bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examining the impact of a rare protein‐truncating SORL1 variant on AD pathology
Authors: DeRosa Brooke A , Simon Shaina A , Cuccaro Michael L. , Cukier Holly N. , Vance Jeffery M. , Vance Margaret A. , Dykxhoorn Derek M. 
Published: December 2022

AbstractBackgroundRecent analyses of rare variants using whole exome sequencing have found an enrichment of SORL1 loss‐of‐function (LoF) variants in early onset Alzheimer’s disease (EOAD). This makes SORL1 one of the highest risk factors for AD, along with other candidate EOAD genes such as APP, PS1, and PS2. SORL1 encodes an endocytic receptor involved in the trafficking of amyloid‐β precursor protein (APP) and the secretion of amyloid‐β. We identified a family with multiple individuals affected with EOAD carrying a single base pair deletion (c.4293del) in SORL1, resulting in a frameshift and premature termination of the protein (p.Cys1431fs; Kunkle et al. JAMA Neurol. 2017). Several recent studies have demonstrated that haploinsufficiency of SORL1 can induce AD‐related phenotypes in cultured neurons. However, the functional consequences of specific variants remain largely undefined. In this study, we used patient‐specific induced pluripotent stem cell (iPSC)‐derived neurons to evaluate the effect of a rare LoF SORL1 variant on AD‐related pathology.MethodPatient‐specific iPSC lines were derived from two related heterozygous p.Cys1431fs carriers with EOAD. Each line was validated for pluripotency through immunocytochemical staining and RT‐PCR. Karyotypic stability was assessed by G‐banding. To evaluate the functional consequences of the SORL1 deletion, patient and control iPSC lines were differentiated into cortical neurons and assessed for AD‐related phenotypes.ResultThe iPSC lines were successfully differentiated into cortical neurons, characterized by immunostaining for various neuronal markers. Our data show that neurons bearing the p.Cys1431fs SORL1 mutation have increased levels of APP accumulated in EEA1+ endosomes compared to neurons from cognitively intact individuals. Additionally, analysis of synaptic density revealed that neurons carrying the p.Cys1431fs variant show a significant reduction of SYN1+ puncta compared to cognitively intact individuals.ConclusionOur results indicate that patient‐derived neurons carrying the p.Cys1431fs variant have cellular defects associated with AD pathology while replicating, at least in part, previous in vitro findings on SORL1 haploinsufficiency.
Verbal recognition declines in later Braak Stages compared to verbal delayed recall
Authors: Arias Jaime Fernandez , Therriault Joseph , Lussier Firoza Z , Pascoal Tharick A , Tissot Cécile , Wang Yi‐Ting , Bezgin Gleb , Servaes Stijn , Kang Min Su , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Poltronetti Nina Margherita , Kunach Peter , Ottoy Julie , Stevenson Alyssa , Mathotaarachchi Sulantha , Massarweh Gassan , Vitali Paolo , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2022

AbstractBackgroundEpisodic memory decline is a hallmark of cognitive impairment due to Alzheimer’s Disease (AD). Literature has consistently indicated that delayed recall is compromised early in the disease. Recognition memory seems disrupted at late stages, although findings are mixed. Recent PET studies have demonstrated that the presence of tau in the medial temporal lobe (MTL) relates to early deterioration of delayed recall, but no PET studies have assessed how recognition memory relates to tau. We sought to investigate this relationship across the Braak staging continuum.MethodTau PET ([18F]‐MK6240) was acquired for 140 cognitively unimpaired elderly (CU), 54 MCI patients and 33 AD patients. Participants were segregated into Braak stages, based on in vivo PET neuroimaging of tau. Episodic memory was assessed using RAVLT delayed recall and recognition tests. MRI were segmented into probabilistic grey (GM) and white (WM) maps, non‐linearly registered to the ADNI template using Dartel and smoothed with an 8mm FWHM gaussian kernel. Independent samples t‐tests or their nonparametric counterparts were conducted to evaluate differences in memory scores by Braak stage. Voxel‐wise linear regression models were applied, using VoxelStats, with either delayed recall or recognition scores as dependent variables and tau PET as a predictor. Global amyloid, age, sex, education and APOE genotype were entered as covariates.ResultsPairwise comparisons revealed that recognition memory is spared in early Braak stages. Voxel‐wise analyses in the whole sample unveiled that delayed recall and recognition memory relate to tau in virtually the same cortical areas. However, the strength of the relationships widely varied by memory type. Tau‐PET in anterior MTL and posterior hippocampus shows stronger associations with delayed recall, while tau binding in lateral temporal, temporooccipital and posterior areas exhibits stronger associations with recognition memory.ConclusionOur findings support the differentiation between delayed recall and recognition across the AD spectrum. Relationships between delayed recall and tau in the MTL are in concordance with previous research. Moreover, the contrast in the strength of the associations between memory and tau aggregation further supports the notion that delayed recall is already impaired in early Braak stages while recognition is damaged in later Braak stages.
