bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of CSF IL‐6 and IL‐8 concentrations with brain atrophy, memory decline and AD biomarkers change in cognitively healthy older adults
Authors: Capogna Elettra , Watne Leiv Otto , Sørensen Øystein , Guichelaar Carlijn Jamila , Halaas Nathalie , Idland Ane‐Victoria , Blennow Kaj , Zetterberg Henrik , Walhovd Kristine B ,   for the Alzheimer’s Disease Neuroimaging Initiative, Fjell Anders M , Vidal‐Piñeiro Didac
Published: December 2023

Background

Aging is characterized by increased neuroinflammation, which plays an early role in the etiology of Alzheimer’s disease (AD) (1) and cognitive decline (2). Cytokines play key roles in neuroinflammation in aging. We investigated whether levels of cerebrospinal fluid (CSF) interleukin‐6 (IL‐6) and interleukin‐8 (IL‐8) were associated with cognitive and brain decline and whether this relationship was mediated by baseline levels of CSF beta‐amyloid (Aβ‐42) and phosphorylated tau (p‐tau). Finally, we tested whether baseline IL‐6 and IL‐8 were related to changes in core AD biomarkers over time.

Method

219 older adults (62‐91 years), with baseline CSF IL‐6 and IL‐8, were followed over time (up to 9.50 years) by collecting longitudinal structural MRI, cognitive, and CSF data (n = 140). Linear mixed models (LME) were used to assess the effect of IL‐6 and IL‐8 on hippocampal atrophy, entorhinal thinning, lateral ventricle expansion, memory performance, and core AD CSF change. False discovery rate (pFDR) correction was applied to the models.

Result

Higher CSF IL‐8 levels at baseline were associated with better memory performance over time, specifically in the context of lower levels of p‐tau (t = ‐2.00, pFDR = 0.05) and p‐tau/Aβ‐42 ratio (t = ‐2.15, pFDR = 0.03, Figure 1), while higher baseline IL‐6 were related to less CSF p‐tau changes over time (t = ‐2.61, pFDR = 0.02, Figure 2a). At trend levels, higher IL‐8 was associated with decrements of CSF Aβ‐42 levels over time (t = ‐2.25, uncorrected p = 0.02, Figure 2b), while higher IL‐6 was related to faster hippocampal volume decline with higher p‐tau/Aβ‐42 ratio (t = ‐2.21, uncorrected p = 0.03, Figure 2c).

Conclusion

IL‐6 and IL‐8 show a complex profile in cognitively healthy aging pointing towards a neuroprotective role, especially with lower levels of the pathological load.
Detection of early Alzheimer’s disease at the eye clinic: The BeyeOMARKER study
Authors: Bader Ilse , Groot Colin , Tan Stevie H. , van der Flier Wiesje M. , Teunissen Charlotte E. , Pijnenburg Yolande A.L. , Bouwman Femke H. , Ossenkoppele Rik
Published: December 2023

Background

Early detection of Alzheimer’s disease (AD) is essential for establishing a patient management plan, and for clinical trial selection and determining who will benefit most from future therapies. Effective screening for early AD will require large‐scale implementation of non‐invasive, scalable, and accessible biomarkers such as blood‐based biomarkers and retinal scans. With a high population throughput and a visually impaired population at increased risk for AD (HR = 1.47 (Kuźma et al., J Alzheimers Dis (2021)), eye clinics provide a prime proof‐of‐concept setting to explore the potential of implementing non‐invasive biomarkers in an alternative clinical setting. The BeyeOMARKER study aims to explore the feasibility of large‐scale screening using non‐invasive tools in eye clinics, with the ultimate goal of providing recommendations for AD screening in alternative clinical settings, and exploring factors underlying the association between eye disease and AD.

Method

The BeyeOMARKER study is a prospective, observational, longitudinal cohort study. At the eye clinic, ∼700 participants (aged ≥45) will be screened for early AD using plasma phospho‐tau181 (p‐tau181) and a short neuropsychological test battery (Montreal Cognitive assessment). After screening, 100 plasma p‐tau181 positive cases and 50 p‐tau181 negative controls (matched based on age, sex and eye disease) will be included into the longitudinal BeyeOMARKER cohort. This cohort will be invited to the memory clinic for a hyperspectral retinal scan, structural magnetic resonance imaging (MRI), and a comprehensive neuropsychological assessment including cortical vision tests (e.g., visuo‐perceptive and visuospatial abilities).

Result

Main outcomes of the BeyeOMARKER study are 1) a prevalence estimate of AD in a large, diverse population of visually impaired individuals, 2) the performance of hyperspectral retinal scans to detect AD pathology in this population and its complementary benefit over‐and‐above plasma p‐tau181, and 3) improved understanding on the eye‐brain connection in the context of AD through comparison of cognitive and cortical vision performance, and brain atrophy across visually impaired p‐tau181 positive and negative individuals.

Conclusion

The BeyeOMARKER consortium aspires to build a detailed roadmap for the implementation of non‐invasive screening for early AD within the eye clinic.
Associations between psychological risk and protective profiles and cognitive status in two independent cohorts
Authors: Bartrés‐Faz David , Demnitz‐King Harriet , Solé‐Padullés Cristina , Saunders Rob , Cattaneo Gabriele , Cabello‐Toscano María , Klimecki Olga M , Sánchez Javier Solana , Tormos‐Muñoz Josep Mª , Chetelat Gael , Pascual‐Leone Alvaro , Marchant Natalie L
Published: December 2023

Background

Positive and negative psychological factors represent pertinent moderators of relative risk and protection for cognitive decline and dementia. For example, repetitive negative thinking has been associated with accelerated cognitive decline and AD pathology1, whereas self‐reflection and purpose in life have been related to better cognition and cognitive resilience2,3. Existing studies predominately focus on individual factors, thus it is unknown whether psychological profiles, combining risk and protective features, are differentially associated with cognitive function.

