bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular dysfunction in health disparities – unraveling contributions to dementia and Alzheimer’s disease in South Alabama
Authors: Bauman Allison J. , Traylor Miranda K , Saiyasit Napatsorn , Butlig Evan‐Angelo R , Chaney Samantha D , Hawley Nanako A. , Randall Ryleigh B. , Bobinger Hanna V. , Frizell Carl A , Hill Benjamin D , Keller Joshua L , Nelson Amy R.
Published: December 2022

Background

It is estimated that nearly 100,000 Alabamians have Alzheimer’s disease (AD). There is strong evidence that neurovascular uncoupling, cerebral blood flow reductions and dysregulation, and breakdown of the blood‐brain barrier (BBB), including the loss of pericytes, are early events in the AD pathophysiological cascade. Health, lifestyle, and socioeconomic risk factors across racial groups, and/or genetic risk factors, may account for this increased AD risk. Aged Black Americans have twice the risk of experiencing AD or other dementias compared to aged Whites. 26.8% of the Alabama population is Black American. Furthermore, over a million people in Alabama live in rural areas (USDA‐ERS), leading to healthcare professional shortages, and in designated medically underserved areas. Relatively little is known about the role of cerebrovascular mechanisms in the pathogenesis of dementia and AD and potential therapeutic targets within the neurovascular system, especially as they relate to health disparities. Thus, determining whether health disparities via vascular or genetic risk factors leads to neurovascular dysfunction and ultimately AD is essential.

Method

Blood was collected from middle‐aged diverse individuals (67% Black, n = 12 and 33% White, n = 6, 61% of participants were female) that reside in the South Alabama vicinity. Plasma and buffy coat were used for biomarker assays and APOE genotyping, respectively. We identified APOE genotype using DNA extraction and PCR‐RFLP. We used MesoScale Discovery’s MESO QuickPlex SQ to quantify vascular biomarkers, tau and neurofilament light chain. Measurements of amyloid‐beta, inflammatory cytokines and other biomarkers are underway.

Result

67% of Blacks and 17% of Whites were APOE‐ε4 carriers. 39% of participants reside in designated rural or medically underserved areas. Blacks had increased bFGF, Flt‐1, VEGF‐C and tau. APOE‐ε4 carriers had increased VEGF‐C and tau. Females had increased Flt‐1 and VEGF‐A. Individuals residing in rural/medically underserved areas had increased bFGF.

Conclusion

We observed a large % of APOE‐ε4 carriers in Black participants. The increase in VEGF‐C and tau in Black participants may have been provoked by APOE‐ε4 genotype. Vascular health and peripheral tau may play a crucial role in the development of AD. Improving modifiable vascular risk factors early with interventions such as exercise may help prevent AD.
Harnessing Chromatin 3D interactions to Understand Ancestry‐Specific Alzheimer Disease (AD) risk
Authors: Wang Liyong , Liu Xiaoxiao , Oron Oded , Xu Wanying , Trittipo Jack , Rajabli Farid , Dykxhoorn Derek M. , Griswold Anthony J. , Pericak‐Vance Margaret A. , Young Juan J , Jin Fulai , Vance Jeffery M.
Published: December 2022

Background

Ancestry‐specific Alzheimer Disease (AD) genetic risk is well recognized. Chromatin 3D interaction map in AD‐relevant cells with different ancestries is lacking but needed to understand the genetic/epigenetic basis for AD in diverse populations. We have shown that the local ancestry (LA) block (∼2Mb in size) surrounding APOE confers differential genetic risk for APOE ε4 carriers in Non‐Hispanic Whites (NHW) and African Americans (AA). Recently, we reported that NHW APOE ε4 carriers have a higher APOE ε4 expression and higher number of astrocytes compared to their AA counterparts in the frontal cortex. We therefore sought to characterize chromatin 3D interactions in astrocytes within different APOE LA.

Method

Induced pluripotent stem cells (iPSCs) with African or European LA block (N=2 individuals for each) were differentiated into astrocytes. Chromatin Hi‐C libraries were constructed with 4‐cutter enzyme and sequenced targeting 500 million pair‐end reads per library. Spatial genome structure was examined at compartment, topological associated domain (TAD), and loop levels. To better define enhancer‐promoter interaction (EPI), high‐resolution contact matrices were built using the HiCorr and DeepLoop algorithms.

Result

Each library generated over 250 million uniquely mapped, non‐redundant reads for Hi‐C analysis. Compartment and TAD had limited variability among samples (correlation co‐efficiency = 0.62∼0.90 for compartment, 0.84∼0.94 for TAD). Chromatin loop, which usually represents EPI, displays higher variability among samples (correlation co‐efficiency = 0.38∼0.75). In the 5kb‐contact‐matrix analysis, a chromatin interactive event involving APOE was detected, which is supported by Capture‐C data. The higher‐resolution 500bp‐contact‐matrix analysis revealed multiple better‐defined interactions within the event. Of particular interest, an interaction between the 5’end of TOMM40 and CLPTM1 (about 100 kb apart from each other) surrounding APOE is only observed on European but not African LA background.

Conclusion

Chromatin loop displays more inter‐individual variations compared to other spatial genome structures and therefore is more informative in elucidating the epigenetic basis for inter‐ancestry differences in gene expression regulation. While identifying chromatin loop from Hi‐C data at higher resolution is challenging, it has the potential to delimitate EPI and offers insights on the ancestry‐specific AD genetic risk by providing functional mechanisms underlying AD‐associated genetic variants.
Describing biomarkers for Alzheimer’s disease: Localization of amyloid‐β in the retina
Authors: Lee Sieun , Xu Qinyuan (Alis) , Boerkoel Pierre , Hirsch‐Reinshagen Veronica , Mackenzie Ian R , Hsiung Ging‐Yuek Robin , Charm Geoffrey , To Elliot , Liu Alice , Schwab Katerina , Jiang Kailun , Sarunic Marinko , Beg Mirza Faisal , Pham Wellington , Cui Jing , To Eleanor , Matsubara Joanne A
Published: December 2022

Background

Retinal glial cells, Aβ deposition and their colocalization were examined in post‐mortem retinal cross‐sections of Alzheimer’s disease (AD) donors and age‐matched controls.

