bluuebunny/crossref_metadata_2025 huggingface dataset:
LDs in AD: Lipid Droplet Dynamics are Modulated by APOE
Authors: Johnson Lance A
Published: December 2023

Background

Aging microglia accumulate lipid droplets (LDs), secrete pro‐inflammatory cytokines, and are defective in phagocytosis. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD), and is associated with increased neuroinflammation and LD accumulation. We hypothesize E4 microglia have increased LD formation under basal conditions and a higher capacity to form LDs under stress, resulting in greater pro‐inflammatory cytokine production. Further, we hypothesize that APOE genotype modulates the LD proteome and lipidome at baseline and with inflammation.

Methods

Primary microglia from ApoE3 and ApoE4 mice were exposed to 250uM oleic acid (OA), 10ug/mL LPS, OA+LPS, dead N2A cells, or dead N2As+LPS, stained with BODIPY, and analyzed for LDs. For quantitative proteomics and lipidomics, we used liver tissue, which provides enough material for analysis. ApoE3 and ApoE4 mice were injected with saline (control) or LPS (5mg/kg) and perfused at 24h. LD‐enriched buoyant fractions were collected after density gradient centrifugation and analyzed for ‘omics.

Results

Primary microglia from ApoE4 mice accumulated significantly more LDs at baseline, with OA, LPS, and N2As compared to E3 with reliable reproducibility. Western blots on LD fractions confirm LD enrichment via surface protein PLIN2. Proteomics revealed that LD fractions from E4 mice are enriched for proteins involved in innate immunity, while E3 LDs are enriched for proteins involved in lipid b‐oxidation. Lipidomics showed an increase in phosphatidylcholine ratio in the LD membrane of E4‐control and LPS‐treated droplets. Finally, many of the LD‐associated proteins identified by our screen are enriched in existing AD proteomics datasets, suggesting a potential role for LDs in AD pathogenesis.

Conclusion

E4 microglia accumulate more LDs compared to E3 microglia under all conditions tested. The proteomic profile of E4 LDs support the hypothesis that E4 expression increases inflammation under basal conditions, and upon stimulation, causes a more robust response. A better understanding of LD dynamics within glial cells and their functional implications during aging and AD may provide targets to improve E4‐related outcomes.
Analysis of Latino family caregiver engagement with CuidaTEXT, a text message intervention for dementia caregiver support
Authors: Perales Jaime
Published: December 2023

Background

The potential of text message caregiver support interventions to improve dementia care outcomes is still to be exploited. This study aims to explore participants’ engagement with a text message intervention for dementia caregiver support, and its association with acceptability and clinical outcomes. We hypothesize that a higher engagement with CuidaTEXT will be associated with increases in caregivers’ satisfaction with the intervention and decreases in depression.

Method

CuidaTEXT is a six‐month, bilingual, and bidirectional intervention tailored to caregiver needs (e.g., education, problem‐solving, resources). We enrolled 24 Latino caregivers in a one‐arm feasibility trial. Participants received approximately one automatic daily text message. Participants could receive automatic on‐demand messages by sending specific keywords (e.g., STRESS for messages about stress coping) and on‐demand responses during business hours by chat‐texting with a live coach. In this secondary analysis, we calculated associations between the total number of text messages (engagement) and outcomes (primarily caregiver satisfaction and depression).

Result

Participants sent 1,847 messages to CuidaTEXT; 6.5% sent no messages (no engagement), 0.0% less than 10 (low), 29.0% between 10 and 49 (medium), 22.6% between 50 and 99, and 19.4% more than 100 (high). Engagement was associated with intervention satisfaction (r = 0.6, p = 0.007) and secondary acceptability outcomes (perceptions that CuidaTEXT provided help for their loved one with dementia: r = 0.6, p = 0.003; and to understand dementia: r = 0.6, p = 0.008) except for perceptions that CuidaTEXT provided help for themselves as caregiver (r = 0.3, p = 0.173). Engagement was not associated with change in caregiver depression (r = ‐0.0, p = 0.922) or secondary clinical outcomes (caregiving competence: r = 0.4, p = 0.104; and behavioral symptom‐related distress: r = 0.4, p = 0.076).

Conclusion

Text message engagement is associated with satisfaction but not depression. Encouraging interaction with CuidaTEXT might lead to higher levels of satisfaction with the intervention. However, future research should determine the directionality of these associations.
Analyzing Phytoextracts based nano‐emulsion system for the neuroprotective activity against Alzheimer’s disease
Authors: Jindal Divya , Singh Manisha
Published: December 2023

Background

According to the WHO projections globally, dementia has afflicted roughly 55 million people worldwide by 2022, with 10 million new cases being identified every year. Thus, from this data information, we can conclude that central nervous system (CNS) disorders are becoming more common and prevalent worldwide. And amongst all CNS‐related diseases, one of the most concerning aspects is the prevalence of Alzheimer’s disease which has become the most common trait in the world’s ageing population. AD is also known as the most challenging kind of dementia to cure. Pathologically in AD, the static loss of cortical neurons causes the deterioration of neuronal connections and circuits, which results in a range of progressive neocortical degeneration linked to the buildup of Aβ plaques. It is challenging to treat AD due to a number of inescapable physiological limits, including circulation blockages, medication permeability and degradation, and other factors. As a result, the drug’s capacity to reach the brain’s afflicted regions is restricted, and the CNS is unable to absorb therapeutic molecules passively.

