bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of inflammasome components in experimental models of Alzheimer’s disease
Authors: Stelzer Gustavo Trevizani , Tiburcio Bruna Vieira , Lima‐Filho Ricardo A S , Ferreira Sergio T.
Published: December 2023

Background

The inflammasome is a multimeric protein complex of the innate immune system commonly related to the development of inflammatory and neurodegenerative diseases. After priming and activation, inflammasome proteins are recruited and activated, leading to cellular death with cytokine release, in a process known as pyroptosis. The NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome has been associated with development and progression of Aβ‐plaque formation and tau hyperphosphorilation in post‐mortem Alzheimer’s disease (AD) brains and in mouse models. In the current study, we evaluated mRNA expression of inflammasome components in cellular and animal models of AD.

Method

RT‐PCR was performed in (1) microglia cultures exposed to 500 nM amyloid‐β oligomers (AβOs) or vehicle for 24 h (N = 4), (2) hippocampi (N = 8) and prefrontal cortices (N = 7) from C57BL/6 mice that received an intracerebroventricular (icv) infusion of AβOs (10 pmol), or (3) hippocampi from APP/PS1 AD mice (N = 4). Target genes evaluated were Nlrp3, Caspase‐1, IL‐1β and IL‐18.

Result

Microglia cell cultures exposed to AβOs showed trends of increased expression of inflammasome genes, except for IL‐18. Cortices of mice that received icv infusions of AβOs showed increased inflammasome genes for IL1β, while hippocampi showed increased expression of Nlrp3 and IL‐18. APP/PS1 hippocampi showed increased Nlrp3 expression, a decrease in Cas‐1 expression, and no alterations in expression of IL‐1b and IL‐18. Among in vivo models, AbO‐infused mice presented the most robust response to AβO treatment.

Conclusion

Mouse models are extremely susceptible to individual variance. Current results showed that the expression of inflammasome components is altered in microglial cultures exposed to AbOs, AbO‐infused mice, and in APP/PS1 mice. AbO‐infused mice appeared more sensitive to AβO‐induced increase in expression of inflammasome components. Further experiments are necessary to evaluate the optimal model to study the relationship between AD pathogenesis and NLRP3 inflammasome.
Associations between structural/social determinants of health and vulnerability for and resilience against Alzheimer’s disease and related dementias: The Healthy Brain Initiative
Authors: Besser Lilah M , Tolea Magdalena I , Chrisphonte Stephanie , Bromfield Jessica , Gibbs Gregory , Riccio Mary Lou , Getz Sarah , Kleiman Michael J , Galvin James E
Published: December 2023

Background

Structural and social determinants of health (S/SDOH) encompass systems such as laws and policies and social constructs imposed by society such as race and class, as well as environmental conditions where people live, learn, work, and play. S/SDOH can significantly impact health throughout the life course by determining access to health promoting resources and opportunities, which in turn impacts modifiable risk factors (e.g., diet, physical activity, social contact) known to influence Alzheimer’s disease and related dementia (ADRD) risk. In this study, we investigate associations between multiple S/SDOH and measures of ADRD vulnerability and resilience among older adults.

Method

We used cross‐sectional data from the Comprehensive Center for Brain Health’s Healthy Brain Initiative (HBI), which is assembling a cohort of 45‐ to 85‐year‐olds with no or mild cognitive impairment (MCI); conducts comprehensive and harmonized clinical, cognitive, behavioral, and functional evaluations; and collects data on residential history and neighborhood perceptions. S/SDOH included the perceived discrimination index (range: 0‐22), area deprivation index (ADI) (range: 1‐99), perceived neighborhood greenspace (inadequate/adequate), and trust in neighbors (low/high). Linear regression (accounting for clustering by Census tract as appropriate) tested associations between the four S/SDOH measures and continuous Vulnerability Index (VI; range: 2‐13) and Resilience Index measures (RI; range: 105‐260). Models controlled for demographics and MCI (versus normal cognition).

Result

Participants (n = 111) were 69±10.5 years old, 62% women, 7% Black, 4% Asian, and 16% Hispanic. Twenty‐eight percent reported inadequate neighborhood greenspace and 16% reported low trust in neighbors. Mean discrimination scores were 5.5±6.7 and mean ADI scores were 30.2±25.9. Participants with higher ADI (estimate = 0.05, 95% CI: 0.02‐0.07), reporting higher discrimination (estimate = 0.15, 95% CI: 0.10‐0.21), and reporting neighborhoods lacking greenspace (estimate = 1.19, 95% CI = 0.38‐1.99) had higher VI scores. No other associations were observed.

Conclusion

These preliminary results suggest that area deprivation, self‐reported lower amounts of neighborhood greenspace, and greater discrimination are associated with greater ADRD risk as measured by VI scores. Observed associations must be replicated with larger and more diverse samples and will be re‐evaluated as the HBI cohort accumulates (with ≥20 enrolling/month, expect ≥100 additional participants by mid‐2023) and compared with imaging and plasma ADRD biomarkers.
Lower autoimmune disease prevalence in patients with early onset Alzheimer’s disease compared to cognitively normal controls
Authors: Lachner Christian , Roemer Shanu F , Frontera Natasha L. , Li Zhuo , White Launia J , Olson Janet E. , Pottier Cyril P , Dickson Dennis W. , Graff‐Radford Neill R
Published: December 2023

Background

Perturbations in immune pathways are strongly associated with Alzheimer’s disease. A positive association between autoimmune diseases and frontotemporal dementia has been reported. We explored whether early onset Alzheimer’s disease (EOAD) would associate with autoimmune diseases.

