bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proximity to parental age at onset exacerbates amyloid burden while mental conditions exacerbate neural loss during midlife
Authors: Arenaza‐Urquijo Eider M , Salvadó Gemma , Operto Greg , Minguillón Carolina , Sánchez‐Benavides Gonzalo , Crous‐Bou Marta , Grau‐Rivera Oriol , Sala‐Vila Aleix , Falcon Carles , Suárez‐Calvet Marc , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

AbstractBackgroundThe identification of the earliest biomarker changes and modifiable factors to be targeted in early interventions is crucial for Alzheimer’s disease (AD) prevention. The objective were (1) to evaluate the hypothesis that proximity to parental age at onset (AAO) in sporadic AD is associated with greater AD and neural injury biomarker alterations during midlife and (2) to assess the role of non‐modifiable and modifiable factors on AD and neural injury biomarkers.MethodA total of 291 cognitively unimpaired (CU) participants with family history (FH) of sporadic AD (aged 49‐73) from the ALFA study. [18F]Flutemetamol‐PET SUVRs, CSF Aβ42/40 and p‐tau were used as AD biomarkers. Hippocampal volumes and CSF t‐tau were used as neural injury biomarkers (Elecsys® immunoassays, Roche diagnostic). Mental and vascular health proxies were calculated. We ran multiple regression models to assess the effect of proximity to parental AAO and its interaction with age on AD and neural injury biomarkers. We also evaluated the effects of FH load (number of parents affected), sex, APOE‐Ɛ4, education, vascular and mental health.ResultProximity to parental AAO was associated with β‐amyloid, but not with neural injury biomarkers, and interacted with sex and age, showing women and older participants increased β‐amyloid (see Fig1). FH load and APOE‐Ɛ4 showed independent contributions to β‐amyloid load. Education, vascular and mental health proxies were not associated with AD biomarkers. However, lower mental health proxies were associated with decreased hippocampal volumes with age (see Fig1).ConclusionProximity to parental AAO may offer a timeline for detection of incipient β‐amyloid changes in women. In risk‐enriched middle‐aged cohorts, mental health may be a target for early interventions.
Sex differences in the relation of mixed TDP‐43 and AD pathologies to risk of dementia and cognitive decline
Authors: Barnes Lisa L. , Yu Lei , Kapasi Alifiya , Lamar Melissa , Bennett David A. , Schneider Julie A. 
Published: December 2020

AbstractBackgroundIt is well‐established that TDP‐43 pathology (also known as LATE) is commonly observed in the brains of older persons, is often mixed with AD pathology, and increases the risk of impairment in episodic memory and Alzheimer’s dementia. It is not known whether there are sex differences in the relation of mixed TDP‐43 and AD pathology with Alzheimer’s dementia and decline in memory.MethodWe included 1,406 autopsied participants who initially enrolled without dementia from three ongoing epidemiologic longitudinal clinical‐pathologic studies of aging: Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study. Participants underwent annual clinical evaluations for diagnosis of Alzheimer’s dementia, including the administration of seven cognitive tests to create summary measures of episodic memory. Systematic uniform neuropathologic examination quantified TDP‐43, AD, and other age‐related pathologies. Persons were categorized into 4 groups; those with no AD or TDP, ‘pure’ TDP, ‘pure’ AD, and mixed AD/TDP. We conducted mixed effects and logistic regression models controlling for age at death, sex, race, and education with cognitive decline and dementia as outcomes, respectively.ResultsIn fully adjusted models that controlled for demographics and other age‐related pathologies, compared to older persons without AD or TDP‐43 pathology, those having either or both pathologies had faster decline in episodic memory. Further, there was a sex difference such that the association of mixed AD/TDP‐43 on episodic memory decline was stronger in women than in men (b = 0.040, SE = 0.018, p = 0.022). Similarly, compared to those with no AD or TDP, having ‘pure’ TDP (OR = 3.261), ‘pure’ AD (OR = 4.176), or mixed AD/TDP‐43 (OR = 10.342) increased the odds of dementia (all p’s <0.001). However, “pure” TDP‐43 pathology increased the odds of dementia more strongly in men than in women (OR = 1.392, 95% CI: 0.555, 0.012), in fully adjusted models.ConclusionThe results suggest sex differences in the effects of mixed AD/TDP‐43 pathology and ‘pure’ TDP pathology on risk of Alzheimer’s dementia and decline in episodic memory. These effects are independent of demographics and other age‐related pathologies.
