bluuebunny/crossref_metadata_2025 huggingface dataset:
The synaptic interplay of Tau and Aβ oligomeric species in Alzheimer’s disease and related tauopathies.
Authors: Marcatti Michela , Fracassi Anna , Montalbano Mauro , Puangmalai Nicha , Bhatt Nemil , Natarajan Chandramouli , Guptarak Jutatip , Krishnan Balaji , Kayed Rakez , Taglialatela Giulio
Published: December 2022

Background

Alzheimer’s Disease (AD) is characterized by gradual cognitive decline driven by the targeting of synapses by small oligomers of both Aβ (AβO) and tau (TauO), which results in synaptic dysfunction that ultimately underscores disease progression. Preventing the interaction of these oligomers with synapses might be effective to treat AD. However, clinical trial failures suggest low effectiveness of targeting Aβ in late‐stage AD thus redirecting the attention onto TauO whose levels increase later in the disease timeline. Here we show that TauO and AβO target synapses with different dynamics.

Method

We used recombinant AbO and TauO as well as human brain derived tau oligomers from AD (BDTO‐AD), and from Progressive Supranuclear Palsy (BDTO‐PSP). Analyses of flow‐cytometry, western blot, immunofluorescence, and proteinase K digestion were performed to study the binding dynamic of the oligomers onto synaptosomes isolated from human frontal cortex and hippocampus. AβO and TauO were injected ICV in 3xTgAD, Tg2576 and h‐Tau mice for our in vivo experiments. The synaptic dysfunction was measured by FASS‐LTP assay.

Result

We found that recombinant TauO, BDTO‐AD and BDTO‐PSP oucompete AβO and become the prevailing synaptic‐associated species, while high concentrations of AβO facilitate the recruitment of tau oligomers at the synapses. Immunofluorescence analyses of mouse primary cortical neurons treated with AβO and/or TauO as well as in vivo experiments using 3xTgAD, Tg2576 and h‐Tau mice injected ICV with AβO or TauO supported these findings. Consistent with these observations, FASS‐LTP analyses demonstrated that TauO‐induced suppression of chemical LTP was exacerbated by AβO. Moreover, depletion of synaptosome surface proteins by PK pre‐treatment abolished the effect of TauO in reducing AβO synaptic binding without affecting the ability of high AbO levels to increase synaptic TauO recruitment. Furthermore, we observed different synaptic engagement and internalization profiles among the analyzed BDTOs.

Conclusion

Overall, our results suggest that, as the disease progresses, TauO outcompete AβO at the synapses, thus becoming the driver of the synaptic dysfunction responsible for the cognitive decline at the late stage of AD. Furthermore, disease‐specific differences in the dynamic of BDTOs engagement of synapses may indicate different synaptic toxicity of TauO across the tauopathies spectrum.
APOE4 blood‐brain barrier dysfunction: relation to cognitive impairment and molecular mechanisms
Authors: Zlokovic Berislav V
Published: December 2022

Background

Apolipoprotein E4 (APOE4), the major Alzheimer’s disease (AD) susceptibility gene, leads to accelerated BBB breakdown and degeneration of brain capillary pericytes that maintain BBB integrity both in humans and APOE4 transgenic mice. To what extent cerebrovascular effects of APOE4 contribute to preclinical and clinical decline is still understudied. Moreover, a comprehensive large‐scale analysis of cell‐specific mechanisms underlying APOE4 effects on the BBB is still lacking.

Method

Here, we use neuroimaging and biomarkers approach in human APOE4 carriers and non‐carriers (ε3/ε3) and “multi‐omics” snRNAseq and proteomics analysis of the BBB in humanized APOE4 and APOE3 knock‐in mice.

