bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex differences in plasma p‐tau181 accumulation is associated with subsequent tau‐PET signal
Authors: Hsieh Stephanie , Townsend Diana , Coughlan Gillian T , Boyle Rory , Klinger Hannah M , Seto Mabel , Hanseeuw Bernard J , Yang Hyun‐Sik , Amariglio Rebecca E. , Hassenstab Jason J. , Hohman Timothy J. , James Bryan D , Risacher Shannon L , Properzi Michael J , Schultz Aaron P. , Baker Suzanne L. , Sperling Reisa A. , Buckley Rachel F.
Published: December 2023

Background

PET and post‐mortem studies show that women consistently exhibit higher medial‐temporal and neocortical tau compared to men, independent of age or diagnostic status. What remains unclear is whether such sex differences are also observed in the plasma biomarkers and related to future tau‐PET deposition. We examined baseline and longitudinal phosphorylated‐tau (plasma p‐tau181‐UGOT), which was derived prior to a tau‐PET scan, in order to determine whether changes in p‐tau181 are associated with higher regional tau‐PET in women relative to men.

Method

We selected 313 participants (clinically normal, n = 169; MCI/dementia, n = 144) from ADNI (Female% = 146(46%); AgeMean = 71(±7)years; APOEe4 = 105(34%); Ab+ = 162(52%)) with at least two timepoints of plasma p‐tau181‐UGOT measured in ADNI1/2/GO (time‐pointsMean = 3.7(±1)). Cross‐sectional Ab‐PET and tau‐PET (Flortaucipir) scan were collected in ADNI3 ((time‐difference from baseline plasmaMean = 7.1y(±1.9)). Two a priori tau‐PET partial volume corrected (PVC) regions were selected: entorhinal (EC) and inferior temporal (IT). We used linear regression to examine the influence of baseline p‐tau181 and sex on subsequent tau‐PET, adjusting for time gap between plasma‐PET and tau‐PET. Linear mixed‐effects models probed how retrospective change in plasma tau were associated with regional tau‐PET and sex, covarying for neocortical Ab‐PET, diagnosis, APOEe4 and age. We also examined interactions between sex and variables of interest.

Result

Baseline p‐tau181 was strongly associated (b = 0.86 and b = 0.53) with subsequent tau‐PET, although sex did not display main effects in the model, nor did sex moderate the plasma‐PET association. Longitudinal p‐tau181 was not associated with subsequent tau‐PET. Women with accumulating p‐tau181 exhibited higher subsequent tau‐PET burden in EC and IT regions than men (p = 0.04 and p = 0.03, respectively; Figure 1). Higher‐order interactions between sex and tau‐PET with APOEe4, diagnosis or Ab‐PET were not significant, although, women diagnosed with MCI/dementia and elevated Ab seemed to drive the interaction (Figure 2).

Conclusion

Elevated tau‐PET burden in women may be more strongly associated with prior increases in plasma p‐tau181 relative to men. Given the pre‐established association between p‐tau181 and Ab, this could be initial evidence that early events related to the deposition of Ab predict later cortical tau deposition in a sex‐specific manner. Given the novelty of examining longitudinal plasma measures, further investigation is necessitated beyond this preliminary evidence.
Synergistic effects of age at menopause and vascular risk on cognitive decline in postmenopausal women
Authors: Wood Madeline
Published: December 2023

Background

Menopause‐related estrogen depletion is linked to greater vascular risk, Alzheimer’s disease (AD) pathology, and dementia risk in women. Age‐at‐menopause and vascular risk may together influence the likelihood of developing AD in women. We investigated whether earlier menopause and elevated vascular risk independently or synergistically contribute to cognitive decline in postmenopausal women compared to men.

Method

We used data from the Canadian Longitudinal Study on Aging. We included 7,678 postmenopausal women (mean age = 64.6±8.49 years, mean age‐at‐menopause = 50.1±5.02 years) and 7,678 age‐matched men (mean age = 64.6±8.49 years). Sex was operationalized using self‐reported sex at birth. Vascular risk was calculated using a summary score tallying the presence/absence of hypertension, diabetes, smoking, obesity, cardiovascular disease, and stroke. Participants completed cognitive assessments at baseline and 3‐year follow‐up. Self‐reported age‐at‐menopause was categorized into tertiles: early (<49), average (49‐52), and late (>52). Linear models tested independent and interactive effects of age‐at‐menopause and vascular risk on 3‐year cognition, adjusting for baseline cognition, baseline age, education, APOE4, and test language (English/French).

Result

In women, vascular risk and age‐at‐menopause were independently associated with cognitive decline (vascular risk: β = ‐0.107, p<.001). Relative to average age‐at‐menopause, early menopause was associated with greater cognitive decline (β = ‐0.026, p = .03), whereas late menopause was associated with less decline (β = 0.025, p = .04). In men, vascular risk was also associated with greater cognitive decline (β = ‐0.112, p<.001). Next, we examined synergistic effects of age‐at‐menopause and vascular risk in postmenopausal women. Early (vs. average) menopause and elevated vascular risk interacted to accelerate cognitive decline (β = ‐0.224, p = .002). There was no interaction between late (vs. average) menopause and vascular risk (β = ‐0.073, p = .3). In a model comparing sexes (Figure 1), vascular risk was more strongly associated with cognitive decline in women with early menopause compared to men (β = ‐0.127, p = .03). In women with average or late menopause, associations of vascular risk with cognitive decline did not significantly differ from men (average: β = ‐0.010, p = .07; late: β = ‐0.024, p = .7). Sensitivity analyses additionally adjusting for physical activity, race/ethnicity, depression, alcohol, and hormone therapy yielded similar results.