Interactions between brain and bile acid ratio profiles predict baseline cognitive status
Authors: Labus Jennifer S , Liu Cathy , Blach Colette , Arnold Matthias , Kaddurah‐Daouk Rima F. , Mayer Emeran A 
Published: December 2022

AbstractBackgroundAlterations in the brain‐gut microbiome system are thought to play an important role in the development of neurodegenerative diseases. While the great majority of secreted primary bile acids (BAs) are reabsorbed in the ileum, about 5% are metabolized by gut microbes and reabsorbed. Alterations in secondary BAs metabolism associated with specific gut‐microbial species, and reflected in altered ratios of primary and secondary BAs have recently been linked with brain atrophy and cognitive decline. The aim of this study was to investigate whether interactions between brain‐derived morphometric phenotypes and BA profiles can predict baseline cognitive status (cognitively normal (CN), mild cognitive impairment (MCI), Dementia (AD)) or conversion status (MCI to AD).MethodThe sample included 1013 CN, MCI, and AD participants from the Alzheimer’s Disease Neuroimaging Initiative cohort. Regional brain morphometry was derived using Freesurfer v5.1 and Desikan‐Killany atlas. Targeted metabolomics profiling quantifed concentrations of 20 BAs from serum samples. Analysis was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO). Data was split into a training and test sets (70/30 split) to determine predictive accuracy.ResultA correlated brain and BA ratio signature predicted cognitive status (CN vs AD) with high predictive accuracy (see Figure 1). The brain signature of AD, compared to CN was characterized by gray matter atrophy in a limited number of regions including the hippocampus, entorhinal cortex, amygdala and medial temporal regions. The BA ratio signature was characterized by higher ratio of glycolithocholic acid and glycodeoxycholic acid to ursodeoxycholic acid, GLCA:UDCA, GDCA:UDCA along with a lower ratio of cholic acid to GLCA in AD. Predicted conversion from MCI to AD at 2 and 4 years had lower predictive accuracy (BER∼ = 34%)ConclusionThese findings demonstrate that interactions between brain signatures and secondary BA profiles predict baseline cognitive status with high accuracy. They support the concept that differences in gut microbial metabolism of certain BAs, possibly related to diet, play a role in shaping the brain signature in AD patients. Compared to previously employed univariate approaches, the supervised multi‐omics multivariate integration approach complements and elucidates the interactions along the brain gut microbiome axis that contribute to AD.
Longitudinal clinical and neuropsychological outcomes in limbic predominant age related TDP_43 encephalopathy vs. Alzheimer’s disease from The 90+ Study
Authors: Sajjadi S. Ahmad , Qian Tianchen , Bukhari Syed , Woodworth Davis C. , Montine Thomas J. , Corrada Maria M. , Kawas Claudia H. 