Method

Individuals without objective cognitive impairment were included from two European studies: the middle‐aged Barcelona Brain Health Initiative (N = 741)
4 and the older‐adult Medit‐Ageing (N = 279)5,6
cohorts. Self‐report questionnaires to assess levels of psychological risk and protective factors were completed and global cognitive assessments obtained in both studies (Table 1). Latent Profile Analysis (LPA) was performed on psychological questionnaire data to identify statistically different groups of individuals in each cohort separately. ANCOVA (adjusting for age, sex, and education), were then conducted to compare different psychological profiles according to cognitive status.

Result

LPA identified a three‐class solution in both cohorts (Table 1 and Figure 1): “low levels of psychological protective factors” (class‐1), “high levels of psychological risk factors” (class‐2), and “average levels of psychological risk and protective factors” (class‐3). In both cohorts, psychological profile membership was significantly associated with cognition. Specifically, individuals with low levels of psychological protective factors had worse global cognitive function compared with individuals with other profiles (BBHI: F:6.05, p<0.002; Medit‐Ageing: F:7.99, p<0.001; Figure 2).

Conclusion

Individual psychological risk and protective factors aggregated into three identifiable psychological profiles that were evident across two independent cohorts. In both cohorts, having a psychological profile with low levels of protective factors rather than high levels of risk factors, was associated with worse global cognitive function. Such observations may have implications for future, more personalized, application of psychological therapies contributing to dementia prevention.
Detecting cortical microstructural alterations secondary to white matter hyperintensity in amyloid positive cognitively normal subjects
Authors: Torso Mario , Ridgway Gerard R , Valotti Michele , Hardingham Ian , Chance Steven A ,   the European Prevention of Alzheimer’s Disease (EPAD) Consortium
Published: December 2023

Background

Previous research showed that cortical diffusivity is sensitive to primary cortical microstructural changes due to amyloid deposition (1). The present study aimed to investigate the cortical microstructural alterations secondary to white matter damage in cognitively normal participants, amyloid positive and negative.

Method

Three hundred and thirty‐five cognitively normal (MMSE > 24) participants with baseline CSF Aβ42 and MRI scans were obtained from the European Prevention of Alzheimer’s Dementia (EPAD) cohort. Participants were classified as Aβ42‐ (N = 231) or Aβ42+ (N = 104), based on a published cut‐off (2). The Fazekas scale deep white matter (FSDWM) score was used to further classify participants as LOW (0 and 1; N = 281) or HIGH (2 and 3; N = 54) FSDWM.

Structural and diffusion MRI (dMRI) were used to calculate whole brain cortical volume fraction, cortical thickness and three neuropathology‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).

Group differences in structural and diffusion metrics were tested using GLM adjusting for scanner manufacturer, number of dMRI volumes, age and sex, with Bonferroni’s correction (p<0.05/5).

Result

The interaction between Aβ42 status and FSDWM revealed significant differences in cortical microstructural measures (GLM: AngleR F17,317 = 7.065, p = 0.008; PerpPD+ F17,317 = 7.976, p = 0.005). The pairwise comparisons showed significantly lower AngleR values in Aβ42‐ HIGH compared to Aβ42‐ LOW and significantly higher PerpPD+ values in Aβ42+ HIGH compared to Aβ42+ LOW (Figure). No significant differences in structural measures (thickness or volume) were detected.

Conclusion

Cortical diffusivity measures can detect differences in cortical microstructure of amyloid positive and negative participants with different WM damage severity. The reduced AngleR value in Aβ42‐ HIGH participants was potentially due to neuroinflammatory processes, consistent with previous findings(1). The higher PerpPD+ values in Aβ42+ HIGH may indicate the secondary cortical microstructural damage.

References:

(1) Torso et al. 2022, PMID:36281682

(2) Ingala et al. 2021 PMID:33811742
Cholinergic pathway modulation by age‐dependent amyloid‐beta pathology in an APP‐knock‐in AD mice model
Authors: Mitra Sumonto , Gera Ruchi , Tambaro Simone , Nilsson Per , Linderoth Bengt , Behbahani Homira , Darreh‐Shori Taher , Eriksdotter Maria
Published: December 2023

Background

Altered cholinergic pathways and memory dysfunction are well‐known changes during Alzheimer’s disease (AD), linked to the early loss of basal forebrain cholinergic neurons (BFCNs). BFCN’s innervates wide regions of the brain, including hippocampus which is a crucial site of neurotrophic factor production like nerve growth factor (NGF) – the master regulator of cholinergic pathways and brain derived neurotrophic factor (BDNF). Hippocampus coordinates memory and cognition and is found affected with amyloid‐beta (Aβ) pathology in AD. Till date, a clear connection between Aβ pathology in modulating cholinergic alteration has not been proven. Recently, the anti‐amyloid antibody Aducanumab and Lecanemab was approved for AD therapy by the United States of America Food and Drug Administration but whether Aβ deposition or clearance modulates cholinergic activity is not established. We evaluated cholinergic status in hippocampus of AD mice model in‐comparison with matched wildtype control.

Method

Hippocampus tissue was isolated from a humanized APP‐knock‐in mouse model of AD (AppNL‐G‐F) at different stages of amyloid pathology – 2‐month age (pre‐plaque stage), 7‐month age (plaques present + initiation of cognitive deficits), and 12‐month age (advanced amyloid pathology), and age‐matched wildtype control (C57BL/6JRj) respectively. Tissues were then processed to isolate total protein which was achieved by extracting them in various buffers (soluble, ionic, and detergent soluble fractions) and pooled together. Enzyme assays for cholinergic markers including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), choline acetyltransferase (ChAT) was performed, along with ELISA for the estimation of total NGF and BDNF levels, respectively.