Conclusion

Early menopause and vascular processes may synergistically contribute to increased AD risk in women. These findings have implications for sex‐specific dementia prevention strategies.
Cortical microinfarcts along the Alzheimer’s disease continuum in adults with Down syndrome ‐ an update
Authors: Aranha Mateus Rozalem , van den Brink Hilde , Bejanin Alexandre , Montal Victor , Pegueroles Jordi , Carmona‐Iragui Maria , Videla Laura , Benejam Bessy , Valldeneu Sílvia , Barroeta Isabel , Altuna Miren , Fernandez Susana , Garzón Diana , Padilla Concepcion , Iulita M. Florencia , Alcolea Daniel , González‐Ortiz Sofía , Blesa Rafael , Sánchez‐Valle Raquel , Biessels Geert Jan , Lleó Alberto , Fortea Juan
Published: December 2023

Background

Cortical microinfarcts (CMI) are emerging biomarkers of vascular damage associated with cognitive decline and are frequent in sporadic AD (sAD) patients. However, no study assessed CMI in Down syndrome (DS), a genetically determined form of AD. Therefore, we aimed to assess CMI’s frequency in adults with DS, sAD, and cognitively unimpaired euploid controls and its relationship with age, sex, clinical status, and APOE ε4 carriership.

Method

Cross‐sectional study. We included 175 participants with 3T‐MRI: 64 with DS (39 asymptomatic [aDS], 11 prodromal AD [pDS], and 14 AD‐dementia [dDS]), 62 with sAD (41 prodromal AD, 21 AD dementia), and 49 controls. A neuroradiologist blind to participants’ data visually analyzed the 3T‐MRI images following a validated protocol to detect CMI (Figure 1). We compared CMI’s prevalence in the different clinical groups along the AD continuum in DS and sAD, in APOE ε4 carriers vs. non‐carriers, and males vs. females using Chi‐square, Mann‐Whitney, or Kruskal‐Wallis tests when appropriate.

Result

CMI’s prevalence was 7.8% in DS (5.1% in aDS, 21.4% in pDS, and 0% in dDS [p = 0.085]), 17.7% in sAD (22.0% in prodromal AD and 9.5% in AD dementia [p = 0.389]), and 10.2% in controls (p = 0.207). CMI frequency increased with age in DS, sAD, and controls (Table 1). Regarding sex, CMI’s frequency was 10% in men and 5.9% in women with DS (p = 0.884), and 27.3% in men and 12.5% in women with sAD (p = 0.267). In controls, CMIs’ frequency was 10% in men and 10.3% in women (p = 1.000). Regarding APOEε4 carriership, CMI’s prevalence was 21.4% in APOEε4 carriers and 9.1% in non‐carriers in sAD (p = 0.428), 8.7% in carriers and 6.0% in non‐carriers in DS (p = 1.000), and 8.3% in carriers and 8.6% in non‐carriers controls (p = 1.000) (Table 2).

Conclusion

CMI’s prevalence increased with age, but was not different in DS, sporadic AD, and controls. Also, sex and APOEε4 carriership did not impact the prevalence of CMI in the three study groups.
Fibrillar tau induces blood brain barrier permeability, endothelial cell activation and bioenergetic alterations
Authors: Guzman‐Hernandez Roberto A , Fossati Silvia
Published: December 2023

Background

Alzheimer’s Disease, the most common form of dementia, is characterized by the accumulation of amyloid‐beta plaques and neurofibrillary tangles formed by hyperphosphorylated tau in the brain, leading to neuronal loss and cognitive decline. The neurovascular unit, a complex system of several cell types surrounding brain vessels, is extremely important for blood flow regulation, amyloid and tau clearance, and proper brain function. Tau aggregates produced by neurons and glial cells reach endothelial cells (EC) at vessel walls by tau spreading. Currently, the mechanisms responsible for the effects of tau on ECs remain to be understood. We hypothesize that aggregated tau fibrils mediate alterations in bioenergetics in these cells, associated to pro‐inflammatory EC activation, BBB permeability and eventually EC death.

Method

Immortalized human brain microvascular endothelial cells (D3) and primary human cerebral endothelial cells (hCECs) were challenged with aggregated 1N4R tau fibrils (5nM‐25nM) for 3‐72h. Trans‐endothelial electrical resistance (TEER) was measured by the ECIS Zθ system as an in vitro model of the BBB. Cytokine production and release was assessed using a V‐Plex Neuroinflammatory Panel 1 (MSD). We performed immunocytochemical analysis of junction protein expression and western blotting for EC activation markers. EC bioenergetics were measured by Seahorse Extracellular Flux Analyzer and EC death was determined by Cell Death Elisa and LDH Release (Roche).

Result

TEER was reduced following incubation with fibrillar 1N4R tau. VCAM‐1 expression significantly increased with 25nM tau (24h) and 5nM (48h), and ICAM‐1 followed similar trends. Junction protein (ZO‐1, VE‐Cadherin) expression was decreased. Aggregated tau (25nM) caused an increase in glycolysis at 24‐hours, which reverted at further timepoints, whereas mitochondrial ATP production increased (48h) and then decreased (72h). After 72h treatment, 25nM tau induced a significant increase in apoptotic cell death and LDH release, yet no significant changes in cell death were observed at previous timepoints.

