bluuebunny/crossref_metadata_2025 huggingface dataset:
Further along the Alzheimer’s disease continuum: associations between mild behavioral impairment with hippocampal and entorhinal volume and incident cognitive decline
Authors: Guan Dylan X. , Rehman Tanaeem , Nathan Santhosh , Durrani Romella , Potvin Olivier , Duchesne Simon , Pike G. Bruce , Smith Eric E. , Ismail Zahinoor
Published: December 2023

Background

Mild behavioral impairment (MBI) identifies a high‐risk group for Alzheimer’s disease and related dementias (ADRD), leveraging the risk associated with later‐life emergent and persistent neuropsychiatric symptoms (NPS). MBI may act as a complementary behavioral analog to later‐life emergent cognitive symptoms (mild cognitive impairment, MCI). These constructs are not mutually exclusive and can co‐occur. We characterized the relationship between MBI, grey matter volume in the hippocampus and entorhinal cortex, and incident cognitive decline in older adults with normal cognition (NC) and MCI.

Method

Seven‐hundred‐forty‐two participants were included from the National Alzheimer’s Coordinating Center Uniform Dataset. The Normative Morphometry Image Statistics tool was used to generate estimates of grey matter volume for the bilateral hippocampi and entorhinal cortices, normalized by age, sex, total intracranial volume, and image quality. NPS were evaluated using the informant‐rated Neuropsychiatric Inventory Questionnaire, from which MBI scores were derived based on a published algorithm. Associations between MBI status and the regions‐of‐interest were modelled separately in NC and MCI using multivariable linear regressions, adjusting for education and clinical‐MRI visit interval time. Associations between MBI status and incident cognitive decline were modelled using Cox proportional hazards regressions.

Result

Participant characteristics are summarized in Table 1. As per Figures 1 and 2, NC participants with MBI had lower grey matter volume in the bilateral hippocampi (B = ‐0.40, 95%CI:[‐0.66, ‐0.15], p = .004), and a greater hazard of incident MCI or dementia, than those without MBI (HR = 3.34, 95%CI:[2.04, 5.48), p<.001). NC MBI+ participants also had lower grey matter volume in the bilateral entorhinal cortices compared to NC MBI‐ participants, although not statistically significant (B = ‐0.13, 95%CI:[‐0.35, ‐0.08], p = .22). In MCI, participants with MBI had lower grey matter volume bilaterally in both the hippocampus (B = ‐0.46, 95%CI:[‐0.80, ‐0.12], p = .01) and entorhinal cortex (B = ‐0.42, 95%CI:[‐0.76, ‐0.12], p = .009), and had greater progression‐rates to dementia (HR = 4.13, 95%CI:[2.45, 6.94), p<.001), than those without MBI.

Conclusion

Our findings suggest that evaluating dementia‐free older adults for MBI status in conjunction with cognitive status identifies a group further along the ADRD continuum than those without MBI, who have greater baseline atrophy in key ADRD regions and greater progression rates to later cognitive stages.
Comparative Performance of the Digital Clock and Recall™ Test, Montreal Cognitive Assessment, and Saint Louis University Mental Status Among Patients in Primary Care
Authors: Hammers Dustin B. , Fowler Nicole R , Brosch Jared R. , Swartzell Kristen L , Banks Russell E , Jannati Ali , Mullavey Judy , Gomes‐Osman Joyce Rios , Murray James F , Willis Deanna R
Published: December 2023

Background

Digital cognitive assessment solutions can overcome some barriers to cognitive screening in primary care by providing rapidly‐obtained objective insights without requiring specialty‐trained examiners. The Linus Health Digital Clock and Recall (DCR™) is a three‐part test consisting of three‐word immediate verbal acquisition, the Digital Clock Test (DCTclock™), and delayed recall of the three words. Our objective was to compare performance on the DCR to the Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005) and the Saint Louis University Mental Status (SLUMS; Tariq et al., 2006), two commonly used screening tests in primary care.

Method

Comparative analyses of DCR, MoCA (Total Score and Memory Index Score [MIS]), and SLUMS results were conducted among 80 primary care patients – 65 years and older presenting for any reason – whose DCR performance was indicative of cognitive impairment.

Result

Of the 80 patients (mean age 74.0 [±7.8]; 60% female) performing as impaired or borderline impaired on the DCR, 67 completed the MoCA and 13 completed the SLUMS. Comparison between the DCR and MoCA Total Score included 78% (52/67) concordance for identifying impairment (cutoff <26). While the remaining 15 of 67 patients (22%) had normal MoCA Total Scores (≥26), 13 (87%) missed points in at least one MoCA cognitive domain and 8 (53%) missed points in multiple MoCA domains (often language and delayed recall). Comparison between DCR and SLUMS revealed that all 13 patients receiving SLUMS assessment had DCR scores 0‐1 and SLUMS scores <27 (indicating cognitive impairment). See Tables 1 and 2 for breakdown of MoCA, MIS, and SLUMS stratified by DCR performance. Logistic regression found that DCTclock metrics of information processing (z = 2.00, p = .045) and spatial reasoning (z = 2.82 p = .005) discriminated cognitive impairment on MoCA Total Score (cutoff <26). Overall, ROC analysis revealed good accuracy of DCR to identify MoCA performance (AUC = .84; Figure 1).

Conclusion

Screening in primary care using the DCR is feasible, takes less time to administer than MoCA or SLUMS, and shows concordant results with these more established screening tools in detecting cognitive impairment. Future research aims to investigate the criterion validity of the DCR among biomarkers for neurodegenerative disease.
Effects of cholesterol depletion, pro‐inflammatory cytokines and the apolipoprotein E isoforms on ABCA7 protein levels in human neural cell lines and brain tissue
Authors: Wiener Joel P. , Garliyev Viktor , Desire Sindy , Pratico Anna , Serrano Geidy E , Lyssenko Nicholas N.
Published: December 2023

Background

Strong evidence from diverse sources points to adenosine triphosphate‐binding cassette transporter subfamily A member 7 (ABCA7) as a major risk factor in Alzheimer’s disease (AD). However, the mode of its involvement with the disease and many aspects of its function are understood incompletely.