Method

Therefore, the idea of nanotherapeutics has evolved into a feasible technique for CNS‐based drug delivery. In our research, we computationally assessed the efficacy of the traditionally renowned Indian Ayurvedic medicinal plants Bacopa monnieri and Withania somnifera, used for their capacity to provide neuroprotective effects, especially in the case of CNS disorders. After being altered to achieve the nanometric size range, they were then created for the nano‐emulsions system.

Result

According to the computational findings, synthetic extracts had a higher binding affinity for CNS‐related biomarkers than conventional medicines. Subsequently, using an aqueous titration approach, an oil‐in‐water (o/w) nano‐emulsion system was devised for Withania somnifera and Bacopa monnieri standard extracts in suitable and optimized excipients (Almond oil, Triacetin, Ethanol). The nanometric size range (100‐300 nm) of the optimized nanoformulations showed a substantially higher level of neuroprotective potential than their extracts, according to the characterization results.

Conclusion

In conclusion, the present study demonstrates that the developed formulation has potential therapeutic effects on improving the pathological state of AD, and might be taken further as a promising candidate for clinical research to evaluate its efficacy in human.
Preliminary results of a feasibility study of CONFIDENCE: An intervention to reduce financial strain among Latino family caregivers
Authors: Meyer Kylie , Gonzalez Alexander , Mage Susanna , Silva David , Rodriguez Rocio Aguila , Benton Donna Marie
Published: December 2023

Background

Latino/Hispanic family caregivers to persons living with Alzheimer’s disease and related dementias (ADRD) spend 47% of their annual income on the out‐of‐pocket costs of caregiving compared to 26% of annual income spent among caregivers of any race or ethnicity.1 This presentation describes the preliminary results of the CONFIDENCE psychoeducational intervention, developed to reduce the out‐of‐pocket care costs and financial strain among ADRD Latino/Hispanic caregivers. Intervention components were designed to build caregiver resourcefulness, posited to help caregivers displace some out‐of‐pocket costs by increasing the use of community resources. CONFIDENCE consists of five, 1.5‐hour group Zoom sessions. To ensure the intervention was culturally tailored, CONFIDENCE was developed with a Community Advisory Council and informed by qualitative interviews with Latino family caregivers.

Method

CONFIDENCE has been delivered at a community agency since May 2022. Data reported here are from the first 5 intervention cohorts. Participation in the study was optional. Study participants were asked to complete a self‐administered online baseline survey before the first session, followed by two surveys sent immediately and 2‐months post‐intervention. Eligible caregivers were Latino/Hispanic, cared for someone living with ADRD for at least 6 months, and were aged 50 or older. (See NCT05292248.) All sessions were delivered in English. Spanish delivery will begin in March 2023.

Result

CONFIDENCE was delivered to 27 caregivers, although 55 caregivers registered to attend (49.1%). Of those who attended any of the five sessions, participants attended an average of 2.9 of 5 (SD = 1.4) sessions. Among those who attended at least one session, 56.5% expressed an interest in learning more about the research study when they registered. Of those, six caregivers were eligible to participate and enrolled into the study. Despite lower‐than‐expected participation, those who completed the intervention report high satisfaction. All study completers “Agreed” or “Strong Agreed” that they would recommend CONFIDENCE to others.

Conclusion

Initial findings suggest a 5‐week, Zoom‐delivered financial psychoeducational intervention may only meet the needs of a narrow portion of ADRD Latino family caregivers. To increase participation, researchers intend to explore alternative forms of delivery that require less time commitment.

References:

1.Skufca L, Rainville C. Caregiving Out‐of‐Pocket Costs. 2021. AARP Research. https://www.aarp.org/content/dam/aarp/research/surveys_statistics/ltc/2021/family‐caregivers‐cost‐survey‐2021.doi.10.26419‐2Fres.00473.001.pdf
Cultural adaptation of a mobile caregiver intervention application for Hispanic caregivers of persons with dementia (PWD)
Authors: Rodriguez Miriam J.
Published: December 2023

Background

Family caregivers for persons with dementia (PWD) in the U.S. who identify as part of a racial or ethnic minority group experience higher levels of depression, receive less support from home and community‐based services, and often cannot access services in their primary language. The Alzheimer’s Association has recommended that proven interventions be adapted to address the needs of informal caregivers from different racial and ethnic backgrounds. Although several clinical interventions have been developed with promising results to improve the overall caregiving experience of PWD, the effectiveness of current interventions for Hispanic caregivers of PWD are unclear. Mobile, technology‐based interventions may address specific needs of Hispanic caregivers of PWD such as providing at home access to culturally tailored interventions, but current mobile caregiver interventions do not sufficiently consider equity factors. In the current study, we will culturally adapt an existing, validated, mobile caregiving intervention app for Hispanic caregivers of PWD using an equity focused framework.

Method

Brain CareNotes was guided by the NIH Stage Model for Behavioral Intervention Development and is a secure mobile telehealth application for informal caregivers to manage behavioral and psychological symptoms of dementia (BPSD) with the aid of a remote care coach. To culturally adapt this intervention, we will addresses stage 0 – 1 of the NIH Stage Model and apply a previously developed equity framework, PROGRESS‐Plus, which identifies specific cultural factors (i.e. Place of Residence, Race/ethnicity, etc) that should be considered in the development of equity focused interventions. We will qualitatively identify specific PROGRESS‐Plus needs that are insufficiently met among Hispanic caregivers of PWD through semi‐structured interviews. We will incorporate this information in the modification of Brain CareNotes, which will be made using a participatory co‐design methodology. Two groups of n = 5 Hispanic English and Spanish speaking caregivers of PWD will participate in five co‐design sessions to adapt the intervention to meet identified PROGRESS‐plus related needs. The adapted intervention will then be pilot tested.

