AD Research Research Articles

Sex differences for clinical correlates of substantia nigra neuron loss and Lewy body pathology

AbstractBackgroundLewy body pathology staging and substantia nigra neuron loss levels are associated with clinical features in Lewy body dementia (LBD). Compared to women, neocortical Lewy body pathology is more common and co‐pathologies are less common in men. Clinical features of people with limbic and neocortical Lewy body also differ based on sex, although sex differences for additional Lewy body pathology stages or nigral neuron loss are unclear.MethodData was obtained from the National Alzheimer’s Coordinating Center Uniform Data Set (UDS) and Neuropathology Data Set for UDS visits conducted between September 2005 and August 2019. Analysis included 31 women and 62 men from 25 AD Research Centers with Lewy body pathology and substantia nigra neuron loss data, excluding those with other neuropathologic diagnoses including moderate/severe Alzheimer’s disease. Linear models assessed the sex differences for clinical associations of nigral neuron loss level and Lewy body pathology staging controlling for age at last visit.ResultWomen were older at last visit and at death, had less years of education than men (Table 1). Men were more likely to have a clinical LBD diagnosis, had cognitive decline at a younger age, worse dementia at last visit, and higher levels of Lewy body pathology staging and nigral neuron loss. Higher Lewy body pathology stage was associated with more nigral neuron loss more for men compared to women (Table 2). Higher Lewy body pathology stage and greater degrees of nigral neuron loss were associated with more severe dementia and behavioral symptoms and a higher likelihood for a clinical Lewy body diagnosis in men compared to women.ConclusionLewy body pathology staging and the level of substantia nigra neuron loss may be worse for men compared to women. These data also suggest that Lewy body pathology and nigral neuron loss affect men more severely than women in terms of dementia severity and behavioral profiles associated with LBD. The blunted clinical manifestations of these pathological features in women add to the difficulty in accurate diagnosis and future work on the reasons for women’s resilience to these pathological features is needed.

28 Variability in Remote, Self-Administered Assessment Performance Associated with Self-Reported Memory Perceptions Among Older Adults

Objective:Remote assessment for cognitive screening and monitoring in the elderly has many potential advantages, including improved convenience/access and ease of repeat testing. As remote testing becomes more feasible and common, it is important to examine what factors might influence performance and adherence with these new methods. Personal beliefs about one’s ability to remember effectively have been shown to impact memory performance, especially in older adults (Lineweaver & Hertzog, 1998). The perception of a low level of personal control over memory may impact a person’s use of memory strategies which might otherwise enhance performance, as well as their beliefs about the efficacy of those strategies (Lineweaver et al., 2021). The present study examined the relationship between perceived memory self-efficacy and performance and adherence on self-administered, smartphonebased remote cognitive assessments.Participants and Methods:Participants were 123 cognitively unimpaired adults (ages 55-80, 68.3% female, 87% White, M= 16.5 years of education) recruited from the Butler Hospital Alzheimer’s Prevention Registry as part of an ongoing study evaluating novel cognitive assessment methods. A cutoff of score of ≥34 on the modified Telephone Interview for Cognitive Status (TICSm) was required for enrollment. Perceived memory self-efficacy was assessed using two subscales of the Personal Beliefs about Memory Instrument (PBMI; Lineweaver et al., 1998): “prospective control”, the perception of control one currently has to influence future memory functioning, and “future control”, the perception of the amount of control over memory function one will have in the future. Participants completed three brief self-administered cognitive testing sessions per day for 8 consecutive days using a mobile app-based platform developed as part of the National Institute of Aging’s Mobile Toolbox initiative. Cognitive tasks assessed visual working memory (WM), processing speed (PS), and episodic memory (EM)(see Thompson et al., 2022).Results:Statistical analyses were conducted using univariate ANOVA tests to look for main effects of each PBMI subscale score on remote assessment adherence and average performance on each task over 8 days. After adjusting for aging, we found a higher rate of false alarms (proportion of misidentified stimuli) on the WM task was associated with higher levels of both self-reported prospective control (F(2, 86) = 4.188, p = .018) and future control (F(2, 96) = 5.003, p = .009). Increased response time on the PS task was also associated with higher levels of future control when adjusted for aging (F(2, 96) = 6.075, p = .003). There was no main effect of memory self-efficacy ratings on EM. We found no main effects of memory self-efficacy ratings on assessment adherence.Conclusions:These findings suggest perceptions of high prospective and future control are associated with positive response bias on a forced-choice WM task, and high perceptions of future control are also associated with slower response times on PS tasks. Future research should examine whether this is due to increased deliberation, cautiousness, or other factors. Limitations include the potentially limited generalizability of this largely White, highly educated, and motivated sample self-selected for AD research. Next steps for this research include comparing these results with the effects of perceived self-efficacy on in-person cognitive assessments.