Method

Immunohistochemistry was performed on paraffin‐embedded cross‐sections of central and mid‐peripheral retinal tissues of AD donors (n = 9) and age‐matched controls (n = 12) to detect Aβ (6F/3D, 12F4, and 6E10) with neuronal profile (TUBB), astrocytes and Muller cells (GFAP), and microglia (IBA‐1). Astrocytes and Muller cells were further distinguished by double‐labelling of GFAP and glutamine synthetase (GS) antibody. The tissues were imaged with a confocal microscope and the degree of immunoreactivity and colocalization were measured layer‐wise and compared (α=.05) between the AD and control groups.

Result

The AD group showed more Aβ load in the mid‐peripheral retina but not central retina. For glial cells, less GFAP immunoreactivity in the central and mid‐peripheral retina and more microglia immunoreactivity in the mid‐peripheral retina were observed in the AD group. In the double‐labelling of GFAP and GS, activated Muller cells (labelled by GFAP and GS) were reduced in the AD group but not astrocytes (labelled only by GFAP). The AD group also showed greater co‐localization of Aβ with neuronal profile but less with microglia.

Conclusion

The reduced Muller cell metabolism and increase amount of microglia but with reduced colocalization with Aβ indicate complex glial dysfunction in the AD retina.
The Relationship between All‐cause Dementia and Acute Diabetes Complications among American Indian and Alaska Native Peoples
Authors: Niu Xiaoyi , Chang Jenny , Corrada Maria M. , Bullock Ann , Manson Spero , O'Connell Joan , Jiang Luohua
Published: December 2022

Background

American Indian and Alaska Native people (AI/ANs) bear a disproportionate burden of diabetes. Growing evidence has shown significant associations between several acute diabetes complications and dementia among diabetes patients in the general population. However, little is known about these relationships among AI/ANs.

Methods

This cross‐sectional study extracted patient registration and health service utilization data from the Indian Health Service’s National Data Warehouse and related administrative databases. A total of 29,337 AI/AN adults with diabetes who were 45+ years old and used IHS or tribal health services during fiscal year 2013 were included. All‐cause dementia and acute diabetes complications were identified using ICD‐9 diagnostic codes in the utilization data. Negative binomial regression models were used to evaluate the associations of interest after adjusting for potential confounders.

Results

Nearly 3% (n = 843) of AI/AN diabetes patients had a dementia diagnosis. Among AI/ANs with diabetes, similar proportions of patients had a history of hospitalization or ED visits for hypoglycemia only (3.6%) or hyperglycemia only (4.1%). About 0.8% had both types of acute diabetes complications. As shown in Fig1, after controlling for demographics, health care coverage, and comorbidities, dementia diagnosis was associated with 94% higher rate of severe hypoglycemia (Incidence Rate Ratio [IRR = 1.94, 95% CI:1.50‐2.51), 52% higher rate of severe hyperglycemia (IRR = 1.52, 95% CI, 1.11‐2.08), and 92% higher rate of any acute complication (IRR = 1.92, 95% CI:1.53‐2.41). Dementia was not significantly associated with diabetic ketoacidosis (DKA) in the adjusted model (IRR = 1.82, 95% CI:0.83‐4.01). Further adjustments on clinical measurements and medications did not substantially change the estimated IRRs for hypoglycemia and hyperglycemia.

Conclusions

AI/AN diabetes patients with dementia suffered from considerably higher rates of severe hypoglycemia and hyperglycemia than their counterparts without dementia. Clinical management of patients with comorbid diabetes and dementia is particularly challenging and requires individualized treatment approaches.
Event‐related‐potentials are sensitive and reliable EEG biomarkers for mild cognitive impairment: A longitudinal study
Authors: Meghdadi Amir H. , Mcconnell Marissa , Richard Christian , Hamilton Joanne M , Boeve Bradley F. , St Erik K , Salat David H , Berka Chris
Published: December 2022

Background

Event‐related‐potentials (ERPs) during cognitive tasks are sensitive measures of cognitive decline [1]‐[2] and could quantitatively measure the trajectory of disease progression or response to clinical interventions. In this longitudinal study, we aimed to compare ERPs between individuals with mild cognitive impairment (MCI) and controls, and to demonstrate the test‐retest reliability of ERP measures to assess their potential utility for future observational studies and treatment trials.

Methods

Participants included individuals with mild cognitive impairment (MCI, n=31) and healthy controls stratified by age: HC2 (n=46, 40‐60 yrs.), HC3 (n=56, 60‐90 yrs.). ERPs during attention, image recognition, and verbal memory tasks were recorded using a wireless EEG to determine amplitudes and latencies of the P200 and late positive potential (LPP) ERP components in response to target (memorized) and non‐target (novel) stimuli. Differences between MCI and HC3 groups were characterized at the initial visit, and longitudinal changes in ERP components were determined at 1‐year follow‐up for both groups. Reliability of ERP measures was demonstrated by computing intraclass correlation coefficient (ICC) measures of test‐retest variability in all healthy controls (HC2 and HC3) from initial visit to 1‐year follow‐up.