Result

Description of this ongoing study will be presented.

Conclusion

This will result in an extensible framework for modifying and culturally tailoring other previously developed caregiver interventions for ethnic minority groups.
The health economics of an Alzheimer’s prevention therapy
Authors: Mattke Soeren , Jun Hankyung , Hanson Mark , Chu Samantha , Kordower Jeffrey H. , Reiman Eric M.
Published: December 2023

Background

Amyloid reducing antibodies have been shown or suggested to slow decline in early Alzheimer’s disease (AD), and prevention trials in preclinical AD are ongoing. We estimate cost‐effectiveness of AD prevention from a payer perspective, which considers cost offsets and QALYs gains, and a societal perspective, which adds reduction in caregiver burden.

Method

We estimate cost‐effectiveness in the 2023 cohort of 55–79‐year‐olds with a Markov model under the following assumptions: Everyone would undergo an AD blood test (cost $125), which would generate positive or negative results in 80% of cases with sensitivity and specificity of 80% and inconclusive results in 20%. Individuals (80%) testing positive would go directly to treatment, the other 20% to confirmatory testing with PET (50%, cost of $4,000) or CSF (50%, cost of $600), receiving treatment accordingly. Individuals testing negative at any stage would return for another blood test in five years and those with inconclusive results in one. We assume average annual therapy cost of $5,850 per person (the list price of the PCSK9 inhibitors) for duration of 12 years, treatment effect of 50%, and four (baseline and 6, 12 and 18 month) MRIs ($400) for ARIA.

Result

The program would be cost‐effective from a payer perspective with cost of $45,157 and value of $53,721 per person. From a societal perspective, it would generate $24,704 in net value per person (Figure 1). If the treatment delayed progression by 25 percent, the program would no longer be cost‐effective from a payer or societal perspective. The treatment would have to eliminate the progression from preclinical AD to MCI to become cost‐neutral (Figure 2). Higher specificity of the blood test would decrease cost per person with no change in value generation and higher sensitivity would increase cost and decrease value

Conclusion

A prevention treatment that reduces the progression from preclinical AD to MCI by 50% could be economically viable from a payer perspective. The results are preliminary and need to be adjusted as more data become available, but the findings should stimulate a discussion among stakeholders about the contours and economic viability of such a prevention program.
A longitudinal multimodal biomarker study of memory clinic MCI patients with MBI – are there links to Alzheimer disease?
Authors: Ismail Zahinoor , Leon Rebeca , Yu Chen Hung‐ , Robert Philippe , Smith Eric E.
Published: December 2023

Background

Mild cognitive impairment (MCI) and mild behavioral impairment (MBI) are at‐risk states for incident dementia. MBI represents behavioral risk, and MCI represents cognitive risk. In memory clinic MCI patients, we interrogated the relationship between MBI status (+/‐), cerebral atrophy, cerebrospinal fluid (CSF) biomarkers, and incident all‐cause dementia and incident Alzheimer disease (AD) dementia.

Method

MBI was operationalized as persistent neuropsychiatric symptoms (NPS) in MEMENTO study participants. MRI regions were selected a priori for Braak stages I‐V. CSF markers included amyloid‐β (Aβ), hyperphosphorylated‐tau (p‐tau), and tau. Linear regression models were fitted with regional thickness/volume or CSF markers as dependent variables, and MBI status as independent variable, adjusted for age, sex, and education. Logistic regression was conducted to investigate if MBI status was associated with amyloid‐β positivity (defined as <813 pg/mL), with MBI status as predictor, adjusting for age, sex, education and MMSE. Kaplan‐Meier curves were generated for dementia‐free survival out to 6 years. Cox proportional hazard regressions, adjusted for age, sex, education, MMSE score, and MCI subtype were utilized to investigate the rates of incident all‐cause dementia, as well as incident AD dementia, in MBI+ vs MBI‐ patients with MCI.

Result

Of the 820 participants (mean age(±SD) 72.54(8.21), 57.80% female), 29.5% had MBI. Compared to MBI‐, MBI+ status was associated with lower entorhinal thickness (b = –0.066, p = 0.04) and smaller hippocampal volume (b = –0.069, p< 0.01). In the CSF subsample (n = 154, mean age = 69.6, 48.1% female), MBI predicted amyloid‐β positivity (odds ratio = 2.19, p = 0.05), and was associated with 7.4% lower Aβ42 level (p = 0.01), 17.8% higher CSF p‐tau/Aβ42 (p<0.01) and 18.9% higher t‐tau/Aβ42 ratio (p = 0.02). Longitudinally, MBI+ had lower dementia‐free survival (log rank test; p<0.0001), with adjusted hazard ratios (HRs) of 2.76 (95%CI 1.99‐3.8; p<0.001) for all‐cause dementia and 2.73 (95%CI 1.83‐4.07; p<0.001) for AD dementia.

Conclusion

MBI served as a clinical marker to identify a subgroup of MCI patients with Alzheimer disease‐related morphological changes in the entorhinal cortex and hippocampus, and CSF biomarkers consistent with AD. MCI with MBI had a greater incidence rate of AD dementia than MCI without MBI. MBI case status may be used to improve detection of prodromal AD in MCI.
Treatment with AV‐001, an Angiopoietin‐1 mimetic peptide, improves dementia outcomes in rats
Authors: Venkat Poornima , Gao Huanjia , Findeis Elizabeth L , Zacharek Alex , Powell Brianna , Landschoot‐Ward Julie , Lu Mei , Chopp Michael
Published: December 2023

Background

Vascular dementia (VaD) is a complex neurodegenerative disease affecting cognition and memory. We investigated the neurocognitive outcomes of multiple‐microinfarct (MMI) dementia in aged female rats. We previously found that treatment with AV‐001, a Tie2 receptor agonist, significantly improves memory and preference for social novelty in middle‐aged male rats subjected to MMI. In this study, we tested the therapeutic effects of AV‐001 in aged female rats subjected to MMI.