Method

We compared 313 patients with EOAD from the Mayo Clinic Florida, Alzheimer’s Disease Research Center (ADRC) Registry with matched cognitively normal controls (NC) based on age (+/‐ 2 years) and gender at 1:2 ratio. NC were derived from Mayo Clinic Biobank Project, Rochester (N = 313) and the Mayo Clinic Study of Aging (N = 313). Data abstraction was performed by trained statisticians using ICD 9&10 codes corresponding to 40 specified autoimmune diseases and/or documentation of specified immunomodulatory treatment. Data was also abstracted via retrospective record review. We further reviewed clinical records from EOAD patients with neuropathologically confirmed Alzheimer’s disease patients enrolled in the ADRC (n = 10). Each autoimmune disease type was compared between cases and controls using Fisher’s exact test. All tests were two‐sided with alpha level set at 0.05 for statistical significance. Continuous variables were summarized as median (range) while categorical variables were reported as frequency (percentage). The prevalence of autoimmune disease in the general population was based off Hayter & Cook, 2012 and Roberts & Erdei, 2020. All data abstraction was done blinded to the clinical diagnosis and baseline demographics.

Result

Autoimmune disease history was abstracted from 949 patient records (313 EOAD, 10 pathologically‐confirmed EOAD, 626 NCI). The median age was 57 years‐old. (EOAD range 28,65 yrs.; NC 30,66 yrs.). Autoimmune thyroiditis (p = 0.0008), ulcerative colitis (p = 0.011, psoriasis (<0.0001), rheumatoid arthritis (p = 0.0005), and Raynaud’s syndrome (p = 0.0021) were less prevalent in patients with EOAD compared to NC. Furthermore, patients with EOAD had a lower prevalence of immune mediated hematologic disorders.

Conclusion

Patients with EOAD have a lower prevalence of autoimmune diseases than NC. Immune activation identified in early onset AD patients may be unrelated to autoimmunity. Findings should be explored in late onset AD patients.
Secretome analysis of APOE3 and APOE4 iPSC‐derived mural cells indicates TGFβ as potential key player in blood‐brain barrier alterations
Authors: Broekaart Diede , Mesentier‐Louro Louise A. , Seo Joon Ho , Blanchard Joel , Pereira Ana C.
Published: December 2023

Background

Loss of blood‐brain barrier (BBB) integrity is present at the earliest stages of Alzheimer’s disease and is important in its pathogenesis. Pericytes, specialized mural cells surrounding brain capillaries, play a crucial role in the regulation of BBB integrity. Interestingly, patients carrying the APOE4 variant of apolipoprotein E gene display accelerated BBB breakdown and pericyte dysfunction. However, the mechanisms through which APOE4 alters pericyte function and contribute to BBB disruption are not fully understood.

Method

APOE4‐induced alterations were investigated using human iPSC‐derived mural cells with pericyte‐like properties (iMCs) with APOE3:3 and APOE4:4 genotype. We investigated the secretome by reanalyzing previously generated RNA‐sequencing of APOE3:3 and APOE4:4 iMCs. Pericyte function was examined using the Wound Maker scratch assay and stimulation with etoposide followed by γH2A.X immunocytochemistry.

Result

We observed senescent‐like phenotypes in APOE4:4 iMC cultures including delayed regrowth after a scratch wound and increased DNA damage compared to APOE3:3 iMCs. Of the 1500 genes identified as encoding for secreted proteins, 70% were differentially expressed between APOE3:3 and APOE4:4 iMCs. Post‐analyses using Qiagen’s Ingenuity Pathway Analysis and DAVID’s Gene Ontology pointed towards senescence inducer transforming growth factor β (TGFβ), increased in APOE4:4 iMCs, as a potential key player in APOE4‐induced BBB alterations. Preliminary studies show that inhibition of TGFβ signaling ameliorates the APOE4‐induced senescent‐like phenotype in pericytes.

Conclusion

These results suggest that APOE4‐induced alterations of the pericyte secretome could play an important role in dysregulating the local homeostasis of the BBB, potentially through induction of a senescence‐like cell state. Our future studies are focused on investigating APOE4‐induced changes in intercellular communication and modulation of TGFβ and senescence using a BBB in vitro model of iPSC‐derived endothelial cells, astrocytes and pericytes.
Protective variants in Alzheimer’s Disease from healthy elderly APOE‐ε4 participants
Authors: Qiao Min N , Reyes‐Dumeyer Dolly , Medrano Martin , Lantigua Rafael A. , Mayeux Richard , Vardarajan Badri N
Published: December 2023

Background

Presence of the APOE‐ε4 allele is the most consistently confirmed genetic risk factor for late‐onset Alzheimer’s disease (AD) in white, non‐Hispanic populations, but the associated risks observed in African Americans and Hispanics are somewhat lower. The objective of this study was to identify protective variants that could modify or reduce the effect of APOE‐ε4 on AD risk.

Methods

We analyzed WGS data in over 3500 individuals from 600 multiplex AD families of non‐Hispanic White (NHW) and Caribbean Hispanic (CH) ancestry to identify protective variants in AD. APOE ε4 homozygosity was found in 48 healthy individuals over the age of 70, and APOE ε4 heterozygosity was found in 155 healthy individuals over the age of 80 were present in families with two of more affected samples. Protective variants were found segregating in the APOE ε4 homozygote and heterozygote individuals. We required that these variants be rare (MAF<0.1%) in GnomAD and prioritized exon coding variants that were putatively damaging to the resulting protein product. Novel or rare coding mutations segregating in ε4 unaffected subjects were tested for the effects on the age of onset of symptoms.