Result

APOE4 carriers are distinguished from APOE3 homozygotes by BBB breakdown in the hippocampus and medial temporal lobe that is not related to CSF or PET measurements of Aβ or tau pathology. High baseline CSF levels of the BBB pericyte injury biomarker sPDGFRβ predicted future cognitive decline in APOE4 carriers but not in non‐carriers. APOE4 compared to APOE3 leads to an early disruption of the BBB transcriptome in APOE4 knock‐in mice followed by dysregulation in signaling networks including proteins regulating cell junctions, cytoskeleton, clathrin‐mediated transport, and translation in brain endothelium which paralleled an early, progressive BBB breakdown.

Conclusion

BBB breakdown contributes to APOE4 associated cognitive decline in humans independently of AD pathology. Disruption of the BBB cell‐specific signaling mechanisms could be an initial central contributor to APOE4‐mediated cerebrovascular disorder as shown in mouse model.
A novel genetic approach to specifically target and manipulate plaque‐associated microglia in mice
Authors: Henningfield Caden M , Kawauchi Shimako , MacGregor Grant R , Neumann Jonathan , Green Kim N
Published: December 2022

Background

Within the Alzheimer’s disease (AD) brain, microglia surround extracellular plaques and mount a chronic inflammatory response. These plaque‐associated microglia (PAMs) are characterized by specific disease‐associated gene expression signatures, including Apoe, Cst7, Trem2, Clec7a, Itgax, and Csf1. Data from animal models of AD have identified that PAMs play critical roles in plaque formation and plaque compaction, but also contribute to synaptic and neuronal dysfunction and loss. To better understand the role of microglia in AD, we need precise models which directly target specific subsets of microglia, however; no such model currently exists. Here, we developed a novel genetic cre‐recombinase approach to specifically target and manipulate PAMs in AD mouse models. We identified that of PAM‐identified genes Cst7 shows no expression in the homeostatic mouse brain and is specifically and highly expressed in PAMs.

Method

To avoid caveats associated with tamoxifen inducible cre recombinase systems, we instead established a destabilized cre‐recombinase (ddCre) mouse line, in which Cre becomes stabilized and facilitates recombination in the presence of the antibiotic trimethoprim. ddCre was knocked‐in to the Cst7 locus (Cst7ddCre), followed by a P2A linker to ensure normal expression of Cst7 transcripts. We crossed these mice to a 5xFAD mouse model of AD and a loxp‐stop‐loxp‐tdTomato (Ai14tdtomato) reporter line. Upon the administration trimethoprim, cre‐recombination at loxp sites in Cst7 expressing cells occurs and tdTomato is expressed.

Result

We found that 5xFAD/Cst7
ddCre/Ai14tdtomato mice showed specific tdTomato fluorescence in PAMs with no expression present in non‐plaque associated microglia, or other cell types throughout the brain.

Conclusion

Altogether, we have shown that our novel Cst7
ddCre mouse line effectively targets PAMs. With this validation, we can alter any single gene specifically in PAMs.
Cardiovascular Risk, Alzheimer’s Disease Biomarkers, and Cognition: The Health and Aging Brain Study
Authors: Jiang Xiaqing , Peltz Carrie , Rissman Robert A. , O'Bryant Sid E. , Yaffe Kristine
Published: December 2022

Backgrounds

Cardiovascular risk (CVR) factors (hypertension, dyslipidemia, diabetes, and smoking) and emerging plasma biomarkers including β‐amyloid (Aβ) 40/42, tau, and neurofilament light (NfL) are each associated with risk of Alzheimer’s Disease (AD), although whether CVR and AD biomarkers affect cognitive aging independently or synergistically is unclear. As part of the Health and Aging Brain Study, we assessed the association of CVR burden and cognition and if this association is modified by AD biomarkers.