Result

Age‐dependent changes were observed in AppNL‐G‐F mice compared to wild‐type controls. Cholinesterase activity was increased for AChE at 7 months, while BuChE activity was less in the AppNL‐G‐F mice from 7 month onwards, with respect to wildtype control mice respectively. ChAT levels were nominally affected but the cholinergic index (ChAT/AChE) was considerably altered in AppNL‐G‐F mice. NGF levels remained unchanged, but BDNF levels increased in an age‐dependent manner in AppNL‐G‐F mice as compared to control mice.

Conclusion

Significant age‐dependent alteration in cholinergic activity and neurotrophic factors were evident in hippocampus tissue of AppNL‐G‐F mice, when compared to wild‐type counterparts underlining the importance of the cholinergic activity in relation to amyloid pathology.
Sleep Quality and Day‐to‐Day Variability: Relation to Alzheimer’s pathology in Cognitively Unimpaired Older Adults At‐Risk of AD Dementia
Authors: Mohammediyan Bery , Baril Andree‐Ann , St‐Onge Frederic , Ourry Valentin , Carrier Julie , Breitner John C.S. , Poirier Judes , Villeneuve Sylvia ,   PREVENT‐AD
Published: December 2023

Background

Increasing evidence suggests a link between sleep and late‐life Alzheimer disease’s (AD) pathology. We investigated whether sleep degradation might be accompanied by faster AD pathology accumulation and/or whether early AD pathologic changes might be accompanied by sleep changes before the onset of cognitive symptoms.

Method

We investigated 228 PREVENT‐AD participants with available sleep data who underwent Aβ, [18F] NAV‐4694, and tau,[18F] Flortaucipir, positron emission tomography (PET). Longitudinal subjective sleep quality data were available for 191 participants (follow‐up:1.03±0.19y), longitudinal objective sleep data measured with actigraphy was available for 152 participants (follow‐up:2.5±1.24y), and longitudinal PET scans were available for 104 participants (follow‐up:4.3±0.24y). We assessed sleep quality using the Pittsburgh sleep quality index (PSQI) global score along with 7‐day actigraphy to indicate sleep duration, efficiency, and fragmentation index. Daily variation in sleep was measured using cross‐sectional and longitudinal standard deviations across the 7 days of actigraphy. Linear mixed effect models tested for longitudinal association of baseline sleep measures with PET outcomes over time. We also examined whether an increase in PET AD tracer uptake predicted changes in sleep quality and day‐to‐day variability. Every model controlled for age and sex.

Result

We found no association between sleep measures and Aβ PET.

Higher baseline PSQI scores were associated with higher levels of tau over time (p = 0.004, R2 = 0.034, 𝛽 = 0.007, Fig.1, A). Higher baseline variability of sleep duration and fragmentation index were also associated with higher levels of tau longitudinally (p = 0.001, R2 = 0.05, 𝛽 = 0.001, Fig.1, B; p = 0.029, R2 = 0.022, 𝛽 = 0.01; Fig.1, C). Furthermore, increased tau at baseline was associated with lower sleep quality (p = 0.006, R2 = 0.026, 𝛽 = 4.12, Fig.2, A), and with higher sleep duration variability over time (p = 0.004, R2 = 0.06, 𝛽 = 61.56, Fig.1, B.)

Conclusion

Poor sleep quality and higher day‐to‐day sleep variability in older age could contribute to faster rate of tau pathology accumulation, which could in turn disrupt sleep further. Targeting sleep disturbances may therefore serve in delaying tau burden and slowing down disease progression.
Blood Biomarkers Improve The Diagnostic Accuracy Of Alzheimer’s Disease As Compared With Current Diagnostic Standard In the Primary Care Setting
Authors: Palmqvist Sebastian , Tideman Pontus , Braunstein Joel B. , West Tim , Kirmess Kristopher M. , Meyer Matthew R. , Smith Ruben , Fawad Ayesha , Stomrud Erik , Janelidze Shorena , Hansson Oskar
Published: December 2023

Background

The first and final level of care for most individuals with cognitive impairment is primary care. The aim was to examine the diagnostic accuracy of plasma phospho‐tau217/non‐phospho‐Tau217 (p‐tau217 Ratio) and Aβ42/40 Ratio for Alzheimer’s disease (AD) as compared to usual care by primary care physicians (PCPs).

Method

In the BioFINDER‐Primary Care study, we recruited patients examined due to cognitive complaints at 25 primary care centers in Sweden (n = 307). After care‐as‐usual (CT/MRI, cognitive testing, and clinical assessment), the PCPs documented the most likely underlying etiology and proposed a treatment plan. Plasma biomarkers included p‐tau217 Ratio, Aβ42/Aβ40 Ratio, and a predefined algorithm combining both (C2N mass‐spectrometry). The outcome was AD pathology defined using FDA‐approved cerebrospinal fluid Aβ42/p‐tau181 (Lumipulse®) or visual read of 18F‐Flutemetamol Aβ‐PET.

Result

The mean age was 76±6.3 years, 48% were women, and 49% had AD pathology. Twenty‐five percent had subjective cognitive decline, 47% mild cognitive impairment, and 28% dementia. Using AD pathology as the outcome, the AUCs were 0.80 (95%CI 0.75‐0.86) for Aβ42/Aβ40 Ratio, 0.91 (0.88‐0.94) for pTau217 Ratio, and 0.94 (0.92‐0.97) for the algorithm. In those with available PCP questionnaires (n = 265), the PCPs correctly classified AD in 54% (50‐59%) of the cases, compared with 77% (73‐81%) for Aβ42/40 Ratio, 85% (82‐88%) for p‐tau217 Ratio, and 87% (84‐90%) for the algorithm. The mean certainty of the PCPs’ diagnosis (1‐10, not at all to completely certain) was 4.7 (5.1 in those with AD pathology who were correctly diagnosed as AD and 4.6 in the missed AD cases). The PCPs’ proposed treatment, which in 87% followed the treatment guidelines, led to 50% of true AD cases not receiving symptomatic treatment and 30% of non‐AD cases incorrectly receiving symptomatic AD treatment (DLB patients excluded).