Results

We identified 632 putatively protective variants that were present in at least 1% of APOE ε4 carriers and were absent in those with other APOE genotypes. 67 protective variants were present in both NHW and CH families. Pathway analysis of these segregating variants in APOE ε4 carriers are enriched in pathways involved in biological pathways and molecular functions such “actin binding”, “microtubule binding”, “extracellular matrix structural constituent”. These results suggest that protective variants promote activity of the extracellular matrix and cytoskeletal proteins leading to enhanced clearing of Aβ peptides. Variants in NBEAL1 delayed the age of onset in AD by 8.33 years respectively.

Conclusions

WGS in CH and NHW families multiply affected by AD identified some healthy elderly, non‐demented APOE ε4 carriers with rare coding variants associated with delayed age of onset. Characterizing the functional role of these protective variants in AD will facilitate the creation of tractable models for investigation of disease mechanisms and potential therapies.
Development of a collaborative music therapy and social work telehealth framework to address the well‐being of community‐dwelling older adults
Authors: Reschke‐Hernandez Alaine E. , Gibson Allison , Buckner Laura Elliott , Sullivan Alisia C. , Posey Caleb , Uecker Stephanie
Published: December 2023

Background

Older adults often experience changes in health, finances, and social support, which impede community involvement and can be compounded by the onset of cognitive decline. Interprofessional collaboration can help counter such challenges. Here, researchers present a feasibility study, which demonstrated support for a novel social work and music therapy telehealth framework to promote well‐being of older adults with and without dementia. We describe the subsequent pilot study design.

Method

During the feasibility phase, researchers field‐tested logistics and provided proof‐of‐concept of our novel framework in a randomized cross‐over design. All participants received 6 music therapy sessions via telehealth across 3 weeks (2x/week for 25 minutes) and one 30‐minute social work wellness session with service referral. Quantitative outcomes included self‐reported feelings, anxiety, depression, and loneliness to inform the utility of this framework to improve well‐being of older adults with and without dementia. We conducted semi‐structured interviews with participants and care partners, who offered input about all aspects of the study.

Results

Lessons gleaned from the feasibility study, and which informed the pilot, were: 1) participants conveyed that the delivery model was acceptable, interesting, convenient, and helpful; 2) given resources and support using digital technology, older adults found telehealth to be an attractive and feasible delivery mode; 2) older adults and care partners liked music therapy and greatly disliked the recorded music option; 3) music therapists could utilize the “Clinical Practice Model” (Reschke‐Hernández, 2021) to inform provision of appropriate levels of support and challenge to older adults with and without dementia via Zoom; and 4) social workers could leverage the rapport music therapists built with participants and the information they gathered during sessions to link older adults to community resources ‐ a service older adults found more helpful and meaningful than in past social work experiences. Pilot results will be available in December 2023.

Conclusion

This project advances a collaborative research partnership to improve research quality and facilitate access to services for older adults with and without dementia. The careful steps of this feasibility and pilot work will inform best practice in an innovative area of music therapy and social work professions.
Characterizing Cerebrovascular Pathologies in Brain Donors Exposed to Repetitive Head Impacts
Authors: Emrani Sheina , Koutures Anne , Tripodis Yorghos , Uretsky Madeline , Abdolmohammadi Bobak , Nowinski Christopher , Daneshvar Daniel H , Katz Douglas I , Goldstein Lee E , Martin Brett M , Palmisano Joseph N , Dams‐O'Connor Kristen , Crary John F. , Mez Jesse B. , Alvarez Victor E. , Huber Bertrand R. , McKee Ann C. , Stein Thor D. , Alosco Michael L
Published: December 2023

Background

Repetitive head impacts (RHI) from American style football (ASF) and other contact sports are a known risk factor for the neurodegenerative disease chronic traumatic encephalopathy (CTE). RHI can also lead to mixed neuropathologies that uniquely contribute to clinical symptoms. Here, we compared various types of vascular and white matter pathologies between brain donors with and without exposure to RHI from different types of contact and collision sports (CCS).

Methods

The sample included 79 deceased male ASF players (RHI‐ASF) and 49 deceased male non‐ASF CCS athletes (RHI‐CCS) from the UNITE brain bank. Each RHI group had a comparison group that included similar aged (+/‐ 5 years) male brain donors without RHI from the Boston University Alzheimer’s Disease Research Center and Framingham Heart Study brain banks. The modified Ischemic Injury Scale (mIIS) served as a global indicator of vascular and white matter pathologies and is a sum of hippocampal sclerosis, infarct/lacune, microinfarct, microbleeds, laminar necrosis, arteriolosclerosis, atherosclerosis of Circle of Willis, cerebral amyloid angiopathy, and white matter rarefaction. Dementia diagnoses were made during consensus conferences. Linear or logistic regression compared the RHI vs non‐RHI groups on the mIIS and its subcomponents. Logistic regression models examined the association between mIIS and dementia. Models were adjusted for age.