Methods

We studied 1,320 dementia‐free participants (63% women, 57% Mexican Americans) aged 50‐74 years (mean age 63.7±6.7) at baseline (2017‐2021) with cognitive testing including Trail Making Tests, verbal fluency, Spanish and English Verbal Learning, and Digit Symbol Substitution. We computed a cognitive composite score by averaging the z‐standardized test scores. Plasma AD biomarkers (Aβ 40/42, tau, and NfL) were assayed using Simoa. CVR burden was assessed using the Framingham Risk Score (FRS, range ‐2 to 25 in woman, ‐2 to 19 in men). We used linear regression to assess the association of CVR (intermediate/high: FRS ≥10 vs. low: FRS <10) with cognition and effect modification by AD biomarker (high level defined as above median plasma level for ≥2 biomarkers).

Results

Participants with intermediate/high CVR (31%) have lower composite cognitive score than those with low CVR adjusting for demographics, education, and APOE ε4 (‐0.10, 95% CI ‐0.16 to ‐0.03). The association between CVR and cognition was significantly modified by AD biomarkers (p = 0.03). Participants with intermediate/high CVR have a lower composite cognitive score only when AD biomarker level was high (‐0.15, 95% CI ‐0.24 to ‐0.07). However, participants with intermediate/high CVR were not more likely (‐0.02, 95% CL ‐0.11 to 0.08) to have worse cognition compared to low CVR among those with low level of AD biomarkers. Stratified analysis by levels of each biomarker showed similar results.

Conclusion

Greater CVR burden is associated with lower cognition in a diverse population, only among those with high AD biomarkers. Future longitudinal study is needed to address whether AD biomarkers modify the association between CVR and cognitive outcomes.
Cultural and ethnic differences in dementia family caregiving: A comparison of the experiences of Chinese American and non‐Chinese American dementia caregivers
Authors: Zeng Alison , Santulli Robert B
Published: December 2022

Background

The responsibilities of caring for a dementia patient are mentally and physically challenging, often resulting in adverse effects on a family caregiver’s psychological well‐being as well as the quality of care that the patient receives. While the experiences of White dementia caregivers from Western cultures have been well studied, there is a lack of understanding on how the racial, ethnic, and cultural nuances of caregivers from minority populations may influence dementia caregiving. Specifically, the research on Chinese American immigrant dementia caregivers is very sparse, which is concerning considering that Asian Americans are the fastest growing ethnic group in the United States and that Chinese Americans are the largest subgroup of Asian Americans. This study aims to explore the experiences of Chinese American dementia caregivers, focusing on processes of grief, coping mechanisms, and perceptions of stigma.

Method

Over 100 adult Chinese American and non‐Chinese American dementia family caregivers were recruited across the U.S. Their experiences with grief, coping, and stigma were surveyed using adapted versions of pre‐existing validated grief, coping, and stigma scales (i.e., the Marwit‐Meuser Caregiver Grief Inventory, the Coping Strategies Inventory, and the Affiliate Stigma Questionnaire). Participants also had the option to elaborate on the ways their cultural values may have influenced their caregiving in open‐ended questions.

Result

Interesting and important differences between Chinese American and non‐Chinese American participants' emotional and psychological reactions to caregiving have been observed. Thematic analysis of open‐ended questions revealed additional challenges characterizing Chinese American caregivers’ experiences with caregiving, including feelings of filial piety, language barriers, and discrimination and lack of support from medical facilities and professionals.

Conclusion

Emotional and psychological reactions to caregiving differ between Chinese American and non‐Chinese American dementia family caregivers. Recognition of these differences is important for those who work with this growing population.
Treatment with losartan, an AT1 receptor blocker, improves cognitive and cardiovascular function in a Dahl salt‐sensitive rat model of age‐associated vascular dementia.
Authors: Santos Carla Rocha Dos , Grigorova Yulia N , McDevitt Ross A , Long Jeffrey M , Cezayirli Defne , Zernetkina Valentina , Wei Wen , Haghkar Mahdi , Morrell Christopher H , Juhasz Ondrej , Lakatta Edward G , Spencer Richard G , Rapp Peter R. , Fishbein Kenneth W , Fedorova Olga V
Published: December 2022

Background

Dementia is characterized by progressive cognitive impairment (CI), which is accompanied by decline in reasoning, planning and memory. Cardiovascular diseases are the major contributors to the pathogenesis of vascular dementia and affect mainly the aging population. Even on a normal salt diet, Dahl salt‐sensitive (DSS) rats exhibit age‐associated hypertension and CI. We hypothesized, that anti‐hypertensive treatment with the angiotensin II receptor blocker losartan (LOS) would improve cardiovascular and cognitive function in aged DSS rats.