Comparison of physiological state and conditions imitating the comorbidity of type 2 diabetes with Alzheimer's disease. The impact on: proliferation, H2O2, Aβ42, S100A8, S100B levels, neuronal protrusion and neurogenesis

Abstract Aim: Recent studies demonstrate that individuals with T2DM more likely to develop AD. While, disturbed glucose or insulin homeostasis, are at the forefront of AD research, not much is known about extra- and intracellular interplay between different forms of Aβ and microenviromental fluctuations of glucose or insulin concentrations in neuronal cells. Methods: We create conditions imitating the coexistence of T2DM with AD and compare the results with state where the neuropathological changes are yet not developed. We have investigated the effect of the physiological (Aβ40) and toxic amyloid form (Aβ25–35) and its co-incubation with glucose or insulin on neuronal proliferation, H2O2, Aβ42, S100B, S100A8 protein concentrations, mature neuronal protrusions and neurogenesis. Results: Aβ40 and Aβ25-35 with hyperglycaemia provoked stronger cytotoxic effect comparing to Aβ alone, while hyperinsulinemia dampen this effect. Opposite results were obtained in H2O2 measurement. Insulin stimulated Aβ42 generation when co-incubated with both Aβ forms. Aβ40 and Aβ25-35 caused similar pattern of extracellular S100B protein influx an concomitant cytosolic efflux. Neuronal protrusions and neurogenesis were initiated by co-incubation of Aβ40 with hyperglycaemia while reduced in Aβ25-35 and hyperglycemia or insulinemia. Significance: Our finding suggest that for understanding the biochemical origins of neuropathological amyloid β progression and potential involvement of metabolic disturbances in this process, it’s crucial to gasp preliminary interactions on cellular level. Our data can lead to hypothesis that S100B protein could be a potential modulator as well as indicator of prodromal neuropathological alterations.

Developing best practices for outreach and recruitment: Updates from the Asian Cohort for Alzheimer’s disease (ACAD) study

AbstractBackgroundDespite investments in AD research to combat this public health crisis, racial/ethnic minorities such as Asian Americans and Asian Canadians (ASACs) remain underrepresented in AD research including clinical trials, biomarker, and genome‐wide association studies. The Asian Cohort for Alzheimer’s Disease (ACAD) is the first large AD cohort for ASACs with a focus on recruiting Chinese, Korean and Vietnamese. We present the outreach and recruitment strategies employed by the ACAD Recruitment and Outreach Workgroup (Workgroup) during the ACAD’s pilot phase.MethodCommunity‐Based Participatory Research (CBPR) principles are embedded through all activities as a fundamental strategy to increase research participant engagement of ASACs. CBPR engages the community in all phases of research (i.e., recruitment; resource sharing; study design; data interpretation). The Workgroup was tasked with a) coordinating and monitoring recruitment activities across all 8 recruiting sites in the US and Canada; b) developing and disseminating recruitment and community outreach/education materials; c) convening the community advisory board (CAB) to elicit feedback on participant referrals, study processes, outreach/recruitment materials and to address community partner needs; d) collaborating with academic and community partners on outreach; and e) developing best practices for community outreach.ResultThe Workgroup developed multilingual and culturally adapted ACAD‐wide outreach, recruitment and retention materials including study flyers, presentation template materials, animated videos, e‐cards, social media accounts and ads. ACAD CAB provided valuable input regarding study procedures and materials as well as promoting ACAD to their respective communities and networks. During the ACAD pilot phase, 26 outreach activities were conducted across sites. Given that ACAD was launched during the COVID‐19 pandemic, many (n = 16) activities were conducted online and some at community centers, clinics, senior apartments, and outdoor events, with an estimated reach of 3,500+ community members. Many (62.5%) events were conducted in English (n = 17), and others in Asian languages such as Cantonese (n = 5), Korean (n = 2), Mandarin (n = 9) and Vietnamese (n = 2).ConclusionACAD’s multifaceted approach to outreach and recruitment aims to optimize community engagement and a step towards representation of ASACs in AD studies. The Workgroup will continue to monitor outreach/recruitment metrics and provide support for overall and site‐specific community engagement needs.