Conclusion

We found that it is difficult for PCPs to identify AD among patients with cognitive impairment in primary care, which leads to diagnostic uncertainty and incorrect treatment. The use of a blood test for AD pathology has great potential for improving the diagnostic accuracy and treatment of AD in primary care. At AAIC, a larger dataset will be presented including the effects of co‐morbidities and medications.
Memory impairment in Alzheimer’s disease is associated with Dentate Gyrus atrophy: A pilot study using the Uniform Data Set Neuropsychological Battery and 7 Tesla MRI
Authors: Hari Ishani , Adeyemi Oluwatobi F , Penny Gowland , Bowtell Richard , Mukaetova‐Ladinska Elizabeta , Hosseini Akram A.
Published: December 2023

Background

The neuropsychological battery of the Uniform Data Set (UDSNB3.0) (Weintraub et al., 2009) assesses cognition. The neuroanatomical correlates of the UDSNB3.0 have not yet been investigated. 7T MRI was used to investigate correlations between hippocampal subfield volumes and the UDSNB3.0 for Alzheimer’s disease (AD) and age‐matched healthy control (HC).

Method

28 (15 AD, 13 HC) participants (61% female; aged 42‐79) were recruited. A Phillips Achieva 7T scanner used a Nova Medical (Wilmington MA, USA) single‐channel transmit, 32 channel receive (1Tx32Rx) head‐coil. PSIR images (TE/TR = 119/59001ms, FA = 90o, 0.38×0.39×1.50 mm3 resolution) were segmented into Cornu Ammonis (CA = CA1+CA2+CA3), Subiculum (SUB), Dentate Gyrus (DG), and Entorhinal Cortex (ERC) (Figure 1). The UDSNB3.0, administered by trained Assistant Psychologists, included the MoCA and a variety of cognitive tests assessing memory (immediate/delayed recall, un‐cued/cued recall, and recognition), attention, language and visuospatial abilities.

Result

In the whole analysed sample (n = 28), there were strong positive correlations between UDS3.0 memory test scores and hippocampal subfield volumes (Figure 2). There were significant reductions in the volume of each hippocampal subfield in AD, compared with controls (p<0.05). No significant decrease in the whole brain volume was noted between the two groups (p>0.05), indicating that hippocampal volume loss was not part of whole brain atrophy. One‐way ANOVA’s demonstrated significant differences between HC and AD test scores (p<0.05), thus HC and AD participants were analysed separately. In AD participants, whole hippocampal volume correlated with MoCA memory category cue scores (R2 = 0.54, p<0.05) but only significantly in the DG of the hippocampal subfields (R2 = 0.52, p<0.05) (Figure 3), supporting Novellino et al.’s (2018) previous finding of associations between the DG volume and cued recall. No such significant correlations were observed in HC participants.

Conclusion

The results of this study confirm that hippocampal atrophy in AD is associated with cognitive decline. Additionally, our results suggest that 7T MRI may be able to detect subtle in vivo DG atrophy in AD that is related to cued memory. The 7T scans appear to reveal DG changes in AD that to date have been confirmed in neuropathological studies only.

Funding: The Medical Research Council, UK has funded AAH (MR/T005580/1).
A polygenic risk score (PRS) predicts cognitive decline in the APOE3 population in an early Alzheimer’s disease clinical trial cohort
Authors: Vasanthakumar Aparna , Gao Qian , Daunt Paula , Flint Simon , Gibson Alex , Florian Hana , Waring Jeffrey
Published: December 2023

Background

Alzheimer’s disease (AD) is one of the most common forms of dementia globally and is defined by accumulation of extracellular amyloid plaques and intracellular tau‐containing neurofibrillary tangles in neuronal cells. These pathological changes occur more than a decade prior to symptom onset. Given that disease modifying therapies are geared towards asymptomatic/early AD patients, identification of asymptomatic individuals at risk of progression is key. Genome‐Wide Association Studies(GWAS) for AD have implicated many single nucleotide polymorphisms (SNPs) associated with disease risk. Whereas a minority of early onset AD cases are driven by mutations in genes, sporadic AD cases have complex genetic architecture and are highly heritable. Polygenic Risk Scores (PRS), which aggregate genome‐wide risk loci, have been shown to predict AD onset with AUCs of 75‐84%.

Methods

The PRS approach used in this study is built from a sum of weighted contributions of over 100,000s SNPs associated with disease. We utilized PRS (genoSCORE™) to predict cognitive function decline in a cohort of 280 AD patients in a Ph2 clinical trial for Tilavonemab, a monoclonal antibody targeting the N‐terminus of human tau. Additionally, genoTOR™ was calculated to identify pathways most impacted by the genetic variants enriched in the cohort.

Results

Given that tilavonemab did not alter Clinical Dementia Rating‐Sum of Boxes(CDR‐SB), we tested differences in cognitive decline between high PRS and low PRS individuals defined using a threshold of 0.6 in the entire cohort and found no difference. Upon stratification by APOE status, higher PRS(> = 0.6) predicted an increase in CDR‐SB of an average of 1.0 at week 72 (p<0.1) and week 96 (p<0.05) compared to participants with lower PRS(<0.6) within the APOE3 population. Additional analyses of the genoTOR™ signaling pathways are ongoing.

