bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility, satisfaction, and test‐retest reliability of repeated remote memory assessments with older adults
Authors: Basche Kristin E , Berron David , Peterson Amanda , Allison Samantha , Johnson Sterling C , Düzel Emrah , Clark Lindsay R.
Published: December 2023

Background

Frequent, remote cognitive assessments may improve sensitivity to subtle cognitive decline associated with preclinical Alzheimer’s disease (AD). To gain insight on how use of this technology can be optimized, the objective of this study is to determine if feasibility, satisfaction, or test‐retest reliability (TRR) vary depending on task frequency schedules or demographic characteristics.

Method

Participants were recruited from a longitudinal aging cohort to complete three memory tasks via smartphone or tablet using the neotiv application: Object‐In‐Room Recall (ORR), Mnemonic Discrimination for Objects and Scenes (MDT‐OS), and Complex Scene Recognition (CSR). Participants were randomly assigned to complete 24 remote sessions over one year either: (1) every other week or (2) for multiple days within one week every other month. Each session lasted approximately 10 minutes, including one memory task followed by a delayed retrieval session 90 minutes later. Chi‐square tests were used to assess differences in feasibility, acceptability for participants who completed at least 3 sessions, and satisfaction based on task schedule, gender, age, or education. ICC was used to determine TRR of visit 2 to 3 (“V2‐V3”) and an average of visits 1+2 and 3+4 (“V1+2‐V3+4”).

Result

115 participants (mean age = 68.4, 66% women) enrolled; 49 completed all remote sessions to date (Table 1). Willingness to enroll differed by education (X2 = 4.2, p = .04), such that participants with at least a bachelor’s degree were more likely to enroll. Withdrawal from the study occurred more often for those scheduled to the every other week condition (X2 = 6.2, p = .01) than the every other month condition. Measures of acceptability and satisfaction did not differ by task schedule or demographics. TRR from V2‐V3 and V1+2‐V3+4 were adequate, (CSR: ICC = 0.56 and 0.64, ORR: ICC = 0.58 and 0.66, MDT‐OS: ICC = 0.38 and 0.52).

Conclusion

Participants with a bachelor’s degree or higher were more likely to enroll. Reported satisfaction was similar for both task frequency schedules; however, drop‐outs occurred more frequently in those assigned to complete tasks every other week, which could suggest that it is a less optimal task schedule. TRR was moderate for all three tasks. Altogether, results suggest that repeated mobile cognitive testing can be utilized to track cognitive performance remotely.
Decline in cognitive trajectories in the neuropathological spectrum of Lewy Body disease
Authors: Choudhury Parichita , Zhang Nan , Boeve Brad F. , Tremblay Cécilia , Choi Alexander , Belden Christine , Mehta Shyamal , Driver‐Dunckley Erika , Shill Holly , Shprecher David , Serrano Geidy E , Beach Thomas G , Atri Alireza
Published: December 2023

Background

Pathological Lewy body disease (LBD) may commonly present clinically as Parkinson’s disease dementia (PDD), Dementia with Lewy bodies (DLB) or Alzheimer’s disease dementia (ADD). Neuropathological definitions also include a group in which ADD is present, but the postmortem Lewy pathology does not meet threshold density and distribution levels for the neuropathological diagnosis of DLB (ADLB). Little is known about the cognitive profiles of patients with ADLB and despite common underlying pathology, studies delineating neuropsychological profiles in LBD are fraught with inconsistencies. We characterized the longitudinal cognitive trajectories defined by neuropsychological profiles in cases along the pathological spectrum of LBD.

Method

Cases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a cognitive diagnosis of dementia at death and who at minimum, had two neuropsychological evaluations were included. Final neuropathological diagnosis was determined as LBD (neocortical or limbic LB ± AD), ADLB, and AD pathology only. LBD cases were categorized by their cognitive clinical syndromes as PDD and DLB. Global cognition was evaluated using MMSE. Neuropsychological domains of Memory, Executive function, language, attention, and visuospatial were evaluated. Mixed linear methods were used to predict longitudinal change for a given baseline MMSE.

Result

287 participants and 1874 participant‐years of data were included in this study. LBD (n = 115), and ADLB (52) groups were predominantly male, while AD (n = 114) group was primarily female. Baseline MMSE was similar across all pathologic groups. Linear mixed modelling methods showed faster decrease in memory domain scores (decreasing 0.22 units/year – 0.42 units/year faster, p = 0.01) in ADLB group compared to other groups. Significantly faster decline was noted in LBD and ADLB group in clock drawing (p<0.001), fluency scores (declining 1.02 unit/year faster p<0.001) compared to AD group. There was no difference between PDD and DLB clinical subgroups.