Method

Female, Wistar, rats were aged to 18m and randomly assigned to Sham, MMI, and MMI+1µg/Kg AV‐001 treatment groups (n = 8‐9/group). MMI was induced by injecting either 1000 (low dose, LD‐MMI) or 6000 (high dose, HD‐MMI), 70‐100µm sized cholesterol crystals into the internal carotid artery. AV‐001 treatment (1µg/Kg, i.p.) was initiated at 1d after MMI and administered once daily. A battery of neuro‐cognitive tests was performed at 21‐28d MMI.

Result

LD‐MMI induces significant (p<0.05) neurological deficits evaluated using the modified neurological severity score (mNSS) test, starting at 1d after LD‐MMI and persisting at least up to 28d after LD‐MMI. Treatment of LD‐MMI with AV‐001 significantly improves neurological function at 21d and 28d after LD‐MMI compared to LD‐MMI control rats. Aged female rats subjected to LD‐MMI exhibit long term memory impairment in an olfactory learning based novel odor recognition test and a significantly lower preference for social novelty in the three‐chamber social test, although there were no changes in overall preference for sociability compared to Sham rats. Treatment of LD‐MMI with AV‐001 significantly improves long‐term memory and preference for social novelty compared to LD‐MMI control rats. HD‐MMI in aged female rats induces significant anxiety‐ and depression‐like behavior with increased freezing time in the open field test and decreased time spent in the open arms of the elevated plus maze compared to Sham rats. Treatment of HD‐MMI with AV‐001 significantly reduces anxiety like behavior indicated by increased time spent in the open arms of the elevated plus maze compared to HD‐MMI control rats.

Conclusion

AV‐001 is a novel therapeutic agent that may improve neurological deficits, memory impairment, and anxiety like behavior in aged female rats subjected to a MMI model of vascular dementia.
EEG network functional connectivity during sleep and in presence of network hyperexcitability in Alzheimer’s disease
Authors: Moguilner Sebastian G , Bender Alex C , Pellerin Kyle R , Sarkis Rani A , Lam Alice D
Published: December 2023

Background

Functional connectivity (FC) studies in Alzheimer’s disease (AD) have focused primarily on the awake resting state. Yet, sleep disturbances in AD are common and occur early in the disease. Network hyperexcitability in AD also arises during sleep, resulting in epileptiform activity and seizures, and impacting memory consolidation. Hence, understanding the FC changes that occur during sleep in AD could provide important biological insights. To date, no studies have examined FC changes occurring during sleep in AD and their relationship with network hyperexcitability.

Method

Using ambulatory scalp EEG recordings, we assessed sleep FC in cognitively normal healthy controls (HC, n = 35), individuals with early clinical stages of AD with no history or risk factors for epilepsy (ADNoEp, n = 44), and individuals with early clinical stages of AD and epilepsy related to AD (ADEp, n = 14). We measured FC using corrected amplitude envelope correlation and assessed FC on different scales, including channel‐pair associations, regional associations, seed‐based connectivity, and graph theory metrics. Machine learning classifiers were developed to determine whether sleep FC measures provide accurate discrimination between HC, ADNoEp, and ADEp.

Result

There were no significant differences in age, sex, or education between HC, ADNoEp, and ADEp. Compared to HC, the ADNoEp group had 1) reduced FC during REM sleep in the alpha band in posterior regions; and 2) increased FC during NREM2 sleep in the gamma‐band in frontal regions. Compared to ADNoEp, the ADEp group had reduced FC in NREM2 sleep in the delta‐band in temporal and posterior regions. Graph theory metrics corroborated these sleep stage‐ and frequency‐specific findings between groups. Machine learning classifiers using graph theory metrics as input features distinguished ADNoEp from HC, and ADNoEp from ADEp, with high performance (AUC>0.85).

Conclusion

AD is associated with sleep stage‐, frequency band‐, and region‐specific changes in FC. Network hyperexcitability in ADEp is also associated with changes in sleep FC, which are distinct from those seen in ADNoEp. Our findings expand understanding of brain network changes in AD to the sleep state and demonstrate sleep‐stage specific alterations in FC that may have important implications for understanding AD neurophysiology and for disease monitoring and therapeutic development.
Circulatory GSK‐3beta a new target against Alzheimer’s disease
Authors: Dey Sharmistha , Kumari Shiwani , Singh Abhinay Kumar , Yadav Yudhishthir
Published: December 2023

Background

Alzheimer’s disease (AD) is the progressive brain disorder which degenerate brain cells connection and causes memory loss. Though, AD is irreversible, it is not impossible to arrest or slow down the progression of the disease. However, this would only be possible if the disease is diagnosed at an early stage and early diagnosis requires clear understanding of pathogenesis at molecular level. Overactivity of GSK‐3β and p53 accounts for tau hyperphosphorylation, and amyloid‐β plaque

Method

We explored GSK‐3β and p53 as blood‐based biomarkers for early detection of AD. Methods: The levels of GSK‐3β, p53, and their phosphorylated states were measured using surface plasmon resonance and verified using Western blot in serum from AD, mild cognitive impairment (MCI), and geriatric‐control (GC) subjects. The neurotoxic SH‐SY5Y cell line was treated with antioxidant Emblica Officinalis (EO) for rescue effect.