Published: December 2022

AbstractBackgroundLimbic predominant age related TDP‐43 encephalopathy‐neuropathologic change (LATE‐NC) is prevalent in the oldest old. Our aim was to determine the association of longitudinal change in clinical and neuropsychological measures in relation to the presence of LATE‐NC and Alzheimer’s disease neuropathologic change (ADNC) in an exclusively oldest‐old cohort.Methods323 participants from The 90+ Study with longitudinal evaluations and autopsy data were studied. LATE‐NC was considered present in those with TDP‐43 in hippocampus and/or neocortex and ADNC in those with high‐likelihood ADNC according to NIA‐AA guidelines. Scores in clinical dementia rating sum of the boxes (CDR‐SB) and neuropsychological tests representing global cognition (MMSE and modified MMSE (3MS)), memory (California verbal learning test‐long delay (CVLT)), language (Boston naming test (BNT)), executive function (TRAIL‐B), attention/concentration (digit span backward), and orientation (from MMSE) were used to calculate standardized effect sizes (SES) of LATE‐NC and ADNC on longitudinal change in the scores. Relationships were estimated using linear mixed effect models accounting for age at death, age at the time of testing, sex, and education.ResultsMean age at death was 97.7 years and 67% were female. Prevalence of LATE‐NC and ADNC in the whole cohort was 28% and 31% respectively and 11.4% had both pathologies. Of 34% who had dementia at death, 42.7% had LATE‐NC and 41.8% had ADNC (Table 1). LATE‐NC alone was associated with decline in global measures [MMSE (SES: ‐0.70), 3MS (SES:‐0.77), CDR‐SB score (SES: 0.89)] and with orientation (SES: ‐0.82). In contrast, ADNC alone was associated with decline in executive function‐ TRAILB (SES: 0.49). Both pathologies, LATE‐NC and ADNC, were related to decline in memory‐CVLT (SES: 0.73 for LATE‐NC & 0.46 for ADNC), language‐BNT (SES: 0.54 for LATE‐NC & 0.45 for ADNC), and attention‐digit span backward (SES: 0.41 for LATE‐NC & SES: 0.36 for ADNC) (Figure 1).ConclusionOur results confirm the importance of LATE‐NC in the oldest old and highlight that LATE‐NC and ADNC are associated with partially distinct patterns of clinical and neuropsychological decline that might aid prediction of LATE‐NC during life.
Plasma pTau 181 concentrations in middle‐aged, community‐dwelling, racially and ethnically diverse adults
Authors: Brickman Adam M. , Lao Patrick J. , Banjoko Michael B. , Mayeux Richard , Simoes Sabrina , Manly Jennifer J 
Published: December 2022

AbstractBackgroundPlasma biomarkers for Alzheimer’s disease (AD) are becoming more widely available, with pTau181 emerging as among the most sensitive and specific. There is a lack of data characterizing plasma pTau181 concentration in diverse cohorts and in middle age. The purpose of this study was to examine the association of age, sex/gender, race/ethnicity, APOE genotype, and memory with plasma pTau181 in the Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease study, a population‐representative study of AD risk in middle aged adults.MethodWe included 1041 participants (56±11‐years‐old [range: 28‐88], 68% women, 13±3 years education, 49% Latinx tested in Spanish, 24% Latinx tested in English, 20% non‐Latinx Black, 7% non‐Latinx White, 28% with APOE‐ε4). Blood samples were analyzed for pTau181 concentration (Quanterix Simoa) and APOE genotype, and memory was evaluated with the Selective Reminding Test (SRT). We used general linear models to examine associations of pTau181 concentration with the variables of interest. We also examined differences in memory among subgroups of participants defined with a model‐based clustering approach based on the distribution of Ptau181 concentrations.ResultPTau181 concentrations were 1.87±1.21 pg/mL (range: 0.071‐16.15). Increased age (β=0.016 [0.009‐0.023], p<0.001) and male sex/gender (β=‐0.274 [‐0.436‐ ‐0.111], p<0.001) were associated with higher pTau181, but APOE‐ε4 genotype (β=‐0.008 [‐0.176‐0.161], p=0.930) was not. PTau181 did not differ between Latinx participants tested in Spanish (reference group) and Latinx participants tested in English (β=0.151 [‐0.048‐0.350], p=0.136), non‐Latinx Black (β=0.150 [‐0.056‐0.357], p=0.153), or non‐Latinx White (β=‐0.031 [‐0.284‐0.345], p=0.849) participants. Higher pTau181 was associated with lower SRT delayed memory scores in an unadjusted model (β=‐0.442 [‐0.661‐ 0.22], p<0.001) and after adjustment for age, sex/gender, race/ethnicity, education, and APOE status (β=‐0.366 [‐0.577– ‐0.154],p<0.001). We identified three clusters of participants, corresponding to relatively low, medium, and high pTau181 concentrations. The highest cluster had poorer memory performance than the other groups in fully adjusted models (F=5.56, p=0.004).ConclusionPlasma pTau181 concentrations are associated with memory, sex/gender, and age in midlife. We do not find evidence of race/ethnicity or APOE related differences in pTau181 concentrations in this age group.