Conclusion

In autopsy confirmed cases, ADLB had an accelerated trajectory of decline in memory tasks, while AD, and LBD appeared to have similar trajectories. In contrast, all groups with Lewy bodies progressed faster and showed accelerated decline compared to AD in measures of frontal‐subcortical functions. These results may inform antemortem classification of patients and diagnostic accuracy in these groups.
The SMOC1‐matrisomal proteomics network M42 controls brain homeostasis and modulates toxicity in fly Alzheimer’s Disease models
Authors: Li‐Kroeger David , Al‐Ramahi Ismael , Smith Nathaniel , Marella Aditi , Amoh Bismark K , Saladi Saathwik , Botas Juan , Seyfried Nicholas T , Levey Allan I. , Shulman Joshua M
Published: December 2023

Background

Recent evidence indicates Alzheimer’s disease (AD) has a complex etiology where insults in multiple pathways collude to disrupt neuronal function, yet the molecular changes underlying AD remain poorly understood. To identify changes associated with AD, we previously performed mass‐spectrometry (MS) on post‐mortem brain tissue and identified protein co‐expression networks correlated to AD pathological and clinical traits. The network most strongly correlated with AD pathology (M42) is enriched in components of the matrisome and consists of 32 proteins including multiple signaling pathways, Aß, APOE, and SMOC1, a predicted driver of network behavior. SMOC1 is a key matrisomal protein with conserved roles in modulating TGF‐Beta and wnt signaling during development, yet its role in the adult brain remains unstudied.

Methods

We evaluate the M42 protein network using the powerful genetics of Drosophila melanogaster to determine its role in the brain and uncover links to specific triggers of AD: Amyloid‐Beta (Aβ) and tau. We use a high‐throughput robotic screening platform and video assisted software which enables quantitative assessments of neurological function to identify proteins that modify Aβ‐ or tau‐induced neurodegeneration. We use Mass‐Spectrometry to identify protein changes in the brains of flies harboring homozygous loss‐of‐function mutations in dSMOC1 and genetics, cell biology, and immunofluorescence to characterize dSMOC1 in the fly.

Results

We identified 13 genes with robust evidence of interactions with either tau or Aβ toxicity including dSMOC1 and multiple signaling components. We focused on dSMOC1, finding that flies homozygous for null mutations (dSMOC1−/−) suffer severely decreased survival upon aging. In the fly brain, dSMOC1 is expressed primarily in glia while the protein is localized around most neuronal cell bodies, consistent with its matrisomal role. Finally, we determined protein changes in the brain of dSMOC1−/− flies and found that ECM/receptor interactions and many metabolic pathways including KREBs/TCA cycle, lipid metabolism, and Oxidative Phosphorylation were perturbed.

Conclusion

The M42 protein co‐expression network contains multiple proteins with links to AD. We identified multiple conserved M42 member proteins interacting with specific AD triggers. Together, the genetics and proteomics data support a mechanistic hypothesis where changes in SMOC1 levels disrupt critical signaling pathways leading to disruptions in metabolism affecting survival.
Induced Epileptiform Activity is Increased in Ex Vivo Hippocampal Slices Derived from the AppNL‐F and AppNL‐G‐F Humanised Knock‐In Mouse Models of Alzheimer’s Disease at a Young Age
Authors: Kelly Tommy L , Turner Richard J , Chen Yuqing , Fuchsberger Tanja , Nagappan P G , Nishimaki T , Paulsen Ole
Published: December 2023

Background

Hyperexcitability of neurons in the hippocampus and entorhinal cortex has been demonstrated in Alzheimer’s disease.

Method

We performed multi‐electrode array (MEA) recordings of hippocampal slices from young wild‐type mice, and the AppNL‐F and AppNL‐G‐F knock‐in (App‐KI) mouse models of Alzheimer’s disease amyloidopathy. To investigate the potential for amyloid pathology to drive early hyperexcitability, epileptiform activity was induced in these slices by treatment with aCSF supplemented with high K+ concentrations. A novel automated analysis pipeline was designed to detect epileptiform activity.

Result

Subsequent analysis demonstrated an increased frequency of induced epileptiform activity in the hippocampus of App‐KI mice from as early as 4‐5 weeks old — the earliest that hyperexcitability has been observed in these mouse models to date. At this age, amyloid deposition has not yet begun, thus suggesting soluble amyloid oligomers are the driving factor behind increased epileptiform activity. In 12‐13 week‐old AppNL‐ F mice, where amyloid plaque deposition is still yet to occur, increased induced epileptiform activity was maintained, however, slices derived from AppNL‐G‐F mice, which have plaques at this age, had comparable levels of epileptiform activity to WT.

Conclusion

These findings suggest that inducible hyperexcitability occurs at an early age in App‐KI mouse models of Alzheimer’s disease amyloidopathy, driven by soluble amyloid oligomers. The paradigm employed — and the robust, comparable metrics which it outputs — are analogous to electroencephalogram recordings and could potentially be used as a clinical biomarker to diagnose Alzheimer’s disease at a pre‐symptomatic, treatment‐sensitive stage.
Lewy body co‐pathology contributes to frontal lobe atrophy in Alzheimer’s disease and primary age‐related tauopathy
Authors: Almeida Francisco , Oliveira Tiago Gil , Jesus Tiago , Coelho Ana , Quintas‐Neves Miguel , Gauthreaux Kathryn , Mock Charles , Kukull Walter A. , Crary John F.
Published: December 2023

Background

Alzheimer’s disease (AD) is a heterogeneous proteinopathy. Co‐pathology with Lewy bodies (LB) is frequent and known to contribute to a differential pattern of executive cognitive impairment compared to typical AD. While primary age‐related tauopathy (PART) presents with neurofibrillary tangles, mainly restricted to the temporal lobe and in the absence of amyloid‐beta plaques, LB co‐pathology is also present. However, it is still unknown how the combination of these proteinopathies affects patterns of brain atrophy, which might help clarify the clinical importance and pathophysiology of combined pathology within these groups. Here we investigated the influence of LB on patterns of brain atrophy in AD and PART.