Result

GSK‐3β, p53, and their phosphorylated state were significantly over expressed (p>0.001) in AD, MCI compared to GC and can differentiate AD, MCI from GC. The expression level of GSK‐3β and p53 proteins were found to be downregulated in a dose‐dependent manner after the treatment with EO in amyloid‐β induced neurotoxic cells.

Conclusion

These proteins can serve as potential blood markers for the diagnosis of AD and EO can suppress their level. This work has translational value and clinical utility in the future.
Validity of cognitive function assessed by a subjective cognitive decline questionnaire as compared with objective cognitive tests in community‐dwelling older adults in China
Authors: Gao Mengyan , Huang Yuhui , Chen Xiao , Shen Jie , Pang Ting , Xu Xin , Zheng Yan , Wang Xiaofeng , Yuan Changzheng
Published: December 2023

Background

Subjective cognitive decline (SCD) has been recognized as an early symptom of age‐related cognitive decline, but research on the validity of SCD questionnaire in the elderly population is limited. Thus, we aimed to evaluate the validity of a 7‐item SCD questionnaire in Chinese older adults.

Method

The study included 1585 participants (53.6% women; mean [SD] age: 78.7 [4.4] years) who completed the SCD questionnaire, Hasegawa Dementia Scale (HDS), and Mini‐Mental State Examination (MMSE) from the Rugao Longevity and Ageing Study (RuLAS) in 2019. MCI was defined according to established education‐specific cut‐off values of HDS and MMSE scores. We used sensitivity, specificity, Youden’s Index, and the receiver operating characteristic (ROC) curves to evaluate the discriminant ability of the SCD questionnaire. Spearman correlation coefficients were also used to measure the strength of correlation between SCD scores and objective cognitive function scores.

Result

The SCD score (range: 0‐7) with the cut‐off value of 4 displayed moderate‐to‐good sensitivity (Sen = 0.52) and specificity (Spec = 0.69), with Youden’s index of 0.21 and the area under the curve (AUC) of 0.62, in distinguishing cognitive impairment defined by objective cognitive tests. In addition, SCD scores have low‐to‐moderate correlations with overall scores of two cognitive tests (rHDS = ‐0.23; rMMSE = ‐0.28). Correlations between domain‐specific SCD and corresponding objective cognitive function scores ranged from ‐0.05 to ‐0.31.

Conclusion

Our study supported a reasonable discriminant ability of a 7‐item SCD questionnaire among Chinese older adults.
Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques
Authors: Lee Hee Yang , Baek Seungyeop , Cha Minhae , Yang Seung‐Hoon , Kim YoungSoo
Published: December 2023

Background

Amyloid‐β (Aβ) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer’s disease. However, anti‐Aβ drug development has been impeded by the lack of a target needed for structure‐based drug design and low permeability of the blood–brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid‐based anti‐Aβ peptidomimetics that exploit the self‐assembling nature of Aβ and penetrate the BBB.

Method

Herein, we designed a dimeric peptide drug candidate based on the N‐terminal fragment of Aβ, DAB. In vitro assays were performed to verify the dissociating ability of DAB against Aβ(1‐42) aggregation. The therapeutic efficacy of DAB against Aβ was evaluated in the 5XFAD, a transgenic AD mouse model with aggressive amyloid accumulation. Following that, peptide mapping assays and molecular docking studies were utilized to elucidate DAB‐Aβ interaction, and we assessed the dissociative activity of DAB with sequence modifications to further understand active regions of DAB.

Result

Through in vitro assay we found that DAB solubilizes both neurotoxic Aβ(1‐42) oligomers and fibrils to monomeric states. Administration of DAB reduced amyloid burden in 5XFAD mice, and down‐regulated neuroinflammation and prevented memory impairment in the Y‐maze test. In peptide mapping assays, DAB was shown to bind and dissociate Aβ aggregates in a manner distinct to the Aβ(1‐17) fragment.

Conclusion

Overall, we designed a dimeric Aβ(1‐17)‐based peptide drug and demonstrated that DAB can solubilize aggregates of Aβ and has therapeutic potential as a structural basis for anti‐amyloid peptide drugs.
Alzheimer’s Disease‐impacted Expression of tRNA‐derived Fragments in Body Fluid: Implication for New Disease Biomarkers
Authors: Wu Wenzhe , Shen Audrey , Lee Inhan , Pappolla Miguel A , Fang Xiang , Bao Xiaoyong
Published: December 2023

Background

Alzheimer’s disease (AD), the most common type of dementia, affects over six million Americans aged 65 years and older. Although numerous research efforts were made on AD, the knowledge of the mechanisms and therapeutic strategies is still very limited. At present, identifying the prodromal stages of AD remains a significant challenge. tRNA‐derived RNA fragments (tRFs), a family of recently discovered small non‐coding RNAs (sncRNAs), express high in both human and primate hippocampus. Our recent discovery also revealed that some hippocampus tRF expression is much higher in AD patients compared with age‐matched health individuals.

Method

Herein, we further characterized the expression of tRFs in CSF and serum from healthy, mild cognitive impairment (MCI), and AD patients, using a combination of T4 polynucleotide kinase (T4 PNK)‐RNA‐seq and qRT‐PCR specific to tRF validation.