Results

Table 1 shows sample characteristics. The RHI‐CCS group was comprised of boxers, amateur wrestlers, and ice hockey, soccer, rugby, and lacrosse players. 94 decedents had CTE, all of whom were in an RHI exposed group. Of the mIIS components, arteriolosclerosis was the most common across all groups. White matter rarefaction was also the most frequent mIIS component for both RHI groups, but not for non‐RHI groups. Compared to their respective controls, RHI‐ASF and RHI‐CCS were associated with higher mIIS scores (Table 2). Higher mIIS scores corresponded to increased odds for having dementia in both the RHI‐ASF and RHI‐CCS groups (Table 2). White matter rarefaction best discriminated both RHI groups from non‐RHI; atherosclerosis also discriminated RHI‐CCS group (Table 3).

Conclusion

These results support vascular and white matter pathologies, specifically white matter rarefaction, as prominent and clinically relevant sequelae of RHI from CCS.
Are social network and nativity status associated with neurocognitive functioning in a sample of middle/older adults from the “Study of African Americans and Latinas/os to Understand Dementia”‐SALUD?
Authors: Oleas Denise S. , Arentoft Alyssa , Cham Heining , Slaughter Alexander W. , Breen Elizabeth Anne , Schuck Lauren A , Camuy Alicia M , Talavera Sandra , Mindt Monica Rivera
Published: December 2023

Background

Older adults may experience decreased social support, which has been linked to cognitive decline and increased risk of dementia. Immigrants may also experience more social isolation due to discrimination and fear of deportation. This study examined social networks, nativity status, and neurocognitive functioning(NC) in an ethnoculturally diverse sample of middle/older adults.

Method

Participants included 26 immigrants (Mage= 64.12, SD = 5.64) and 109 U.S.‐born adults (Mage= 65.37, SD = 7.10). Participants completed a comprehensive NC battery and the Berkman‐Syne Social Network Index(SNI; a well‐validated self‐reported questionnaire assessing close social support, where higher scores represent more social support). Demographically‐adjusted norms were used to compute average global NC and domain T‐scores. A series of hierarchical multiple regressions were computed to predict global and domain NC T‐scores. SNI and age were entered at Step‐One, the interaction term(age*SNI) was entered at Step‐Two, and nativity status was entered at Step‐Three.

Result

Results revealed that the omnibus model was significantly associated with Attention/Working Memory(A/WM) (R² = .13; ps = .009) and Processing Speed(PS) (R² = .20; ps = .002). Notably Step‐Three of the model significantly contributed to the association of AWM (R²Δ= .11; ps<.05) and PS (R²Δ= .09; ps<.05) beyond Step‐One and Step‐Two. For A/WM, the interaction term, and nativity status (𝛽s = .04‐6.96, respectively; ps<.05) were significantly associated with A/WM. For PS, SNI, the interaction term, and nativity status (𝛽s = ‐3.91‐8.17; ps<.05) were significantly associated with PS. Such that, there is a main effect of nativity status with immigrants scoring lower on measures of A/WM by 6.96 and PS by 8.17 units. Overall, there is a negative association between age and A/WM and PS but as SNI increases the relation between age and NC becomes positive. Only nativity status (𝛽s = 5.99‐8.23; ps<.05) significantly predicted Memory, Verbal Fluency, and Global NC functioning scores.

Conclusion

Findings show that among middle/older adults, both SNI and nativity status are associated with A/WM and PS, suggesting that a larger SNI can serve as a protective factor against the effects of aging on NC functioning. Importantly, even when SNI and age were not significantly related to NC T‐scores, nativity status was. Nativity status likely serves as a proxy for other risk factors (e.g., healthcare access), which should be explored in future studies.
Investigating the effect of neuropsychiatric symptoms on Alzheimer’s diagnosis using multi‐modal brain networks
Authors: Guo Lei , Zhang Yanfu , Tang Haoteng , Mackin Scott R , Thompson Paul M , Huang Heng , Zhan Liang
Published: December 2023

Background

Studies suggested that the comorbidity between Neuropsychiatric Symptoms (NPS) and dementia highlights the prognostic value in prodromal phases. Our central hypothesis is that the accurate prediction of NPS can improve the Alzheimer’s diagnosis. We adopt deep learning techniques to simultaneously predict MCI and depression, one of the most frequently observed NPS and measured by GDS score.

Method

We analyzed 114 subjects from the ADNI‐D project, including 77 NC (70.91±5.3, 19 males) and 37 MCI (70.51±4.66,17 males). (No difference in age or GDS between groups). 85×85 brain structural and functional networks were reconstructed for each subject. We propose a multi‐view graph neural network (GNN) (Figure 1) to predict cognitive status (classification) and NPS score (regression) simultaneously. To verify our method and hypothesis, we selected five baselines, including three non‐deep methods (logistic regression, random forest, and SVM) and two deep methods (two‐layer MLP and GNN which uses the same model as ours but only considers the classification task).

Result

We firstly conducted traditional regression analyses (Y ∼ Age + Sex + GDS) and Y can be brain functional or structural network edges or the derived network measures. Our results show that none of these measures are survived after applying the Bonferroni correction to account for multiple comparisons, which indicates that the GDS and brain network may not predict each other using a linear model. Then, we tested the deep learning approach, and our proposed framework achieves the best performance among all three evaluation matrices (Acc, F1 score, and AUC) in comparison with other baseline methods. (Figure 2)

Conclusion

These results demonstrate that the depression score can be used to improve the MCI diagnosis, apparently favoring our central hypothesis. Our future work will focus on conducting more analyses on different NPS and different stages of dementia.

Figure 1. Proposed multi‐view GNN. The first layer considers both node features (red) and edge features (blue) to compute the hidden representations for the next layer. The second layer only considers node representations (brown). The node‐level embeddings are then max‐pooled and concatenated to yield the final multi‐view graph‐level embedding.