Methods

We selected 214 patients with AD neuropathological change (ADNC) with no LB (n = 102), ADNC with LB (ADNC+LB) (n = 77), PART with no LB (n = 22) and PART with LB (PART+LB) (n = 13) with ante‐mortem volumetric MRI from the National Alzheimer’s Coordinating Center, after exclusion of other neurodegenerative pathologies. Dementia severity was compared using Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB). Cortical and subcortical MRI volume residuals were compared between groups after correction for age. Statistical significance was considered at p‐value < 0.05 after false discovery rate correction for multiple comparisons.

Results

We found that ADNC, ADNC+LB and PART+LB presented similar levels of dementia severity, whereas PART with no LB was the least affected group. MRI revealed higher atrophy of the right frontal operculum and amygdala in ADNC+LB compared to ADNC. ADNC and ADNC+LB showed increased atrophy in regions across all cortical lobes, hippocampus, amygdala and putamen compared to PART, but did not reveal significant differences compared to PART+LB. Interestingly, PART+LB showed higher atrophy of the frontal poles bilaterally, right superior frontal gyrus, left frontal operculum and right putamen compared to PART.

Conclusions

Altogether, these results suggest that LB co‐pathology contributes to frontal lobe regional atrophy in ADNC and likely drives it in PART. Particularly in PART+LB, it suggests that cognitive impairment might derive from alpha‐synuclein pathology rather than tauopathy. These findings indicate that LB pathology determines disease severity within the PART‐ and AD‐continuums.
Clearance of intracellular lipids by lipophagy impaired in APOE ε4 human astrocytes
Authors: Rosa Juao‐Guilherme S , Qian Lu , Tuck Tony , Scrivo Aurora , Cuervo Ana Maria , TCW Julia
Published: December 2023

Background

Apolipoprotein E (APOE) ɛ4 is the strongest known genetic risk factor for Alzheimer’s disease. APOE ɛ4 has been found to impair lipid metabolism in human glia causing accumulation of intracellular lipid droplets. We hypothesized that this phenotype in human APOE ɛ4/ɛ4 astrocytes was due to defective clearance via lipophagy.

Method

Global transcriptomic analyses were performed on astrocytes derived from isogenic and population model human induced pluripotent stem cells (iPSCs). Fluorescent reporters, immunocytochemistry, and western blotting were used to quantify lipid droplets and autophagic machinery in iPSC‐based models.

Result

Global transcriptomic analyses reveal that APOE ε4 drives autophagy dysregulation in astrocytes from human iPSCs. High‐content imaging of fluorescent autophagy reporters and immunocytochemistry revealed accumulation of lipid droplets and autophagy machinery in APOE ɛ4/ɛ4 astrocytes which was ameliorated by induction of autophagy.

Conclusion

Human iPSC‐derived APOE ɛ4/ɛ4 astrocytes exhibit impaired lipophagy.
The unappreciated roles of oligodendrocytes in the etiology of Alzheimer’s disease
Authors: Herrup Karl
Published: December 2023

Background

Dementias such as Alzheimer’s disease are characterized as neurodegenerative diseases. While researchers accept that the etiology of dementia involves multiple cell types, the use of “neuro” as a prefix to “degeneration” biases our mechanistic thinking towards the nerve cell. The cell type that has been most marginalized by this bias is the oligodendrocyte and its myelin ensheathment of the larger axons of the brain. As early as the 1960’s the involvement of myelin pathology had been recognized in the Alzheimer’s disease (AD) brain. Later, with advances in imaging technology, a strong argument was advanced for the mechanistic involvement of myelin, a cholesterol rich membrane, in the etiology of dementia.

Method

Fixed frozen human prefrontal cortex (BA9), hippocampus, and cerebellum were received from both the University of Pittsburgh ADRC and the NIH‐sponsored NeuroBioBank. Mouse brain from wild type and AD models (R1.40 and APP/PS1) were also obtained. Cryostat sections were immunostained for APP and various myelin‐related peptides.

Result

This myelin hypothesis will be reviewed and put in the AD context by summarizing recent results on the impact of APOE, a cholesterol carrier and a major risk factor gene for sporadic AD, on the cells of the oligodendrocyte lineage. Observations on the presence of APP and its processing secretases in oligodendrocytes will deepen the connection to the etiology of AD

Conclusion

Both past and present data support the assignment of an important role for oligodendrocytes in the initiation and progression of Alzheimer’s disease. Broadening our current “neurocentric” view will speed progress towards meaningful therapeutic approaches.
Association of plasma biomarkers with imaging markers of brain atrophy and white matter disease across three neurodegenerative diseases and cerebrovascular disease
Authors: Sanchez Erlan , Coughlan Gillian T , Wilkinson Tim , Baril Andree‐Ann , Binns Malcolm , Bartha Robert , Symons Sean , Hegele Robert , Black Sandra E. , Lang Anthony E , Tartaglia Carmela , Finger Elizabeth , Freedman Morris , Swartz Richard H. , Kvartsberg Hlin , Zetterberg Henrik , Munoz Douglas , Masellis Mario
Published: December 2023

Background

It is necessary to better understand the value of plasma biomarkers in reflecting ongoing neurodegenerative processes before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of disease progression in trials. Herein, we investigate their association with imaging markers of brain atrophy and white matter disease across three common neurodegenerative diseases and cerebrovascular disease.