Results

At the initial visit, the MCI group demonstrated reduced LPP amplitude (Hedges‐g=0.8, p=10‐3) and delayed P200‐latency (Hedges‐g=0.89, p=10‐4) when compared to HC3. Reliability in healthy controls was high for LPP (0.85 and 0.75 for target and non‐target stimuli, respectively) and moderate for P200‐latency (0.67 and 0.53 for target and non‐target stimuli, respectively), without longitudinal changes after 1‐year follow‐up. Individuals with MCI demonstrated increased P200‐latency (Hedges‐g= 1.05, p=0.02, df=8).

Conclusions

Individuals with MCI demonstrated quantifiable memory ERP deficits at baseline with detectable change in the P200 component at 1‐year follow‐up, demonstrating that ERPs are sensitive measures for quantifying mild cognitive impairment. Test‐retest reliability of these measures was good or moderate after 1‐year, supporting their feasibility for longitudinal monitoring of patients during disease progression or quantifying the cognitive impact of potential interventions.
Evaluation of COVID on cognitive performance using a mobile application (DANA)
Authors: Hwang Phillip H , Leibel Daniel , Popp Zachary T , Drane James , Lee Marissa , Prabhu Meha , Kohli Anisha , Chen Herbert , Kumar Anupama , Lathan Corinna , Au Rhoda , Vannorsdall Tracy D
Published: December 2022

Background

The neurocognitive impact of having COVID is receiving greater awareness, with greater COVID severity potentially conferring risk of more negative cognitive outcomes. Current cognitive assessment methods are limited by factors, such as time and location, which can be mitigated by the use of mobile applications. We aimed to assess the relationship between COVID severity and cognitive performance at baseline and over time using a mobile cognitive assessment.

Method

Participants in the analytic sample included 27 COVID‐positive (COVID+) Johns Hopkins Post‐acute Covid Team patients who received care in the intensive care unit (COVID+/ICU+; n = 6) or in other units (COVID+/ICU‐; n = 21). Another 23 participants from a separate study investigating the use of mobile cognitive applications in older adults were included as non‐COVID controls (COVID‐). Cognition was assessed via cognitive efficiency (CE) scores, a derived measure of speed and accuracy, for the Procedural Reaction Time (PRT) task of the Digital Automated Neurobehavioral Assessment (DANA) mobile application. Participants with missing or unavailable PRT assessment data were excluded from the analytic sample. PRT CE scores between COVID‐, COVID+/ICU‐, and COVID+/ICU+ participants were analyzed at baseline using ANOVA, as well as longitudinally over a six‐week period.

Result

Table 1 presents demographic characteristics. At baseline, average PRT CE scores were highest among the COVID‐ group (mean = 86.55; standard deviation = 17.06), followed by the COVID+/ICU+ group (mean = 80.41; standard deviation = 15.83), and then the COVID+/ICU‐ group (mean = 76.93; standard deviation = 14.03). There was no significant difference in average baseline PRT CE scores between the three groups (p = 0.135). Those in the COVID‐ group and COVID+/ICU‐ group appeared to achieve higher PRT CE scores over the six‐week assessment period, while those in the COVID+/ICU+ group did not improve relative to their baseline (Figure 1a&b).

Conclusion

We observed qualitative differences in the rate of recovery for cognitive performance between participants with COVID who did and did not require ICU admission. Given the limited sample size and other potential confounding factors, further analyses with additional data collected are needed in order to more rigorously compare cognitive performance cross‐sectionally and longitudinally between COVID groups.
Protecting cognitive function and delaying dementia: preliminary evidence from Lebanon
Authors: Darwish Hala J
Published: December 2022

Background

In Lebanon, it is projected that dementia will become a health crisis within the next 20 years. Therefore, the protection and management of cognitive impairment in older adults are of great significance for the aging population. We will present findings from research examining the role cognitive reserve factors and vitamin D play in cognitive impairment among older adults.

Methods

In the first study, we investigated the cognitive function and cognitive reserve factors of 508 community‐based Lebanese older adults aged 65 years using secondary data analysis. In a second cross‐sectional study, we explored the cognitive performance and serum vitamin D levels in 254 older (>60 years) as well as younger (30‐60 years) adults.

Results

Study 1. Older adults with dementia had lower education levels and attained lower occupational complexity. High education, complex occupation attainment, and leisure activity significantly predicted better global cognitive function. An older adult who gained high education levels or high complexity level occupation was 7.1 or 4.6 times more likely to have better global cognitive function than another who attained lower education or complexity level occupation, respectively. Study 2. Pearson’s correlation and stepwise linear regression analyses showed that a low serum 25 dihydroxy vitamin D (<30ng/ml) level was associated with a higher risk of cognitive impairment in older as well as younger adults (30 years).

Conclusion

These results suggest that cognitive reserve factors should be taken into consideration clinically during dementia diagnosis and when initiating community‐based preventive strategies in Arab populations. These findings also suggest that vitamin D correction needs to be explored as an intervention to prevent cognitive impairment. Other evidence supporting lifestyle changes and cognitive rehabilitation for the prevention and treatment of cognitive impairment should also be considered. Such interventions may reduce the risk of cognitive impairment and Alzheimer’s disease in older adults.
Racial disparities in predictors of dementia in a population‐based cohort
Authors: Borelli Wyllians Vendramini , Ferreira Pamela C.L. , Formoso Carolina Rodrigues , Pascoal Tharick A , Castilhos Raphael Machado , Zimmer Eduardo R
Published: December 2022

Background

Identifying predictors of dementia may reduce its burden across the globe. Herein, we aimed at investigating predictors of probable dementia in different race groups of a middle‐income country.