Method

Human microglia cells C20 and HMC3 and neuronal cells SK‐N‐SH were either depleted in cholesterol using methyl‐β‐cyclodextrin and/or rosuvastatin or treated with pro‐inflammatory cytokines IL‐1β, IL‐6 or TNFα, and ABCA7 protein levels in these cells were then assessed using a validated monoclonal antibody. ABCA7 levels were also assessed using the antibody in the parietal cortex from 170 donors, who were genotyped for the APOE isoforms.

Result

Large (∼75%) reductions in intracellular cholesterol and saturating amounts of pro‐inflammatory cytokines IL‐1β and TNFα reduced ABCA7 protein by, respectively, 36.8±9.1% (mean±standard deviation, two‐tailed t test p = 0.0002, n = 4), 53.0±22.6% (p = 0.002, n = 4) and 59.2±8.0% (p = 0.0006, n = 4) in C20 cells and by similar percentages in HMC3 cells. Similarly severe cholesterol depletion had no effect on ABCA7 and IL‐1β and TNFα moderately increased ABCA7 amounts in SK‐N‐SH cells. IL‐6 had no effect on ABCA7 expression in any cell line. IL‐1β and TNFα significantly cross‐induced each other’s secretion in C20 cells. We have previously shown that ABCA7 protein levels drop suddenly during AD pathogenesis between Braak and Braak stages I and II in the human brain. Among the individuals without AD pathology or with Braak stage I pathology, ABCA7 levels were lower in APOE4 carriers without reaching statistical significance (0.74, 0.35‐2.51 vs 1.5, 0.30‐3.16 ABCA7/GAPDH ratios; median, 25%‐75% interval; Mann‐Whitney p = 0.44, n = 68 vs 14); among the individuals with Braak stages II‐V, ABCA7 was also lower in APOE4 carriers (0.21, 0.07‐1.07 vs 0.55, 0.11‐1.35; Mann‐Whitney p = 0.18, n = 53 vs 35). The comparison groups were matched for age, sex and PMI.

Conclusion

The effect of cholesterol depletion on ABCA7 expression is tissue specific. ABCA7 functions are homeostatic and not compatible with inflammation in microglia. If APOE4 has an effect on ABCA7 levels, it is smaller than the reduction in ABCA7 between Braak stages I and II. These findings improve our understanding of ABCA7 pathophysiology.
Novel Framework for Brain Age Prediction using Graph Neural Networks
Authors: Sihag Saurabh , Mateos Gonzalo , Wolk David A. , Ribeiro Alejandro , McMillan Corey T
Published: December 2023

Background

Aging is among the largest risk factors for neurodegeneration which can be accelerated by age‐related pathologies. Hence, individuals may age at different rates reflected by a gap in biological estimates of age and actual chronological age. Graph neural networks (GNN) are deep learning models that leverage spatial information inherent in the dataset for inference. Here, we develop an MRI cortical thickness (CT) based brain age prediction framework using GNNs and illustrate that it provides a feasible mechanism to identify contributing regions leading to elevated brain age gap in Alzheimer’s disease (AD).

Method

We used ANTs to calculate CT in 100 parcels from 3T MRI of 170 healthy controls (HC; age = 64.26±8.27y, 101 females), 53 mild cognitive impairment (MCI; age = 68.56±8.58y, 22 females), and 62 AD (age = 67.25±8.83y, 30 females) individuals. A GNN model based on the anatomical covariance matrix from HC cohort was trained to predict chronological age from associated CT for HC cohort. GNN output was evaluated as an unweighted mean of entities associated with the brain regions in the final layer. Hence, individual contributions to the GNN output by each brain region could be quantified. Final brain age prediction was obtained after removing age‐bias from GNN outputs using linear regression model. For all subjects, we evaluated residuals at regional level (regional age‐gap) by comparing the contribution of each parcel with corresponding GNN output. The residual between predicted brain age and chronological age (age‐gap) was also evaluated. See Figure 1 for an overview.

Result

ANCOVA (with correction for age and gender) with post‐hoc analyses revealed that regional age‐gap was greater for AD relative to HC in inferior parietal, temporal pole, inferior temporal, medial temporal, and superior frontal regions (Bonferroni corrected p‐value<0.05). Also, regional age‐gap was greater for MCI relative to HC for inferior parietal and temporal pole regions (Figure 2). Subsequently, age‐gap was elevated in AD (mean = 5.64y) and MCI (mean = 2.66y) relative to HC (mean = 0y) reflecting a linear increase in age‐gap with disease stage (Figure 3).

Conclusion

Our novel framework identified regional CT associations with age‐gap in AD and MCI, suggesting that this GNN approach may be used to further our understanding between aging and neurodegeneration.
Hippocampal‐to‐ventricle ratio (HVR) is better related to age and cognition than Hippocampal Volume
Authors: Fernandez‐Lozano Sofia , Fonov Vladimir S , Dadar Mahsa , Collins D Louis ,   for Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Hippocampal volume (HCvol) is an important biomarker in the study of neurodegeneration (1‐3). Given its high variability (4) HCvol is commonly normalized using the intracranial volume (HCvol/ICV) (5). The Hippocampal‐to‐ventricle ratio (HVR) considers instead the nearby expanding ventricular space and has shown stronger negative association with age and positive association with delayed memory compared to HCvol in healthy aging (6).