Genetic risk prediction of late‐onset Alzheimer’s disease based on tissue‐specific transcriptomic analysis and polygenic risk scores
Authors: Jung Sang‐Hyuk , Nho Kwangsik , Kim Dokyoon , Won Hong‐Hee ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundLarge‐scale genome‐wide association studies (GWAS) have identified more than 25 genomic regions related to Alzheimer’s disease (AD). Recent studies showed polygenic risk score (PRS) could be used to identify individuals at high risk of AD. Despite this success, prediction and early intervention of AD still remain challenging. In this study, we constructed prediction models for AD with clinical features, PRS, and tissue‐specifically predicted gene expression levels, and evaluated prediction performance.MethodWe used whole‐genome sequencing data of 446 European participants (207 AD cases and 239 cognitively normal controls) from the Alzheimer’s disease Neuroimaging Initiative (ADNI), and performed quality control of genotyped data using PLINK (Table 1). PRS was derived based on a large‐scale GWAS summary statistics (Lambert et al. 2013) using PRS‐CS. We selected genes significantly associated with AD in brain using MetaXcan and the GWAS summary statistics. For these genes, we predicted gene expression levels in 13 brain regions for our study participants by using PrediXcan and GTEx V7. Then, we built a set of different prediction models that incorporated clinical features, PRS, and transcriptomic features using the Random Forest algorithm for the comparison. We evaluated prediction performance in 10‐fold cross‐validation.ResultAn AD prediction model using only demographic information and APOE ε4 status yielded an AUC of 0.726 (±0.055). As shown in Table 2, the inclusion of PRS significantly improved the prediction performance with an AUC of 0.758 (±0.0489). In addition, the inclusion of PRS and transcriptomic features produced much higher performance with an AUC of 0.794 (±0.061). Furthermore, the top 10 overlapping genes in 13 brain regions used in the prediction model were known AD susceptibility genes (Table 3).ConclusionOur study has improved the performance of existing AD genetic risk prediction models by incorporating tissue‐specific transcriptomic factors and PRS, suggesting that tissue‐specific transcriptomic factors and conventional PRS may be partly independent and complementary, so that both are important genetic risk predictors for the classification of AD. In particular, predicted brain expression factors could further provide an indication of tissue‐specific regulatory effects in AD.
Chaperone imbalance drives tau pathogenesis
Authors: Criado‐Marrero Marangelie , Blair Laura J. , Gebru Niat , Blazier Danielle , Baker Jeremy D. 
Published: December 2020

AbstractBackgroundThe microtubule associated protein tau pathologically aggregates in neurons, a central component of ∼15 neurodegenerative diseases termed tauopathies, which include Alzheimer’s and Parkinson’s disease. Our work has demonstrated that age‐ and disease‐related changes to the cellular chaperone repertoire likely contribute to the abnormal buildup of tau. Recently, we have found that two Hsp90 co‐chaperones, the 52kDa FK506‐binding protein (FKBP52) and the activator of 90 kDa heat shock protein ATPase homolog 1 (Aha1), promote tau aggregation in vitro and in the brains of tau transgenic mice. This led us to hypothesize that imbalances in these chaperones may trigger tau misfolding in the aging brain.MethodTo test this, we overexpressed Aha1, FKBP52, or control protein using adeno‐associated virus serotype 9 (AAV9) bilaterally injected into the hippocampus of 10‐month‐old wild‐type mice (n = 6/AAV). After 7 months of expression, we collected brain tissues to determine the effects on tau accumulation.ResultWe have found that high levels of these chaperones can promote abnormal tau phosphorylation and aggregation, but that the species of tau that was affected was different depending on which chaperone what expressed. While we did see an overall increase in silver‐positive staining, we did not detect any true tau tangles in the brains of these mice.ConclusionBased on these studies, we would expect that with enough time, or in the presence of human tau, high levels of these pro‐aggregation chaperones may be sufficient to drive tau pathogenesis. Overall, these findings demonstrate that imbalances in specific chaperones may have a significant impact on the tau in the aging brain.