Biophysical analysis of TREM2 interactions reveals a shared binding site for Alzheimer’s disease ligands apoE and oligomeric amyloid beta
Authors: Greven Jessica A , Song Jong Hee , Kober Daniel L , Alexander‐Brett Jennifer M , Gross Michael L , Brett Thomas J 
Published: December 2022

AbstractBackgroundThe development of new innovative treatments to prevent and ameliorate AD requires knowledge of molecular mechanisms that are critical to neuronal health. The triggering receptor expressed on myeloid cells 2 (TREM2) receptor is part of a signaling complex that modulates inflammatory responses, phagocytosis and cell survival in microglia, resident immune cells in the brain that play a critical role in clearing misfolded aggregates. Examples include neurotoxic aggregates consisting largely of amyloid beta (Ab) and apoliproteinE (apoE). Both molecules have emerged as important signaling ligands for TREM2. Although TREM2 signaling in microglia is generally associated with beneficial outcomes, intense or prolonged signaling may produce overactivated microglia leading to neuronal damage. Such events may also contribute to other diseases such as Parkinson’s or cancers. Furthermore, rare TREM2 variants, most notably R47H and R62H, have been identified that are associated with a significantly increased risk of developing AD. Given these significant roles, TREM2 has emerged as an important yet challenging therapeutic target for AD. Although a number of ligands for TREM2 with relevance to AD have been identified, little is known regarding the molecular details of how TREM2 engages them. Detailed knowledge of the molecular mechanisms underlying TREM2 signaling in microglia is urgently needed to facilitate the development of specific, potent, safe and efficacious therapies for AD that target the TREM2 signaling pathway. The objective of this study was to identify the critical surfaces on TREM2 that mediate interactions with both apolipoproteinE (apoE) and oligomeric amyloid b1‐42 (oAb42) using rigorous structural and biophysical methods.MethodWe used structure‐based mutations and comprehensive biolayer interferometry (BLI) analysis to investigate TREM2 interactions with apoE and oAb42.ResultWe found that TREM2 utilizes a distal hydrophobic surface, consisting of the CDR1, CDR2, and CDR3 loops, to engage apoE. Surprisingly, we found that this same surface is utilized to engage oAb42.ConclusionOur results indicate that the hydrophobic site on TREM2 (consisting of the CDR1, CDR2, and CDR3 loops) is the critical ligand‐engaging surface on TREM2. They also indicate that therapeutics that either directly bind or allosterically alter the hydrophobic site on TREM2 should modulate TREM2 signaling as potential AD treatments.