Method

Patients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer’s disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson’s disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted using the semi‐automated SABRE pipeline on 3T structural MRI sequences harmonized across sites. Fractions of supratentorial total intracranial volume were used when appropriate. Linear regression models controlling for age and sex were used to test the association between plasma biomarkers and MRI variables in each group separately.

Result

In AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with extensive grey matter atrophy, ventricular expansion and, excluding p‐tau181, with increased white matter hyperintensities. In FTD, increased Aβ42/40 ratio was associated with frontal grey matter atrophy, and higher levels of NfL were associated with ventricular expansion. In PD, higher levels of NfL were associated with frontal, temporal and hippocampal grey matter atrophy. In CVD, higher levels of GFAP and NfL were associated with temporal and subcortical grey matter atrophy and ventricular expansion. Higher levels of GFAP were also associated with enlarged perivascular spaces, while higher levels of NfL were associated with increased lacunes. Finally, still in CVD, higher levels of GFAP and p‐tau181 were associated with increased stroke volumes.

Conclusion

Excluding Aβ42/40, plasma biomarkers appear to reflect various levels of brain atrophy in all neurodegenerative diseases studied, but reflect markers of white matter disease only in AD/MCI and CVD.
Preliminary neurocognitive finding from a multi‐site study investing long‐term neurological impact of COVID‐19 using ultra‐high field 7 Tesla MRI‐based neuroimaging
Authors: Tannous Jonika D , Vahidy Farhaan S , Patira Riddhi , Luckey Alison M. , Gonzales Mitzi M. , Hosseini Akram A. , Girard Timothy D. , Ibrahim Tamer , Jacobs Heidi I.L. , Roman Gustavo C , Masdeu Joseph C. , Karmonik Christof , Li Karl , Garbarino Valentina R. , Goss Monica , Nair Rejani R , Patel Vibhuti N , Snyder Heather M , de Erausquin Gabriel A. , Ganguli Mary , Seshadri Sudha , Snitz Beth E.
Published: December 2023

Background

Globally, over six hundred million cases of SARS‐CoV‐2 have been confirmed. As the number of individuals in recovery rises, examining long‐term neurological effects, including cognitive impairment and cerebral microstructural and microvascular changes, has become paramount., We present preliminary cognitive findings from an ongoing multi‐site study investigating the long‐term neurological impacts of COVID‐19 using 7 Tesla MRI‐based neuroimaging.

Methods

Across 3 US and 1 UK sites, we identified adult (> = 18) COVID‐19 survivors (CS) and healthy controls (HC) without significant pre‐existing medical, neurological, or psychiatric illness. Using the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS‐3) battery and Norms Calculator, 12 cognitive scores were adjusted for age, sex, and education and classified as either unimpaired or mild (<9th percentile), moderate (<2nd percentile), or severely impaired (<1st percentile). The observed frequency of impairment across the two groups is reported along with proportional differences (PD) and confidence intervals (CI). Illness severity and time since infection were evaluated as potential associates of cognitive impairment.

Results

Over a period of 11 months, we enrolled 108 participants. At the time of reporting, 80 (46.3% female; mean age: 60.3 ± 8.6; 61 CS, 19 HC) had completed cognitive assessments. Of the participants for whom we ascertained time since symptom onset and illness severity (n = 51 and 43, respectively), 31.4% had their index COVID‐19 infection within the past year, and 60.5% had a severe to critical infection (Table 1). Table 2 reports observed frequency of impairment for each metric. Aggregating all 12 cognitive metrics, we found 45 (73.8%) of CS had at least one impairment [vs HC: 10 (52.6%)]. A significantly greater proportion of CS had at least one moderate to severe or severe impairment (Figure 1). CS also had significantly higher frequencies of presenting with two or more mild to severe impairments [PD 0.33 (0.13, 0.54)]. Illness severity and time since infection were not significantly associated with cognitive impairment.

Conclusion

Our preliminary results are consistent with potentially sustained COVID‐associated cognitive impairment in a subset of participants. Enrollment in the multi‐site cohort is ongoing, and updated results will be presented along with ultra‐high field MRI‐based neuroimaging correlates.
Plasma tau phosphorylation at T217 predicts amyloid deposition in dominantly inherited and late onset Alzheimer disease participants without clinical symptoms
Authors: Barthélemy Nicolas R. , Li Yan , Janelidze Shorena , He Yingxin , Xiong Chengjie , Stomrud Erik , Fagan Anne M. , Karch Celeste M. , Benzinger Tammie L.S. , McDade Eric , Hansson Oskar , Gordon Brian A. , Bateman Randall J.
Published: December 2023

Background

Progressive amyloid plaque accumulation in the brain precedes the emergence of clinical symptoms in Alzheimer disease (AD). This asymptomatic phase, referred to as preclinical AD, induces significant modification of tau phosphorylation in the cerebrospinal fluid (CSF). CSF tau phosphorylation occupancy at Threonine 217 (T217) becomes abnormal more than 20 years before cognitive decline in dominantly inherited AD (DIAD). CSF hyperphosphorylation at T217 also associates with amyloid pathology in late‐onset AD (LOAD) individuals with preclinical AD. In this study, we examined the performance of plasma T217 phosphorylation to detect amyloid plaques deposition measured by amyloid‐PET in asymptomatic participants with DIAD or late‐onset AD (LOAD).