Method

Using a Convolutional Neural Network (7) we extracted the volumes from the hippocampus and the surrounding temporal horn of the lateral ventricles to obtain the HCvol, HCvol/ICV and HVR on the baseline T1w MRI scans from the ADNI dataset (CN = 502, MCI = 814, AD = 323). We converted these measurements to Z‐scores using the mean and standard deviation of the CN cohort to facilitate comparisons. We used Pearson’s correlation coefficient to compare the relationships between each of the three Hippocampal measures with age, ADAS13, and the Immediate, Learning, Forgetting and Forgetting‐percentage metrics of the Rey’s Auditory Verbal Learning Test (RAVLT). Finally, we compared the correlations of HCvol/ICV and HVR with a bias‐corrected‐and‐accelerated bootstrap (BCa; 10,000 resamples) (8).

Result

The correlations of HCvol and HCvol/ICV were similar for age (‐.41 [‐.32, ‐.48] vs ‐.38 [‐.3, ‐.45]), ADAS13 (‐.28 [‐.19, ‐.45] vs ‐.26 [‐.17, ‐.45]) and RAVLT subtests (absolute values: .2 [0, .4] vs .2 [.01, .41]). HVR showed significantly stronger negative correlations with age compared to HCvol/ICV (Fig. 1; CN: BCa = .144 [.102‐.187]; MCI: BCa = .128 [.096‐.160]; AD: BCa = .068 [.012‐.122]). While the negative correlations between HVR and ADAS13 scores were higher than HCvol, the comparison was not statistically significant (Fig. 2). Figure 3 shows the relationships between HC measures and RAVLT subtests: HVR had stronger correlations than HCvol for CN and AD on the Immediate subtest, while HCvol’s relationship with Forgetting score was higher for MCI. None of these were statistically significant.

Conclusion

Considering ventricular expansion and hippocampal shrinkage in the HVR better explains the variance related to age and cognition than using hippocampal volume by itself in healthy controls and patients with mild cognitive impairment and dementia.
The Adult Changes in Thought (ACT) Medical Records Abstraction Project: A resource for research on the aging brain and Alzheimer’s disease and related dementias
Authors: Crane Paul K , Lind Bonnie , Dodd Tammy S , Lyons Mary , Macuiba Jennifer A , Gray Shelly L , Meyers Kelly P , Kelley Ann , Nemerever Leslie C , Covey Jennifer M , Campbell Camille C , Lederman Becky , Sheridan Leigh , Tom Sarah E. , Larson Eric B , Nelson Jennifer C , LaCroix Andrea Z. , Renz Anne
Published: December 2023

Background

Adult Changes in Thought (ACT) is a prospective cohort study of older adults from Seattle, Washington, USA. Participants are enrolled from Kaiser Permanente Washington membership and may consent for autopsy. Many participants have decades of medical records prior to ACT enrollment. We describe an ambitious project to abstract medical records to facilitate epidemiological investigation.

Method

Abstractions include medication data preceding 1977 (the start of automated pharmacy data), laboratory data preceding 1988 (the start of automated laboratory data), women’s health history elements, blood pressures, several cardiovascular conditions, several neurological conditions, physical injuries, psychiatric conditions, and other medical conditions, among many others. Data are entered in a Microsoft Access front‐end interface linked to a Microsoft SQL Server database engine. The database comprises 15 tables in a relational structure. We summarize chart review data and other data according to dementia status.

Result

We have completed abstractions on 1329 individuals, of whom 908 had an autopsy. For the first 380 people with an autopsy, it took an average of 6.2 hours (SD 3.8 hours) to abstract >30 years of medical data. More recent electronic medical record data take longer to abstract. In this sample, 236 (62%) died without Alzheimer’s Disease or Related Dementias (ADRD) dementia, and 144 (38%) died with an ADRD dementia diagnosis. Demographic and clinical data are summarized in the Table. Over 60% had pharmacy data preceding 1977 with a median of more than a half decade’s worth. Over 90% of the cohort had additional laboratory data preceding 1988, with a median of a decade’s worth. Medical conditions were similarly common across people without and with ADRD, except cerebrovascular accidents, diabetes, depression, and confusion during hospitalization were more common among people with dementia. We will update all numbers for AAIC.

Conclusion

The ACT Medical Records Abstraction Project transforms medical records into data ready for analyses of associations with outcomes derived from other data from the ACT study. For the autopsy cohort in particular, the Medical Records Abstraction Project provides unmatched detailed longitudinal clinical data to support a wide variety of epidemiological research on clinical‐pathological correlations.
Cortical and substantia nigra 18F‐PI‐2620 tau PET signal in Lewy body disease
Authors: Winer Joseph R. , Vossler Hillary , Young Christina B. , Romero America , Shahid Marian , Abdelnour Carla , Anders David , Shen Bin , Morales Aimara Pacheco , Davidzon Guido , Mormino Elizabeth C. , Poston Kathleen L.
Published: December 2023

Background

Tau PET imaging is a potential tool for measuring comorbid tau pathology in patients with Lewy body disease. Furthermore, tau PET ligands are known to bind to neuromelanin within substantia nigra (SN), with reduced binding in Parkinson’s disease relative to healthy individuals. We sought to characterize 18F‐PI‐2620, a next generation PET tracer, in patients from across the Lewy body disease spectrum.

Method

A total of 126 participants from the Stanford Alzheimer’s Disease Center (ADRC) and the Stanford Aging and Memory Study (SAMS) were recruited for PET scanning with 18F‐PI‐2620. We compared 18F‐PI‐2620 uptake within medial temporal (entorhinal cortex, amygdala) and occipital (precuneus, lingual gyrus) regions as well as SN across patients with Parkinson’s disease (PD, n = 26), dementia with Lewy bodies (DLB, n = 6), and Alzheimer’s disease spectrum (AD, n = 21), in addition to cognitively normal older adults (healthy controls, HC, n = 73). Mean bilateral signal was extracted from cortical regions of interest in native space 18F‐PI‐2620 SUVRs (inferior cerebellar gray reference). Amyloid status was determined either by 18F‐florbetaben PET or CSF. To quantify SN, SUVRs were normalized to template space and an anatomical mask was used to extract mean signal. MDS‐UPDRS‐III motor exam scores, collected in an off‐medication state for all patients, were used as a measure of motor impairment.