Functional hyperconnectivity is associated with higher levels of sPDGFRβ, a marker of blood brain barrier breakdown, in older adults

AbstractBackgroundApolipoprotein E4 (APOE4) has toxic effects on the cerebrovascular system, neuronal function, and functional connectivity of brain networks (e.g., default‐mode, frontal‐attention, and salience networks). The thalamus, a vital structure that acts as a relay station between many networks, has become of interest in AD research with studies showing atrophy among those with early AD and diminished cortical‐thalamic connections among those with vascular impairment. Additionally, CSF soluble platelet‐derived growth factor receptor‐β (sPDGFRβ), a marker of blood‐brain barrier breakdown, has been associated with AD risk, especially in APOE4 carriers. The present study investigated the relationship between CSF sPDGFRβ and functional connectivity in APOE4 carriers and non‐carriers.MethodOne hundred sixty‐six older adults from the Los Angeles area were selected from a larger cohort (96 females, mean age±SD = 67.4±10.7, 68 APOE4 carriers) based on availability of rsfMRI data. Image data was processed using CONN‐toolbox v19c. Grey matter was parcellated using Harvard/Oxford brain atlas, excluding cerebellum. ROI‐to‐ROI analyses were conducted selecting the thalamus as seed region averaging mean connectivity between the left and right structure of other parcellated brain regions. Linear regression models evaluated significant associations between blood oxygen level‐dependent (BOLD) and network connectivity among seed‐target regions and CSF sPDGFRβvalues, while covarying for age and sex. Comparison of averaged functional connectivity values between seed and all target regions among APOE4 carriers and non‐carriers was also examined.ResultHigher functional connectivity between the thalamus and resting state network hub regions were associated with higher CSF sPDGFRβ (Fig 1A, 1C). Cortical regions within the networks included posterior cingulate gyrus, anterior cingulate gyrus, and frontal eye field. Averaged functional connectivity between these areas was significantly higher in APOE4 carriers compared to non‐carriers (Fig 1B).ConclusionThe thalamus is a key subcortical structure for relaying signals across the brain for memory, attention and sleep/wakefulness cycles, and more recently with relevance to AD. These findings suggest a link between early BBB breakdown and elevated functional connectivity in brain regions known to have high synaptic activity and early pathology among non‐demented older adults at risk for AD.

Assessing inflammasome activity in mouse models of Down syndrome and organotypic brain slice cultures

AbstractBackgroundDown syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is a leading genetic cause of Alzheimer’s disease. Neuroinflammation occurs in the DS brain, with altered microglial morphology and transcriptional profiles, and upregulated proinflammatory cytokines, including IL‐1β. IL‐1β is produced by inflammasome activity. We hypothesize that IL‐1β levels are raised in the DS brain via upregulation of inflammasome activity or heightened sensitivity to inflammasome stimuli, which persists when people with DS develop AD.MethodLevels of 10 cytokines, including IL‐1β, TNFα and IL‐6 were measured (MSD) in the 3‐month hippocampus of a panel of segmental duplication mouse models of DS; Dp1Tyb, Dp2Tyb, Dp3Tyb, Dp9Tyb, Dp10Yey and Dp17Yey. These models have a duplication on one chromosome of a number of orthologues for Hsa21 genes. Organotypic brain slice cultures (OBSCs) were prepared from Dp1Tyb mice and stimulated with LPS ± nigericin, to determine if they have an altered response to inflammasome stimuli, as measured by ELISA for cytokines and IHC for IBA1 and ASC.ResultRaised IL‐1β abundance was identified in the hippocampus of the Dp1Tyb mouse, which has an additional copy of 148 mouse orthologues for Hsa21 genes. No difference in IL‐1β or other cytokines measured were identified in the Dp3Tyb, Dp9Tyb, Dp2Tyb, Dp10Yey or Dp17Yey hippocampus, which have 37, 76, 33, 31 and 19 genes in three copies respectively. LPS + nigericin treatment does not affect the secretion of IL‐1β from Dp1Tyb OHSCs compared to WT controls, nor the number of ASC specks formed.ConclusionRaised IL‐1β in the Dp1Tyb brain is a multigenic phenotype, with three‐copies of more than one gene/region of Hsa21 required to drive the phenotype. This is not due to increased sensitivity to inflammasome stimuli in Dp1Tyb OBSCs. Next, we will determine what products are raised in the Dp1Tyb brain that have the potential to increase IL‐1β production, and Dp1Tyb OBSCs will be treated with these products, E.g. Aβ. Here, we are further understanding the mechanisms of neuroinflammation in DS, which is critical in determining how AD‐DS differs from AD, and if people with DS can be included in AD research and clinical trials.