Method

The ELSI‐Brazil cohort consists of 9412 individuals (63.55+‐10.14 years of age). This cohort comprises individuals at/ or above 50 years of age from across the country. Complex sampling warrants nationwide representativity for diseases with low prevalence. Probable dementia was defined as a brief cognitive screening (using category fluency test) score below normative data for age and education, associated with a Katz scale score below 6. Multivariate logistic regression models were performed to measure predictors of dementia in Black, Brown, White and Indigenous individuals. Asian ancestry individuals were excluded from this analysis due to the small sample size (n = 90).

Result

The frequency of individuals with probable dementia was statistically similar between groups, especifically 8.7% (n = 74/887) in black individuals, 7.8% (n = 17/220) in indigenous individuals, 7.5% (n = 301/4283) in Brown individuals, and 7.2% (n = 245/3590) in White individuals (p = 0.51). Indigenous individuals with probable dementia were significantly younger than other groups (59.1 years, p<0.001). Predictors of dementia differ significantly between groups, except for depression, which was the only predictor universally present. In Brown individuals, stroke and myocardial infarction were associated with predictors of dementia (OR: 2.34 [1.5 ‐ 3.5] and OR: 2.57 [1.69 ‐ 3.84] respectively), while the feeling of loneliness (OR: 1.69 [1.20 ‐ 2.42]) and being economically inactive (OR: 2.89 [1.68 ‐ 4.80]) were associated with dementia in White individuals. In Black individuals, recent hospitalization was a strong predictor (OR: 2.86 [1.47 ‐ 5.42]), while in Indigenous individuals, only depression was a predictor (OR: 19.22 [3.74 ‐ 352]), potentially associated with its small sample.

Conclusion

Distinct profile of predictors for probable dementia should be accounted for when evaluating distinct races groups. While depression was a predictor for all races, Brown individuals presented a clinical profile more vulnerable to cardiovascular events.
Whole genome sequence association analysis of Brain MRI measures
Authors: Shade Lincoln MP , Satizabal Claudia L , Glahn David C , Mosley Thomas H , Heckbert Susan R. , Launer Lenore J. , Yanek Lisa R , Bis Joshua C , Smith Jennifer A , DeCarli Charles S. , Arnett Donna K , Psaty Bruce M. , Nyquist Paul A , Mathias Rasika A , Rotter Jerome I , Rich Stephen S , Blangero John , DeStefano Anita L. , Fardo David W. , Fornage Myriam , Seshadri Sudha , Sarnowski Chloé ,   TOPMed Neurocognitive working group
Published: December 2022

Background

Genome‐wide association studies (GWAS) of brain volumes have identified common genetic variants with modest effect sizes that lie mainly in non‐coding regions. We sought to identify low frequency and rare variants influencing brain volumes by performing association analyses using whole‐genome sequence data from the Trans‐Omics for Precision Medicine (TOPMed) Program.

Method

We analyzed up to 7,607 participants (57% women; 62% European ancestry, 21% African‐Americans, 15% Hispanic/Latino, 2% Chinese‐American), mean age of 60.5 (16.2), from eight TOPMed population‐ or family‐based studies (FHS, GENESTAR, CHS, GENOA, ARIC, CARDIA, MESA, and SAFS). We excluded participants with dementia, stroke, presence of large brain infarcts, tumor or low‐quality scans. We tested the association of hippocampal (HV), total brain (TBV), lateral ventricular (LVV) and intracranial (ICV) volumes to individual genetic variants with minor allele counts ≥ 15 using mixed‐effect linear regression models adjusted for age, age2, sex, study and the first 10 principal components. Models for HV, TBV and log(LVV) were adjusted for ICV. We accounted for relatedness using an empirical kinship matrix and trait variance variability by using a random effect for study.

Result

We detected one novel region with low frequency variants associated with HV (13q14, P = 5.8×10−9). The top 13q14 variant for HV (rs115674829) minor allele frequency (MAF) was 2% in our pooled sample but was more common in the pan‐African 1000 Genomes population (MAF = 14%). This variant lies in LINC00598 at 237kb from FOXO1, a member of the forkhead family of transcription factors that has been linked to Alzheimer’s Disease. Additionally, we detected new suggestive associations (P≤10−7) for TBV (16p11) and LVV (1q25, 2q22, 3q13, 5q14, and 10q23), including common variants. Finally, we confirmed the association of common variants in GWAS loci for all traits.

Conclusion

Our whole genome sequence analyses revealed intriguing new loci of low‐frequency and common variants, and replicated loci previously associated with brain volumes. Future work will include ancestry‐specific and conditional analyses, as well as gene‐based and scan tests.

Supported by: AG058589, AG052409, AG054076, NO1‐HC‐25195, HHSN268201500001I and 75N92019D00031, R01HL131136, P30 AG066546, and K99AG066849.
Leukocyte Surface Biomarkers Implicate Deficits of Innate Immunity in Late‐onset Alzheimer’s Disease
Authors: Li Yihan , Huang Xin , Fowler Christopher , Doecke James D , Trounson Brett , Pertile Kelly , Rumble Rebecca , Lim Yen Ying , Maruff Paul , Mintzer Jacobo E. , Dore Vincent , Rowe Christopher , Fripp Jurgen , Wiley James S , Masters Colin L. , Gu Ben J
Published: December 2022

Background

Alzheimer’s disease (AD) is characterized by amyloid‐β (Aβ) plaques, neurofibrillary tangles, reactive astrogliosis, and microgliosis. Aberrant Aβ accumulation starts 20–30 years before clinical onset, so biomarker test is essential to diagnose people living with early AD. PET imaging and CSF measurements allow the diagnosis of preclinical and prodromal AD in research and clinical trials, but their invasiveness and costliness might limit their application in hospital setting. Therefore, developing non‐invasive population screening tests is necessary for the early diagnosis of AD. Recent genetic findings strongly implicate the role of innate and adaptive immunity in AD and suggest that a systemic failure of cell‐mediated Aβ clearance contributes to AD onset and progression. Our research question was to develop an immune‐related blood‐based biomarker test to facilitate the diagnosis and prognosis of AD. It was hypothesized that the pattern of immune‐related receptors and molecules expressed on peripheral leukocytes could differentiate people living with AD from healthy population.