Amyloid pathology, but not vascular pathology, is associated with risk of incident dementia in non‐demented memory clinic participants
Authors: Haan Renée , Bos Isabelle , Leeuwis Anna E. , Ebenau Jarith L. , van den Bosch Karlijn A. , Barkhof Frederik , Van Berckel Bart N.M. , Teunissen Charlotte E. , Scheltens Philip , Visser Pieter Jelle , van Der Flier Wiesje 
Published: December 2020

AbstractBackgroundCerebral accumulation of amyloid contributes to cognitive decline and progression to dementia. Also vascular pathologies have been suggested to contribute to dementia. We investigated the putative additional effects of vascular and amyloid pathology in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI).MethodWe included patients with SCD (n=294; age 62±6, 40%F, MMSE 27±2) or MCI (n=266; age 66±7, 34%F, MMSE 27±2) from the Amsterdam Dementia Cohort (ADC), with available baseline amyloid status (by CSF or PET), available MRI and longitudinal follow‐up (>1 year). Patients were defined as amyloid positive (A+) when either CSF Aβ 1‐42 or amyloid‐PET scan was abnormal. Vascular positive (V+) was defined as having at least one abnormal vascular MRI marker (Fazekas score 2 or 3, microbleeds ≥1 or lacunar infarcts ≥1). We used Cox proportional hazard models to analyze progression to dementia with sex and age as covariates, firstly analyzing A+ and V+ separately, followed by both simultaneously. In addition, we analyzed the effect of each vascular component separately. All analyses were stratified for baseline clinical diagnosis (SCD, MCI).ResultAt baseline 59 (20%) SCD patients were A+ and 75 (26%) V+, 142 (54%) MCI participants A+ and 124 (47%) V+. At follow‐up (3.0 ± 1.9yrs), 21 (7%) SCD and 92 (35%) MCI developed dementia (Table 1). In both SCD and MCI, amyloid pathology was associated with increased risk of dementia (SCD: HR[95%CI]=4.8[2.5‐9.0]; MCI: 1.7[1.2‐2.5]), while the presence of vascular pathology was not (SCD1.5[0.8‐2.7]; MCI: 0.9[0.6‐1.2]). When we entered both determinants simultaneously in one model, associations remained largely similar. There was no interaction between amyloid and vascular pathology (SCD: HR=0.7, CI95%=0.2‐2.6; MCI: HR=0.89, CI95%=0.4‐1.78). When analyzing the three vascular components separately, we found a trend association of microbleeds with incident dementia in SCD, but not in MCI (SCD: HR[95%CI]=2.3[0.96‐5.4]; MCI: 0.8 [0.5‐1.3]).ConclusionIn this memory clinic cohort of patients with SCD and MCI, we found that – although amyloid pathology and vascular pathology were equally prevalent – only amyloid pathology was associated with incident dementia.
Grey zone amyloid burden heralds future memory decline: The SCIENCe Project
Authors: Ebenau Jarith L. , Verfaillie Sander C.J. , van den Bosch Karlijn A. , Timmers Tessa , Wesselman Linda M.P. , van Leeuwenstijn Mardou , Barkhof Frederik , Prins Niels D. , Scheltens Philip , van Der Flier Wiesje , Van Berckel Bart N.M. 
Published: December 2020

AbstractBackgroundWe aimed to compare different thresholds for amyloid‐beta pathology and their associations with memory decline, and to investigate the clinical significance of ‘grey zone’ amyloid‐beta burden in cognitively normal individuals.MethodWe included 162 cognitively normal participants with subjective cognitive decline (SCD) from the SCIENCe cohort (64±8yr, 38%F, MMSE 29±1). Each underwent a 70‐minutes dynamic [18F]florbetapir PET, T1‐weighted MRI and longitudinal neuropsychological assessment (n=149≥2 visits). PET scans were classified as positive/negative for amyloid pathology by visual assessment (VA). We calculated a mean binding potential (BPND) and mean standardized uptake value ratio (SUVr50‐70) for a composite region of interest (orbitofrontal, temporal, anterior/posterior cingulate, precuneus). Using Gaussian mixture modelling and k‐means clustering (2 clusters: 90% of low cluster, 10% of high cluster), we derived 3 thresholds for amyloid positivity (A+) based on both BPND and SUVr. We compared associations with memory decline for each threshold using linear mixed models (LMM). To investigate whether grey zone amyloid burden is clinically meaningful, we divided the sample into quantiles, and additionally predefined a grey zone using K‐means thresholds (K‐low/K‐grey/K‐high).ResultThe low K‐means thresholds (BPND=0.18, SUVr=1.27) were most comparable to VA (specificity 76% and 71%, Table 1). LMM showed that all A+ thresholds had comparable associations with rate of memory decline to VA (range β ‐0.39 − ‐0.48). With increasing quantile‐levels, memory slopes gradually became steeper for both BPND and SUVr. The predefined grey zone (BPND 0.18‐0.27, SUVr 1.27‐1.42) was significantly associated with memory decline for both BPND (β ‐0.29(SE 0.14)) and SUVr (β ‐0.43 (SE 0.14)).ConclusionWe showed that amyloid positivity thresholds for BPND and SUVr are similar to visual assessment in their association with memory decline. Furthermore, the association between A+ and memory decline is not only driven by individuals with the highest amyloid values, but individuals with grey zone amyloid burden are also at risk of steeper memory decline. Therefore, in case a binary classification is required, we suggest using a relatively low threshold, e.g. BPND 0.18, which includes the grey zone.