Simultaneous mediation effect estimation of APOE through multiple neuropathological pathways on cognitive outcomes

AbstractBackgroundIndividual associations of APOE genotype with Alzheimer’s disease neuropathologic changes (ADNC) have been studied extensively, but the effects through comorbid neuropathological pathways are rarely evaluated simultaneously. In addition, conventional statistical methods for mediation analysis rely heavily on assumptions on causal directions among different pathologies.MethodUsing the National Alzheimer’s Coordinating Center database, we use state‐of‐the‐art mediation analysis methods for multiple mediators effect decomposition to simultaneously estimate the indirect effects of the APOE ε4 allele through different pathologies, including ADNC, TDP‐43, and Lewy body disease, on cognitive outcomes. Unlike the conventional Baron and Kenny approach, we do not assume a causal structure between different pathologies, making causal interpretations under fewer assumptions. We control for cerebrovascular diseases, cardiovascular diseases, and age at death that are potentially affected by the APOE ε4 allele and could confound the pathologies.ResultOur results show that the APOE ε4 allele has a negative effect on cognitive outcomes (MoCA: ‐4.97 (‐6.92, ‐3.03); CDR Sum of Boxes: 1.34 (0.70, 1.98)). Most of the effect goes through ADNC (MoCA: ‐3.37 (‐4.68, ‐2.05); CDR Sum of Boxes: 1.20 (0.92, 1.49)), and there is evidence that the indirect effect through ADNC is significant for both outcomes. There is a small indirect effect through TDP‐43 pathology of the same direction as the total causal effects. It is significant for the standard CDR sum of boxes (0.26 (0.13, 0.39)) but not for the MoCA score (‐0.37 (‐0.81, 0.07)). There is little evidence of an indirect effect through Lewy body pathology for both outcomes. In addition, the effect that goes through the dependence or interaction between the pathologies is small.ConclusionWe utilize novel causal mediation analysis methods on neuropathology data to quantify the effects of APOE genotype on dementia risk through different ADRD pathologies without requiring knowledge of their causal relationship. Most of the effect of the APOE ε4 allele goes through ADNC, as expected, but there is also evidence of a smaller indirect effect through TDP‐43. This work provides insights into the understanding of the dementia disease process and introduces a new statistical tool for future AD and related dementias research.

Longitudinal characterization of white matter degeneration in early stages of AD

AbstractBackgroundWhite matter (WM) degeneration in older adults is often characterized unimodally by diffusion tensor imaging (DTI), T1w and T2‐FLAIR MRI. However, approaches integrating multimodal MRI information will be necessary for better understanding WM degeneration in early stages of AD.MethodThis study characterizes the longitudinal changes of WM structure among 66 participants with marked baseline white matter hyperintensity volume (WMHv > 2000 mm3). 42 cognitively normal [CN, 72±7.2y, F = 25] and 24 mild cognitive impairment [MCI, 74±5.7y, F = 14]) adults underwent longitudinal MRI (scan interval: 2.8±0.85 years) within the Wake Forest AD Research Center. DTI metrics were estimated using FMRIB’s Diffusion Toolbox, voxel‐wise volumetric changes of WM (Jacobian Determinant [JD]) were estimated from fractional anisotropy (FA) maps using SPM CAT12, and WMHv were quantified using SPM’s Lesion Segmentation Toolbox. We segmented WM into WMH and normal‐appearing WM (NAWM) to characterize different degeneration patterns by integrating multimodal MRI information. We performed a linear regression analysis of %WMHv change with cognitive status, scan interval, and baseline WMH volume as covariates.ResultDecreased FA and increased mean diffusivity (MD) were observed in WMH regions compared with NAWM. Within WMH, interestingly, volume and FA increased, while MD decreased (p <0.001) during the longitudinal follow‐up (Figs. 1 and 2). Baseline WMHv was not significantly associated with cognitive status, but trended toward higher WMHv in MCI compared to CN (p = 0.07). Adjusted for baseline WMHv, cognitive status was associated with WMHv change (p = 0.036, MCI faster than CN, Fig. 3). While FA (p = 0.99) and MD (p = 0.16) did not change in the NAWM, volumetric change rate (JD) indicated volumetric contraction (p<0.001, Figs. 4 and 5). WMH progresses with time in older adults at risk of AD dementia by occupying neighboring NAWM regions, resulting in relative increases in FA and decreases in MD.ConclusionIn NAWM, WM degeneration can be better characterized by volumetric contraction than white matter microstructural integrity. This observation could implicate that secondary or peripheral WM fibers may reveal more vulnerable tracts in early stages of AD. Further investigation incorporating imaging makers of blood perfusion and metabolism could better explain structural mechanisms of WM degeneration.

The Peruvian Alzheimer Disease Initiative (PeADI): An international effort model to increase diversity in AD research (S15.002)