Method

We recruited 180 and 200 participants from AIBL in two discovery phases and validated our findings by an independent cohort of 112 participants from AIBL. A total of 34 innate and adaptive immunity‐related leukocyte antigens on peripheral lymphocytes, monocytes, and neutrophils were examined by flow cytometry immunophenotyping. Data was analysed by logistic regression and ROC analyses.

Result

We identified upregulated CD35, CD59, CD91, RAGE, and Scara‐1 expressions and downregulated CD11c, CD18, CD36, CD163, MerTK, and P2X7 expressions on leukocytes of MCI/AD patients. Significant correlation between them and Aβ burden, episodic memory, and PACC score was observed, such as CD59 and CD91. Pathway analysis revealed upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance in AD. We proposed a marker panel including CD11c, CD59, CD91 and CD163 and this panel predicted patients’ PET Aβ status with AUC of 0.93 (0.88 to 0.97), which was repeated in validation cohort. Regarding adaptive immunity, we did not see significant results.

Conclusion

Our study suggested deficits in innate immunity in AD, which is consistent with genomic studies. Our proposed leukocyte‐based biomarker panel might be sensitive and practical for AD screening and diagnosis.
Effect of SUPERBRAIN program in Amyloid PET positive mild dementia patient: Cognitive outcome, EEG and stool microbiome
Authors: Lee Eun Hye , Choi Seong Hye , Jeong Jee Hyang
Published: December 2022

Background

The effect of SUPERBRAIN (multi‐domain lifestyle intervention program), on the mild stage of AD positive mild stage of dementia for an 8‐week treatment in the cognitive function, EEG and stool microbiom outcome.

Method

A total of 58 amnestic MCI or early stage of mild dementia patient (CDR 0.5‐1) with amyloid PET positive, were recruited. Patients were randomized to either three group of 1) Superbrain with Memory pack group, 2) Memory pack only group, 3) control group. Memory Pack is nutritional support that is supplied by Daesang Yuup that is specially designed for brain reinforcing formula such as choline, serine, glycine, etc. Cognitive training programs and exercise programs were conducted two persons in a group session twice in a week for the 8 week in the hospital. The primary outcome was the change in the total scale of index score of the Repeatable Battery for the Assessment of Neuropsychological Status (RBARNS) after 2 months of training. Analysis of covariance was used to compare the index score of the RBANS between the three groups.

Result

The age was 75.70 (5.26) in treatment group, 75.75 (5.80) for Memory pack only group, 75.00 (6.50) for control group (P value. 0.967). The baseline MMSE scores were 22. 38 (3.50) in treatment group, 20.75 (1.75) for Memory pack only group, 21.63(2.50) for control group (P value. 0.492). RBARNS score showed improvements in the total RBARNS scale index score (72(15.78) in Baseline to Fup 78.88(16.51) in the treatment group (P value 0.05) compared to Memory pack only (75.38(9.02) in Baseline to Fup 79.00(8.68) (P value 0.045) and control group (75.38(11.90) in Baseline to Fup 75.75(18.79) (0.970). The MMSE were significantly improved in both treatment group (22.38, 24.13; p = 0.013) and Memory pack only group(20.75,22.57, P = 0.045) as well but worsened in control group (21.63, 20.00 P = 0.142) compared to baseline. The CDR sum of box statistically worsened in the control group compared to treatment group and memory pack group.

Conclusion

Cognitive improvement was evident even in this short term 8 weeks of multi‐domain intervention program of for AD dementia which needs further study for the long‐term outcome.
Integrating genetic correlation, polygenic risk scores, and Mendelian randomization to identify modifiable risk factors for Alzheimer’s disease
Authors: Andrews Shea J , Fulton‐Howard Brian , Bennett David A , Goate Alison
Published: December 2022

Background

To reduce the population prevalence of Alzheimer’s disease (AD), it is critical to identify risk factors that modify AD risk. Methods of causal inference that exploit genomic information, such as genetic correlation (rg), polygenic risk scores (PRS) and Mendelian randomization (MR), can overcome some of the limitations of observational studies such as confounding and reverse causation. Here we use rg, PRS, and MR to investigate causal associations between twenty‐two risk factors and eleven AD outcomes.

Methods

Using GWAS summary statistics, rg was estimated using GNOVA and bidirectional MR causal estimates using LHC‐MR. The exposures included alcohol intake, physical activity, lipid traits, blood pressure traits, diabetes, BMI, depression, insomnia, social isolation, smoking, diet, and education. The outcomes included AD, AD age of onset, hippocampal volume, CSF Aβ42, tau, and Ptau181 levels, and amyloid, tau, cerebrovascular neuropathology. PRS for the exposures were constructed using PRSice in ADGC (n = 25,431), ADNI (nmax = 1,718), and ROSMAP (nmax = 1,675), and their association with AD diagnosis, CSF biomarkers, PET imaging, MRI imaging, and neuropathology was evaluated.

Results

After accounting for multiple testing, 71, 1, and 38 trait pairs were significant in the rg, PRS, MR models respectively. The only significant trait pair identified across all three methods was a protective effect of higher educational attainment on AD (rg = ‐0.161, p = 3.78e‐14; bPRS [se] = ‐0.07 [0.014], p = 8.88e‐7; bMR [se] = ‐0.21 [0.042], p = 2.43e‐7). Seventeen trait pairs had both significant genetic correlations and causal MR estimates. In particular, increased cortical surface area was positively correlated with higher educational attainment (rg = 0.261, p = 1.46e‐18), with MR indicating that genetically predicted cortical surface area was causally associated with higher education (bMR [se] = 0.27 [0.042], p = 3.21e‐10), but not vice versa (bMR [se] = ‐0.09 [0.072], p = 0.224).