Modeling the trajectory of tau deposition in autosomal‐dominant Alzheimer’s disease using the high‐affinity tau tracer [18F]MK6240
Authors: Lussier Firoza Z , Therriault Joseph , Pascoal Tharick A. , Benedet Andréa Lessa , Tissot Cécile , Savard Mélissa , Kang Min Su , Mathotaarachchi Sulantha , Stevenson Jenna , Robb Laura , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundEvidence suggests that Alzheimer’s disease (AD) pathology may appear many years prior to the manifestation of clinical symptoms. While autosomal‐dominant AD (ADAD) only accounts for approximately 1% of AD cases, evidence shows it has similar pathophysiological features to sporadic AD. ADAD provides a unique and powerful means to model the pathophysiological cascade of events leading to clinical dementia during this asymptomatic stage, due to the complete penetrance of ADAD genetic mutations and the consistency of age at symptom onset between generations. Objective: To investigate tau deposition in vivo across the course of ADAD in mutation carriers (MC) and noncarriers (NC) using the high‐affinity tau PET tracer [18F]MK6240.MethodCross‐sectional data was acquired for 12 MC, 6 of whom were symptomatic, and 11 asymptomatic NC. The majority of participants (91%) were from families with PSEN1 mutations. Estimated years from symptom onset (EYO) was obtained by subtracting the age at symptom onset of a parent or sibling from the participant’s age at assessment. [18F]MK6240 standardized uptake value ratio (SUVR) was calculated 90‐110 minutes post‐injection using inferior cerebellar grey matter as the reference region. Statistical analyses performed included ROI‐based and voxel‐based regressions to examine the association between tau load and EYO in MC and NC.ResultROI‐based analyses of [18F]MK6240 SUVR as a function of EYO in mutation carriers revealed strong positive correlations for Braak I‐II, III‐IV, and V‐VI. None of the associations between [18F]MK6240 SUVR and EYO were significant in NC. Voxel‐based analyses showed significant correlation between [18F]MK6240 retention and EYO bilaterally in the entorhinal cortex and in the right posterior cingulate and precuneus in MC, while no associations survived correction for multiple comparisons in NC.ConclusionOur results support a common pathophysiological cascade between ADAD and sporadic AD, as tau aggregation appears to follow Braak stages in both cases. Our study suggests that tau pathology appears up to 10 years before the onset of clinical symptoms. The identification of affected individuals using biomarkers early in the course of disease is crucial for better clinical outcomes. These results support the applications of disease‐modifying therapeutic interventions in the preclinical stage of AD.