Conclusion

Our results suggest that tau fibrils mediate a stress response with a metabolic shift in ECs, in association with pro‐inflammatory EC activation. These molecular changes can contribute to BBB permeability and eventually cell death, further exacerbating cerebrovascular dysfunction.
Characterizing plasma biomarkers of the ATN framework among a diverse community‐dwelling cohort: A HABS‐HD study
Authors: Petersen Melissa , Zhang Fan , Hall James , Ances Beau , Cohen Annie , Meeker Karin L. , Mason David , Barber Robert , Johnson Leigh , O'Bryant Sid E.
Published: December 2023

Background

The A/T/N research framework for Alzheimer’s Disease calls for the importance of examining differences in these biomarkers across racial and ethnic groups. This study aims to address this need and examine the correlation and application between A/T/N plasma and neuroimaging biomarkers among a diverse cohort.

Method

Data were analyzed on Non‐Hispanic White (NHW) (n = 14 A+, n = 117 A‐; n = 4 T+, n = 83 T‐; n = 204 N+, 388 N‐) and Mexican American (MA) (n = 2 A+; n = 75 A‐; n = 3 T+, n = 27 T‐; n = 205 N+, n = 443 N‐) participants from the Health and Aging Brain Study‐ Health Disparities. Participants underwent a blood draw and neuroimaging (MRI, PET Amyloid and Tau). Plasma A/T/N biomarkers of Amyloid Beta (Aβ) 40, 42, Total Tau (T‐Tau), PTau‐181, and Neurofilament Light Chain (Nf‐L) were derived using Single Molecule Array (SIMOA) technology on HD‐X. Pearson correlations were conducted using plasma and neuroimaging A/T/N biomarkers. Due to the limited sample size of A+ and T+, support vector machine models were run in the total sample to examine the application of plasma biomarkers in predicting neuroimaging derived A+/T+/N+.

Result

In the total sample, Aβ 42 correlated with all PET amyloid ROIs. Ptau‐181 correlated with PET Tau SUVR in the Medial Temporal and Posterior Cingulate and clinical read of Tau +, same with T‐Tau. Nf‐L also correlated with MRI derived N+. Aβ 40 and 42 produced an AUC of 69% in detecting PET Amyloid + while T‐Tau and Ptau‐181 produced an AUC of 86% in detecting PET Tau +. Nf‐L alone produced an AUC of 66% in detecting MRI derived N+. Among MAs, Aβ 40 correlated with PET amyloid Frontal, Anterior Posterior Cingulate, Lateral Parietal, and Global SUVR while Ptau‐181 correlated with clinical read of Tau +. Nf‐L correlated with MRI derived N+ among MAs. Among NHWs, Aβ 40 and 42 correlated with clinical read of Amyloid +, while the later correlated with all PET amyloid ROIs. Neither T‐Tau, Ptau‐181 nor Nf‐L correlated with respective T or N neuroimaging biomarkers among NHWs.

Conclusion

This work supports prior findings and highlights ethnic specific differences in the interconnection between A/T/N plasma and neuroimaging biomarkers.
APOEe4*TREM2 and sickle cell trait in a late onset Alzheimer’s disease mouse model
Authors: Propsom Kat , Gowru Srivani , Wandu Sylvia , Hyacinth Hyacinth I
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disease associated with neuroinflammation, dysregulated neurovascular coupling, abnormal neuroplasticity, and neuropathological makers, including tau and β‐amyloid deposition. Advancing age is the greatest risk factor, and apolipoprotein E (APOE) e4 and triggering receptor expressed on myeloid cells 2 (TREM2) are genetic risk factors for late‐onset AD, which comprises >95% of all AD cases. Sickle cell trait (SCT) refers to the heterozygous inheritance of the sickle cell hemoglobin mutation. Studies from our laboratory and others show that SCT is associated with increased risk of microvascular complications and peripheral inflammation. Given the role of cerebral small vessel disease and inflammation in the pathogenesis of AD, we hypothesized that SCT may interact with late‐onset AD gene variants, resulting in earlier development of cognitive impairments, possibly via promoting neuroinflammation.

Method

To test our hypothesis, 10‐12 weeks old mice carrying APOE e4*TREM2 combined late‐onset AD genes were transplanted with bone marrow from humanized Townes mice with SCT (AS) or normal (AA) hemoglobin, following irradiation. Using a longitudinal cross‐sectional design, 3 cohorts were evaluated at 8, 12, and 18 months for presence of cognitive deficits using rodent behavioral testing. Mice were sacrificed immediately following behavioral testing, and brain tissue was evaluated using immunohistochemistry and Golgi‐Cox impregnation histology.

Result

Behavioral testing suggested only age‐related cognitive impairments. There were no significant differences in neuroinflammation at any age between AS and AA mice in the hippocampus or corpus callosum and external capsule. Within genotypes, there was an age dependent increase in neuroinflammation, between 8 and 12 months in the hippocampus (p < 0.0001, p = 0.0002) and 12 versus 18 months in white matter tracts (p < 0.0001, p < 0.0001). There were no significant differences in the dendritic spine density or the proportion of immature spines between AS and AA mice. However, within genotypes there was significant differences between 12 and 18 months (p < 0.0001, p < 0.0001), with 18 months having lower spine density and higher proportion of immature spines.