<h3>Objective:</h3> We have developed an international collaborative research initiative to ascertain a Peruvian cohort for AD and other related dementias for genetic studies of Amerindian individuals. <h3>Background:</h3> Peru is one of the five largest countries in Latin America and harboring a high Amerindian ancestry component in this population. The Latin American population, including Peruvians, are underrepresented in research studies of AD. <h3>Design/Methods:</h3> PeADI was developed to recruit and enroll Peruvian adults aged 65 and older to a comprehensive genetic AD study. Individuals will get whole genome sequencing and plasma biomarkers. Participants included cases with AD and ADRD, healthy controls as well as multiplex AD families. Since 2019, we have established a multisource ascertainment approach including recruitment at main hospitals, outreach community activities and more recently due to the COVID19 pandemic remote recruitment and home visits in Lima, the capital city. Our recruitment has expanded to three regions from the Andes highlands (Puno, Huancayo, Cusco) and one region from the southern coast (Tacna). All participants are enrolled using a standard clinical and cognitive protocol administered by neurologists and neuropsychologists. <h3>Results:</h3> As of September 2022, we have enrolled 132 AD and other dementia cases, 292 controls and 6 multiplex AD families. While the majority of participants was recruited in Lima,45% controls and 7% of cases have been recruited in regions outside Lima. We have confirmed a significant association between APOE and AD in Peruvian Population higher than we have observed in non-Hispanics. In addition to ascertainment activities, we are working closely with the respective sites to develop a network and resources for AD research across Peru. To date, we have developed local research capacities within each region, including training opportunities for investigators, coordinators and lab technicians, and basic equipment for all regions. <h3>Conclusions:</h3> PeADI study shows the importance of equitable international north-south cooperation and local network cooperation to increase representation of understudied admixed populations to help us understand Amerindian ancestry in drug target discovery. <b>Disclosure:</b> Dr. Illanes-Manrique has nothing to disclose. Dr. Mena has nothing to disclose. Karina Milla-Neyra has nothing to disclose. Larry D. Adams has nothing to disclose. Dr. Mejia has nothing to disclose. Ms. Rios Pinto has received personal compensation in the range of $500-$4,999 for serving as a PSYCHOLOGIST with DOMINGO OLAVEGOYA HOSPITAL. The institution of Prof. Isasi has received research support from NIH. Dr. MEDINA has nothing to disclose. The institution of Dr. Beecham has received research support from NIH. The institution of an immediate family member of Dr. Beecham has received research support from NIH. Dr. Cornejo-Herrera has nothing to disclose. Dr. Vance has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for neurology genetics. Dr. Ochoa has nothing to disclose. The institution of Dr. Suarez has received research support from Alzheimer’s Association. Michael L. Cuccaro has nothing to disclose. Dr. Sarapura-Castro has nothing to disclose. Miss Cubas-Montecino has received research support from Fundacion San Marcos. Miss Cubas-Montecino has received personal compensation in the range of $500-$4,999 for serving as a Lab Technician with Fundacion San Marcos. The institution of Dr. Cornejo Olivas has received research support from CONCYTEC-PROCIENCIA PERU. Dr. Cornejo Olivas has a non-compensated relationship as a Board member at Rare Disorders Burou (CCI-MINSA) with Ministry of Health in Peru that is relevant to AAN interests or activities. Dr. Pericak-Vance has nothing to disclose.

Construction and evaluation of Alzheimer's disease diagnostic prediction model based on genes involved in mitophagy.

Alzheimer's disease (AD) is a common neurodegenerative disease. The concealment of the disease is the difficulty of its prevention and treatment. Previous studies have shown that mitophagy is crucial to the development of AD. However, there is a lack of research on the identification and clinical significance of mitophagy-related genes in AD. Therefore, the purpose of this study was to identify the mitophagy-related genes with the diagnostic potential for AD and establish a diagnostic model for AD. Firstly, we download the AD gene expression profile from Gene Expression Omnibus (GEO). Limma, PPI, functional enrichment analysis and WGCNA were used to screen the differential expression of mitophagy-related AD gene. Then, machine learning methods (random forest, univariate analysis, support vector machine, LASSO regression and support vector machine classification) were used to identify diagnostic markers. Finally, the diagnostic model was established and evaluated by ROC, multiple regression analysis, nomogram, calibration curve and other methods. Moreover, multiple independent datasets, AD cell models and AD clinical samples were used to verify the expression level of characteristic genes in the diagnostic model. In total, 72 differentially expressed mitophagy-related related genes were identified, which were mainly involved in biological functions such as autophagy, apoptosis and neurological diseases. Four mitophagy-related genes (OPTN, PTGS2, TOMM20, and VDAC1) were identified as biomarkers. A diagnostic prediction model was constructed, and the reliability of the model was verified by receiver operating characteristic (ROC) curve analysis of GSE122063 and GSE63061. Then, we combine four mitophagy-related genes with age to establish a nomogram model. The ROC, C index and calibration curve show that the model has good prediction performance. Finally, multiple independent datasets, AD cell model samples and clinical peripheral blood samples confirmed that the expression levels of four mitophagy-related genes were consistent with the results of bioinformatics analysis. The analysis results and diagnostic model of this study are helpful for the follow-up clinical work and mechanism research of AD.