Conclusions

The results of these analyses demonstrate that genoSCORE™ may be helpful to enrich for APOE3 individuals most susceptible to cognitive decline over time. Since the majority of genetic risk studies have focused on an APOE4 population, this method provides a novel tool to enrich for individuals at high risk for cognitive decline over time in a less studied population in which there is difficulty with prediction of disease progression.
Uncovering the Role of an ABCA7 Frameshift Deletion in African American Alzheimer’s Disease Cellular Pathology
Authors: DeRosa Brooke A. , Nam Younji , Golightly Charles G. , Simon Shaina A. , Arvizu Jamie , Adams Larry D. , Starks Takiyah D. , Laverde‐Paz Juliana , Cukier Holly N. , Vance Jeffery M. , Cuccaro Michael L. , Haines Jonathan L. , Byrd Goldie S. , Beecham Gary W. , Pericak‐Vance Margaret A. , Dykxhoorn Derek M.
Published: December 2023

Background

The ATP Binding Cassette Subfamily A Member 7 (ABCA7) gene is a risk factor for Alzheimer’s disease (AD). While ABCA7 has been implicated as a genetic determinant of AD across populations, the risk effect is the strongest in African Americans (AAs). We previously identified a common 44 base pair deletion in ABCA7 (p.Arg578Alafs) that is predicted to truncate the protein and is significantly associated with AD in AAs (frequency in cases = 15.2%, cognitively unimpaired (CU) = 9.74%, p = 1.41×10−5). Clinically, deletion homozygotes are similar to deletion heterozygotes, supporting dominant gain‐of‐function as a putative disease‐causing mechanism. We sought to determine if the deletion transcript is stable and if the truncated protein is expressed as steps to understanding the mechanism leading to AD risk.

Method

RT‐PCR analysis of heterozygotes was conducted to assess the stability of the deletion transcript. FLAG‐tagged Arg578Alafs and wildtype ABCA7 vectors were constructed then overexpressed in HEK293APPsw cells. Western blot analysis of FLAG‐Arg578Alafs was performed to determine if the deletion produces a truncated protein. Induced pluripotent stem cell (iPSC) lines from six AA individuals with AD bearing the Arg578Alafs mutation (three heterozygous; three homozygous) were created in pair with isogenic CRISPR‐corrected control lines. These iPSC lines were validated for pluripotency, genomic stability, and lack of off‐target editing. The isogenic ABCA7 deletion and CRISPR‐corrected control iPSC lines will be differentiated into microglia and neurons and functionally assessed for cell type‐specific AD phenotypes.

Result

Initial results comparing AD patients to CU individuals show that patient‐derived microglia have normal rates of phagocytosis but are impaired in the uptake and clearance of fibrillar Aβ. RT‐PCR analysis of the deletion in heterozygotes demonstrates that a stable RNA transcript is expressed from the ABCA7 deletion allele. Western blot analysis of overexpressed FLAG‐Arg578Alafs shows that the truncated protein is expressed, albeit at low levels compared to the wildtype protein.

Conclusion

This ABCA7 deletion produces a stable transcript which appears to be translated into low levels of protein. This supports a potential gain of function as the disease risk mechanism. Studies in isogenic lines will further elucidate the functional effects of this ABCA7 deletion on AD pathology in AAs.
Do preclinical serum biomarker levels or their changes predict cognitive decline in clinical AD?
Authors: De Meyer Steffi , Blujdea Raluca E. , Vandenberghe Rik , Poesen Koen , Teunissen Charlotte E.
Published: December 2023

Background

Blood‐based biomarkers have shown good prognostic performance to predict cognitive decline in well‐controlled asymptomatic cohorts. We now investigated whether preclinical serum levels (sampled on average five years prior to Alzheimer’s Disease (AD) diagnosis) or longitudinal changes in GFAP, a glial activation marker, or NfL, a marker of neurodegeneration could predict the rate of cognitive decline rate following initial memory clinic presentation.

Method

Preclinical serum samples from 115 clinical AD patients (mean age at diagnosis = 74 years, 58% female, 40% biomarker‐proven) were retrospectively retrieved from the Leuven university hospital long‐term sample storage. All preclinical samples were collected during routine clinical visits on average 5 years (range: 2‐10 years) prior to AD diagnosis. GFAP and NfL were measured using Simoa at VUmc Amsterdam. For a subset of 51 AD patients, longitudinal serum biomarker data were available with follow‐up samples taken either before (N = 16), after (N = 16) or at the time of diagnosis (N = 40). Using linear mixed‐effects models, we assessed (i) the relationship between preclinical baseline biomarker levels and MMSE decline following memory clinic presentation, (ii) the annual rates in longitudinal serum biomarker change and (iii) the relationship between longitudinal serum biomarker changes and MMSE decline. Biomarker levels were natural log‐transformed for statistical analyses and reported p‐values were Bonferroni corrected.

Result

High preclinical GFAP serum levels were predictive of faster MMSE decline after initial memory clinic presentation (βs = ‐0.97, p < 0.001). Preclinical NfL levels demonstrated no such predictive value (Figure 1). Across the total time period, serial NfL levels (βs = 0.091, 95% CI: 0.060‐0.13) increased more steeply than GFAP levels (βs = 0.052, 95% CI: 0.035‐0.072). However, within the preclinical time window, only serial GFAP levels (βs = 0.057, p = 0.03), and not NfL, displayed a significant time‐dependent rise (Figure 2). Not longitudinal GFAP nor NfL changes since preclinical sampling were associated with subsequent MMSE decline.

Conclusion

Serum GFAP levels measured on average five years prior to clinical diagnosis are informative of the rate of global cognitive decline once patients present at the memory clinic and serum GFAP levels increase towards diagnosis.
Longitudinal tau binding in tau‐PET negative patients with clinical Alzheimer’s disease
Authors: Rikken Roos M. , Coomans Emma M. , de Koning Lotte A. , Visser Denise , Verfaillie Sander C.J. , den Braber Anouk , Collij Lyduine E. , Golla Sandeep S.V. , Barkhof Frederik , Visser Pieter Jelle , Scheltens Philip , van der Flier Wiesje M. , Boellaard Ronald , Ossenkoppele Rik , van Berckel Bart N.M. , Vijverberg Everard G.B. , van de Giessen Elsmarieke
Published: December 2023

Background

Different tau‐PET patterns have been observed in Alzheimer’s disease (AD) which may be associated with demographic factors, copathology and resilience. We and others previously found that not all Aβ‐positive AD patients are tau‐PET positive. It is currently not known whether tau pathology develops in these groups over time. Therefore, we aimed to examine longitudinal tau binding in tau‐PET negative individuals with symptomatic AD.