Result

Entorhinal and amygdala SUVR were significantly elevated in the AD group relative to all other groups, and in amyloid‐positive relative to amyloid‐negative HC (Fig 1). Tau burden in all regions was low across PD and DLB groups and did not differ based on amyloid status. SN SUVR was significantly lower in the PD group compared to the HC and AD group (Fig 2A). In patients with Lewy body disease (PD & DLB), MDS‐UPDRS‐III scores were negatively associated with SN SUVR (Fig 2B).

Conclusions

These findings suggest that cortical tau is low in Lewy body disease. Neuromelanin‐related 18F‐PI‐2620 signal within SN carries information about disease severity. Cortical tau and SN binding represent two unique signals in the same tau PET image that may be informative in the context of Lewy body disease.
Delaying Cognitive Decline Through Dietary Approaches and Evidence‐based Practices
Authors: Jackson Yolanda , Roberts Celeste , Glover Rosby , Rhodus Elizabeth K.
Published: December 2023

Background

Alzheimer’s disease and related dementias (ADRD) disproportionately impact African Americans compared to non‐Hispanic Whites. Lifestyle factors, such as diet and exercise, may contribute toward this difference. Health campaigns tailored to these populations related to healthy lifestyle choices, such as the cognitive benefits seen with the MIND diet (Mediterranean‐dietary approaches to stop hypertension, Intervention for Neurodegenerative Delay) paired with evidence‐based guidelines, may improve self‐efficacy related to healthy behaviors. Utilizing the constructs of the Integrative Model, this study examines behavior change intention after an intervention using a health campaign encouraging MIND diet compliance and evidence‐based healthy aging guidelines.

Methods

This study implemented a culturally tailored health campaign related to healthy brain aging and an educational workshop led by experts in nutrition, Alzheimer’s disease, and behavioral science with older African American adults at a local faith‐based center. Upon completion of the workshop, participants completed select items of the 36‐Item Short Form Survey Instrument (SF‐36) and the Client Satisfaction Questionnaire (CSQ). Analyses of demographic and frequency reports illustrate likelihood to follow through with MIND diet principles.

Results

Eighty‐five percent of participants (N = 20) reported little to no knowledge of the health campaign content prior to this study. Following the workshop, all participants reported that they were likely (66.7%) or very likely (33.3%) to incorporate principles learned from the evidence‐based workshop at home. Further, 71.4% reported being confident to follow the diet at home with an additional 28.6% of participants being very confident.

Conclusion

Culturally tailored health campaigns play an integral role in nutrition education, healthy aging, and lifestyle modification for ADRD reduction in the African American community. This approach enabled communication of evidence‐based practices of dietary modifications, cognition, and brain health as a mechanism to increase knowledge and self‐efficacy to carry out healthier behaviors at home. Community‐based nutrition education utilizing culturally appropriate health messages has potential to improve lifestyle behaviors, health disparities, and reduction of ADRD among African American older adults. Larger pragmatic, and implementation‐based studies using community‐engaged methods are needed to increase evidence and reach of this approach specific for aging African American adults.
Amyloid burden was associated with worse memory performance but no associated with conversion to mild cognitive impairment in SuperAgers
Authors: Neto Adalberto Studart , Coutinho Artur Martins , Carneiro Camila de Godoi , Moraes Natália Cristina , Aranha Mateus Rozalem , Spera Raphael Ribeiro , Parmera Jacy Bezerra , Yassuda Monica Sanches , Brucki Sonia Maria Dozzi , Leite Claudia da Costa , Buchpiguel Carlos A , Nitrini Ricardo
Published: December 2023

Background

The term “SuperAgers” (SA) was proposed to define older adults with 80 years or more who have a memory equivalent to 20‐30 years younger. The study aimed to investigate cortical amyloid deposition and follow‐up in a cohort of SA.

Method

We identified eleven SA seniors from an initial sample of 66 older adults who sought the study because they believed they had exceptional memory. Nine were evaluated in two time points (enrollment and 1 year follow‐up). PET with Pittsburgh Compound‐B labeled with carbon‐11 (11C‐PIB) was acquired on a hybrid PET/MR equipment and analyzed individually using semiquantitative analyses with 3D‐SSP. SPM8 software was used for group comparisons.

Result

Four SA (36.4%) were PIB‐PET positive, without significant differences compared to the age‐matched healthy controls. Three out of four SA with PIB‐PET positive had subjective cognitive decline (SCD). Another three SA with SCD were negative PIB‐PET. A negative association between memory tests and the amyloid burden was found in the SA group. At one year of follow‐up, three of the nine SA evolved as non‐amnestic MCI, and six (66.7%) remained cognitively unimpaired. No SA group participant converted to amnestic MCI. There was no association between conversion rate to MCI and amyloid status (p = 0.583). Only one SA classified as MCI on the second visit had PIB‐PET positive. We found no association between the presence of memory complaints and conversion rate to MCI in SA group (p = 0.524).