Multifactorial glial responses and their contributions to Alzheimer's disease continuum

AbstractAlzheimer's disease (AD) is the most common neurocognitive disorder. Various factors are intricately intertwined before clinical symptoms appear, although both amyloid‐β peptide deposition and neurofibrillary tangle formation (i.e. pathological hallmarks of the AD brain) are established. Among such factors, glial responses have been increasingly recognized as important roles in the progression of these pathologies and viewed as one component of the AD continuum. However, the detailed molecular and cellular mechanisms of glial function underlying AD pathogenesis remain to be elucidated. Recent studies showed that peripheral immunity, gut microbiota or environmental factors influence brain pathophysiologies through communication with glial cells in the brain. This disease complexity makes understanding AD etiology difficult and hinders the development of effective therapeutic strategies to tackle this disease. Conversely, aged patients often suffer from multiple – not a single – diseases as multimorbidity, and AD pathogenesis might be related to pathologies caused by other diseases. Hence, investigating AD as a systemic disease has become critical for identifying therapeutic interventions. This review aimed to summarize current knowledge on AD research and share perspectives for understanding glial functions regarding AD pathophysiology.

3D genome-selected microRNAs to improve Alzheimer's disease prediction.

Alzheimer's disease (AD) is a type of neurodegenerative disease that has no effective treatment in its late stage, making the early prediction of AD critical. There have been an increase in the number of studies indicating that miRNAs play an important role in neurodegenerative diseases including Alzheimer's disease via epigenetic modifications including DNA methylation. Therefore, miRNAs may serve as excellent biomarkers in early AD prediction. Considering that the non-coding RNAs' activity may be linked to their corresponding DNA loci in the 3D genome, we collected the existing AD-related miRNAs combined with 3D genomic data in this study. We investigated three machine learning models in this work under leave-one-out cross-validation (LOOCV): support vector classification (SVC), support vector regression (SVR), and knearest neighbors (KNNs). The prediction results of different models demonstrated the effectiveness of incorporating 3D genome information into the AD prediction models. With the assistance of the 3D genome, we were able to train more accurate models by selecting fewer but more discriminatory miRNAs, as witnessed by several ML models. These interesting findings indicate that the 3D genome has great potential to play an important role in future AD research.

Nutritional assessment models for Alzheimer's disease: Advances and perspectives

AbstractAlzheimer's disease (AD) is a neurodegenerative disease of uncertain pathogenesis that develops in the elderly population and is characterized by loss of cognitive function, memory loss, and deterioration of everyday behavior. The development of biological models of AD is constrained by the complexity of the pathogenesis and multiple causes. Creating disease models can aid in understanding the pathophysiology of AD and developing effective therapeutic drugs. In this review, the animal and cellular models that are currently being utilized to research AD are outlined and described in detail according to modeling approaches. The main animal models are natural aging models, transgenic models, and drug‐induced models. The main cellular models are traditional 2D cells, human induced pluripotent stem 2D cells (neurons and glial cells), and 3D cells, as well as organoid models, and the benefits and drawbacks of their various biological models are assessed. They do have their limitations due to an incomplete reflection of AD pathology. Therefore, new models for AD research are needed in the future. The summary of existing models is intended to provide a basis for the subsequent development of new disease models and to provide a reference for the study of disease mechanisms, clinical research, and new drug development in AD.

Catalpol Mitigates Alzheimer's Disease Progression by Promoting the Expression of Neural Stem Cell Exosomes Released miR-138-5p

Alzheimer’s disease (Alzheimer’s disease, AD) is a neurodegenerative disease characterized by senile plaque deposition and neurofibrillary tangles. The pathogenesis of AD is complicated and the drugs used to treat AD are single-targeted drugs, which can only improve or alleviate the symptoms of patients, but cannot delay or prevent the progress of the disease. Because of its ability to act on multiple targets, multiple systems, multiple links, and multiple pathways, Chinese herbal compound prescriptions have shown unique advantages in the research and treatment of AD. Our previous study has demonstrated the protect role of the Chinese medicine Rehmannia in AD. However, the underlying mechanism remains unclear. In the present study, both in vitro and vivo experiments were employed, and we found Catalpol (Ca), the main extract of Rehmannia, could mitigate AD progression both in vitro and in vivo by promoting miR-138-5p level in neural stem cell secreted exosomes