Method

We included 97 Aβ‐positive participants with clinical diagnosis of mild cognitive impairment or dementia due to AD (MCI/AD) of which 12 (13%) were tau‐PET negative. To compare, we included 131 tau‐PET negative cognitively unimpaired individuals (CU) of which 93 (71%) were Aβ‐negative and 38 (29%) Aβ‐positive. Tau‐status was defined by [18F]flortaucipir PET consensus visual read of two nuclear physicians according to US Food and Drug Administration‐approved guidelines. [18F]flortaucipir SUVr at baseline (N = 225) and after ±2 years (N = 81) was quantified in an early tau region reflecting Braak I (entorhinal cortex), the medial temporal lobe (MTL), and a combined visual read region of interest (ROI) (parietal, occipital, and posterior lateral temporal lobe). We used age‐and sex‐adjusted linear mixed models to compare tau accumulation.

Result

Demographics are shown in table 1. Compared to MCI/AD A+T+, MCI/AD A+T‐ were older (p<0.001) and more often male (p = 0.015). MCI/AD A+T‐ did not differ from CU A‐T‐ in baseline tau‐PET SUVr, but had a slightly lower SUVr in Braak I compared to CU A+T‐ (p = 0.040) (figure 1). After ±2 years, all MCI/AD A+T‐ participants who underwent follow up remained visual read tau negative. However, MCI/AD A+T‐ showed a steeper increase in Braak I and MTL tau‐PET SUVr compared to CU A‐T‐ (figure 2A,B) and in Braak I compared to CU A+T‐ (β = 0.31, p = 0.036). Interestingly, MCI/AD A+T‐ showed a significantly steeper tau‐PET SUVr increase compared to MCI/AD A+T+ in Braak I (β = 0.29, p = 0.029) (figure 2A).

Conclusion

Although visual read tau‐PET status remains stable over time, our results indicate that tau‐negative MCI/AD patients do accumulate tau over time, most pronounced in early tau regions. This highlights the relevance of quantifying tau regionally over time in tau‐PET negative individuals with clinical AD diagnosis.
Updated Appropriate Use Criteria for Amyloid and Tau PET
Authors: Rabinovici Gil D. , Knopman David S. , Arbizu Javier , Benzinger Tammie L.S. , Donohoe Kevin , Hansson Oskar , Herscovitch Peter , Kuo Phillip , Lingler Jennifer H , Minoshima Satoshi , Murray Melissa E. , Price Julie C , Salloway Stephen , Weber Christopher J. , Carrillo Maria C. , Johnson Keith A.
Published: December 2023

Background

The Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging convened a Workgroup to update previous Appropriate Use Criteria (AUC) for amyloid PET (Johnson 2013) and develop the first AUC for tau PET. The AUC represent general guidelines and should not be considered a substitute for clinical judgment exercised in the care of individual patients.

Method

The Workgroup included 14 researchers with multidisciplinary expertise. Meetings were held between June 2020 and August 2021. Key research questions were identified using the PICOTS framework, triggering an independent systematic literature review. Using established methods (Fitch 2001), the Workgroup identified 17 clinical scenarios in which amyloid/tau PET may be considered. Appropriateness of amyloid and tau PET as independent, stand‐alone modalities were ranked for each scenario using a 9‐point scale (Table 1). Consensus was achieved using a modified Delphi process. Online surveys were completed iteratively by Workgroup members, followed by discussion, until all votes for each scenario fell within one of the following categories: Appropriate/Uncertain/Rarely Appropriate.

Result

As an over‐arching principle, amyloid/tau PET should be considered in patients who: (1) have undergone a comprehensive assessment by a dementia expert; (2) Alzheimer’s disease (AD) is a diagnostic possibility but uncertainty remains; and (3) knowledge of amyloid/tau PET results is expected to help establish diagnosis and guide patient management. Consensus ratings for clinical scenarios are shown in Table 2. More evidence was available to inform recommendations for amyloid than tau PET. Amyloid PET was considered “Appropriate” to inform diagnosis of MCI or dementia due to suspected AD; clarify diagnosis when CSF biomarkers are equivocal; to inform prognosis in MCI; and to determine eligibility for amyloid‐targeting therapies. Tau PET was considered “Appropriate” to clarify diagnosis in patients with MCI/dementia under age 65 or those with atypical presentations; and to inform prognosis in MCI or dementia due to suspected AD.

Conclusion

The updated AUC highlight a growing role for amyloid PET and an emerging role for tau PET in the clinical evaluation of cognitively impaired patients. AUC are expected to further evolve based on data from ongoing studies of clinical utility and a rapidly developing therapeutic landscape.
Cognitively healthy Indians with higher Framingham Cardiovascular Risk Scores have higher WMH burden with lesser grey matter, white matter and hippocampal volumes
Authors: Sundarakumar Jonas S. , Lingegodwa Abhishek Mensegere , Issac Thomas Gregor ,   SANSCOG and TLSA Study Teams
Published: December 2023

Background

Increasing evidence indicates the important role of cardiovascular risk factors in dementia risk, particularly in Indians. It is known that cardiovascular risk factors tend to cluster together, and a widely used multivariable risk scoring is the Framingham Cardiovascular Risk Score (FRS). However, very little is known about the association between FRS and structural brain MRI parameters in cognitively healthy Indians.