Conclusion

Amyloid burden was associated with worse performance on memory tests and SCD but was not associated with conversion to MCI at a one‐year interval. SCD was also not associated with cognitive decline in SA.
The role of cerebrovascular pathology in the association between amyloid‐β and tau in cognitively unimpaired and impaired individuals
Authors: Coomans Emma M. , van Westen Danielle , Binette Alexa Pichet , Strandberg Olof , Spotorno Nicola , Palmqvist Sebastian , Stomrud Erik , Ossenkoppele Rik , Hansson Oskar
Published: December 2023

Background

Although cerebrovascular pathology often co‐exists with Alzheimer’s disease pathology, it remains incompletely understood to what extent it can contribute to the progression of Alzheimer’s disease pathology. We investigated whether cerebrovascular pathology (white matter lesions [WML] and microbleeds) modified the association between amyloid‐β (Aβ) and both cross‐sectional and longitudinal tau in cognitively unimpaired (CU) and cognitively impaired (CI) individuals.

Method

We included 1240 participants from the Swedish BioFINDER‐2 cohort including 402 Aβ‐negative CU, 147 Aβ‐positive CU, 257 Aβ‐negative CI (MCI and non‐AD dementia) and 434 Aβ‐positive CI participants (MCI and AD dementia) (Table 1). All underwent baseline [18F]RO948 (tau)‐PET, and a subset (n = 678) underwent longitudinal tau‐PET (2.6±1.0‐years). We extracted tau‐PET SUVr in a temporal meta‐region‐of‐interest. For Aβ, we used global [18F]flutemetamol‐PET SUVr for CU and Aβ‐status (+/‐) for CI participants. Global WML volume was calculated using the SPM lesion segmentation tool, corrected for intra‐cranial volume and log‐transformed. Presence of microbleeds was dichotomized into absent or present (≥1) by visual read. Primary analyses included age‐, sex‐ and APOE ε4‐corrected linear mixed models between tau‐PET (outcome) and interactions between time, Aβ and WML volume/microbleeds (predictors).

Result

Upon correcting for age, sex and ε4‐carriership, Aβ‐positive CU and CI participants showed significantly more microbleeds compared to Aβ‐negative participants of the same cognitive stage (both p<0.05), but no differences in WML volume was observed (both p>0.05). In CU, we observed a significant interaction effect between ≥1 microbleed and higher Aβ‐load with both greater cross‐sectional tau (β = 0.67 [CI: 0.45‐0.89], p<0.001) and longitudinal tau (β = 0.11 [CI: 0.07‐0.16], p<0.001) (Fig‐1, Table‐2). In CU, we also observed a significant interaction effect between larger WML volumes and higher Aβ‐load with greater cross‐sectional tau (β = 0.14 [CI: 0.06‐0.22], p = 0.001). When including both microbleeds and WML volume in the same model, only effects of microbleeds remained significant (Table‐2). No significant effects were observed in CI participants.

Conclusion

In CU (but not CI) individuals, cerebrovascular pathology may modify the association between Aβ and tau by accelerating tau accumulation in the presence of Aβ. These results might suggest an early effect of cerebrovascular pathology on the interplay between Aβ and tau.
Loneliness and social isolation association with incidence of disability, dementia and mortality in Mexican older adults: three follow‐up years
Authors: Sánchez Brenda Sarai Miranda , Acosta‐Castillo Gilberto Isaac , Sosa‐Ortiz Ana Luisa
Published: December 2023

Background

Loneliness is defined as the feeling of being alone and can be considered as persistent, unavoidable and unpleasant. Social isolation is characterized by low frequency of contact with the social network, which may or may not include family members. The study of each of these entities is important because of their high frequency in OA and their association with negative outcomes as disability, dementia even mortality.

Method

We performed a secondary analysis of 1,668 adults aged 65 years or older, evaluated within Dementia Research Group 10/66 protocols in Mexico, after 3‐year follow‐up. Loneliness presence was assessed based on three questions included in the Geriatric Mental State Inventory (GMS): do you feel lonely, does this feeling of loneliness generate discomfort or sadness, can you avoid feeling lonely. Social isolation was identified by assessing friends, relatives and neighbors contact frequency; co‐residence; church attendance and social gatherings. Association of loneliness with and without emotional discomfort, as well as social isolation with incidence of disability, dementia, and mortality after three years of follow‐up was estimated using multivariate competing risk models.

Result

Loneliness without emotional discomfort was about 35.4%, 24.0% reported loneliness with emotional discomfort, meanwhile social isolation prevalence was 41.1%. A differential distribution of loneliness with and without emotional discomfort, age groups and education by catchment area was observed (Table 2). After three years of follow‐up loneliness was found to be associated with incident dementia subHR = 1.5 (95%CI:1.1‐2.1), and social isolation with mortality, subHR = 1.5 (95%CI:1.1‐2.0).

Conclusion

After three years follow‐up one out 3 OA reported feeling lonely without emotional discomfort, 1 out 4 felt lonely with emotional discomfort, while 2 out 5 reported social isolation. Loneliness without emotional discomfort showed an association with dementia development, meanwhile social isolation was associated with mortality. Finally, no association was found between loneliness with emotional discomfort with disability, dementia or mortality in the analyzed sample.
The association between 73 Alzheimer’s disease risk variants and white matter microstructural decline in aging
Authors: Archer Derek B , Shashikumar Niranjana , Jasodanand Varuna , Moore Elizabeth E. , Murray Sydney , Pechman Kimberly R. , Bilgel Murat , Beason‐Held Lori L , An Yang , Risacher Shannon L , Landman Bennett A. , Jefferson Angela L. , Saykin Andrew J. , Resnick Susan M. , Hohman Timothy J.
Published: December 2023

Background

Although several prior diffusion MRI studies have indicated a role of medial temporal lobe (MTL) white matter microstructural decline in Alzheimer’s disease (AD), it is unclear which AD risk genes are associated with this decline. The goal of this study is to leverage multi‐site harmonized diffusion MRI data to investigate the relationship between 73 AD risk variants and microstructural decline in MTL tracts.