Global and local ancestry modulate APOE association with Alzheimer's neuropathology and cognitive outcomes in an admixed sample
Authors: Naslavsky Michel S , Suemoto Claudia Kimie , Brito Luciano Abreu , Scliar Marília Oliveira , Ferretti‐Rebustini Renata Eloah de Lucena , Rodriguez Roberta Diehl , Leite Renata Elaine P. , Araujo Nathalia Matta , Borda Victor , Tarazona‐Santos Eduardo , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Nitrini Ricardo , Yaffe Kristine , Zatz Mayana , Grinberg Lea Tenenholz 
Published: December 2022

AbstractBackgroundDementia affects more Black individuals, likely due to a combination of environmental and biological factors1,2,3. APOE ε4 allele risk of dementia is different between individuals with European (EUR) and African (AFR) ancestries4,5,6. It is unclear what drives these differences in Alzheimer’s disease (AD) neuropathology among patients with cognitive decline, both outcomes influenced by different sets of biological and environmental factors. We studied the interaction between global and local APOE African ancestry, e4 allele, burden of neuritic plaques (NP) and neurofibrillary tangles (NFT), and cognition in a postmortem sample of admixed individuals with AD pathology.MethodCommunity‐dwelling autopsied brains (n=400) without neuropathological changes or with NP scored using CERAD and NFT scored by Braak stage but lacking others comorbid neuropathologies. Subject’s cognitive function prior to death as assessed using Clinical Dementia Rating sum of boxes (CDR‐SOB). APOE genotypes were assessed with allele‐specific amplification. Global ancestry was inferred using Admixture and local ancestry using RFMix, derived from panels of variants interrogated by microarray.ResultWhen dichotomously ascertained at 2% of AFR, and adjusting for age, sex, educational attainment and APOE ε4 carrier status, the admixed group is significantly protected of neuritic plaques (NP, beta=‐0.21, p=0.04) but not neurofibrillary tangles (NFT, beta=0.137, p=0.39). However, CDR‐SOB was associated with continuously distributed AFR (Table 1) only among individuals with severe levels of NFT (beta=7.04, p<0.001) and NP (beta=3.9, p<0.001). Stratifying the same analysis between APOE status, only APOE ε4 noncarriers presented significant associations between AFR and CDR‐SOB, but APOE ε4 carriers lost significance. APOE local ancestry inference of showed that non‐European admixed APOE ε4 noncarriers had lower NP burden outcomes (Table 2, beta=‐0.28, p=0.032 and beta=‐0.27, p=0.015 with and without adjusting for AFR, respectively), but worst cognitive decline compared to European APOE of the same genotype group when adjusting by NP levels (beta=1.01, p=0.041, without adjusting for AFR). Lastly, APOE ε has a significant effect on neuropathology, but not cognition, only within European local ancestry contexts (Table 3, beta=0.61, p<0.001).ConclusionOur results demonstrate a complex relation between APOE genotypes and local ancestry, AFR global ancestry and AD‐related neuropathology and cognition outcomes.
Investigation of brain networks activity and their association with transfer of cognitive training gains
Authors: Faraza Sofia , Hergert Lena , Dyrba Martin , Wolf Dominik , Fischer Florian U , Knaepen Kristel , Kollmann Bianca , Tüscher Oliver , Binder Harald , Mierau Andreas , Riedel David , Fellgiebel Andreas , Teipel Stefan 
Published: December 2022

AbstractBackgroundAge‐related cognitive decline increase the need for cognitive interventions to maintain cognitive function. Transfer of training gains to untrained tasks is a key indicator for the effectiveness of cognitive training. However, the underlying brain mechanisms need to be further investigated. We implemented a cognitive training study to assess functional connectivity determinants of transfer of training gains.MethodA sample of 181 healthy older adults (mean age: 68 years) underwent a 4‐week cognitive training across three sites. The control group consisted of 54 older adults. To evaluate transfer and training effects, participants underwent a neuropsychological assessment before and after the training. A second follow‐up assessment was applied 12 weeks after the training. The training group was divided in subjects who had and who did not have successful transfer, which was defined as higher improvement in cognitive tasks than the control group. We used cognitive scores representing working memory, verbal and visuospatial memory and executive functions. Baseline resting‐state functional magnetic resonance imaging was assessed in order to investigate the functional connectivity of brain networks associated with cognitive functions.ResultCognitive performance of the training group remained stable across time and did not show a significant improvement. Transfer of training gains directly after the training was limited. However, our participants were able to maintain gains 12 weeks after the training. We hypothesized a higher functional connectivity of brain networks, such as Default Mode Network or the Executive Network, to be associated with successful transfer of cognitive gains. Investigation of brain networks activity and the association with transfer of training gains is currently ongoing and complete results will be presented at the conference.ConclusionTransfer of training gains in aging is possible, but it remains limited. Cognitively healthy older adults might not have major benefits from a 4‐week cognitive training. Our results could help to identify healthy older adults who will most benefit from training and understand the brain mechanisms underlying transfer of cognitive gains.