Conclusions

We evaluated causal relationships between risk factors and AD endophenotypes using genomic information. The protective effect of education on AD is supported by genetic correlation, PRS and MR, potentially due to increased cognitive resilience resulting from increased cortical surface area.
Broad‐ranging effects of APOE4 on cellular protein expression in neural precursors
Authors: Paul Pradip , Ramakrishna Sarayu , Ghose Vivek , Dey Gourav , Muddashetty Ravi S , Purushottam Meera , Viswanath Biju , Jain Sanjeev , Sud Reeteka
Published: December 2022

Background

It is increasingly becoming evident that ApoE4 isoform contributes to AD risk over the life course of individuals. Much remains unknown about the biological pathways that connect APOE4 genotype with the development of pathology that eventually leads to AD, nor do we know how early in life these cellular alterations begin. To answer these questions, we derived neural precursor cells (NPCs) from induced pluripotent stem cells (IPSCs) that were CRISPR‐edited at APOE locus (Ramakrishna et al. 2021; Schmid et al. 2019). We intended to characterize the protein expression landscape in the NPCs subsequent to targeted deletion of E4 from a parent IPSC line of APOE3/4 genotype.

Methods

Protein isolates from NPCs were analyzed on the Thermo Scientific‐ Orbitrap Fusion instrument and the resulting Mass Spectrometer data was searched against a reference human protein database using Proteome Discoverer 2.2. Differentially expressed proteins (DEP) were determined from the protein abundance fold change values obtained for each protein. Proteins which showed >1.2‐fold difference with FDR adjusted P‐value < 0.05 were considered differentially expressed. DEPs were mapped to STRING database (v11.5) for retrieval of interacting proteins and functional enrichment.

Results

CRISPR‐editing of E4 from the parent line revealed 105 differential expressed proteins. Of these, 62 were upregulated, and 43 were downregulated. Further analysis of the DEPs via STRING database showed that these changes primarily affect pathways linked to RNA processing, plasma membrane repair, and cytoskeleton organization.

Conclusions

Our primary motivation was to determine proteomic alterations with targeted deletion of E4. And indeed, we find the effects of E4 extend beyond proteins considered central to AD pathology. Knowing more about the protein interactions regulated by ApoE, in an isoform‐specific manner, has the potential to reveal novel drug targets. In future experiments, we intend to follow the DEPs identified here and the associated pathways through the course of neural differentiation.
In vivo biomarkers of arteriolosclerosis are associated with ADRD biomarkers
Authors: Rundle Melissa M. , Peavey Jeremy J. , Barcus Richard A. , Okonmah‐Obazee Stephanie E. , Espeland Mark A. , Sai Kiran K Solingapuram , Whitlow Christopher T. , Williams Benjamin J. , Craft Suzanne , Bateman James R. , Lockhart Samuel N. , Hughes Tim M.
Published: December 2022

Background

Brain arteriolosclerosis, which involves thickening of the vessel wall and stenosis of arterioles, is one of the main pathologies of cerebral small vessel disease, and often co‐occurs with other pathology indicative of Alzheimer’s disease and related disorders (ADRD). A novel classifier of arteriolosclerosis, ARTS, was recently developed by the MarkVCID consortium for in vivo studies of arteriolosclerosis. We hypothesized that higher levels of arteriolosclerosis are associated with worse ADRD biomarker levels.

Method

109 participants from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core underwent clinical and cognitive evaluation, 3T brain MRI, and PiB (amyloid) PET (n=92). Participants were adjudicated by NIA‐AA criteria as having normal cognition (n=69), mild cognitive impairment (n=25), or dementia (n=15). Raw T1, FLAIR, and TOPUP and Eddy Current Corrected DTI images along with age and sex were inputs to a machine learning based classifier generating ARTS scores; higher ARTS indicates higher likelihood of arteriolosclerosis. For variables of interest, T1 MRI were processed (FreeSurfer v5.3) to calculate cortical gray matter (GM), hippocampal, and intracranial (ICV) volumes, and temporal meta‐ROI cortical thickness. White matter hyperintensity (WMH) volumes were calculated on FLAIR with LST in SPM12. NODDI were processed using AMICO to generate mean Free Water (FW) in hippocampus and global GM and white matter (WM). A set of AD‐sensitive cortical ROIs were used to extract mean PET SUVr signal. Separate multivariable general linear models (GLM) examined relationships between ARTS and variables of interest adjusted initially for age and total ICV (Table 1), and then again after adjusting for additional covariates (sex, race, education, APOE‐e4 carrier status, and clinical diagnosis).

Result

Among 109 participants (71±7 years, 60% women), ARTS ranged from ‐.80 to .29 (mean±SD = ‐.37±.20), suggesting a low overall likelihood of arteriolosclerosis in our sample. Higher ARTS was significantly associated with lower cortical thickness, higher WMH, higher WM FW, and greater amyloid deposition (Table 1). When adjusting for additional covariates, only amyloid no longer significantly associated with ARTS (p=0.19).