Method

The dataset used in this study was collated from three longitudinal cohorts of aging [Alzheimer’s Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory & Aging Project (VMAP)]. In total, this dataset included 1,308 participants (70% cognitively unimpaired, 27% MCI, 3% AD) aged 50+ who had both diffusion MRI and genotype data and includes a total of 3,442 imaging sessions (mean number of visits: 2.68 ± 1.66, interval range: 1 ‐ 12 years). Genotype data was preprocessed using a standardized approach, and the dosage of the 73 AD risk variants was extracted. Diffusion MRI data was preprocessed using the PreQual pipeline and free‐water (FW) correction was conducted to obtain FW and FW‐corrected fractional anisotropy (FAFWcorr) maps. FW and FAFWcorr were quantified within 5 MTL tracts, including the cingulum, fornix, uncinate fasciculus, inferior longitudinal fasciculus, which were subsequently harmonized using the Longitudinal ComBat package. Linear regression was conducted to investigate the association between AD risk variants and MTL microstructure at baseline, while linear mixed effects regression was used for longitudinal analysis. All models were corrected for age at baseline and sex and corrected for multiple comparisons using the FDR approach.

Result

At baseline, APOE‐ε4 dosage was strongly associated with MTL FW in all tracts, with additional associations for TMEM106B and CR1 dosages with fornix FW (Table 1). Longitudinally, APOE‐ε4 dosage was a strong predictor of MTL FW decline in all tracts, and KAT8, CR1, and TMEM106B dosages exhibited significant associations with fornix microstructural decline (Table 2 and Figure 1).

Conclusion

This study suggests that although APOE‐ε4 is the strongest predictor of white matter microstructural decline, several other AD risk genes (i.e., CR1, SPI1, TMEM106B, KAT8) contribute to decline, particularly in the fornix.
Burden of cerebral small vessel disease modifies relationship between some plasma Abeta 42/40 assays, but not p‐tau181 assays, with amyloid PET
Authors: Lesman‐Segev Orit H. , La Joie Renaud , Rozen Yael , Leibovici Anat , Livny Abigail , Yaffe Kristine , Weiner Michael S. W. , Silbert Lisa C , Shaw Leslie M. , Gardner Raquel C.
Published: December 2023

Background

We aimed to determine if burden of cerebral small vessel disease (CSVD) modifies the relationship of plasma amyloid‐beta (Abeta) 42/40 ratio and/or plasma p‐tau 181 with amyloid PET.

Method

We studied N = 100 participants from the Alzheimer’s Disease Neuroimaging Initiative with 1) Abeta‐42/40 biomarker levels using Quanterix SIMOA (Quanterix), Washington University Mass Spectroscopy (WashU), Simoa HD‐X 4Plex, Roche Elecsys, Shimadzu Mass Spectroscopy, and Gothenburg Mass Spectroscopy, 2) p‐tau181 plasma biomarker levels using Lumipluse G, Roche Elecsys, Simoa p‐tau181V2 Advantage (Simoa Advntage), Simoa p‐tau181, 3) MRI brain, and 4) amyloid‐PET. We stratified by CSVD bruden tertile (calculated from total white matter FLAIR hyperintensity volume). Amyloid positivity was defined as standardized uptake value ratio ≥ 1.11 for florbetapir PET scans. We used box plots to visualize plasma Abeta‐42/40 and p‐tau181 levels stratified by Amyloid‐PET positivity and CSVD tertile. Using logistic regression models, we tested for an interaction between CSVD and plasma Abeta‐42/40 ratio or p‐tau181 on amyloid PET positivity in unadjusted models and models adjusted for age, Clinical Dementia Rating, and presence of ≥1 apolipoprotein E4 allele (ApoE4+).

Result

The cohort had an average age of 77 years, was 56% female, 50% cognitively normal, and 42% ApoE4+ (Table1). We found significant interactions between CSVD and plasma Abeta‐42/40 ratio on amyloid‐PET positivity for Quanterix (raw/adjusted: p = 0.035/p = 0.049), Simoa HD‐Plex (p = 0.047/p = 0.047), and Gothenburg assays (p = 0.026/p = 0.030), with worst discrimination between amyloid‐PET positivity among participants with highest CSVD burden (Figure1A). The Quanterix and Gothenburg assay demonstrated near total overlap between amyloid‐PET positive vs. negative groups at the highest tertile of CSVD. No significant interaction was found between CSVD and any plasma p‐tau181 assay on amyloid‐PET positivity (all p>0.2, Figure1B).

Conclusion

Our findings suggest that individuals with a high burden of CSVD are at risk for incorrect Abeta‐42/40 ratio on certain assay platforms but not others. No interaction was found between CSVD and any plasma p‐tau181 assay on amyloid‐PET positivity. Further research in diverse cohorts with a high burden of CSVD is warranted to inform appropriate use of these blood assays and unravel mechanisms of this unexpected finding.
Reports of responses to coconut oil and medium‐chain triglyceride oil in 288 persons with Alzheimer’s and other cognitive impairment
Authors: Newport Mary T
Published: December 2023

Background

Glucose hypometabolism is an early key feature of AD. Ketones provide alternative fuel to glucose during fasting, ketogenic diet (KD), and ketogenic oil consumption, and are taken up normally in the AD brain (Croteau J Alz Dis 2018). RCTs of KD ± MCT oil or CO (in program recipes) report improvement in people with cognitive impairment (reviewed in Cunnane NRDD 2020; Phillips Alz Res Therapy 2021), usually attributed to generation of ATP by circulating ketones. Ketones are also anti‐inflammatory (Kim Frontiers Immunol 2022) and reduced beta‐amyloid plaques and tau tangles in animal models (Kashiwaya PNAS 2000; Wu FASEB 2020). While blood ketones from CO are lower than from MCT oil, lauric acid (50% of CO) potently stimulated ketone production in cultured KT‐5 astrocytes (Nonaka J Oleo Science 2016), suggesting a more direct effect. Virgin CO also contains antioxidants and substances that inhibit amyloid plaque formation (Chatterjee Mech Ageing Devel 2020).