Method

Baseline clinical and brain MRI data of 487 cognitively healthy Indians (Clinical Dementia Rating score of ‘0’), who are part of two ongoing, large, aging cohort studies in India – Srinivaspura Aging, Neuro Senescence and COGnition study (SANSCOG) study (n = 200) and Tata Longitudinal Study of Aging (TLSA, n = 289) were utilized. FRS was calculated using clinical and blood biochemistry data, whereas brain MRI scans were performed on 3T MRI scanners. White matter hyperintensity (WMH) lesion segmentation was performed using Lesion Segmentation Toolbox (LST) and brain volumes (total grey matter, total white matter, 3rd ventricle, right and left hippocampus) were derived using FreeSurfer software and normalized according to total intracranial volumes of the respective subjects. Linear regression analysis was performed with FRS as independent variable and various structural MRI parameters as dependent variables. A p value of <0.05 was considered significant.

Result

Urban subjects with higher FRS had significantly higher WMH volume (β = 0.00011, p<0.001, R2 = 0.130), lower grey matter (β = ‐0.00285, p<0.001, R2 = 0.206), white matter (β = ‐0.00180, p<0.001, R2 = 0.106), right hippocampal (β = ‐0.00004, p<0.001, R2 = 0.180), left hippocampal (β = ‐0.00003, p<0.001, R2 = 0.156) volumes and higher 3rd ventricle volumes (β = 0.00003, p<0.001, R2 = 0.150). Rural subjects higher FRS had lower grey matter (β = ‐0.00166, p<0.001, R2 = 0.118, white matter (β = ‐0.0011, p<0.001, R2 = 0.060), right hippocampal (β = ‐0.00002, p<0.001, R2 = 0.087), left hippocampal (β = ‐0.00002, p<0.001, R2 = 0.084) volumes and higher 3rd ventricle volumes (β = 0.00004, p<0.001, R2 = 0.264) but no significant association was seen with WMH volume.

Conclusion

These findings indicate that cardiovascular risk is associated with structural brain changes in cognitively healthy Indians. Since cardiovascular risk can be reduced through cost‐effective community level strategies, such as lifestyle‐based interventions, promptly addressing this risk in Indians could be an important part of dementia prevention strategies.
Path integration deficits related to Alzheimer’s disease pathology in clinically normal older adults
Authors: Colmant Lise , Boyer Emilien , Gérard Thomas , Bierbrauer Anne , Kunz Lukas , Sleegers Kristel , Axmacher Nikolai , Lefèvre Philippe , Hanseeuw Bernard J
Published: December 2023

Background

The entorhinal cortex (EC) is the first cortical region affected by tauopathy in Alzheimer’s disease (AD) and is implicated in path integration. In early stages of AD, path integration deficits could be present, even before overt memory deficits. Furthermore, path integration deficits are found among older individuals at risk for AD, such as APOE ε4 carriers. We investigated whether this deficit was related to AD pathology or to APOE genotype using a pure path integration task, the “Apple Game” (Bierbrauer et al. 2020).

Method

Participants navigated through a virtual arena and were asked to drop a basket to its initial location after visiting one intermediate location. We recruited 175 clinically normal participants (MMSE>24/30, median age = 65). We genotyped the APOE gene and classified participants as ε4 carriers (n = 60) or non‐carriers (n = 115). We measured the plasma ratio of Aβ42 and Aβ40 using Simoa. We defined a threshold of Aβ42/Aβ40 with a gaussian mixture model to classify participants as Aβ+ (Aβ42/Aβ40<0.047, n = 54) or Aβ‐ (Aβ42/Aβ40> = 0.047, n = 121). We analyzed path integration performance depending on APOE genotype and amyloid status with a linear mixed model including age as covariate. A subset of participants (n = 49) underwent a second generation Tau‐PET (18F‐MK‐6240). Task performance was related to EC tauopathy using a linear mixed model.

Results

The path integration performance was lower among older individuals Aβ+ compared to Aβ‐ (Fig.1, p = 0.04). There was no APOE effect after taking Aβ into account. This indicates that path integration performance was more related to Aβ pathology than to APOE genotype. In participants with Tau‐PET, we observed that the angular error, a component of the task performance, increased with the EC Tau signal (Fig.2, p = 0.05).

Conclusion

We detected a path integration deficit among clinically normal older individuals that depended on Aβ. Furthermore, path integration performance was related to tauopathy in the EC, possibly reflecting impairment of grid cells. These observations suggest that path integration deficits observed in older individuals carrying an APOE ε4 allele are related to incipient AD pathology.
Identifying microglial CSF biomarkers specifically dysregulated in either the preclinical or the dementia stage of Alzheimer’s disease
Authors: Blujdea Elena Raluca , Vermunt Lisa , Irwin David J. , Chen‐Plotkin Alice , Boiten Walter , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , del Campo Marta , Teunissen Charlotte E.
Published: December 2023

Background

Transcriptomic and pathological studies indicate that microglia play a key role in the progression of Alzheimer’s disease (AD). Through the cellular theory of AD (De Strooper, Karran, 2016), microglia are shown to have dynamically heterogeneous states that could be both beneficial and detrimental. The states may present in time‐dependent waves of upregulation and/or downregulation of microglial‐specific proteins (Paolicelli et al., 2022), that could feature in the AD continuum. This study aims to find useful biomarkers to stage early versus late AD through CSF protein expression profiling of microglia.

Method

Proximity ligation‐based immunoassays panels were used to measure 637 proteins in 565 cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort and University of Pennsylvania from three groups: 1) subjective cognitive decline (SCD) with amyloid/tau ratio positivity (SCD(ratio+): n = 49, mean age = 58 years, 64% males), 2) AD‐dementia (n = 234, mean age = 66 years, 59% males), and, 3) non‐AD ratio negative controls (Controls(ratio‐): n = 282, mean age = 68 years, 66% males). In total, we selected 300 proteins for the comparisons, based on enrichment in microglia from human‐derived single‐cell RNA‐sequencing data. One‐way ANOVA with age, sex, and Tukey’s post‐hoc multiple comparison correction was performed to infer the group differences per protein and detect differing patterns between the three groups.