R1P DISPERSION IN WHITE MATTER CORRELATES WITH COGNITIVE IMPAIRMENT IN OLDER ADULTS

Abstract Alzheimer‘s disease is the most frequent form of dementia in older adults and has a total estimated worldwide cost that rises to $2 trillion by 2030. Much previous neuroimaging research in AD has focused on the roles of amyloid and tau proteins using PET, but there have also been several studies that have implicated microvascular changes as an early indicator of damage related to later dementia. Here, we developed and refined a non-invasive 3D-R1ρ dispersion imaging technique using different locking fields to quantify microvasculature changes within brain tissues in persons with mild cognitive impairment (MCI) compared to healthy controls. The fractional difference in R1ρ comparing different locking fields provides a unique way of characterizing changes in the geometry and structure of microvasculature. After providing informed consent, 40 adults aged 62 to 82 years (n=17MCI) underwent cognitive assessments and MRI scan at 3T. We found the fractional change in R1ρ of the whole brain white matter is significantly greater in persons with MCI, and the correlation remained significant (ß=-0.4, p-value=0.01) after introducing age (ß=0.2, p-value=0.2) and sex (ß=-0.1, p-value=0.5) as covariates. The white matter hypertonicity lesion volume measured from conventional MRI was also correlated with the health status (p-value &amp;lt; 0.05); however, the size of the regression coefficient was substantially smaller (53% lower), and it was no longer significant (p-value=0.14) after adjusting for age and sex. This work establishes a new non-invasive method that can potentially characterize changes in microvasculature anatomy with the progression of cognitive impairment regardless of an age effect.

R1p Dispersion in White Matter Correlates with Cognitive Impairment in Older Adults

Abstract Alzheimer‘s disease is the most frequent form of dementia in older adults and has a total estimated worldwide cost that rises to $2 trillion by 2030. Much previous neuroimaging research in AD has focused on the roles of amyloid and tau proteins using PET, but there have also been several studies that have implicated microvascular changes as an early indicator of damage related to later dementia. Here, we developed and refined a non-invasive 3D-R1ρ dispersion imaging technique using different locking fields to quantify microvasculature changes within brain tissues in persons with mild cognitive impairment (MCI) compared to healthy controls. The fractional difference in R1ρ comparing different locking fields provides a unique way of characterizing changes in the geometry and structure of microvasculature. After providing informed consent, 40 adults aged 62 to 82 years (n=17MCI) underwent cognitive assessments and MRI scan at 3T. We found the fractional change in R1ρ of the whole brain white matter is significantly greater in persons with MCI, and the correlation remained significant (ß=-0.4, p-value=0.01) after introducing age (ß=0.2, p-value=0.2) and sex (ß=-0.1, p-value=0.5) as covariates. The white matter hypertonicity lesion volume measured from conventional MRI was also correlated with the health status (p-value &amp;lt; 0.05); however, the size of the regression coefficient was substantially smaller (53% lower), and it was no longer significant (p-value=0.14) after adjusting for age and sex. This work establishes a new non-invasive method that can potentially characterize changes in microvasculature anatomy with the progression of cognitive impairment regardless of an age effect.

DEMENTIA CARE THROUGHOUT THE TRAJECTORY AND ACROSS SETTINGS: RESULTS FROM THE DEVELOP AD RESEARCH STUDY

Abstract About 1 in 8 older adults in the United States has dementia, making it one of the biggest public health issues facing society today. The impact of dementia ranges across health and social systems, yet consideration of these contexts--which are of great relevance to patients and families--has been underexplored in prior research. In this symposium, we will present findings from the Deploying High-Value Longitudinal Population-Based data in Dementia Research (DEVELOP AD Research) study. This multicenter collaboration leverages existing population-based data sources to examine the health and social impacts of dementia throughout the trajectory of decline and across acute, long-term, and community-based settings. Session one will describe how acute care utilization increases in the years before the onset of incident dementia. Session two will examine the association between dementia and increased mortality risk after disruptive medical events, including hip fracture and pneumonia. Session three will report on the prevalence and patterns of medication overuse and misuse in community-dwelling people with dementia. Session 4 will estimate how many community-dwelling individuals, including those with dementia, could benefit from home-based medical care. Session 5 will focus on hospice use patterns and hospice care quality rating in people admitted to hospice for dementia versus other conditions. Together, these presentations provide a wide lens on the health and social experiences and needs of people with dementia at the national level, leading to a better understanding of how society can better address the challenges of caring for this growing population.

TWO DECADES EVALUATING EXERCISE TREATMENTS FOR ALZHEIMER'S DISEASE: THE ANECDOTES OF AN EVIDENCE-BASED PATH

Abstract The last 20 years have produced accumulative evidence supporting the benefits of regular exercise to improve cognition in older adults with cognitive impairments (OAwCIs). Thus, multiple systematic reviews, including meta-analyses, have contributed to the current literature. Although the field advanced significantly our understanding of the role of exercise on AD, still there is limited information on the overall prescription effectiveness. Thus, a novel overview review to evaluate the available meta-analysis studies from the randomized exercise trials for OAwCI will help in synthesizing the best evidence to generate prescription precision. Dr. Heyn will discuss her path, her studies, and the future of AD research and exercise prescription.