Method

Response/non‐response to CO ± MCT oil from all communications about persons with AD and other memory impairment collected by the author from 2008 to mid‐2014 were analyzed. Respondents were not prompted regarding expected improvements. Verbatim phrases allowed further categorization of improvements.

Result

288 reports were tabulated (33‐94yo; 48% male/52% female; 55% AD, 25% other dementia, 6% Parkinson’s, 2.4% MCI, 12% other memory complaints). 72% consumed only CO, 26% CO+MCT, and 2% MCT only. 89.2% reported improvements overall, further categorized as Memory/Cognition (72.6%), Social/Behavior/Mood/Personality (37.4%), Speech/Conversation (37.7%), Resumption of Self‐Care/Other Activities (28.4%), Physical Symptoms (20.7%), and Sleep (3.9%).

Conclusion

Just a few targeted FDA‐approved drug therapies claim slowing of cognitive decline. However, nutritional ketosis broadly addresses important pathological changes in the AD brain, including insulin resistance, glucose hypometabolism, and inflammation. A growing number of RCTs of KD ± MCTs/CO with positive cognitive outcomes and improvement in biomarkers add weight to this large collection of communications reporting meaningful improvements while consuming CO and/or MCT oil in cognition, social interaction, self‐care, and other areas important to daily life. Nutritional ketosis deserves more attention from funding organizations and greater public awareness for the potential to improve the lives of people with AD and other neurological impairments.
Longitudinal Cognitive Associates of the ATN Model in Down Syndrome
Authors: Peven Jamie C
Published: December 2023

Background

Individuals with Down syndrome (DS) are genetically at risk of Alzheimer’s disease (AD) due to the triplication of the amyloid precursor protein, resulting in overproduction of amyloid‐beta. In autosomal dominant AD (ADAD) and late‐onset AD (LOAD), the cascade of pathology begins with amyloid‐beta (A) accumulation, followed by tau (T) accumulation, and finally neurodegeneration (N), known as the ‘ATN model.’ The goal of this study was to understand the relationship between ATN and cognitive functioning in DS.

Method

Data on two time points (16 months apart) from a subset of adults with DS (N = 93) in the Alzheimer’s Biomarkers Consortium for Down Syndrome were analyzed. Participants completed a cognitive battery at both time points including the modified Cued Recall Test (mCRT) to measure episodic memory. Change scores were calculated subtracting baseline from cycle 2 performance. Baseline PET imaging assessed A+ and T+ defined by previously published regional cutoffs. Baseline hippocampal volume was extracted from structural MRI and N+ was defined as one standard deviation below the mean controlling for intracranial volume. General linear models examined follow‐up cognitive performance and total change by baseline ATN group controlling for age, premorbid intellectual disability, and, when appropriate, baseline scores using Bonferroni correction.

Result

Participants were 39.15 years old (SD = 8.99) and 55.9% male. Participants were classified as: A‐T‐N‐ (65; 69.9%), A+T‐N‐ (15; 16.1%), A+T+N‐ (8; 8.6%), A+T+N+ (5, 5.4%). At follow‐up, the A‐T‐N‐ and A+T‐N‐ groups produced significantly fewer mCRT intrusions than the A+T+N‐ and A+T+N+ groups (F(3,86) = 4.41, p = .006). ATN status was not associated with any other follow‐up or change score. However, patterns of change reflect greater decline with conversion to T+ for recall, switching, visual construction, and overall cognitive ability.

Conclusion

Adults with DS with greater AD biomarkers, and particularly the presence of T+, show poorer memory functioning compared with those who have lower neuropathological burden. At follow‐up, only intrusions were significantly associated with baseline ATN status. Adults with DS show similar trends of neuropathology and related cognitive decrements as have been reported in both ADAD and LOAD, although individuals with DS may require greater accumulation of neuropathology to detect more subtle impairments.
APOE genotype vs Local ancestry: what contributes the most to Alzheimer’s disease risk?
Authors: Moura Sofia , Celis Katrina , Muniz Maria , Rajabli Farid , Rivero Joe , Hamilton‐Nelson Kara L. , Whitehead Patrice , Gearing Marla , Bennett David A. A , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Scott William K. , Schuck Theresa , Jin Fulai , Dykxhoorn Derek M. , Pericak‐Vance Margaret A. , Griswold Anthony J. , Young Juan I. , Vance Jeffery M.
Published: December 2023

Background

The APOEε4 confers the highest genetic risk factor for Alzheimer’s disease (AD). Specifically, Non‐Hispanic Whites (NHW) are more susceptible to developing AD than African American (AA) individuals (OR∼15 vs 8, respectively). Local ancestry (LA) surrounding the APOE region has been implicated in this risk difference, with APOEε4 carriers of European LA (ELA) having increased chromatin accessibility and higher APOEε4 expression than individuals of African LA (ALA). In contrast, carriers of APOEε3, the most common allele, are not predisposed to AD. We here sought to investigate whether this differential accessibility and gene expression are solely due to APOE LA or whether the APOE genotype also contributes to the different disease risk.

Method

We screened 94 brains from individuals self‐identified as either AA or NHW of which we identified a total of 22 AD autopsy samples (18 with ELA and 4 with ALA) by GSA, all homozygous for LA and APOEε3. We performed single nuclei ATAC‐seq and single nuclei RNA sequencing (snRNA‐seq) using frozen frontal cortex using the 10x Genomics.