Result

Our results indicated tRF5‐ProAGG altered by AD in both CSF and serum samples, and serum AD‐impacted tRF5‐ProAGG showed a correlation to the disease severity. Notably, serum tRF5‐ProAGG showed a change tendency when MCI progresses to AD, suggesting that it is a promising biomarker for AD. We also predicted putative targets of tRF5‐ProAGG using our in‐house computational program and confirmed that some targets, such as SV2B, CDH8, and NEFL, were decreased in AD’s hippocampus. Interestingly, SV2B and tRF5‐ProAGG showed a negative correlation.

Conclusion

tRF5‐ProAGG shows the potential as an AD biomarker and plays a vital role in disease progression.
Persistent Systemic Inflammation Mediates the non‐Hispanic Black vs non‐Hispanic White Disparity in Cognitive Function: A Longitudinal Analysis
Authors: Higgins Cesar , Ware Erin B , Hicken Margaret , Zawistowski Matthew , Kobayashi Lindsay C , Adkins‐Jackson Paris AJ , Muhkerjee Bhramar , Bakulski Kelly M
Published: December 2023

Background

Racialization is the process of grouping individuals into “races” based on phenotypic characteristics, assigning value to these groups, and disproportionately treating them. Racial health disparities may capture the differential impact of racialization, and subsequently, discrimination on these groups. In a longitudinal study of C‐reactive protein (CRP), a marker of systemic inflammation, we explored trajectories of inflammation between non‐Hispanic Black vs non‐Hispanic White participants and tested if persistent inflammation mediated the racial disparity in cognitive function.

Methods

In the US Health and Retirement Study (n = 4,719 adults aged >50), we used three repeated CRP and global cognitive measures at baseline (2006 or 2008), at year 4 (2010 or 2012), and year 8 (2014 or 2016). In multivariable generalized estimating equation models, we compared changes in cognitive function between non‐Hispanic Black vs non‐Hispanic White participants as a function of sustained elevated levels of CRP (all time points >3 vs. ≤3mg/L). We decomposed the racial disparity in cognitive function onto 1) the mediated effect due to elevated CRP, and 2) the portion attributable to the interaction between race and CRP.

Results

The average age at baseline was 68.8 years. Non‐Hispanic Black participants (n = 599) had 24% higher CRP at year 4 and 18% higher at year 8, relative to non‐Hispanic White participants (n = 4,120). Non‐Hispanic Black participants with elevated CRP had 2.9 (95% CI: ‐3.2, ‐2.7) lower points on the global cognitive assessment than non‐Hispanic White participants. In a randomized analogue model, we found that 4% (95% CI: 1%, 6%) of the racial disparity in cognitive function was mediated by sustained elevated CRP, and 14% (95%CI: 5%, 23%) attributable to the interaction between race and sustained elevated CRP.

Conclusions

Systemic inflammation mediates racialized disparities in cognitive function. The effect of persistent elevated levels of systemic inflammation on cognition differs when individuals are racialized as non‐Hispanic Black had they been racialized and treated as non‐Hispanic White.
Leveraging MODEL‐AD mouse strains to understand the role of toxicant exposures on LOAD risk
Authors: Howell Gareth R , Kotredes Kevin P , Minaeva Olga , Moncaster Juliet A , Haber Annat , Pandey Ravi S , Rizzo Stacey J Sukoff , Territo Paul R , Lamb Bruce T , Sasner Michael , Oblak Adrian L , Carter Gregory W , Goldstein Lee E ,   MODEL‐AD consortium
Published: December 2023

Background

Late‐onset Alzheimer’s disease (LOAD) is caused by interactions between genes and environment. However, current mouse models do not fully recapitulate LOAD phenotypes, limiting translatability to clinical needs. To address this, MODEL‐AD (Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease) Consortium was established to create and phenotype new mouse models. The IU/JAX/PITT MODEL‐AD Center focuses on developing models with combinations of genetic risk factors, as well as humanizing APP (hAb) and MAPT. One use of these models is to determine the contribution of environmental factors to LOAD risk. Studies show associations between LOAD risk and exposure to ubiquitous environmental neurotoxicants, including arsenic (As), lead (Pb), and cadmium (Cd). All three are ranked in the “Top 10 Toxicants” of public health concern (As #1, Pb #2, Cd #7; ATSDR Toxic Substance Priority List). However, mechanisms driving increased risk are unknown.

Method

Novel mouse models were created by genetic engineering or editing in C57BL/6J. Four to 24 months old mice and controls were phenotyped using a human‐relevant battery that includes cognitive performance, imaging, biometrics, transcriptomics, proteomics, metabolomics, neuropathology, and fluid biomarkers. Toxicants (As, Pb, Cd) were delivered using human‐relevant doses in drinking water. Exogenous toxicants (Pb, Cd, As) and endogenous biometals (Zn, Cu, Fe) in brain and blood samples were analyzed by elemental mass spectrometry mapping.

Result

More than 40 mouse models have been created carrying combinations of genetic risk factors in genes including APOE, Trem2, Abca7 and Mthfr. One strain, LOAD2 (triple homozygous for APOE4, Trem2*R47H, and hAb) shows molecular and transcriptomic changes associated with human LOAD. Short‐term exposure to As, Cd, or Pb also modified expression of LOAD‐relevant genes in LOAD2 mice and controls, including App and Vgf, in a toxicant‐specific manner. Elevated toxicant levels were detected in both brain and blood samples from exposed mice.