Conclusion

Addition of SCT to a background of APOE e4*TREM2 did not result in earlier onset of cognitive impairment or more severe neuroinflammation.
The Prediction of Alzheimer’s Disease through Multi‐Trait Genetic Modeling
Authors: Clark Kaylyn , Fu Wei , Liu Chia‐Lun , Ho Pei‐Chuan , Wang Hui , Lee Wan‐Ping , Chou Shin‐Yi , Wang Li‐San , Tzeng Jung‐Ying
Published: December 2023

Background

Previous studies have indicated that prediction performance of a genetic risk score is improved when the score is built using information about multiple traits/risk factors associated with the target trait. To better capture the polygenic architecture of Alzheimer’s Disease, we developed a joint genetic score, MetaGRS.

Method

We incorporated genetic variants for AD and 24 other traits from two independent cohorts, NACC (n = 3,174, training set) and UPitt (n = 2,053, validation set).

Result

One standard deviation increase in the MetaGRS is associated with about a 57% increase in the AD risk (HR = 1.577, p = 7.17 E‐56), showing little difference from the HR for AD GRS alone (HR = 1.579, p = 1.20E‐56), suggesting similar utility of both models. We also conducted APOE stratified analyses to assess the role of the e4 allele on risk prediction. Similar to that of the combined model, our stratified results did not show a considerable improvement of the MetaGRS.

Conclusion

Our study showed that prediction power of the MetaGRS significantly outperformed that of the reference model without any genetic information, but was effectively equivalent to the prediction power of the AD GRS in both the full and stratified analyses. Our findings are broadly consistent with previous studies of Stroke and T2D.
Supporting informed decision‐Making about Alzheimer’s biomarker disclosure: identifying areas of knowledge and information needs in a research cohort
Authors: Ketchum Fred B , Erickson Claire M , Chin Nathaniel A. , Basche Kristin E , Rosario Hannah , Johnson Sterling C. , Clark Lindsay R.
Published: December 2023

Background

Education and counseling are recommended prior to Alzheimer’s disease (AD) biomarker disclosure to allow individuals to make an informed decision about whether they want to learn their results. Disclosure is occurring more frequently in research settings, and will likely be implemented in clinical populations in the future. Effective and feasible approaches to education and counseling are needed to ensure individuals are appropriately informed and supported prior to biomarker testing and disclosure.

Methods

Eligible participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) elected to learn their amyloid PET results (n = 97). The disclosure process included an education session, disclosure visit, and lifestyle counseling visit. At the education session, baseline knowledge was assessed using a 15‐item quiz. Next, participants were guided through a 15‐minute interactive presentation on dementia, lifestyle and genetic risk factors for AD, significance of PET results, and potential psychosocial outcomes post‐disclosure. The quiz was then administered again.

Results

Participants (age = 71.9±4.8, 94.8% non‐Hispanic White) with elevated (n = 28) and not‐elevated (n = 69) biomarker results were enrolled. Mean quiz scores were 12.1 before the educational session and 14.3 after the session, and did not differ based on amyloid positivity. Most participants correctly answered pre‐test questions about the progression of AD and risk factors, the significance of amyloid, and that biomarker results were part of research. The main areas of knowledge gained were about the causes of dementia (22.7% pre‐test vs 69.1% post‐test), significance of APOE genes (57.8% vs 90.7%), and extent of existing protections against discrimination on the basis of genetic tests (48.5% vs 93.8%). For one question about early symptoms of AD, knowledge decreased (70.1% vs 58.8%).

Conclusion

In a cohort of currently enrolled AD research participants, baseline knowledge about amyloid and research was high, but information needs existed around causes of dementia, early AD symptoms, genetic information, and protections against psychosocial consequences such as discrimination. To support informed decision‐making about disclosure, future research should determine educational needs among clinical populations and adapt materials to effectively and feasibly communicate this information.
Association of plasma biomarkers with cognitive domains across three neurodegenerative diseases and cerebrovascular disease
Authors: Sanchez Erlan , Wilkinson Tim , Coughlan Gillian T , Baril Andree‐Ann , Binns Malcolm , McLaughlin Paula , Kwan Donna , 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 critical to better understand the value of plasma biomarkers in predicting cognitive deficits before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of neurodegenerative disease progression in trials. Herein, we investigate their association with five cognitive domains 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 spectrum disorders (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. Scores from a 26‐test comprehensive neuropsychological assessment were used to compute composite z‐scores for five cognitive domains: attention & working memory, executive function, language, memory, and visuospatial function. Linear regression models controlling for age, sex, education and APOE E4 allele were used to test the association between plasma biomarkers and cognitive domains in each group separately.

Result

In AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with worse attention & working memory, executive function, and memory. In PD, higher levels of NfL were associated with worse attention & working memory, executive function, and visuospatial function; higher levels of GFAP were also associated with worse executive function. In CVD, higher levels of GFAP were associated with worse executive function, memory and visuospatial function; higher levels of p‐tau181 were also associated with worse memory. In FTD, no associations were found.