Figure 2. The comparison of prediction results.
Neuroimaging Correlates of Alzheimer’s Disease biomarkers in a mid‐life, racially diverse high‐risk cohort
Authors: Munkombwe Chinkuli , Misiura Maria , Igwe Kay C. , Likos Kelly D. S. , Verble Danielle D , Zetterberg Henrik , Brickman Adam M. , Hu William T. , Dotson Vonetta M , Wharton Whitney
Published: December 2023

Background

Clinicians and researchers utilize neuroimaging (NI) biomarkers of Alzheimer’s disease (AD) at an increasing rate. It is crucial that we determine whether these biomarkers generalize to underrepresented populations, particularly Black Americans (BAs), as they are 64% more likely as white individuals to develop AD. BAs may exhibit unique AD biomarker profiles across disease states, including NI biomarkers. Investigating biomarkers in at‐risk individuals may allow for early identification and intervention. Here we analyze comprehensive NI biomarkers including resting state fMRI, white matter lesions, and hippocampal volumes in conjunction with cerebrospinal fluid (CSF) markers in a midlife, racially diverse, cognitively normal cohort with a parental history of AD.

Method

Data included 57 cognitively normal, middle‐aged individuals, 14 BAs and 43 white. CSF was acquired via lumbar puncture to determine CSF t‐tau and Aβ1‐42 concentrations. Using resting state fMRI data, we analyzed default mode network connectivity between the posterior cingulate & precuneus, parrahippocampal gyrus (PHG), temporal pole, hippocampus, and lateral temporal cortex. We obtained regional WMH data from FLAIR images using an in‐house algorithm, and hippocampal volumes from Freesurfer. In our multivariate model, outcome variables were connectivity values, regional WMH and hippocampal volumes, with race and CSF t‐tau and Aβ1‐42 as our independent variables with a race X CSF interaction term.

Result

We identified a significant race X t‐tau and race X Aβ1‐42 interaction term for temporal and parietal WMH volumes and connectivity between PHG and temporal pole. Higher AD CSF biomarkers negatively correlated with brain connectivity (p = 0.01), and positively with WMH volume (p<0.001) in BAs.

Conclusion

We extend our previous work to a middle‐aged cohort to show that DMN connectivity may be a predictor of AD risk in middle‐age, particularly for BAs, and that BAs may exhibit earlier vulnerability to vascular lesions. We support previous work that the temporal lobe is the first region to experience AD‐related connectivity changes, and that WMHs may predispose this region to AD vulnerability. This study emphasizes the need for recruitment of diverse cohorts in NI studies of AD.
Subcortical deformation is uniquely related to cortical thickness among FTLD mutation carriers
Authors: Stocks Jane K , Heywood Ashley , Beg Mirza Faisal , Cobigo Yann , Rosen Howard J. , Wang Lei
Published: December 2023

Background

Frontotemporal lobar degeneration (FTLD) due to familial mutations results in heterogenous clinical phenotypes for which there are no specific biomarkers. Here, we test whether subcortical deformation differs in FTLD genetic mutation carriers, and if deformation was uniquely related to cortical thickness.

Method

317 participants from ALLFTD with familial FTLD (C9orf72 (n = 139), GRN (n = 77), and MAPT (n = 101)) and 27 controls without mutations (NCC) were evaluated. MRI data underwent FreeSurfer processing to estimate cortical thickness (CT). High‐dimensional, large‐deformation diffeomorphic metric mapping was used to model surfaces of the caudate and putamen. Regression analyses investigated the effect of mutation on CT and subcortical surface deformation, after controlling for age, sex, and education. Finally, linear models were constructed in each mutation group to explore the association between areas of significant surface deformity and CT, corrected for age and multiple comparisons.

Result

Figure 1 shows significant (corrected p<.05) T‐scores where mutation carrier groups differ in CT from NCC (red = greater atrophy in mutation). Figure 2 shows greater outward local deformation in the caudate body among C9 and MAPT compared to NCC. Significant relationships between deformation and CT (corrected p<.05) were observed in bilateral temporoparietal, frontal and cingulate cortex in both C9 and MAPT carriers. C9 and MAPT mutation carriers have greater outward deformation in postero‐lateral putamen. Deformation was associated with CT in C9 within the left temporal and prefrontal lobes, and in the right temporoparietal, occipital and cingulate cortices for MAPT (Figure 3). No significant deformation was observed in GRN compared to NCC.

Conclusion

Familial FTLD mutations are associated with subtle subcortical shape variations that show unique relationships to cortical atrophy.
Multi‐cohort genome‐wide association study on flortaucipir PET identifies novel risk loci associated with tau deposition and its role in AD pathology
Authors: Gunasekaran Tamil Iniyan , Lee Annie J , Dumitrescu Logan C , Mormino Elizabeth C. , Sperling Reisa A. , Saykin Andrew J. , Hohman Timothy J. , Vardarajan Badri N ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Amyloid‐β plaques and tau neurofibrillary tangles are the pathological hallmarks of Alzheimer’s disease (AD). Previously, genetic studies on amyloid‐β mediated AD pathogenesis dominated the field, and genetic studies on tau pathology are limited by comparison. Prior studies suggest that the spread of tau neurofibrillary tangles within the medial temporal lobe occurs following abnormal deposition of amyloid‐β, leading to cognitive impairment. Although amyloid‐β and tau both play a role in AD pathogenesis, exact genetic pathways associated with them are still unknown.