Method

We measured plasma T217 phosphorylation using tau immunoprecipitation and high‐resolution mass spectrometry. Phosphorylation abundance at T217 was expressed as p‐tau217 ratio defined using the level of T217 phosphorylated tau peptide normalized to total tau level. The DIAD cohort included 355 samples from 176 CDR0 and 51 CDR>0 participants in the DIAN Observational study with 62% mutation carriers, all collected in relation to the estimated years to symptom onset (EYO). The LOAD cohort included 321 cross‐sectional samples from BioFINDER‐2 study. Amyloid positivity was determined using cross sectional amyloid‐PET scan available for each participant.

Result

We observed abnormal plasma p‐tau217 ratio in DIAD mutation carriers more than 15 years before EYO (Figure 1). Plasma p‐tau217 ratio accurately predicted amyloid PET positivity for individuals across multiple preclinical stages (Table 1, AUC respectively 0.89 and 0.98 for EYO brackets ‐20 to ‐10 and ‐10 to 0). The plasma test had similar performance in distinguishing amyloid status in the DIAD and the LOAD cohorts (AUC respectively 0.96 and 0.97, Table 1). In LOAD, plasma p‐tau217 ratio identified amyloid positivity independently of the cognitive status (AUC respectively 0.96 and 0.97 for asymptomatic and symptomatic).

Conclusion

Our results support the use of plasma p‐tau217 ratio to screen cognitively normal populations at risk of developing AD dementia. This blood‐based biomarker can support the recruitment of asymptomatic participants for prevention trials and help identifying patients who might benefit from early care using future AD drugs more than a decade before the detection of cognitive symptoms.
Capturing polygenic risk for Alzheimer’s disease using induced pluripotent stem cells
Authors: Young‐Pearse Tracy
Published: December 2023

Background

Over 70 loci have been implicated in AD pathogenesis through genome‐wide association studies. Understanding of how these genetic variants interact with one another, as well as with unknown genetic variants of weak effect size to impinge upon biological processes and molecular pathway to affect risk and resilience to AD is key to unlocking appropriate therapeutic strategies for AD.

Method

We have generated iPSC lines from over 50 deceased individuals in the Religious Order Study (ROS) or Rush Memory and Aging Project (MAP) that span the clinical and neuropathological spectrum of aging. About one third of these individuals had clinical and neuropathological diagnoses of AD and Alzheimer’s dementia. We differentiated these lines into cortical neuronal fates, astrocyte fates and microglial fates and measured RNA and protein profiles as well as quantitative measures of APP cleavage products and tau species. In addition, we have measured autophagic and proteasome capacity, as well as synatic vesicle release and cytokine production.

Result

We identify specific proteins and pathways in neuronal and glial cultures that are associated with AD polygenic risk score (PRS), neuropathological burden, and/or cognitive trajectory in the donors and validate these findings through analyses of brain tissue. We identify an association of cognitive decline and measures of specific amyloid beta peptides and phospho‐tau species in iPSC‐derived neurons. We find that proteasome capacity and autophagic flux are influenced by genetic background, which in turn affects tau proteostasis. Intriguingly, different genetic backgrounds respond differentially to modulation of these protein degradation networks.

Conclusion

The data presented establish this iPSC collection as a resource for investigating person‐specific processes in the brain that are encoded in part by polygenic risk for AD that can aid in identifying and validating molecular pathways underlying AD.
Multivariable regression techniques for sparse polygenic risk models based on individual‐level genotype data
Authors: Klinkhammer Hannah
Published: December 2023

Background

Polygenic risk scores (PRS) evaluate the individual genetic liability to a certain trait and are expected to play an increasingly important role in clinical risk stratification. Most often, PRS models are based on summary statistics of univariate effects estimated from genome‐wide association studies. Despite various approaches to account for linkage disequilibrium and to select the most informative variants, methods based on summary statistics cannot fully account for interdependencies between genetic variants.

Recently, multivariable regression models have been proposed to fit PRS directly on individual‐level genotype data and various algorithms have been developed to overcome the computational challenges imposed by high dimensional genotype data. Multivariable models are fitted based on the genetic information of all variants simultaneously and might therefore contribute to an improved prediction performance of PRS. While many multivariable approaches do not incorporate variable selection, sparser PRS models might be more generalizable to out‐of‐target data, e.g. different populations. Variable selection can be induced by using a‐priori knowledge, such as LD structures used to pre‐define chunks of variants and limiting the number of included variants per chunk, or by using regularized regression techniques like Lasso or statistical boosting which select variants based on the observed data only.

Method

In a comparative study, we fitted PRS models for several phenotypes from the UK Biobank using both, a) summary statistics‐based (including PRScs and LDpred) and multivariable approaches (including snpnet, snpboost and BayesR), as well as b) sparse and non‐sparse models. To evaluate the different PRS models, we used a range of performance measures focussing on association, risk stratification and individual‐level prediction accuracy.