Result

To date, we have performed snRNA‐seq in a total of 16,099 nuclei for four brains (2 ELA and 2 ALA). We identified 27 distinct cell clusters at a resolution of 0.6. The proportion of cells per cluster between ELA and ALA samples was similar for all clusters, except for 8 clusters (primarily neurons) which had a greater than 2‐fold difference in ELA. Preliminary results show that APOEε3 carriers with ELA have a significantly higher APOE expression in astrocytes (cluster 11) than those of ALA similar to previous reports in APOEε4 carriers (Griswold, A. et al, (2021)). Interestingly, we also observed an increase in APOE expression in ALA for one oligodendrocyte cluster and four neuronal clusters (inhibitory and excitatory neurons) independent of those mentioned above.

Conclusion

We report novel insights on the effect of APOE LA and genotype and its contributions to Alzheimer’s disease risk. Specifically, as APOEε3 allele expression follows a similar pattern of overexpression in ELA vs ALA as observed for APOEε4 carriers, our data support that LA and not allele status contribute to the differential APOE expression observed among different ancestral populations.
Examining practice effects within the GENFI pre‐symptomatic FTD cohort
Authors: Adams‐Carr Kerala L , Convery Rhian S , Bouzigues Arabella , Goldsmith Sophie E , Rohrer Jonathan D. , Russell Lucy L.
Published: December 2023

Background

Practice effects can be observed on repeated cognitive testing and are often viewed as potential sources of bias. However, there is mounting evidence that their absence or reduction can indicate early changes in cognition, with decreased ‘learning over repeated exposure’ seen in those with mild cognitive impairment. A recent GENFI study demonstrated practice effects are diminished in C9orf72 and GRN mutation carriers proximal to disease onset compared to controls at testing intervals of one year. The aim of this study is to explore how practice effects differ in the GENFI cohort at shorter time intervals using Ignite, an iPad‐based set of cognitive tests, with the aim of exploiting this understanding to detect subtle cognitive impairment within clinical trials.

Method

36 individuals from the UCL GENFI cohort took part, 26 of whom were presymptomatic mutation carriers and 10 were non‐carrier controls. They completed Ignite at baseline and at 3 months. Change scores were calculated for each task, and linear regressions were performed comparing mutation carriers with non‐carriers, controlling for significant co‐variates of age, education, and sex.

Result

There was a trend towards improvement on repeat testing in both the carrier and non‐carrier groups, but a difference emerged on the Think Back Level 1 task, a test of working memory analogous to the ‘N‐back’ task, where the non‐carriers improved on a speed‐accuracy trade‐off score to a greater degree than mutation carriers (mean improvement 16.4 vs 5.2 respectively, p = 0.026). There was also a trend towards a difference on the Path Finder Level 1 and 2 tasks, adaptations of the Trail Making Tests Parts A and B, where the non‐carriers improved more than the mutation carriers.

Conclusion

Practice effects were observed across the majority of tasks in both the carrier and non‐carrier groups, except for a working memory task, where a difference was observed between the groups. This was a small pilot study, and a larger scale study of ‘burst testing’ within the GENFI cohort is underway to examine practice effects in greater detail, at shorter time intervals. Subanalyses to stratify by genetic subtype and proximity to disease onset are required.
Modulation of inflammatory regulation by plasma exchange with albumin replacement revealed by deep plasma and CSF proteomic profiling of the AMBAR study
Authors: Feng Chunmiao , Gonzalo Ricardo , Minguet Carla , Ortiz Ana Maria , Bravo Isabel , Lohr Scott , Boada Mercè , Lopez Oscar L. , Páez Antonio , Braithwaite Steven P , Costa Montserrat , Lehallier Benoit
Published: December 2023

Background

AMBAR trial (phase 2b/3 clinical trial) evaluates plasma exchange efficacy with albumin replacement (PE‐Alb) in mild‐to‐moderate Alzheimer’s Disease (AD) patients. It includes an intensive period (IP) comprising 6‐weeks of conventional therapeutic PE‐Alb (TPE; 1 TPE/week) followed by 12‐month maintenance period of low volume PE‐Alb (LVPE; 1 LVPE/month). Our previous study reporting deep plasma and CSF proteomics profiling identified multiple AD‐associated pathways modulated by PE‐Alb (Feng et al. CTAD2022). Here we dissected immune pathways changes over time and reported their crosstalk between plasma and CSF to further understand molecular mechanisms of PE‐Alb.

Method

7288 proteins were measured by SomaScan technology in 671 plasma samples (148 patients, 5 visits) and 422 CSF samples (144 patients, 3 visits). Acute effects (post‐TPE/LVPE versus pre‐TPE/LVPE samples) for plasma, and lasting effects (baseline to either end of IP or end of study (EOS)) for both matrices were calculated through a mixed model approach comparing PE‐Alb‐treated patients versus placebo. Network features of the top identified proteoforms were explored in STRING and OmniPath databases. Relationships between enriched pathways were analyzed by pathway crosstalk based on Jaccard coefficient and correlations between plasma and CSF proteomes at each visit were calculated by spearman correlation.

Result

Plasma samples showed that 90 proteoforms from acute TPE, 16 from acute LVPE, and 14 at the end of IP were significantly decreased and enriched in immune and inflammation‐related pathways. Three proteins involved in immunoglobulin‐mediated immune pathways were in the core of the interactome network and were consistently decreasing over time, one of them also significantly decreased in the CSF proteome. Finally, 113 proteins with spearman correlations >0.5 at least at one of the 3 visits were detected and were significantly enriched in immune system functions (adjusted‐pvalue<0.05).

Conclusion

This analysis demonstrates acute and lasting PE‐Alb effects on immune and inflammatory pathways. We identified 3 potential players and a crosstalk between plasma and CSF immune proteomes, suggesting the importance of the modulation of peripheral inflammation in AD treatment. This study further helps understand the molecular basis of AMBAR therapeutic approach that may contribute to slowing down AD progression.