Conclusion

Plasma biomarkers indicative of neuronal and glial pathology are useful to predict the severity of widespread cognitive deficits in AD/MCI, PD, and CVD. Interestingly, p‐tau181 predicted memory deficits in both AD/MCI and CVD, suggesting potential mixed disease or pathological overlap. Plasma Aβ42/40 does not appear to predict any cognitive deficits in any of the neurodegenerative diseases studied. As FTD is highly heterogeneous and had the least number of patients, we are possibly lacking power to detect effects in this group.
Development of neuroimaging biomarkers in non‐human primate model of sporadic Alzheimer’s disease pathology
Authors: Murray Sean , Veraart Jelle , Szabo Jakub , Akers Carolyn , Genovese Thomas S , Goldman Hannah , Llanos Michael , Rusinek Henry , Hopkins William D , Gray Stanton B , Wisniewski Thomas , Zaim‐Wadghiri Youssef , Scholtzova Henrieta
Published: December 2023

Background

Squirrel monkeys (SQMs) are a non‐human primate (NHP) model of Alzheimer’s disease (AD) pathology with extensive cerebral amyloid angiopathy (CAA). Our work characterizes neuroimaging biomarkers associated with aging and neurodegeneration. Previously, we demonstrated the sensitivity of 1) in vivo regional quantitative R2* alterations to track age‐related changes in neuropathology and 2) ex vivo diffusion‐weighted (DWI) MRI metrics to visualize changes in brain microstructure. We recently extended our analyses to in vivo multi‐shell diffusion metrics for detection and classification of amyloid‐related imaging abnormalities (ARIA), which have been linked to parenchymal vasogenic edema and sulcal effusions. To further facilitate quantitative analysis of MR markers (diffusion and R2*) we have built a novel pipeline for atlas‐based region‐of‐interest (ROI) segmentation using a SQM brain atlas modified from Schilling et al. (2017). Here we evaluate age‐related changes in R2* values and region‐specific volume using this automated workflow.

Method

Young and geriatric female SQMs underwent 2D T2‐weighted (T2‐w) Turbo Spin Echo (TSE) RARE and FLAIR MRI scans, in addition to multi‐shell DWI acquisitions. DTI and DKI metrics were derived from DWI datasets, including mean diffusivity (MD), mean kurtosis (MK), and fractional anisotropy (FA). We utilized in vivo multi‐gradient echo (MGE) scans to generate R2* maps for ROI‐based quantitative assessments of SQM neuropathology.

Result

We identified multiple instances of asymmetric hyperintensities (ARIA‐E) in geriatric SQMs using 2D T2‐w TSE RARE, FLAIR, and DWI MRI sequences in vivo. While RARE and FLAIR scans demonstrated abnormalities in SQM brains, diffusion metrics MD and MK revealed greater propagation of the lesions through WM tracks. Histological analyses of the underlying neuropathology (e.g. myelin, neuroglia, and amyloid burden) are underway. Significant increases in R2* values with age were observed in all defined cortical regions, with subsequent histological confirmation of severe CAA, microhemorrhages, and iron deposits. Preliminary volumetric measurements revealed significant decreases with age in the prefrontal cortex. Additional morphometric analyses are ongoing.

Conclusion

We safely monitored age‐dependent changes in neuroimaging parameters derived from diffusion‐weighted, T2‐w TSE RARE, and FLAIR acquisitions. Our study highlights the utility of the SQM model to uncover potential long‐term consequences of ARIA and validates diffusion MRI methodologies to target brain integrity.
Differential Effects of Anticholinergic Medications in a Human Neuronal Model of AD
Authors: Schwarze‐Taufiq Tiara A. , Sammeth Eleanore , Crane Paul K , Gray Shelly L , Young Jessica E.
Published: December 2023

Background

Anticholinergic (ACh) use remains common in older adults despite evidence of safety risks, including dementia risk. Evidence from population studies suggests that dementia risk may vary by ACh class. This variation might be explained by confounding by indication. In vitro models, using human neural cells where cells are directly experimentally exposed to a drug and phenotypic outcomes are measured, may address this issue. We identified classes of ACh medications that have different degrees of dementia risk based on a population study. We then treated human induced pluripotent stem cell‐derived neurons (hiPSC‐Ns) with each medication and performed cellular assays to examine the effects on AD phenotypes.

Method

We used CRISPR/Cas9 to generate an isogenic set of hiPSCs that harbor the autosomal dominant Swedish mutation in APP (APPSwe) and compared these to wild‐type control cells developed using the same pipeline. We differentiated neurons (hiPSC‐Ns) from these cells using established protocols in our laboratory. We treated these neurons with different classes of ACh medications: antidepressants (amitriptyline, doxepin, paroxetine), antihistamines (diphenhydramine, chlorpheniramine), bladder antimuscarinics (oxybutynin, tolterodine), and antispasmodics (atropine). As a control, we treated cells with the classic cholinergic compound carbachol. Cells were treated with two drug doses (0.01 and 0.01mM) at two time points (24 and 48hrs). We used molecular assays to test AD‐associated cellular outcomes (neurotoxicity, Amyloid beta [Ab], and pTau).

Result

We document differential effects of medications on all AD outcomes measured. Several drugs demonstrated dose‐dependent (doxepin, oxybutynin, paroxetine, amitriptyline) and/or time dependent (oxybutynin, paroxetine) neurotoxicity. We also observed differential effects on Ab secretion, with paroxetine, doxepin, and diphenhydramine lowering Ab and chlorpheniramine having no effect. Interestingly, medications not demonstrating neurotoxicity (diphenhydramine, chlorpheniramine, tolterodine, atropine, carbachol) also reduce intracellular pTau at lower concentrations.

Conclusion

Stem cell‐derived neuronal models provide a useful strategy to complement pharmacoepidemiological studies to help distinguish molecular versus environmental actions of drugs associated with dementia risk. Preliminary results suggest that different ACh drugs have differential effects on AD‐associated cellular outcomes. Future work will test this panel of medications on hiPSC‐Ns derived from Adult Changes in Thought (ACT) cohort subjects with high and low AD genetic risk
The impact of Alzheimer’s disease pathology and cardiovascular risk factors on cross‐sectional brain structure in the U.S. POINTER Imaging study
Authors: Harrison Theresa M. , Ward Tyler J. , Lockhart Samuel N. , Vemuri Prashanthi , Lovato Laura , Snyder Heather M , Baker Laura D , Koeppe Robert A. , Decarli Charles , Jagust William J. , Landau Susan M. ,   the U.S. POINTER Study Group
Published: December 2023

Background

The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate the effect of lifestyle interventions in cognitively unimpaired older adults (60‐79 years) at risk for decline/dementia. Here, using data from the POINTER Imaging ancillary substudy, we explore how Alzheimer’s disease pathology and cardiovascular risk influence brain structure, cognition and their relationship.

