 years was 93.8% for participants with strong social networks and 89.0% (11% incidence) for those with weak networks. In Cox regression models adjusting for baseline age, education, presence of at least one ApoE ɛ4 allele, prevalent stroke, depressive symptoms (CES‐D score ≥9), and CASI score, weak social networks were significantly associated with increased risk of DEM (HR = 1.52, 95%CI = 1.11‐2.08, p = 0.009) and AD (HR = 1.67, 95%CI = 1.11‐2.51, p = 0.014).ConclusionStrong social networks may protect against incident dementia and Alzheimer’s disease. Effective strategies should be devised to prevent the social isolation of older adults.