Conclusion

These data indicate that exposure to common environmental toxicants may increase LOAD risk by modifying expression of specific genes and molecular pathways previously implicated in human LOAD. Studies are underway using additional MODEL‐AD models to determine the long‐term effects of neurotoxicant exposures.
Aging × Genetics × Environment: Characterization of Precision Disease Models for Preclinical Testing for Late‐onset Alzheimer’s disease
Authors: Rizzo Stacey J Sukoff , Haynes Katy A , Santos Diogo Francisco S. , Doolen Suzanne , Williams Sean‐Paul , Little Gabriela , Reddy Aman , Heaton Nicholas , Hart Jason T , Sasner Michael , Kotredes Kevin P , Garceau Dylan , Ingraham Cynthia , Pandey Ravi S , Preuss Christoph , Uyar Asli , Seyfried Nicholas T , Territo Paul R , Howell Gareth R , Carter Gregory W , Oblak Adrian L , Lamb Bruce T ,   IU/JAX/PITT MODEL‐AD Center
Published: December 2023

Background

The ability to effectively translate therapeutic efficacy from the bench to clinical success for Alzheimer’s disease (AD) has been hampered in part due to limited recapitulation of the complexity of the disease in animal models. While analogous AD risk mutations have been engineered into animal models and have dominated the research field, these have primarily been familial, early onset risk alleles which do not capture the risk for AD for the majority of patients that present with sporadic late onset AD (LOAD).

Method

The IU/JAX/PITT MODEL‐AD consortium is focused on developing mouse models with genetic risk variants associated with LOAD, in combination with environmental risk factors and aging to enable improved translation. The present studies aimed to characterize mice expressing humanized Aβ in combination with multiple genetic risk factors (APOE4 and the R47H risk variant in the Trem2 gene; LOAD2) and aged in the presence of a high‐fat, high‐sugar diet (HFD).

Result

LOAD2 mice exposed to HFD from adolescence (LOAD2+HFD) demonstrated aging changes relative to LOAD2 mice in the absence of HFD, including presentation of insoluble Aβ42 in brain and plasma, and increased inflammatory cytokines. 12‐month aged LOAD2+HFD mice also demonstrated increased NfL in CSF, as well as vascular and perfusion changes as measured by PET/MRI. By 18 months, LOAD2+HFD mice demonstrated reductions in hippocampal neurons as well as cognitive impairment relative to LOAD2 mice in the absence of HFD on a translational touchscreen task. Intriguingly, gene expression profiles and proteomic signatures of aged LOAD2+HFD mice aligned with ‘omics signatures of AD patients in the absence of core neuritic plaques, which were not detected up to 24 months of age.

Conclusion

Mice with genetic risk for LOAD coupled with environmental risk factors demonstrate aging‐dependent changes in line with a spectrum and trajectory of features of clinical LOAD. From a precision medicine approach, our MODEL‐AD Preclinical Testing Core and our TREAT‐AD colleagues are prioritizing LOAD2+HFD mice as an important model system for evaluating the therapeutic potential of non‐amyloid targeting therapeutics as well as for prophylactic interventions initiated prior to significant amyloid accumulation.
Bioinformatics pipeline to guide post‐GWAS studies in Alzheimer’s: a new catalogue of disease candidate short structural variants
Authors: Lutz Michael W , Chiba‐Falek Ornit
Published: December 2023

Background

Short structural variants (SSVs) including indels are common in the human genome and impact disease risk. The role of SSVs in late onset Alzheimer’s disease (LOAD) has been understudied. Previously we developed a bioinformatics pipeline that characterizes and prioritizes candidate regulatory SNPs in enhancers located in LOAD‐GWAS regions. Here we developed a bioinformatics pipeline of SSVs within LOAD‐GWAS regions to prioritize regulatory SSVs based on the strength of their predicted effect on transcription factor (TFs) binding sites. The impact of the genes and TFs prioritized by the pipeline are assessed in two LOAD single cell rna‐seq datasets.

Methods

The pipeline utilized publicly available functional genomics data sources. Primarily, candidate cis‐regulatory elements (cCREs) from ENCODE and publicly available single‐cell RNA‐seq data from LOAD patient samples from human prefrontal cortex brain samples obtained from UCI MIND’s Alzheimer’s Disease Research Center (ADRC) and ROSMAP. For TF binding analysis we employed motifs from MotifDb. In addition, we used various bioinformatics software including motifbreakR.

Results

We catalogued 1230 proximal CTCF‐bound candidate cis‐regulatory elements in LOAD‐GWAS regions, 912 showed epigenetic evidence in relevant brain tissue. We catalogued 426 indels in these cCREs. These indels disrupted 391 TFs, 362 of these had snRNA‐seq data from LOAD samples. Of note, TF motifs within the APOE‐TOMM40, SPI1 and MS4A2 regions were significantly disrupted by the candidate regulatory indels. Amongst these TFs are RUNX3, SPI1 and SMAD3. Interestingly, these significant findings with the APOE‐TOMM40, SPI1 and MS4A2 regions are consistent with our prior results for SNPs.

Conclusions

This study provides an analytical framework to catalogue noncoding indel variation in cis‐regulatory elements located in LOAD‐GWAS loci and characterize their likelihood to perturb TF binding. The approach integrates multiple data types to prioritize genes and variants for validation experiments using disease models and gene editing technologies.
Contribution of Life Course Cardiovascular Risk Factors to Racial Disparities in Dementia Incidence
Authors: Ferguson Erin L , Vittinghoff Eric , Hazzouri Adina Zeki Al , Allen Norrina , Fitzpatrick Annette L. , Yaffe Kristine
Published: December 2023

Background

Racial disparities in dementia outcomes exist in the United States. Targeting modifiable risk factors, including cardiovascular risk factors (CVRFs), is a conceivable way to reduce health disparities. Life course CVRFs are often higher in non‐White adults and are associated with risk of dementia, but it is unknown whether they contribute to racial disparities in dementia and cognition.