Method

POINTER Imaging participants underwent cross‐sectional MRI, [18F]Florbetaben (FBB) Aβ‐PET and [18F]MK6240 tau‐PET. FBB and MK6240 data were processed using previously validated methods. MRIs were processed with voxel‐based morphometry. To quantify cardiovascular risk, the Framingham risk score (FRS) was calculated for each participant. We used linear regression models in the whole sample as well as in Aβ status subgroups to evaluate voxel‐wise associations of brain structure, measured using voxel‐based morphometry, with age, FRS, AD pathology (cortical summary Aβ and entorhinal cortex (ERC) tau burden), and a global cognition composite score.

Result

Across all 624 participants (Table 1), cognition (age‐adjusted) was positively related to brain structure across temporal, frontal and medial parietal cortices (Fig. 1A). ERC tau‐PET was negatively associated with brain structure in bilateral medial temporal lobes (MTL) and, notably, in bilateral basal forebrain (Fig. 1B). FRS showed significant negative associations in superior temporal gyrus and occipital cortex (Fig. 1C), but tau‐PET associations remained similar when adjusting for FRS. In Aβ+ participants, cognition‐ and FRS‐structure relationships were weaker but tau‐PET‐structure associations were stronger and extended outside the MTL. In Aβ‐ participants, cognition‐ and FRS‐structure relationships were similar to those observed in the whole cohort and tau‐PET associations were no longer significant.

Conclusion

In this heterogeneous cohort of older adults, tau was associated with brain structure in strikingly specific patterns that were related to Aβ but not to cardiovascular risk as measured by the FRS. Tau‐structure associations were restricted to temporal lobes and basal forebrain and were independent of more widespread cognition‐structure associations, indicating that factors other than tau may play a critical role. Our next steps include comparing the current cohort to others with different at‐risk characteristics (e.g., ADNI, Berkeley Aging Cohort Study).
Differential Microglial activation and Astrocyte reactivity in Alzheimer’s trajectory
Authors: Edison Paul
Published: December 2023

Background

Microglial activation and astrocyte activation plays a significant role in the pathogenesis of AD. Here, we evaluate microglial activation, the interrelationship between microglial activation, amyloid and tau pathologies, and the impact of microglial activation in Alzheimer’s disease trajectory. We specifically focus on microglia as a major player in neuroinflammation and evaluate the spatial and temporal variation of microglial activation in the disease trajectory. Additionally, we evaluate astroglial activation using novel astrocyte marker and evaluate the relationship between amyloid, MRI volume changes and glucose metabolism in Alzheimer’s trajectory.

Method

We evaluated AD, MCI and cognitively normal subjects using amyloid PET, tau PET and neuroinflammation using TSPO PET scans. A separate group of AD, MCI and control subjects were evaluated using novel astrocyte marker [11C]BU99008 PET along with [18F]FDG PET and amyloid PET. [11C]PBR28 and [11C]BU99008 PET scans were analysed using two tissue compartmental model, while [18F]Flutemetamol was analysed using target to cerebellar ratio. [18F]FDG PET was analysed using pons as a reference region. We performed regional and voxel wise analysis for all the tracers.

Result

Microglial activation was elevated in different cortical regions in both AD and MCI subjects. Microglial activation was associated with lower grey matter density in later stages of the disease, while higher grey matter volume was associated with increased microglial activation in early mild cognitive impairment subjects. There were areas of increased astrocyte activation in both AD and MCI. Higher microglial activation was associated with increased tau formation and neuronal damage in later stages of the disease. Interestingly, there was increased astrocyte reactivity in the early stages of the disease.

Conclusion

While microglial activation in the late phase of the disease is associated with neuronal damage, however, in the early stages microglial activation was associated with higher grey matter volume. Microglial activation demonstrated a biphasic pattern of activation. In contrast to microglial activation, astrocyte activation was prominent in the early stage of the disease and may be associated with neuroprotection. This suggests that in targeting glial activation as a therapeutic strategy, we must target astrocyte and microglia separately and in different stages of the disease.
Effect of Interaction between APOE genotype and Type 2 diabetes on Cognitive and Neuropathology features
Authors: Karanth Shama D , Abner Erin L , Katsumata Yuriko
Published: December 2023

Background

Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are common diseases in aging populations. Multiple large epidemiological studies suggest that T2DM is strongly associated with cognitive impairment and dementia. Prior studies suggest T2DM may be an important modifier of the relationship between AD and APOE, which is the strongest known genetic risk factor of AD.

Method

We obtained study data from the National Alzheimer’s Coordinating Center (NACC) and included 30,483 participants aged ≥60 years at baseline. T2DM status was determined based on any self‐reported diabetes diagnosis or anti‐diabetes treatment during annual assessments. To facilitate analysis, we created two binary variables to classify participants with regard to T2DM (presence or absence) and APOEε4 (carrier or non‐carrier) status. Cognitive domain scores for memory, attention, language and executive function were standardized using z‐scored neuropsychological tests administered at annual visits. Multivariable linear mixed‐effects models with a cross‐product interaction term between T2DM and APOEε4 status, including main effects, assessed whether the association of APOEε4 with domain‐specific cognitive change was modified by T2DM status. In the subset of participants who underwent autopsy (n = 5,663), we examined whether T2DM modified the association between APOEε4 and neuropathological features using multivariable logistic regression.