Result

Out of 107 significantly dysregulated proteins compared to controls, only 5 had clear divergent effects in the two groups. IDUA, FURIN, and LGMN were lowered in AD‐dementia and elevated in SCD(ratio+), while IL18 and CTSC were elevated in AD‐dementia and lowered in SCD(ratio+), figure 1. IDUA is associated to lysosomal degradation, whereas FURIN and LGMN are both proteases that activate downstream pathways controlling cell growth and remodelling. IL18 is linked to macrophage activation and CTSC is involved in activation of inflammatory mediators.

Conclusion

Overall, this study shows preliminary patterns as a first step for precise biological staging of the AD continuum. Through identifying the microglial protein profiling at different stages of disease, we eventually aim to create biomarker panels to map the inflammatory profile and possibly find biomarkers for the hypothesized dual‐wave of inflammation response in AD.
The Association Between Levels of Plasma Biomarkers and Cognitive Performance in the Oldest Old
Authors: Lorenz Linda M.C. , Zhang Meng , Tesi Niccoló , van der Lee Sven J , Hulsman Marc , Gouda Mariam , Sikkes Sietske A.M. , Teunissen Charlotte E. , Holstege Henne
Published: December 2023

Background

Lower cognitive performance in Alzheimer’s Disease (AD) patients has been correlated with changes in blood‐based biomarkers Amyloid‐βeta‐40 (Aβ40), Amyloid‐βeta‐42 (Aβ42), phosphorylated Tau (pTau), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). However, it is still unclear whether there is an association between cognitive performance and plasma biomarkers in the oldest old. Here we investigate I) The association of plasma biomarkers with age across a wide age‐continuum until extreme age (≥100 years); II) To what extent plasma biomarkers associate with cognitive performance ≥100 years.

Method

The Dutch 100‐plus study cohort comprises of self‐reported cognitively healthy centenarians. Biomarkers were measured in 202 centenarians (137 females) on the Simoa platform. We also included centenarian siblings, offspring and their respective partners (N = 318), who were cognitively healthy. I) To investigate the relationship between age and biomarkers, we standardized all biomarkers and performed linear regression analyses. II) Cognitive performance in centenarians was determined using a comprehensive neuropsychological test battery assessing several cognitive domains. Biomarker concentrations were divided into tertiles. Cognitive performance was assessed adjusting for age, sex and education.

Result

I) We observed an age‐related increase Aβ40 (rs = 0.70; range 46.5‐286.5 pg/mL), Aβ42 (rs = 0.53; range 1.4‐17.7 pg/mL), pTau‐181(rs = 0.68; range 0.5‐12.8 pg/mL), NfL (rs = 0.81; range 4.5‐378.7 pg/mL) and GFAP (rs = 0.76; range 24.4‐1085.1 pg/mL), or decrease in Aβ42/40 (rs = ‐0.43; range 0.01–0.10 pg/mL; P<0.001 for all biomarkers, Figure 1). II) Lower Aβ42/40 was associated with lower cognitive performance on global cognition (based on composite z‐score of all tests) β(95%CI) 0.26(0.00–0.51), P = 0.002) and domain executive functioning β(95%CI) 0.16(‐0.07–0.40), P = 0.039), but not with the Mini‐Mental State Examination (MMSE) or the other cognitive domains. Higher concentrations of NfL were associated with lower cognitive performance on MMSE β(95%CI) ‐0.22(‐1.48–1.04), P = 0.005), but not with the separate cognitive domains tested.

Conclusion

Levels of plasma biomarkers rise with age, also in cognitively healthy individuals. However, correlation with cognitive performance varies across biomarkers and cognitive tests, and deserves further evaluation.
A Multi‐disciplinary Team Approach for Educating Providers to Recognize Delirium in the Post Anesthesia Care Unit
Authors: Chapin Benjamin Albert , Radhakrishnan Nila , Perera Estefania , Kimmett Faith , Mortimer Brenda , Crescioni Charles , Price Catherine C.
Published: December 2023

Background

Postoperative delirium is common in older adults and has significant associated morbidity and mortality. However, screening is rarely performed in the post anesthesia care unit (PACU). For this reason, clinical researchers of delirium and a tertiary care interdisciplinary delirium Task Force Team proposed to address this area of patient safety.

Method

A multidisciplinary team met to complete 3 hospital learning objectives. First, to develop an educational toolkit on PACU delirium identification with feedback from hospital stakeholders on topics to be trained, implementation into medical records, and finalizing training videos/powerpoint/quiz modules. Second, to train every PACU nurse on delirium identification. An EPIC form was created with detailed instructions for completing and documenting the CAM‐ICU and included in the PACU discharge checklist. All PACU nursing staff were assigned the module, and delirium screening was made mandatory for all patients aged 65 years or older. Following module assignment, perceived value, satisfaction, and barriers were surveyed to inform modification of training and implementation. Third, delirium screening rates were monitored.

Results

Nurses (n = 110) were assigned postoperative delirium training modules across 3 PACUs starting July 2022 with a 2‐week deadline. Training completion rate was 83% after 3 months. Nurses provided positive feedback on the importance of delirium. Compliance in delirium screening in the PACU was low (<10%). After meeting with nursing staff to hear concerns/barriers to training and implementation, 1 on 1 training with research staff was initiated and all PACU nursing staff completed additional training between September and October. Before project implementation, no delirium screening was performed in the PACU. Over 3 months following completion of training, of 683 patients aged 65 years and older discharged from the PACU, 83 (12%) had delirium screening documented, and 0% were flagged as positive. Rate of screening differed by surgical service and hospital location.

Conclusion

This hospital learning study documents the challenges and promise of implementing a PACU delirium screening program in a tertiary care academic medical center. We present data on improved delirium recognition at the hospital level, but variation in compliance rates by surgical service. Future research needs to examine reasons for variable delirium compliance screening.