Result

Overall, we found multivariable approaches to have a higher prediction accuracy than summary statistics‐based models. A clear pattern for the level of induced sparsity was not detectable, but results depended on the genetic architecture of the underlying trait. However, the ranking of the PRS models differed among the chosen performance measures.

Conclusion

Our study shows that all approaches have their advantages and disadvantages depending on the underlying and accessible data and the aim of the study. It underlines the importance of careful model choice including adequate performance measures.
The Engaging Communities of Hispanics for Aging Research (ECHAR) Network: Denver Hispanic/Latino Bootcamp Translation
Authors: Mullen Rebecca , Pressman Peter S.
Published: December 2023

Background

Hispanic/Latino (H/L) individuals have higher rates of Alzheimer’s disease and related dementias (ADRD) yet are less likely to be diagnosed with ADRD and engage in ADRD research. Almost 30% of the population is H/L in Denver, Colorado. We carried out the Boot Camp Translation (BCT) process with our local H/L community to increase awareness of medical issues and enhance the uptake of evidence‐based interventions.

Method

During the BCT process, participants learn about a medical issue, share their personal expertise and knowledge, and create locally relevant, culturally informed health messages and plans for message dissemination. The Denver H/L BCT on ADRD was conducted over a series of virtual meetings led by two University of Colorado academic co‐facilitators and a real‐time Spanish interpreter

Result

16 H/L individuals with a broad array of lived experience participated in the Denver H/L BCT on ADRD. The group met over a period of 8 months. Four dominant themes emerged: 1) Awareness of ADRD; 2) Brain health; 3) ADRD risk reduction; and 4) Exclusion of H/Ls in the ADRD health care and research. The target audience for these messages included H/L middle age and older adults and undocumented individuals in Denver. The group worked with a local designer to create flyers and t‐shirts displaying the messages, which were disseminated through local mercados, churches, and libraries. After the project, 12 of the 16 members agreed to serve on a community advisory board (CAB) to help guide future community‐academic partnership work.

Conclusion

BCT is an effective approach to engaging H/L individuals in ADRD research. The Denver H/L BCT successfully conducted the BCT using virtual meetings and a live interpreter. The partnership developed during the BCT led to the formation of a CAB, which will provide infrastructure for sustainable community engaged ADRD work.
Multi‐polygenic score model informs the genetic basis of heterogeneity in Alzheimer’s disease
Authors: Tanigawa Yosuke , Sun Na , Li William F , Boix Carles A , Galani Kyriaki , Mathys Hansruedi , Bennett David A. A , Tsai Li‐Huei , Kellis Manolis
Published: December 2023

Background

Alzheimer’s Disease (AD) is a polygenic and multifaceted disease with many implicated biological pathways across diverse cell types. The heterogeneous phenotypic manifestation, beyond the common characteristic signature of Amyloid beta plaque, across cognition, pathology, and treatment response is well recognized. However, how the polygenic basis of the disease influences the disease heterogeneity across individuals at genomic and cellular levels remains largely uncharacterized.

Method

Here we develop multi‐ polygenic score (PGS) model to assess the genetic basis of molecular phenotypes associated with AD by systematically integrating large‐scale single‐cell RNA‐seq profiling data of 1.9 million cells from 427 human subjects and hundreds of PGSs trained on more than 269,000 individuals in UK Biobank.

Results

We summarize commonly observed transcriptional changes associated with AD as 21 transcriptional hallmarks (Tx1‐Tx21) by applying multivariate differential expression on single‐cell profiling data. Each of our Tx hallmarks consists of dozens to hundreds of cell type‐resolved gene expression patterns across six major cell types. Those 21 Tx hallmarks capture several known cellular and pathological signatures in AD, pinpointing their candidate driver genes, pathways, and cell types of action. Combinations of Tx hallmark burdens lead to a classification of our 427 donors into 14 AD and non‐AD subtypes (G1‐G14) with distinct phenotypic enrichments. For example, one of the AD groups (G5) driven by excitatory neuron‐associated hallmarks shows elevated levels of amyloid burden (p‐value = 6.4×10‐3) but minimum enrichment for tangles (p‐value > 0.5) and cognitive measurements (p‐value > 0.05).

We take advantage of pervasive pleiotropy and systematically assess the polygenic basis of Tx hallmarks by evaluating the cross‐trait predictive performance of publicly available ancestry‐matched PGS models across our 427 subjects. We find distinct patterns of PGS‐Tx hallmark associations models, including cholesterol PGS models that predict oligodendrocyte Tx hallmarks, and volume of the gray matter in different regions of the brain predicts Tx hallmarks in excitatory and inhibitory neurons, indicating the ability to infer dysregulated AD hallmarks, risk groups, and subtypes across individuals decades before symptoms occur.