The COMT rs4680 polymorphism is associated with rate of cognitive decline in older adults with type 2 diabetes
Authors: Manzali Sigalit , Beeri Michal Schnaider , Ravona‐Springer Ramit , Lin HungMo , Liu Xiaoyu , Heymann Anthony , Greenbaum Lior 
Published: December 2020

AbstractBackgroundThe single nucleotide polymorphism (SNP) rs4680 (Val158Met) in the Catechol‐O‐Methyltransferase (COMT) gene affects dopamine level and has been consistently associated with cognitive functioning; the A allele, encoding Methionine, is linked to better cognition (and higher cortical dopamine levels) and lower risk of dementia than the G allele, encoding Valine. Type 2 diabetes (T2D) older adults have greater cognitive decline and higher dementia risk than non‐T2D persons but the role of COMT in this association has not been examined.MethodUsing data from the Israel Diabetes and Cognitive Decline (IDCD; N=964) study, we examined associations of COMT rs4680 with cognitive decline over a 48‐month period. Approximately every 18 months, participants completed a comprehensive neuropsychological battery of 15 tests transformed into z‐scores and summarized into four cognitive domains: episodic memory, attention/working memory, executive functions and language/semantic categorization. The average of the z‐scores of the four domains defined global cognition. Mixed regression models examined the associations of rs4680 with cognitive decline adjusting for age, sex, education and Jewish origin (Ashkenazi or Sephardi).ResultParticipants were on average 71.6 (SD 4.6) years old; 42% women; 13.2 (3.5) years of education. Compared to carriers of rs4680 GG genotype (N=249, 25.8%), carriers of the A allele (AA genotype [N = 216, 22.4% ]+ AG genotype [N = 499, 51.8% ]) had faster rates of decline in global cognition (estimate= ‐0.004; p=0.03), executive functions (estimate= ‐ 0.009 ; p= 0.01) and episodic memory (estimate= ‐0.007 ; p=0.04), but not in attention/working memory nor language. For language, there was a main effect with significantly and consistent better function among the GG genotype carriers over time (estimate= ‐0.50; p=0.001). Additionally adjusting for numerous cardiovascular and T2D‐related risk factors and T2D medications did not alter the results.ConclusionOur finding suggests that among T2D elderly, COMT SNP rs4680 affects cognitive decline over time. In contrast to the anticipated direction, A allele carriers had poorer cognitive outcomes. There is evidence indicating that the GG genotype protects against onset of T2D and hyperglycemia; our results suggest a more global protective effect of this genotype against T2D and its complications, including cognitive impairment.
Hippocampal volume and shape features in superagers
Authors: Cobia Derin , Paxton Holly , Sridhar Jaiashre , Makowski‐Woidan Beth , Engelmeyer Janessa , Weintraub Sandra , Mesulam Marsel , Rogalski Emily J 
Published: December 2020

AbstractBackgroundInterest in factors contributing to superior cognitive aging has increased in recent years with the study of “SuperAgers” – individuals over age 80 with episodic memory performance similar to average middle‐aged adults. Given hippocampal involvement in memory formation, this project aimed to assess the integrity of this structure in the context of “SuperAging.”MethodParticipants included 67 SuperAgers (SA), 28 cognitively average 80+ year‐old cognitively average normal controls (O‐NC) and 25 middle‐aged cognitively average controls (MA‐NC). SA were age >80 with memory performance at or above normative values for individuals 50‐60 years of age and other cognitive scores normal for age. Control groups scored within the average range for age and education on all cognitive domains. Volume and shape of bilateral hippocampi in each participant was estimated using high‐dimensional surface mapping. Comparisons between groups included the use of repeated measure GLM designs.ResultNo significant effect for hippocampal volume by group (SA: left=2006.33, right=2550.02; O‐NC: left=2017.25, right=2537.94; MA‐NC: left=2208.98, right=2589.70; F
117,2=1.453 p=0.23), but a significant hemispheric effect (Right>Left; F
117,1=632.40, p<0.001) and group x hemisphere effect (F
117,2=6.65, p=0.002). Shape models revealed a significant difference among groups in left (F
216,20=9.23, p<0.001) and right (F
216,20=1.81, p=0.02) hippocampal shape. Follow‐up ANOVAs revealed this effect was primarily driven by MA‐NC shape differences (SA vs MA‐NC Left: F
81,10=16.71, p<0.001; Right: F
81,10=3.26, p=0.001). Hippocampal shape did not differ between SA and O‐NC (Left: F
93,10=0.95, p=0.5; Right: F
93,10=1.10, p=0.41), but did significantly differ between O‐NC and MA‐NC in the left hemisphere (F
42,10=12.02, p<0.001), but not the right hemisphere (F
42,10=1.10, p=0.42).ConclusionDespite exceptional episodic memory performance, hippocampal integrity does not appear to be a strong discriminating factor in older adults with superior memory function. While no differences in global hippocampal volume between groups emerged, significant shape differences were noted in both SuperAgers and their age similar controls relative to middle‐aged controls. Overall, our findings may represent a phenomenon where memory ability in old age serves more as a function of a diffuse network of cortical structures rather than a single region. Future exploration would include evaluating connectivity of hippocampal‐involved networks that include regions such as medial temporal cortical and diencephalic structures.