Method

Male DSS rats (n=30) were kept on a normal salt diet (0.5% NaCl) for the duration of the study. Baseline measurements were taken at 6‐mo of age. After that, treatment with 30mg/kg/day of LOS, added to the drinking water (n=14), or control (n=16) was started and continued for 6‐mo. Systolic blood pressure (SBP), aortic pulse wave velocity (aPWV), a measure of aortic stiffness, and behavioral testing in a visually cued reaction task to assess attention and inhibitory control were assessed every 3‐mo. Elevated plus maze (EPM) and Morris Water Maze (MWM) tests were performed at 12‐mo of age to measure anxiety‐like behavior and to evaluate spatial memory, respectively. Data were analyzed by 2‐way repeated measures ANOVA or t‐tests as applicable.

Result

Prior to the treatment, LOS and control groups did not display differences in any parameter analyzed. Control rats exhibited gradual increase in SBP and aPWV from 6 to 12‐mo of age. Following 3‐ and 6‐mo of treatment, LOS rats exhibited lower SBP and aPWV vs. controls (Table 1). At 12‐mo of age, LOS rats had improved performance in the reaction task (Figure 1), and exhibited lower anxiety levels, spending less time on the closed arm in EPM and 1.5‐fold more time in the open arm vs. control rats. LOS rats also spent less time to find a hidden platform in the MWM vs. controls, indicating that LOS treatment improved spatial memory (Table 1).

Conclusion

Improvement of cardiovascular function and reduction in aortic stiffness by LOS were associated with better attentional control and memory and lower anxiety levels, demonstrating an association of CI with cardiovascular changes in the DSS rat model of vascular dementia.
Association of social support with mild cognitive impairment and dementia among older women: the Women’s Health Initiative Memory Study
Authors: Posis Alexander Ivan B. , Golaszewski Natalie M. , McEvoy Linda K. , Jain Purva , Kroenke Candyce H. , Saquib Nazmus , Ikramuddin Farha , Schnatz Peter F. , Bellettiere John , Rapp Stephen R. , Espeland Mark A. , Shadyab Aladdin H.
Published: December 2022

Background

Women comprise approximately two‐thirds of older adults with Alzheimer’s disease in the United States. Social support may be a modifiable risk factor for cognitive impairment. However, few long‐term, large prospective studies have examined associations of various forms of social support with cognitive impairment. Therefore, we examined the association of perceived social support with incident mild cognitive impairment (MCI) and dementia among older women.

Method

This prospective cohort study included 6,670 older women from the Women’s Health Initiative (WHI) Memory Study (WHIMS), a sub‐cohort of the WHI hormone therapy (HT) trials, who were free of dementia upon enrollment. Perceived social support was assessed at baseline using nine items from the Medical Outcomes Study Social Support Survey. All item ratings were summed to generate a summary score (range = 9‐45), with higher scores indicating greater perceived social support. Incident MCI and dementia were ascertained using a comprehensive neuropsychological battery and central adjudication by a panel of specialists with expertise in dementia diagnosis during up to 25 years of follow‐up. Cox proportional hazards models were used to assess associations of perceived social support with incident MCI, dementia, and overall cognitive impairment (MCI or dementia). We also examined associations of four types of social support (emotional/informational, affection, tangible, and positive social interaction) with MCI/dementia.