Conclusion

Overall, our results pave the way toward genetics‐based prognosis and transcriptional subtyping in complex and heterogeneous traits, even in inaccessible tissues.
Association of LATE‐NC with other neuropathologies and cognition in the oldest‐old: Evidence from The 90+ Study and NACC
Authors: Woodworth Davis C. , Nguyen Katelynn M. , Bukhari Syed A. , Montine Thomas J. , Kawas Claudia H. , Corrada María M. M. , Sajjadi S. Ahmad
Published: December 2023

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is a prevalent and important contributor to dementia. A previous study suggested that associations between LATE‐NC and other neuropathologies, namely Alzheimer’s disease neuropathologic change (ADNC) and Lewy bodies (LB), were attenuated in oldest‐old (≥90 years at death) compared to younger‐old individuals. However, this remains an open question. Our objectives were: Objective‐1) Examine the association of LATE‐NC with other neuropathologies and cognition in oldest‐old participants from The 90+ Study and National Alzheimer’s Coordinating Center (NACC). Objective‐2) Compare the associations of LATE‐NC with other pathologies and cognition in oldest‐old vs younger‐old NACC participants.

Method

We included participants from both The 90+ Study and NACC, excluding those with frontotemporal lobar degeneration and rare pathologies. LATE‐NC was defined as presence of TDP‐43 in amygdala, hippocampus, or neocortex. Neuropathologies of interest were dichotomized as follows: ADNC: intermediate/high; LB: limbic/neocortical; hippocampal sclerosis (HS): presence; arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy (CAA): moderate/severe. We used diagnoses of dementia and clinical AD as measures of cognitive function. For Objective‐1 we performed logistic regressions of LATE‐NC with neuropathologies and cognitive measures in oldest‐old participants from The 90+ Study and NACC. For Objective‐2 we tested the interaction between LATE‐NC and age‐group (≥90 vs 65‐90) for associations with neuropathologies and cognitive measures in NACC. Regressions were adjusted for sex and education.

Result

Objective‐1): Both cohorts had similar prevalence of LATE‐NC in the oldest‐old (NACC, N = 393, 44% with LATE‐NC; 90+Study, N = 394, 37% with LATE‐NC, Table‐1). LATE‐NC was consistently associated with HS (P<0.001, 90+Study & NACC), ADNC (P = 0.008, 90+Study; P = 0.002, NACC), dementia (P<0.001, 90+Study & NACC), and clinical AD (P<0.001, 90+Study & NACC), but the association with arteriolosclerosis was specific to NACC (P<0.001; P = 0.7 for 90+Study, Figure‐1).

Objective‐2): NACC participant characteristics are shown in Table‐1. We found trends for the interaction between LATE‐NC and age‐group for ADNC (P = 0.055, stronger in younger‐old) and arteriolosclerosis (P = 0.051, stronger in oldest‐old, Figure‐2).

Conclusion

In the oldest‐old, associations of LATE‐NC with other neuropathologies and cognitive measures were consistent across two independent cohorts. The association of LATE‐NC with ADNC and arteriolosclerosis might be age dependent although further studies are needed.
Young Adult Boot Camp Translation in the Engaging Communities of Hispanics for Aging Research (ECHAR) Network
Authors: Martinez Michelle N
Published: December 2023

Background

Hispanic/Latin American (H/L) populations are at an increased risk for developing Alzheimer’s disease and related dementias (ADRDs). Yet, H/Ls are less likely to participate in research due to several recruitment barriers such as research related stigma, health literacy, and institutional mistrust. Considering family dynamics, household composition, and cultural scripts, young H/L individuals may serve as mediators to help facilitate H/L recruitment and mitigate these key barriers.

Method

Following the Boot Camp Translation (BCT) approach of the ECHAR Network, we recruited 10‐15 H/L young adults, ages 18 to 35, to carry out the BCT in Houston, Texas. Through the BCT, we (1) developed community relevant awareness, education, and recruitment materials and (2) designed outreach and dissemination strategies that will be used to target H/Ls young adults and their older‐adult family members for participation in ADRD research.

Result

10 young adults (mean age (range) = 21.50± 3.75 (18‐31), mean education (range) = 14.60± 1.65 (12‐16), 80% female) participated in the Houston young adult BCT. Participants agreed that the central message should convey a sense of urgency and accountability (i.e., “Alzheimer is real. Healthy or not: On which side do you want to be?”) and focused on dispelling common myths associated with ADRDs. Participants categorized H/Ls by age groups to be targeted according to the sense of urgency of the message. Finally, graphic materials should be intergenerational, representative of the H/L community, informative, and simple.

Conclusion

The young adult BCT leveraged intra‐familial health communication to enhance ADRD‐specific health education. Results demonstrated that culturally relevant messages can be communicated by young adult children to their parents and/or grandparents with downstream effects for engagement and recruitment into ADRD research.
A new fly model of Alzheimer’s disease unveiled targets that mediate coexistent Aβ42 and tau toxicity
Authors: Varte Vanlalrinchhani , Munkelwitz Jeremy W , Scott Raymond , Limas Diego E Rincon
Published: December 2023

Background

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by dementia and cognitive decline due to progressive cerebral cortical atrophy. Brains of AD patients are characterized by the accumulation of microscopic extracellular amyloid‐beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. The deposition of Aβ42, which is one of the fragments of amyloid precursor protein (APP), has been known to play a role in initiating the events leading to the formation of amyloid and subsequently hyperphosphorylation of tau. However, animal models expressing either Aβ42 or tau individually do not mimic the complexity of the human condition. Indeed, recent evidence suggests that Aβ42 and pathological tau interact synergistically to modulate neurotoxicity in AD

Method

To shed light on their concerted roles in AD pathogenesis and to discover pathways mediating Aβ42 and tau interactions, we generated transgenic flies co‐expressing human Aβ42 fused to a signal peptide along with the longest wild‐type tau isoform.