Feasibility and reliability of telephone‐based cognitive assessment in middle‐aged and older adults in the Wisconsin Alzheimer’s Disease Research Center

AbstractBackgroundUse of telephone‐based cognitive assessments became more widespread during the COVID‐19 pandemic. The National Alzheimer’s Coordinating Center (NACC) developed the telephone‐based cognitive battery (T‐Cog) to ensure continued data collection and participant retention. The objective of this study was to (1) assess the feasibility and reliability of T‐Cog data collected during the pandemic, (2) evaluate these data in the context of prior in‐person data and (3) inform future use of remote data collection.MethodThe Wisconsin ADRC Clinical Core staff administered T‐Cog batteries to participants with normal cognition, mild cognitive impairment (MCI), or dementia (n = 380, mean age = 68.7±8.9, 66.1% female, 78.4% white, mean education = 16.2±2.48) (Table 1). Examiners rated the validity of the testing session and noted reasons for an invalid session. Reliability was assessed by comparing individual neuropsychological test performances from the T‐Cog to the most recent in‐person evaluation using intraclass correlation coefficients (ICC). Chi‐square was used to test if research diagnoses (normal cognition, MCI, dementia) varied by modality (T‐Cog, in‐person).ResultsMost T‐Cog sessions were rated as valid by examiners (87.8%). The most common reasons for questionable or not valid session included hearing impairments, distractions, and interruptions (Figure 1). Measures of verbal fluency (Animal Naming (ICC = 0.69), F+L Fluency (ICC = 0.73)), list‐learning and memory (RAVLT Trials 1–5 (ICC = 0.75), RAVLT Long Delay Recall (ICC = 0.70), RAVLT Recognition (ICC = 0.71)), and story memory (Craft Story‐Immediate (ICC = 0.65), Craft Story‐Delayed (ICC = 0.73)) showed moderate to excellent reliability and were significant (p&lt;0.01), suggesting good agreement between T‐Cog and in‐person assessments (Table 2). Measures of attention (Digit Span Forward (ICC = 0.66), Digit Span Backward (ICC = 0.15)) varied from moderately reliable to not reliable, respectively. Lastly, research diagnoses did not differ by testing modality.ConclusionThese results suggest T‐Cog assessments are feasible for participants who cannot complete in‐person visits, given adequate hearing and limited distractions and interruptions to ensure test validity. Preliminary comparisons of T‐Cog vs in‐person performances suggest good reliability for verbal fluency, story memory, and list‐learning measures. Although remote assessments can expand access and diversify the population involved in AD research, identifying assessments that are both feasible and reliable across varied administrations will be essential to track longitudinal change in cognitive status.

Functional hyperconnectivity is associated with higher levels of sPDGFRβ, a marker of blood brain barrier breakdown, in older adults

AbstractBackgroundApolipoprotein E4 (APOE4) has toxic effects on the cerebrovascular system, neuronal function, and functional connectivity of brain networks (e.g., default‐mode, frontal‐attention, and salience networks). The thalamus, a vital structure that acts as a relay station between many networks, has become of interest in AD research with studies showing atrophy among those with early AD and diminished cortical‐thalamic connections among those with vascular impairment. Additionally, CSF soluble platelet‐derived growth factor receptor‐β (sPDGFRβ), a marker of blood‐brain barrier breakdown, has been associated with AD risk, especially in APOE4 carriers. The present study investigated the relationship between CSF sPDGFRβ and functional connectivity in APOE4 carriers and non‐carriers.MethodOne hundred sixty‐six older adults from the Los Angeles area were selected from a larger cohort (96 females, mean age+SD=67.4+10.7, 68 APOE4 carriers) based on availability of rsfMRI data. Image data was processed using CONN‐toolbox v19c. Grey matter was parcellated using Harvard/Oxford brain atlas, excluding cerebellum. ROI‐to‐ROI analyses were conducted selecting the thalamus as seed region averaging mean connectivity between the left and right structure of other parcellated brain regions. Linear regression models evaluated significant associations between blood oxygen level‐dependent (BOLD) and network connectivity among seed‐target regions and CSF sPDGFRβvalues, while covarying for age and sex. Comparison of averaged functional connectivity values between seed and all target regions among APOE4 carriers and non‐carriers was also examined.ResultHigher functional connectivity between the thalamus and resting state network hub regions were associated with higher CSF sPDGFRβ (Fig 1A, 1C). Cortical regions within the networks included posterior cingulate gyrus, anterior cingulate gyrus, and frontal eye field. Averaged functional connectivity between these areas was significantly higher in APOE4 carriers compared to non‐carriers (Fig 1B).ConclusionThe thalamus is a key subcortical structure for relaying signals across the brain for memory, attention and sleep/wakefulness cycles, and more recently with relevance to AD. These findings suggest a link between early BBB breakdown and elevated functional connectivity in brain regions known to have high synaptic activity and early pathology among non‐demented older adults at risk for AD.