Result

Overall, (mean age at baseline = 70.0 [SD 3.8] years; 97.0% non‐Hispanic/Latina; 89.8% White) 753 women had incident MCI, 697 had incident dementia, and 1,197 had incident overall cognitive impairment. There were no significant associations of social support with MCI (HR = 0.99; 95%CI = 0.98‐1.00), dementia (HR = 0.99; 95% CI = 0.98‐1.01), or overall cognitive impairment (HR = 0.99; 95% CI = 0.98‐1.00) after adjusting for age, education, income, race, ethnicity, marital status, smoking, alcohol intake, body mass index, history of diabetes, hormone therapy trial assignment, history of hormone therapy use, history of hypertension, and depressive symptom severity. There were no significant associations between the four types of social support and MCI/dementia.

Conclusion

Perceived social support was not significantly associated with incident cognitive impairment among older women. Future studies should explore other social factors, such as social isolation and loneliness, particularly in larger and racially/ethnically diverse populations.
Reproductive experience and APOEe4 genotype interact to influence neuroplasticity and neuroinflammation in the middle‐aged brain
Authors: Lee Bonnie H , Duarte‐Guterman Paula , Lieblich Stephanie E , Ibrahim Muna , Eid Rand S , Wen Yanhua , Cevizci Mel , Galea Liisa A
Published: December 2022

Background

Females have a greater lifetime risk of Alzheimer’s disease (AD) compared to males, differences which are further exacerbated with possession of APOEe4 alleles, the greatest genetic risk factor for sporadic AD. Although studying sex and gender differences is important, so is studying sex‐linked factors such as parity (pregnancy and motherhood). Previous parity influences brain aging trajectories in both humans and rodents and may be associated with a greater risk of AD and greater neuropathology. Neuroinflammation is increased with AD, reduces hippocampal neurogenesis, and activates the tryptophan‐kynurenine pathway (TKP), and all these factors are influenced by aging and parity. We investigated whether previous parity influences neuroinflammation and neuroplasticity in middle‐aged rats, dependent on APOEe4 genotype.

Method

Age‐matched wildtype (WT) and humanized (h) APOEe4e4 knock‐in female rats were nulliparous (never mothered) or primiparous (first‐time mothers). Middle‐age (13‐14 months old) rats were euthanized to examine markers of hippocampal neuroinflammation (microglia and cytokine signalling) and neurogenesis.

Result

In line with previous research, wildtype primiparous rats had greater levels of neurogenesis than nulliparous rats – however, the reverse was true in hAPOEe4 rats, as hAPOEe4 primiparous rats had lower levels of neurogenesis than hAPOEe4 nulliparous rats in the ventral hippocampus. Perhaps paradoxically, hAPOEe4 primiparous rats had fewer microglia and less proinflammatory cytokine expression (IL‐l1β, IFNγ, TNFα) than wildtype primiparous rats in the ventral hippocampus.

Conclusion

These findings indicate that past reproductive experience and APOEe4 genotype need to be considered in aging and Alzheimer’s disease research.
Gonadal Hormones Contribute to Sex Differences in Autoimmunity, Pathology and Behaviour in the 3×Tg‐AD Mouse Model of Alzheimer’s Disease
Authors: Fahnestock Margaret , Song Wei , Ma Donglai , Creighton Samantha D , Mian Firoz , Michalski Bernadeta , Forsythe Paul , Sakic Boris , Zovkic Iva
Published: December 2022

Background

Sex‐dependent discrepancies in prevalence and autoimmune markers are characteristics of Alzheimer’s disease (AD). Using the 3xTg‐AD mouse model, we previously reported that adult males show early systemic autoimmunity along with behavioural dysfunction, altered epigenetic factors, and lack of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain AD‐like pathology and behaviour. The present study examines whether gonadal hormones play a role in the etiology of these traits in current cohorts of 3xTg‐AD mice.