Result

A significant interaction exists between T2DM and APOE genotype. APOEε4 carriers with T2DM had more rapid declines in attention, language, memory, and executive cognitive scores over time. APOEε4 non‐carriers with T2DM had lesser impairment compared to APOE ε4 carriers without T2DM. Among the autopsied participants, non‐APOE ε4 carriers with T2DM had larger odds of infarcts/lacunes and atherosclerosis. Compared to non‐APOE ε4 carriers without T2DM, APOE ε4 carriers with or without T2DM showed higher odds of AD neuropathological changes (ADNC), but lower odds of ADNC among non‐APOE ε4 carriers with T2DM.

Conclusion

T2DM modifies the association between APOE ε4 and cognitive decline and AD neuropathological features. T2DM in non‐APOE ε4 carriers increased the risk of infarcts/lacunes but not ADNC.
Blood‐based biomarkers for predicting treatment response in the Apathy in Dementia Methylphenidate Trial 2 randomized clinical trial
Authors: Tumati Shankar , Vieira Danielle , Bawa Kritleen Kaur , Andreazza Ana C. , Mintzer Jacobo , Scherer Roberta , Rosenberg Paul B. , van Dyck Christopher H , Padala Prasad R , Brawman‐Mintzer Olga , Porsteinsson Anton P. , Lerner Alan J. , Craft Suzanne , Levey Allan I. , Burke William J , Perin Jamie , Shade David , Herrmann Nathan , Lanctôt Krista L.
Published: December 2023

Background

The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate (MPH) was modestly efficacious is treating apathy in Alzheimer’s disease (AD) with 66% response (> = 4 point decrease on Neuropsychiatric Inventory – apathy (NPI‐A). Here, we evaluated if blood‐based biomarkers potentially associated with treatment‐limiting neuronal damage predicted the probability of treatment response.

Method

ADMET 2 participants with baseline and endpoint (6 month) NPI‐A and baseline concentrations of (i) neuronal damage: neurofilament light (NFL) and S‐100B, (ii) inflammation: interleukin (IL)‐6, IL‐10, Tumor Necrosis Factor‐alpha (TNFα), and (iii) oxidative stress: lipid hydroperoxide (LPH), 4‐hydroxynonenal (4‐HNE), 8‐isoprostane (8‐ISO) were included. Biomarkers were normalized by log transformation and pareto scaling. Univariate models examined whether each biomarker interacted with the treatment condition to predict a change of at least 2 points on the NPI‐A. Next, biomarkers with significant associations were included in a multivariate logistical regression model that was used to predict treatment response to MPH and placebo. The index score (difference between response probabilities for MPH and placebo) of each participant indicated their favourability for MPH treatment. Participants were grouped into quartiles by their index score with confidence intervals estimated using non‐parametric bootstrapping.

Result

Forty‐nine participants (placebo = 26, MPH = 23, age = 75.4 years (standard deviation [SD] = 7.6), 57% males, Mini Mental State Examination = 19.7 [SD = 4.6]) were included. MPH was more efficacious than placebo in those with higher baseline NFL (‐5.8, t = ‐3.1, p = 0.003), and less efficacious in those with higher LPH (2.0, t = 1.48, p = 0.15). Apathy worsened in participants with high TNFα (2.71, t = 1.94, p = 0.06) in both MPH and placebo groups. Participants in the top quartile of the biomarker index score (66.7% on MPH) were more likely to respond to MPH than placebo (index score = 0.58, 95%CI: 0.48, 0.69).

Conclusion

Individuals with greater neuronal injury were more likely to respond to MPH, suggesting that MPH supplementation provides more benefit when neuronal injury is more severe. Combining blood biomarkers yielded a prediction score where participants with high NFL and low LPH levels were more likely to respond to MPH. This approach utilizes biomarkers to address heterogeneity in treatment response to MPH.
Cerebral perfusion and amyloidosis in the oldest‐old
Authors: Dutt Shubir , Woodworth Davis C. , Sajjadi S. Ahmad , Kawas Claudia H. , Corrada María M. M. , Nation Daniel A.
Published: December 2023

Background

Cerebrovascular contributions to cognitive aging and Alzheimer’s disease (AD) risk represent a growing field in aging research. Studies in the young‐old have demonstrated the critical role of vascular dysregulation (i.e., altered cerebral blood flow) in relation to cognitive decline prior to the appearance of amyloid/tau biomarkers. However, cerebral perfusion has not been well‐studied in the oldest‐old (ages 90 and over), a rapidly growing population that may provide unique insight into resilience and protective factors against dementia in later life. We characterized amyloid and cerebral perfusion profiles of cognitively normal (CN) and cognitively impaired without dementia (CIND) oldest‐old individuals.

Method

Participants were 97 dementia‐free older adults (70 CN and 27 CIND) from the 90+ Study who had available neuroimaging (T1‐MRI, ASL‐MRI, Florbetapir‐PET), demographic, and clinical data. We examined differences between CN and CIND in regional perfusion in areas associated with AD risk (medial temporal lobe, posterior cingulate, precuneus, frontal cortex, inferior parietal lobe) and in amyloid burden using linear regression models controlling for age, sex, education, APOE4 status, and vascular risk factors.