Method

We performed genome‐wide association study (GWAS) with brain Tau standard uptake value ratios (SUVRs) measured from positron emission tomography (PET) images from the A4 ((N = 311 with preclinical AD;female = 62%;tau mean‐SUVR = 1.076±0.06) and ADNI studies (N = 375‐280 cognitively normal, 76 mild cognitively impaired and 19 AD;female = 53%;tau mean‐SUVR = 1.12±0.13). Models were adjusted for age, sex and APOE‐ε4 dosage. Additionally, we evaluated the association of amyloid‐β and tau SUVRs with AD polygenic risk scores (PRS). PRS was calculated using genome‐wide variants, excluding 1MB region flanking APOE, and effect sizes from Kunkle et al GWAS study of clinical AD.

Result

Analysis of tau‐SUVR in 686 participants, identified five genome‐wide significant loci: rs78636169 (P = 1.37×10−9) in JARID2, rs114272033 (P = 7.87×10−9) in ISCA1P2, rs7292124 (P = 1.73×10−8) in RP1‐272J12.1, rs114742337 (P = 2.85×10−8) in RP4‐771M4.2, and rs138338441 (P = 3.91×10−8) in AC092684.1. Rs13412014 in AC007364.1 and rs9393067 in RP11‐314C16.1 were also associated with amyloid‐SUVR in a previous large GWAS. Two loci previously associated with clinical AD in a recent large GWA study, INPP5D (rs10933431) and SEC61G (rs76928645), were also nominally associated (P<0.05) with tau deposition in our study. Genes associated with Tau‐SUVR are enriched in the Schaffer axonal collaterals (P<1×10−05) that form synapses in hippocampus. Genome‐wide PRS of AD (excluding APOE region) was strongly associated with amyloid‐SUVR (P = 3.21×10−11;R2 = 0.077) but only weakly associated with tau‐SUVR (P = 1.38×10−04;R2 = 0.027). We are in the process of replicating our results in an independent cohort of 700 participants with measurements of tau deposition.

Conclusion

We identified five novel genetic loci associated with tau pathology. Several genes involved in tau deposition were also associated with amyloid load in the brain. Taken together, our findings will clarify the genetic pathways that effect both amyloid and tau pathology in AD.
Tau and amyloid PET associations with impaired sleep and 24‐hour rhythms across aging and neurodegenerative disease
Authors: Winer Joseph R. , Romero America , Lok Renske , Vossler Hillary , Young Christina B. , Anders David , Shen Bin , Morales Aimara Pacheco , Davidzon Guido , Henderson Victor , Poston Kathleen L. , Zeitzer Jamie M , Mormino Elizabeth C.
Published: December 2023

Background

Disrupted sleep and fragmentation of sleep‐wake rhythms are common in the context of healthy aging as well as in neurodegenerative disease. As wearable devices become increasingly popular among older adults, there is a growing need to understand how metrics of sleep‐wake behavior might be able to identify neurodegenerative disease and differentiate disease etiology and severity.

Method

Participants (n = 145) from the Stanford Alzheimer’s Disease Center (ADRC) and the Stanford Aging and Memory Study (SAMS) were recruited for 14 days of at‐home actigraphy (wrist‐worn accelerometry) data collection. A subset of participants received 18F‐PI‐2620 and 18F‐florbetaben PET scans to assess tau and amyloid burden. The cohort included cognitively normal older adults (healthy controls, HC), patients with Alzheimer’s disease (AD) spectrum, and patients on the Lewy body (LB) disease spectrum. Actigraphy analyses focused on nocturnal sleep efficiency, 24‐hour diurnal amplitude, and 24‐hour activity fragmentation (intradaily variability, IV). Amyloid burden was quantified in centiloids and tau burden was quantified as 18F‐PI‐2620 SUVR within bilateral inferior temporal cortex. The Neuropsychiatric Inventory Questionnaire (NPI‐Q) was used as a measure of neuropsychiatric symptom severity.

Result

LB patients had lower 24‐hour activity levels relative to AD and HC participants, as measured by diurnal amplitude (W’s≥650, p’s<0.01; Fig 1A & B). AD patients had marginally higher IV relative to HC (W = 1084.5, p<0.1; Fig 2A & B), whereas sleep efficiency was comparable across etiologies and cognitive status (Fig 1C). Higher IV was associated with higher NPI‐Q scores in cognitively impaired patients (rho = 0.31, p = 0.03; Fig 2C). Greater amyloid burden was associated with lower diurnal amplitude in HC and AD (rho = ‐0.29, p = 0.02; Fig 3A). Inferior temporal tau was associated with sleep efficiency both within HC and AD (rho = ‐0.28, p = 0.07; Fig 3B) and in all amyloid‐positive participants (rho = ‐0.41, p = 0.02; Fig 3C).