Method

3xTg‐AD and wild‐type mice were gonadectomized or sham‐operated at 3 months of age. After behavioural phenotyping at 6 months of age, the animals were assessed for serologic markers of autoimmunity, T splenocyte distribution, molecular markers of AD pathology, and expression of genes and histone variants associated with neurodegeneration.

Result

In female transgenic (AD) mice, gonadectomy resulted in reduced levels of circulating antinuclear/nucleosome autoantibodies and poorer spatial learning performance, but did not affect the T cell population. In contrast, in transgenic male animals, gonadectomy improved spatial memory and cognitive flexibility, diminished splenic CD8+ T cells, yet had no impact on anti‐nuclear/nucleosome autoantibodies. Sex hormone‐related effects on anti‐nucleosome autoantibodies led us to focus on histones. Gonadectomized AD females exhibited enhanced expression of mouse (m) and transgenic Mapt genes, consistent with reduced binding activity of the repressive histone variant macroH2A1 at the mMapt gene body, compared to their sham counterparts. In contrast, gonadectomized AD males showed reduced expression of App and H2afy genes, reduced cortical soluble Aβ42 levels, and increased macroH2A1 binding at the mPsen1 promoter, compared to sham‐operated AD males.

Conclusion

Female sex hormones enhance autoimmunity and spatial learning, whereas male sex hormones may be detrimental to spatial memory, cognitive flexibility, and autoimmunity in young adulthood. Furthermore, female sex hormones increase expression of the Mapt gene, but have no effect on App expression or Aβ42 levels. Conversely, male sex hormones increase App expression and Aβ42 levels, but have no effect on tau expression. Our work suggests that gonadal hormones contribute to sex differences in autoimmunity, AD‐like pathology, and “cognitive” function in this model. Moreover, histone variants may contribute to sex‐specific differences in AD pathology.
Dissociating the pro‐cognitive effects of donepezil and an M1 PAM
Authors: Hassani Seyed‐Alireza , Neumann Adam , Russell Jason K , Jones Carrie K , Womelsdorf Thilo
Published: December 2022

Background

Donepezil, an FDA approved drug for dementia in Alzheimer’s disease, increases the extracellular concentration of acetylcholine non‐selectively stimulating cholinergic receptors indiscriminately leading to dose‐limiting side effects. Muscarinic M1 sub‐receptor specific positive allosteric modulators (PAMs) have shown promise in addressing symptoms in Alzheimer’s disease, Schizophrenia and more1. M1 PAMs have little to no agonistic properties, avoiding peripheral side effects, and are mostly centrally located allowing for the modulation of endogenous signaling of the brain2.

Method

We tested non‐human primates in two tasks measuring cognitive flexibility and attentional control3 at varying doses of donepezil and an M1 PAM (VU0453595). Attentional control was measured with a visual search task requiring animals to search for a learned target object among distractors of variable number and similarity to the target object. Cognitive flexibility was measured with a feature‐reward learning task that required animals to learn the value of objects of varying feature complexity by trial and error. Flexibility was indexed as the speed of learning, the degree of latent inhibition and the amount of target perseveration after switching the rewarded feature.

Result

Donepezil enhanced attention control at a high dose (0.3 mg/kg) but enhance flexibility only moderately at a lower dose (0.06 mg/kg). In contrast, VU0453595 did not modulate attention, but at 0.1 mg/kg enhanced flexible learning, reduced target perseverations, and increased reaction time measures of decision confidence. At the dose with the most pronounced cognitive benefits donepezil resulted in gastrointestinal side effects, while VU0453595 did not cause side effects.

Conclusion

These results suggest that donepezil engages the brain networks underlying cognitive flexibility and interference control at different doses4, while the M1 receptor plays a major role in facilitating flexible behavioral adaptation but with no role in controlling interference. Such receptor specific results can be used to better curate to patient‐specific needs in order to address the most debilitating symptoms with the highest efficacy.