Conclusion

Higher ARTS scores are cross‐sectionally associated with other abnormalities in ADRD biomarkers. Future directions will examine the relationship between ARTS and Flortaucipir (tau) uptake.
Using Technology to Overcome the Challenges of COVID‐19 Pandemic in India: The DEMCARES Model of Virtual Intervention Delivery
Authors: Vaitheswaran Sridhar , Natarajan Nirupama , Ramanujam Vaishnavi , S Subashini , Venkatesan Shreenila , Srinivasan Nivedhitha , Nagarajan Gayathri , Balasubramanian Suhavana
Published: December 2022

Background

The COVID‐19 pandemic and associated restrictions have greatly affected the delivery of treatment and access to in‐person interventions for dementia, especially in low‐ and middle‐income countries such as India. Technology use could potentially help bring the above‐mentioned services to persons with dementia (PwD) and their caregivers in the safety of their homes. The aim of this study is to evaluate the dementia care services delivered by the Dementia Care in SCARF (DEMCARES) team in the densely populated city of Chennai in South India during the COVID‐19 pandemic.

Methods

We reviewed teleconsultation logs, records of dementia‐related services and interventions offered to both PwD and their caregivers at the DEMCARES clinic between July 2020 and December 2021 during the COVID‐19 pandemic. Moreover, we collected feedback from PwD and caregivers regarding virtually delivered dementia interventions and analyzed them to understand benefits, barriers, and facilitators.

Results

In addition to in‐person outpatient clinic, teleconsultation for PwD and behavioral and psychological symptoms of dementia management training for caregivers through audio/videoconferencing was provided to those with access to technology. Interventions, such as STrAtegies for RelaTives (START) and Cognitive Stimulation Therapy (CST) that were originally delivered face‐to‐face, were adapted for virtual delivery to cater to the needs of persons with dementia and their caregivers in Chennai, India. Furthermore, dementia awareness course for caregivers and caregiver support groups were also conducted online. Feedback from PwD and their caregivers were largely positive, and the numbers reached were higher during the pandemic than before.

Conclusion

Being situated in an urban setting, the DEMCARES team of professionals were able to reach many PwD and their caregivers who had access to technology. Despite some of its limitations, technology holds a great potential for providing uninterrupted treatment and interventions for dementia in addition to considerably improving access to care, especially during the pandemic.
Cell‐Level Transcriptomic Network Analysis Provides Insights into Distinct Biological Mechanisms for Alzheimer’s Disease Enabling Targeted Drug Repositioning
Authors: Sahelijo Nathan , Hu Junming , Priyadarshi Dhawal , Panitch Rebecca , Shen Li , Thompson Paul M , Saykin Andrew J. , Huang Heng , Nho Kwangsik , Crane Paul K. , Davatzikos Christos , Jun Gyungah R
Published: December 2022

Background

The phenotypic and genetic heterogeneity of Alzheimer’s disease (AD) complicates efforts to identify the underlying biological mechanisms. Cell‐specific biologically connected gene networks may explain some of the observed pathophysiological and cognitive heterogeneity, leading to more effective patient stratification and drug targeting strategies.

Method

We conducted cell‐level network analysis using single nuclei RNA‐sequencing data from post‐mortem prefrontal cortex areas of 24 AD and 24 control brains in the Religious Orders Study and Memory and Aging Project (ROSMAP) for discovery and 12 AD and 9 control brains in the South‐West Dementia Brain Bank study for validation. We selected the AD associated modules from the preserved modules with significant differences between AD cases and control brains. The mbPRS was validated by previously defined (1) distinct brain atrophy clusters, and (2) cognitively defined AD subgroups including AD‐Executive, AD‐Language, AD‐Memory, AD‐Visuospatial functioning, AD‐No Domains, and AD‐Multiple‐domains. We conducted an association test with each mbPRS using the assigned membership variable as a binary outcome in a logistic regression model. We identified existing drugs targeting genes from the top‐ranked modules for repurposing in AD therapeutics.

Result

Among 60 cell‐level modules, 12 modules were preserved in the validation set and significantly associated with AD (P<0.05). The mbPRSs for an astrocyte and an oligodendrocyte module M45 showed significant association with diffuse brain atrophy linked with proportionally lower executive functioning scores (PM2=7.40E‐5; PM45=2.12E‐4), and medial temporal atrophy likely representing early stages of AD (PM2=2.72E‐6; PM45=2.40E‐5). The mbPRS for M2 was significantly (PM2=2.72E‐2). Pathway analysis of the module gene sets revealed potential drug candidates for repositioning, including drugs targeting ApoE and IL1b pathways.

Conclusion

By integrating genetics, cell‐level transcriptome networks, and endophenotypes of AD we confirmed cell‐level polygenic risk scores can stratify individuals into different target groups that are correlated with previously classified subgroups using cognitive functions and imaging biomarker data.
Retention of Participant and Study Partner Dyads in Alzheimer’s Disease Clinical Trials
Authors: Nuño Michelle M , Gillen Daniel L. , Grill Joshua
Published: December 2022

Background

Study retention is crucial to clinical trial success. Greater than expected dropout rates can lead to reduced power and biased results. Alzheimer’s disease (AD) trial success depends not only on participants but also on their study partners. We investigated whether study partner type was associated with the risk of dropout in large Phase 3 registration trials.

Method

We used data from two trials of bapineuzumab for patients with mild‐to‐moderate AD. Data were provided by the sponsor of the trials, Janssen Research & Development, LLC for use in these analyses. The co‐primary endpoints were the change from baseline to week 78 in the Disability Assessment for Dementia (DAD) and the 11‐item AD Assessment Scale (ADAS Cog‐11). We defined completers as participants with baseline and week 78 scores on ADAS Cog‐11 or DAD. Participants were excluded from our analyses if they did not declare a study partner type in the Resource Utilization in Dementia‐Lite (RUD‐Lite) or if they were missing ADAS Cog‐11 and DAD at baseline. Time‐to‐dropout was defined as the time from study enrollment to the time of the last visit during which ADAS Cog‐11 or DAD were conducted.