Result

CN and CIND groups did not differ in the characteristics compared (Table 1). CIND participants had lower CBF in the posterior cingulate/precuneus than the CN group, but groups did not differ in posterior cingulate/precuneus amyloid SUVR (Figure 1). Additionally, CIND had lower CBF than CN in the inferior parietal lobe but higher CBF in the medial temporal lobe and orbitofrontal cortex (Figure 2).

Conclusion

CIND individuals had lower regional perfusion in the posterior cingulate/precuneus, but groups did not differ in amyloidosis, highlighting the relationship between cerebrovascular function and cognitive status in the oldest‐old independent of amyloidosis. Our findings complement previously reported posterior cingulate/precuneus hypoperfusion in younger‐old individuals with cognitive impairment and AD. Interestingly, we observed greater medial temporal/frontal perfusion in CIND than CN, similar to previous studies demonstrating initial hyperperfusion preceding hypoperfusion across the CN‐CIND‐Dementia spectrum. This may represent a compensatory vascular mechanism supporting cognition in individuals at greater risk of developing dementia. Future studies will further characterize this cohort with longitudinal perfusion analyses, neuropsychological correlates, and relationships between perfusion and other indices of cerebrovascular dysfunction.
The European Platform for Neurodegenerative Diseases (EPND)
Authors: Visser Pieter Jelle , Brookes Anthony J. , Scordis Phil , Bose Niranjan
Published: December 2023

Background

Biomarker discovery, development, and validation are reliant on large‐scale analyses of high‐quality samples and data. However, discovery, access, and sharing of data and samples are hindered both by silos that limit collaboration, and by complex requirements for secure, legal, and ethical sharing. The European Platform for Neurodegenerative Diseases (EPND) project aims to address these challenges and accelerate biomarker discovery, development and validation, by building a scalable, sustainable platform for collaboration, data and sample sharing. In this presentation we will give an overview of the design of EPND and the achievements in the first year of this 5‐year project.

Method

EPND is a multidisciplinary consortium of 29 public and private partners with expertise on data discovery, ethical, legal and regulatory aspects of data sharing, biomarker studies, stakeholder engagement and sustainability. EPND will leverage existing data and research infrastructures, including the Alzheimer’s Disease Data Initiative (ADDI) AD Workbench, which will allow the platform to connect to a global research network. EPND was launched in November 2021 and is funded by the Innovative Medicines Initiative (IMI, grant agreement number 101034344, epnd.org).

Result

In this first year of the project, the design of the data platform has been finalised. EPND has launched its Cohort Catalogue, which features information on participants, samples and data from 60+ neurodegeneration cohorts, spanning 17 countries and 13 disease areas, and involving over 155,000 patients. In addition to standardised operational procedures on sample selection, biobanking, and data harmonisation, we have also developed a white paper on legal, ethical and regulatory aspects of data and sample sharing. Finally, we have performed case studies on ATN biomarkers in plasma and blood in 350 patients with Alzheimer’s disease, Parkinson’s disease and Lewy body dementia.

Conclusion

We initiated a multidisciplinary consortium with the goal to accelerate collaborative research into the discovery and validation of biomarkers, to support development of diagnostics and disease‐modifying therapies for AD and other neurodegenerative diseases.
The role of nurses in recruiting Filipino, Korean, and Hispanic/Latino participants to preclinical Alzheimer’s disease trials.
Authors: Tallakson Melanie B , Shin Hye‐Won , Duran Edwin , Sultzer David L , Grill Joshua D , Salazar Christian R.
Published: December 2023

Background

The factors that influence clinical trial participation in the Filipino, Korean and Hispanic/Latino communities remain poorly understood. Nurses are well positioned to play a dynamic role in the recruitment of underrepresented communities to preclinical Alzheimer’s disease (AD) trials. This study used a community‐based nursing partnership model to gain insights into whether and how nurses serve as key gatekeepers within these communities.

Method

Sixty in‐depth stakeholder interviews were conducted with 20 Hispanic/Latino, 20 Filipino, and 20 Korean American nurses via Zoom. Nurses were recruited through a unique collaboration between community‐based Filipino, Korean and Hispanic/Latino professional nursing organizations and academic investigators. A semi‐structured interview guide was used to collect sociodemographic information and to assess nurses’ research attitudes and perspectives regarding the recruitment of underrepresented community members to AD preclinical trials.

Result

Overall, 63% of nurses had >20 years of clinical practice experience, 93% had a bachelors or graduate degree, 75% were fully employed, 14% were part‐time employed, 12% were retired, and 72% knew someone with a diagnosis of AD. Most Filipino (90%) and Korean (90%) nurses were not born in the US, as compared to Hispanic/Latino nurses (25%). Emergent themes were identified including the role of nurses as a (1) trusted source of health information, (2) patient advocate and community educator, and (3) liaison connecting key community stakeholders to AD trials. Commonalities in perspectives among the nursing groups about community members’ participation in trials included the role of familism in decision‐making, the need for strong family support, and reliance on family members, such as adult children, to communicate important health information. A notable difference between the nursing groups was that Hispanic/Latino nurses more often communicated in a non‐English (Spanish) language with patients as compared to Filipino and Korean nurses. All nursing groups, on average, exhibited positive attitudes towards research.

Conclusion

Our findings suggest that nurses can serve as a valuable vehicle for improving recruitment to preclinical AD clinical trials. Nurses are well positioned to engage with the community and provide culturally tailored patient, family, and community education.