1. Melancon, B. J. et al. (2013) Drug Discovery Today https://doi.org/10.1016/j.drudis.2013.09.005.

2. Ghoshal, A. et al. (2016) Neuropsychopharmacology doi:10.1038npp.2015.189

3. Womelsdorf, T. et al. (2021) Frontiers in Behavioral Neuroscience https://doi.org/10.3389/fnbeh.2021.721069

4. Hassani, S.A. et al. (2021) Biological Psychiatry Global Open Science https://doi.org/10.1016/j.bpsgos.2021.11.012.
Evaluation of the antioxidant potential of Neem (Azadirachta indica) leaf supplement in alleviating Alzheimer’s Disease like behaviour induced by Aluminum neurotoxicity
Authors: Memudu Adejoke Elizabeth Elizabeth , Jibaniya Grace Mchibuma , ANZAKU FATIMA AYINDA
Published: December 2022

Background

To evaluate the antioxidant potential of Neem (Azadirachta indica) leaf supplement in attenuating Alzheimer’s disease (AD) pathology induced by aluminum neurotoxicity (Animal model of AD). Y‐ maze test, neuro‐morphology and astrocytic proliferation will be study in the fronto‐hippocampal and cerebellar cortices to elucidates the therapeutic role of neem leaf in AD pathology.

Methods

Twenty (20) adult male Wistar rats were grouped (4 groups, n = 5); Control group (A), Aluminum treated group for 7 days (B), 200mg/kg body weight Neem leaf supplement for 7 days (C), and the AD model post‐treated with 200mg/kg Neem leaf supplement for 7 days (D). Study was done for 14 days via oral administration of study materials. Neurobehavioral test for memory and learning done using Y‐maze test. Excised brain was fixed in 10% formol calcium, processed for Cresyl fast violet (CFV) stain for Nissl (chromatophilic) bodies and astrocytes immunohistochemistry using glial fibrillary acidic protein (GFAP) monoclonal primary antibodies in biotinylated secondary antibodies. Behavioural test data were analyzed using ANOVA, post hoc test and significance set at p<0.05.

Results

Aluminum treated group cortical area was characterized by necrosis, chromatolysis, neuropil vacuolations and astrocytes proliferation with impaired memory demonstrated by a reduction in the number of arm entries and spontaneous alternations as compared with the control and neem treated groups. However, these pathological changes were reversed by neem leaf supplementation seen in AD model neem leaf post‐treated group (D) showing an increased number of arm entries and spontaneous alternations, regeneration of neurons and a reduced reactive astrocytes (astro‐gliosis) proliferation.

Conclusion

Neem leaf supplement neuroprotective and repair role in AD pathological is proposed to be via ameliorating astrocytes mediated neuroinflammatory response via the neuron‐astrocytes interaction and antioxidant role during neuroinflammation induced by aluminum in the fronto‐hippocampal and cerebellar cortices
Assessing the Biological Mechanisms linking Smoking Behavior and Alzheimer’s Disease: Mediation Analysis of Metabolomic Data
Authors: Choi Jerome , Koscik Rebecca Langhough , Jonaitis Erin M. , Johnson Sterling C. , Engelman Corinne D. , Schmitz Lauren
Published: December 2022

Background

Smoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which also have both been linked to the development of Alzheimer’s disease and related dementias (ADRD). However, the molecular mechanisms between smoking and ADRD are not well established. This study characterized these mechanisms using metabolomics data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP).

Methods

Based on 1,266 people who enrolled in WRAP and had the necessary data to assess whether the smoking‐cognitive function relationship is mediated by CSF or plasma metabolites, we broke down our analyses into four steps, based on the product method (Figure 1). The associations between smoking status and cognitive functions, smoking and metabolites, and metabolites and cognitive functions were assessed. All models were adjusted for age, sex, race, education level, CES‐D score, body mass index, and weekly alcohol consumption. The outcomes were Preclinical Alzheimer Cognitive Composite III (PACC3) and composite scores for Immediate Learning, Delayed Recall, and Executive Function. Mediation analyses were then implemented, and the mediation effect of metabolites was computed to explore the role of metabolites in smoking‐cognitive function pathways. False discovery rate (<0.05) were applied as criteria for each step and 95% confidence intervals were used to verify the statistical significance for the metabolites that satisfied criteria.