Method

Using a pooled cohort of 4,159 White and 939 Black participants aged 65‐95 years, we conducted a mediation analysis to estimate the proportional effect of race on dementia that is explained by four CVRFs imputed over the life course (20‐49, 50‐69, and 70‐89 years of age): body mass index, fasting glucose, systolic blood pressure, and low‐density lipoprotein cholesterol.

Result

Compared to White participants, Black participants had greater risk of dementia (adjusted OR = 1.37; 95% CI: 1.17‐1.60). BMI and fasting glucose over the life course were significant mediators of the effect of race on dementia risk, mediating 39.1% (95% CI: 10.5‐67.8%) and 8.2% (95% CI: 0.1‐16.2%) of the effect, adjusted for sex and age. All four CVRFs together were also significant mediators of the effect of race on scores on global cognition and processing speed, accounting for approximately 11% of the effect.

Conclusion

We found that CVRFs across the life course partially explain disparities in dementia risk and cognition in late‐life. Improved prevention and treatment of CVRFs across the life course may be important to reduce health disparities for dementia.
Neurocognitive analysis of topographical memory disorder in Alzheimer’s disease from fictional autobiography
Authors: Taiebine Mohamed
Published: December 2023

Background

Topographical disorientation is very common in Alzheimer’s disease as dementia worsens; however, it is often one of the earliest manifestations. This study examined whether fictional autobiography might be a source for analyzing linguistic features in terms of toponomy and neurocognitive aspects of topographical disorientation in Lalla Fatma, a patient with Alzheimer’s disease. Additionally, we investigated how the toponymy of old, current, and new names overlapped in the novel About my Mother (2016), which was written by the Moroccan author Tahar Ben Jelloun.

Method

The neurocognitive approach followed the taxonomy described by Aguirre and D’Esposito (1999) to determine the clinical subtype that best described topographical disorientation or spatial agnosia from Lalla Fatma’s discourse. Text mining and toponymic approaches were used to develop patterns of spatiotemporal themes across novel corpora coupled with computational analysis (T‐Lab plus 21).

Result

In Ben Jelloun’s narrative, the overlapping of Tangier and Fez creates a temporal framework to remap memories that have been trapped between the walls, ramparts, and fortresses of imperial Moroccan cities. Lalla Fatma’s house in Tangier seems to have been neglected, similar to her dilapidated and lost memories. The house involves seeking self and identity in a physical and material reality that is subject to spatiotemporal disorientation. It was also a trigger for expressing the present moment of melancholy and nostalgia aggravated by Lalla Fatma’s declining health and mental status. According to the taxonomy by Aguirre and D’Esposito (1999), two types of topographical disorientation have been found in the novel (landmark agnosia and anterograde disorientation)

Conclusion

This study provides evidence suggesting that fictional autobiography should be investigated cross‐culturally in terms of linguistic and neurocognitive aspects in the context of Alzheimer’s disease.
Quality of life in patients with subjective cognitive impairment compared with those diagnosed with mild cognitive impairment or dementia referred to a rural and remote memory clinic
Authors: Sun Gloria , Kirk Andrew , Karunanayake Chandima P , O'Connell Megan E , Morgan Debra G
Published: December 2023

Background

Perceived cognitive decline is a significant source of anxiety for many patients, especially as awareness of dementia grows. We sought to compare whether quality of life (QOL) in patients with subjective cognitive impairment (SCI) who performed normally on a neuropsychological battery significantly differed from those diagnosed with mild cognitive impairment (MCI), Alzheimer’s disease (AD), or non‐Alzheimer’s dementia (non‐AD) at initial assessment in a rural and remote memory clinic.

Method

610 patients referred to our Rural and Remote Memory Clinic (RRMC) between 2004‐2019 were included in this study. As part of their RRMC assessment, each patient and their caregiver independently rated the patient’s QOL using the Quality of Life of the Patient (QOLPT) scale. We compared self‐reported and caregiver‐reported patient QOL scores in those with SCI (n = 166) to those diagnosed with MCI (n = 98), AD (n = 228), and non‐AD (n = 118).

Result

Patients with SCI self‐reported significantly lower QOL compared to patients with AD (mean 34.55 vs 35.96, p<0.05). Interestingly, the reverse was seen in caregivers: SCI caregivers rated patient QOL higher than AD caregivers (mean 34.61 vs 31.72, p<0.001). Patients with SCI also reported lower QOL than patients with MCI (mean 35.55 vs 36.97, p<0.05). SCI caregivers reported higher patient QOL than their non‐AD counterparts (mean 34.61 vs 31.17, p<0.001). Caregiver‐rated patient QOL was higher in those with MCI compared to AD (mean 34.52 vs 31.72, p<0.001). Patients with MCI self‐reported higher QOL scores compared to patients with non‐AD (mean 36.97 vs 34.81, p<0.05). Similarly, MCI caregivers reported higher patient QOL than non‐AD caregivers (mean 34.52 vs 31.72, p<0.001). No other comparisons were statistically significant.

Conclusion

Although they lacked clinically significant cognitive deficits, patients with SCI self‐reported significantly lower QOL than patients with MCI and AD, although patients with MCI self‐reported higher QOL than patients with non‐AD. Conversely, caregiver‐reported patient QOL was higher for patients with SCI than patients with AD and non‐AD. MCI caregivers also reported higher patient QOL compared to AD and non‐AD caregivers. This shows that SCI seriously impacts QOL. More work needs to be done on how we can better support patients with SCI to improve their QOL.