Result

Data were available for 1,234 participants in the non‐carrier study and 1,221 participants in the carrier study. Table 1 presents baseline characteristics for participants included in our analysis (n = 1,229 non‐carriers and n = 1,097 carriers). In both trials, we observed a higher proportion of participants enrolled with a spouse (non‐carriers: 817, 66.3%; carriers: 837, 76.3%). Approximately 75% of spousal dyads completed the non‐carrier trial, while 60% of adult‐child dyads and 54% of dyads with other study partners completed the trial. Differences in the proportion of completers were lower in the carrier study, with approximately 75%, 73%, and 70% of completers among spousal, adult child, and “other” dyads. The same trend for time‐to‐dropout can be seen in Figure 1.

Conclusion

We found that a higher proportion of spousal dyads completed the trials compared to other dyad types. Understanding the factors driving these associations may help understand reasons for dropout and could lead to the development of retention strategies.
Impact of Mild Behavioral Impairment and Mild Cognitive Impairment on Risk for Dementia
Authors: Rouse Hillary J , Small Brent J , Ismail Zahinoor
Published: December 2022

Background

There has been a shift in research to explore early indicators associated with preclinical/prodromal dementia. Recent research highlights the importance of non‐cognitive factors, such as neuropsychiatric symptoms (NPS), as articulated in criteria for mild behavioral impairment (MBI). Previous research suggests MBI is a risk factor for dementia regardless of if one is cognitively healthy or diagnosed with mild cognitive impairment (MCI). The goal of this study is to examine risk for dementia subtypes based on the presence of MBI and/or MCI.

Method

Secondary data analysis of participants (n = 17,289) from the National Alzheimer’s Coordinating Center who were cognitively healthy (n = 11,770) or diagnosed with MCI (n = 5,519). Risk for dementia, Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) were examined using Cox proportional hazard models.

Result

Almost 25% of the entire sample met the operationalized diagnostic criteria for MBI (n = 4,274). The risk for dementia almost tripled among persons with MBI and increased by almost seven‐fold if they had MCI. Among persons with MBI, the risk for FTD was six times greater and the risk for DLB and AD was three times greater, compared to those without MBI. Additionally, for participants who had MCI, the risk for DLB was six times greater, the risk for AD was over nine times greater, and the risk for FTD was almost sixteen times greater, compared to those who were cognitively healthy. There was a significant interaction found between MBI and MCI status. For cognitively healthy older adults with MBI, the risk was almost eleven times greater for FTD, whereas for older adults with MCI and MBI, the risk was three times greater for DLB.

Conclusion

Older adults with MBI and MCI are at an increased risk for all types of dementia. Additionally, cognitively healthy participants with MBI are found to have a greater risk for FTD, where participants with MCI and MBI had a greater risk for DLB. These results provide support for MBI as a prodromal state of all‐cause dementia, and highlight the importance of recognizing these symptoms across the spectrum of cognitive decline.
Genetic heterogeneity of four MCI/AD neuroanatomical dimensions discovered via deep learning
Authors: Wen Junhao , Cui Yuhan , Yang Zhijian , Bao Jingxuan , Chen Jiong , Erus Guray , Abdulkadir Ahmed , Mamourian Elizabeth , Singh Ashish , Yang Shu , Fan Yong , Saykin Andrew J. , Thompson Paul M , Jun Gyungah R , Ritchie Marylyn D. , Shen Li , Wolk David A. , Shou Haochang , Nasrallah Ilya M. , Davatzikos Christos
Published: December 2022

Background

Data‐driven unsupervised and semi‐supervised clustering methods have parsed neuroanatomical heterogeneity of Alzheimer's disease (AD) and/or mild cognitive impairment (MCI) into multidimensional neuroimaging representations (Vogel et al., 2021; Wen et al., 2021b, 2021a; Yang et al., 2021; Young et al., 2018; Zhang et al., 2016). However, whether this neuroanatomical heterogeneity is partly underpinned by genetic heterogeneity remains unanswered.

Method

Whole‐genome sequencing (WGS) data were analyzed for individuals in the Alzheimer’s Disease Neuroimaging Initiative. WGS data underwent a standard genetic pipeline. This resulted in 1,487 participants (428 healthy controls, 489 MCI and 570 AD; age = 78.96 ± 7.72; 44.05% females) with 24,773,167 single nucleotide polymorphism (SNP). The deep learning Smile‐GAN model (Yang et al., 2021) generates expression scores (ES) across each of the four subtypes of MCI/AD (Fig. 2). The ES of each subtype were used as phenotypes in genome‐wide association studies (GWAS). Specifically, we performed multiple linear regressions controlling for age, sex, intracranial volume, disease diagnosis, and the first four genetic principle components using Plink (Purcell et al., 2007). We then performed clumping to define the independent significant variants (ISVs).

Result

GWAS discovered 17 ISV‐ES pairwise associations. WGS data allowed us to identify four de no ISVs that were not included in dbSNP (Fig. 1). P1 and P4 detected similar AD‐related genetic variants (e.g., APOE, NECTIN2, and TOMM40, Fig. 1 and 2), but with opposite directions of effect, i.e., protective factors for P1 and risk factors for P4, consistent with respective patterns of neurodegeneration in these phenotypes. In particular, for rs429358 (APOE‐4), the P4 subtype had more C alleles (minor allele) than the P1 subtype (P‐value < 1e‐20). The four ISVs identified for P2 and P3 were not previously associated with any clinical trait.

Conclusion

The current study identified genetic heterogeneity related to the expression of four MCI/AD subtypes previously defined via Smile‐GAN. Notably, our results confirmed previous findings that AD is genetically heterogeneous (Nacmias et al., 2018), identifying known genetic risk factors and several novel variants. Further research is needed to understand how these variants may affect AD pathophysiology and determine if any may provide a therapeutic target.