Conclusion

These findings suggest that sleep and 24‐hour rhythms show meaningful variation across individuals and are associated with AD and LB disease severity. While sleep efficiency and IV did not robustly differ between AD and LB groups, the measures were associated with disease‐related features such as biomarkers of amyloid and tau pathology and neuropsychiatric symptoms.
The Ethics of Past and Future Memory Care Models: Perspectives from the Dutch and Danish Dementia Villages
Authors: Roberts Emily
Published: December 2023

Dementia care organizations face a range of daunting environmental changes and challenges. Internationally, there is a long history of efforts to improve quality of care and life for individuals with dementia. In a time of particular attention to the images of older adults confined to a single or shared room in a care facility due to COVID‐19, autonomy becomes the overarching problem, not only because in general institutions limit the freedom of frail elders, but because the existential conditions that create the need for long term care such as chronic disease, cognitive decline, and the need for general support with activities of daily living (ADLs) rail against the autonomy of independent self‐sufficiency. Additionally, these environments are institutional in design and size, with little access to outdoor spaces and other amenities. This perspective manuscript addresses the ethics of past and future memory care models, looking specifically at the European Dementia Village model. This model allows for autonomy and continuation of patterns of daily living through housing integrated with large exterior walks and gardens, restaurants shops and amenities within familiar and normal surroundings, reducing resident anxiety and fear. This pioneering health care experiment negotiates rivaling discourses of intimacy, professionalization and medicalization. In order to get a deeper understanding of the culture and ethics of the model, the first two dementia village sites were visited which included meetings with care staff and administrators. Those conversations and observations led to a series of aligned themes relating to the ethics of the DV model which include: the strength of the social approach, clinical support, resident/staff collaborations and advocating for ethical dementia care.
Serum Arachidonic Acid Oxylipins Indicate Small Vessel Injury And the Related Executive Function Decline In Stroke Patients
Authors: Yu Di , Liang Nuanyi , Xiong Lisa Y. , Shen Qing , Lin William Z. , Ozzoude Miracle , Goubran Maged , Rabin Jennifer S. , Ramirez Joel , Symons Sean , Haddad Seyyed MH , Tan Brian , Nanayakkara Nuwan D. , Dilliott Allison Ann , Binns Malcolm , Beaton Derek , Arnott Stephen R. , Lawrenece‐Dewar Jane M , Sahlas Demetrios J. , Casaubon Leanne , Otoki Yurika , Lanctôt Krista L. , Masellis Mario , Swartz Richard H. , Taha Ameer Y. , Swardfager Walter ,   The ONDRI Investigators
Published: December 2023

Background

Cerebral small vessel disease (SVD) frequently co‐occurs with other neurodegenerative pathologies and collectively lead to cognitive deficits. Previously, we found that the ratios of soluble epoxide hydrolase (sEH)‐ derived diols to the parent epoxides (generated by CYP2J/2Cs) linoleic acids were associated with greater white matter hyperintensities (WMH) and poorer executive function in patients with transient ischemic attack. However, the associations with the diol and epoxide species derived from arachidonic acid (AA) have not been explored.

Methods

The study cohort is comprised of 159 stroke patients (mean age = 69.2, 32.1% female) from the Ontario Neurodegenerative Degenerative Research Initiative. EpETrEs (AA epoxides) and DiHETrEs (AA diols) were quantified by a targeted ultrahigh pressure liquid chromatography mass spectrometry (UPLC‐MS/MS). Executive function was assessed using a composite score that included Digit Symbol Substitution Test (DSST), Trial‐Making Test Part B, Stroop Color‐Word Interference Test, and FAS Verbal Fluency Test. WMHs were quantified from T2‐Fluid‐Attenuated‐Inversion‐Recovery MRI through Lesion Explorer (https://imaging.brainlab.ca/lesion‐explorer.html).In linear models controlling for age, sex, education or age, sex, glucose, cholesterol, and waist circumferences were used for cognitive and imaging out comes, respectively.

Results

11(12)‐EpETrE was found to be associated with less WHM (ρ = ‐0.175, p = 0.040) and better executive function (ρ = 0.166, p = 0.039). In a sub‐cohort of patients with small vessel stroke (n = 50), the relationship between WMH and 11(12)‐EpETrE became stronger (ρ = ‐0.390, p = 0.014). 14(15)‐EpETrE was also associated with less WMH (ρ = ‐0.416, p = 0.009). Similar relationships were not seen with the diols or diol to epoxide ratios.

Conclusions

Oxylipins derived from sEH activity may be potential biomarkers of vascular cognitive impairment and small vessel disease in stroke patients.
Disseminating COVID‐19 and Alzheimer’s Disease Information to Underrepresented Communities Using Social Media
Authors: James Taryn T. , Levy George , Hills Ornella J , Ellis Tiffany , Benitiz Ashley , Lawrence Sacheen L. , Gleason Carey E. , Metoxen Melissa , Pinzon Maria C Mora
Published: December 2023

Background

To help address the impact of disinformation pertaining to the COVID‐19 pandemic on underrepresented groups (URG), members of the University of Wisconsin Alzheimer’s Disease (AD) Center formed a strategic team consisting of experts in communications, health research scientists, community advocates and community agencies to disseminate information to URG communities on social media platforms. Three Wisconsin communities were included: African American, American Indian (i.e. Oneida Nation) and Latinx communities. Our goals were 1) to share culturally tailored and medically accurate messages on the virus, vaccine, and related topics, 2) to quell disinformation, and 3) to offer information on pertinent health topics such as Alzheimer’s disease (AD) dementia that also disproportionately affect URG and for which COVID‐19 is now a risk factor.

Method

Our experts convened weekly to discuss possible topics suggested by team scientists or community advocates based on feedback from their respective community. Our team scientist developed lay format materials which were further translated into culturally appropriate social media messages by community advocates. Advocates posted at least one social media message per week for a total of 804 posts across all three communities. Social media metrics (Reach, Engagement, Impressions) were collected at 10 months, 17 months, 24 months and 28 months after initial post, using Hootsuite, Sprout Social and Facebook Analytics. Posts focused on mental health (n = 38) and Alzheimer’s disease (n = 7) were tagged on the Facebook and Instagram pages targeting African Americans.