Result

Overexpression of Aβ42 or tau in Drosophila using the UAS‐Gal4 system causes mild to the moderate rough eye. In comparison, co‐expression of Aβ42 with tau causes severe roughening and reduction of the eye size. The level of neuronal cell death in eye tissues was also significantly enhanced in flies co‐expressing Aβ42 and tau. To identify pathways mediating Aβ42+tau interactions, we are currently using the Aβ42+tau eye phenotype as platform to screen 1,500 UAS lines expressing a variety of human genes.

Conclusion

We have identified few enhancers and suppressors not previously known to be involved in AD pathogenesis, which will be helpful to uncover new molecular pathways and potential therapeutic targets. This work is supported by NIH grant R21AG069050 to DERL.
LAS‐Face‐ Name Associative Memory Exam: Discriminant validity for the detection of associative memory disorders in people with mild cognitive impairment in Argentina
Authors: Keller Greta , Carello Agostina , Arruabarrena Micaela Maria , Palermo Cecilia , Corvalan Nicolas , Calandri Ismael Luis , Vila‐Castelar Clara , Allegri Ricardo Francisco , Quiroz Yakeel T. , Crivelli Lucía
Published: December 2023

Background

The Latin American Spanish version of the Face‐Name Associative Memory Exam (LAS‐FNAME) is a validated version of the test that has been used to detect subtle cognitive changes in cognitively unimpaired adults at increased risk for Alzheimer’s disease (AD). Performance in this test has also been associated with markers of brain pathology in cognitively unimpaired older adults at increased risk for AD due to genetic factors or subjective cognitive decline (Papp et al., 2014;Vila‐Castelar et al., 2020). However, this test has not yet been used for the detection of Mild Cognitive Impairment (MCI) in the Latin American population. This study aims to analyze the discriminative validity and diagnostic performance of the LAS FNAME for the detection of verbal associative memory disorders in patients with MCI.

Method

We recruited 30 patients with MCI according to Petersen’s criteria (2010) and 20 healthy controls matched by age, sex and educational level. All participants completed the LAS‐FNAME, which consists of 12 learning trials of novel pairs of face‐names (immediate learning), followed by a delayed recall condition, and a neuropsychological assessment that included: Montreal Cognitive Assessment (MoCA), Craft Story 21, Multifactorial Memory Questionnaire (MMQ‐S) and a Functional Activity Questionnaire (FAQ).

Result

The groups did not differ in age, sex or education (p = 0.25, p = 0.54, p = 0.54). The age range was 61 to 86 years (M = 74.66; SD = 6.65) and the education range was 7 to 18 years (M = 14.63; SD = 3.41). The LAS‐FNAME showed an ability to discriminate against healthy controls from patients with MCI, both in its immediate (AUC = 0.81) and delayed (AUC = 0.79) conditions. The predictive ability was superior than a screening measure (MoCA, AUC = 0.74). The sensitivity and specificity was 68.4% and 89.3%, respectively. The LAS‐FNAME also showed evidence of concurrent validity with a standard memory test (Craft Story 21) in both immediate (r = 0.52, p<0.01) and delayed (r = 0.63, p<0.01) conditions, and reliability was excellent (α = 0.91).

Conclusion

Performance on the LAS‐FNAME was able to distinguish MCI patients from healthy controls, suggesting that the LAS‐FNAME can detect early cognitive changes in prodromal stages of Alzheimer’s disease in Spanish‐speaking individuals.
2023 Annual Report of the Japanese Brain Bank Network for Neuroscience Research (JBBNNR)
Authors: Murayama Shigeo , Saito Yuko ,   JBBNNR Member
Published: December 2023

Background

The Japanese Brain Bank Network for Neuroscience Research (JBBNNR) received the renewal of Grant‐in‐Aid for Transformative Research Areas, MEXT, Japan from 2022 to 2027, whose center is the Brain Bank for Aging Research (BBAR), the first and only Japanese Brain Bank dedicated for aging and dementia research.

Method

JBBNNR, in close collaboration with the Brain Bank Committee, the Japanese Society of Neuropathology (JSNP), is recruiting brain donors, propagating the BBAR protocols for neuropathological examination, and keeping the policy of open resource. JBBNR member consists of BBAR, the Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, Mihara Memorial Hospital and Fukushimura Hospital.

Result

In 2022, the effect of the pandemic of COVID‐19 still influenced the recovery of postmortem brains, owing to the recommendation of the National Institute of Infectious Disease (NIID), Japan, not to use electrical scissors in autopsy. This year, JBBNNR conducted a small number of COVID‐19 autopsies with prion format, following the informal permit of NIID. The total number of hospital autopsy cases slowly recovered. The effort to include legal autopsy of suicide victims and accidental death cases of developmental disorders experienced difficulty in Japanese culture and law. This year JSNP acknowledged ten board certified neuropathologists, whose main aim is to keep the Japanese brain bank system. JBBNNR is based on full autopsy and provided pathological basis to support brain‐ first, body‐ first hypothesis of Parkinson disease (PD). The high quality resource of JBBNNR contributed to first‐ line research, published in Nature and Cell this year.

Conclusion

JBBNNR continued to contribute neuroscience research, focused on AD and PD/ DLB in Japan.