Result

Overall from September 2020 – January 2023, the 804 mixed‐media informational posts on social media platforms, garnered 166,917 impressions and over 11,202 engagements (Table 1). Topics including mental health and AD were well received (Figure 1). Audiences resonated with personal posts surrounding health topics from the community advocates.

Conclusion

Facebook had higher engagement rates than Instagram, but AD posts had lower reach and engagement than those of mental health, suggesting that more efforts are necessary to increase awareness about AD. Using mixed‐media approaches, and utilizing community advocates to communicate health information to URG were impactful. These strategies could be extrapolated to other initiatives, including the recruitment of URG into dementia clinical trials which can aid in dismantling dementia related health disparities.
Exposure‐response modeling to describe the change in brain amyloid following lecanemab administration in patients with early Alzheimer’s disease
Authors: Willis Brian A. , Hussein Ziad , Hayato Seiichi , Takenaka Osamu , Penner Natasha , Yasuda Sanae , Reyderman Larisa
Published: December 2023

Background

Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils. Lecanemab has been tested as a disease‐modifying treatment for early Alzheimer’s disease in two clinical studies (NCT01767311 and CLARITY‐AD, NCT03887455). As part of these studies, amyloid PET scans were collected in a subset of patients, demonstrating that lecanemab leads to pronounced reduction in brain amyloid.

Method

A model describing the relationship between serum lecanemab exposure and brain amyloid reduction from baseline was developed using data pooled from Phase 2 and 3 studies. Individual serum lecanemab exposure was estimated using a population PK model and correlated with amyloid PET using an indirect response model, with a lecanemab‐dependent increase in the degradation rate of amyloid, introduced as linear function. The model was parametrized in terms of baseline amyloid load, elimination rate constant for amyloid removal (Kout) and exposure effect (DESLP). Inter‐subject variability was estimated for each of the model parameters. Covariates were included in the model using a forward‐inclusion (p<0.01) /backwards‐elimination (p<0.001) approach.

Result

A total of 4129 observations from 1088 subjects were included in the dataset. The model estimate of Kout was 0.0496 yr−1 (95% confidence interval: 0.0206, 0.0827), suggesting a re‐accumulation half‐life of brain amyloid of ∼14 years. APOE4 carrier status (homozygous and heterozygous together) was a statistically significant predictor of baseline amyloid (APOE4 noncarriers: 65 CL; APOE4 carriers: 83 CL). Age was a significant covariate on DESLP, with older patients removing amyloid at a faster rate than younger patients. None of the other covariates explored, including presence of antidrug antibodies or baseline MMSE score, had a statistically significant effect on any model parameter.

Conclusion

An exposure‐response model has been developed that describes the change in brain amyloid over time during treatment with lecanemab and after stopping lecanemab treatment. This model provides additional insights into factors that may drive differences in the rate of brain amyloid removal between patients.
In‐depth evaluation of protein domains improves classification of SORL1 variant pathogenicity in Alzheimer’s Disease patients
Authors: de Waal Matthijs W J , Hulsman Marc , van der Lee Sven J , Andersen Olav M. , Holstege Henne
Published: December 2023

Background

Rare pathogenic SORL1 gene variants have been identified as strong risk‐increasing factors in Alzheimer’s disease (AD). Recent analysis indicated that SORL1 loss‐of‐function (LoF) variants associated with a ∼40‐fold increased risk for early‐onset AD, while missense variants that were prioritized using in silico variant pathogenicity‐prediction algorithms associated only with a 2‐fold risk increase. However, current risk‐prediction strategies do not take SORL1‐specific features into account. We aimed to design a variant classification strategy that adds in‐depth knowledge of SORLA structural folding and function to the variant risk prediction.

Method

We identified coding SORL1 variants in a discovery/replication sample of whole exome sequencing data from the ADES/ADSP studies comprising 18,959 cases and 21,893 controls after quality control. We selected only the extremely rare variants (MAF<0.05%) and further divided these into LoF(n = 77) and missense variants(n = 539). With an in‐depth evaluation of protein functional domains (informed by pathogenic variants in homologous genes) combined with their predicted pathogenicity (REVEL algorithm) we prioritized missense variants into ‘high priority’, ‘moderate priority’ and ‘low priority’. We compared the age‐dependent penetrance of missense variants for each priority‐category and LoF variants, in context of APOE genotype.

Result

Carriers of prioritized missense variants had a similar age‐dependent penetrance as LoF variants, with median age at AD‐onset of ∼65 years which is significantly lower compared to non‐carriers (∼72 years). In addition, carriers of prioritized SORL1 missense variants have an expedited age at onset by ∼7 years independent of their APOE genotype. If we look at a 80% penetrance level, SORL1 carriers with homozygous ε4 background had AD by age 61 (95%CI 60‐NA, n = 6) compared to age 73 (95%CI 72‐73, n = 1091) for SORL1 WT carriers. Carriers with a heterozygous background had AD by age 71 (95%CI 68‐76, n = 62) compared to 78 (95%CI 78‐78, n = 4816) for WT. For a non‐ε4 background the age at onset for carriers was 83 years (95%CI 78‐90, n = 54) compared to 85 years (95%CI 85‐85, n = 5773) for WT. The moderate and low priority group showed no significant difference compared to WT.

Conclusion

Our prioritization model can successfully identify likely pathogenic missense SORL1 variants, allowing for better identification of patients with possible SORL1‐associated‐AD.