Results

Six plasma metabolites were associated with smoking status and cognitive composite scores. Among them, N‐acetylneuraminate was significantly associated with PACC3 [95% confidence interval (CI): 0.00051‐0.01504] and Immediate Learning [95% CI: 0.00098‐0.01846] and was a significant mediator of the association between smoking status and these cognitive composites. The proportion of the total effect that was mediated by N‐acetylneuraminate was 12% for PACC3 and 13% for Immediate Learning.

Conclusions

As a mediator, N‐acetylneuraminate contributes to the association between smoking status and cognitive function. Interestingly, N‐Acetylneuraminate is a sialic acid and sialic acids have been found to be involved in several major changes associated with AD. For example, the CD33 sialic acid‐binding domain confers protection for late‐onset Alzheimer’s disease.
Increased Serotonin Synthesis Capacity is Associated with Longitudinal Cortical Atrophy and Worsening Depressive Symptoms
Authors: Markova Teodora , Ciampa Claire J , Parent Jourdan H , Furman Daniella J , D'Esposito Mark , Jagust William J. , Berry Anne S.
Published: December 2022

Background

Serotonin‐producing raphe nuclei are sites of age and Alzheimer’s disease‐related alterations in structure and function.

Method

We used [18F]Fluoro‐m‐tyrosine ([18F]FMT) positron emission tomography (PET) to measure serotonin synthesis capacity in younger (mean age = 22.08, n = 62) and older adults (mean age = 77.8, n = 49). [18F]FMT net tracer influx (Ki) was higher in older adults in both the dorsal and median raphe nuclei (both p < 0.001). To examine the functional relevance of higher raphe [18F]FMT Ki in older adults, we tested relationships with β‐amyloid status as defined by [11C]Pittburgh compound B ([11C]PiB) PET, retrospective longitudinal declines in cortical thickness, and retrospective longitudinal changes in depression symptoms measured using the geriatric depression scale (GDS).

Result

[11C]PiB positive (n=14) older adults showed trend‐level elevation in dorsal and median raphe [18F]FMT Ki relative to [11C]PiB negative older adults (n = 35; both p < 0.09). Higher dorsal raphe [18F]FMT Ki was associated with decreasing cortical thickness over time in the banks of the superior temporal sulcus (BanksSTS) (Monte Carlo, p < 0.05, r = ‐0.513), consistent with the interpretation that serotonin synthesis may be upregulated in response to neural losses. Decreasing cortical thickness was also associated with increasing GDS. We did not find evidence that higher dorsal raphe [18F]FMT Ki had a beneficial impact on affective function. Instead, interaction analyses revealed relationships between atrophy and increasing GDS were strongest in individuals with highest dorsal raphe [18F]FMT Ki (t = ‐2.056, p = 0.049; adjusting for age, sex, and [11C]PiB status).

Conclusion

Together, these findings suggest serotonin synthesis capacity increases with age, and appears to signal poor aging trajectories. Most elevated serotonin synthesis capacity was associated with greatest cortical atrophy and drove relationships between atrophy and worsening depressive symptoms over time.
Exploration of Multidimensional Poverty and Dementia in Adults older than 50 years old in South Africa
Authors: Trani Jean‐Francois , Moodley Jacqueline , Thu May Maw Thu , Babulal Ganesh M
Published: December 2022

Background

Multidimensional poverty is associated with chronic health conditions. However, limited research exists investigating the association between multidimensional poverty and dementia on a population level in low‐and middle‐income countries (LMICs).

Method

This study was conducted in Soweto between 11 November 2019 and 28 February 2020. Participants included older adults above 50 years old. Data analysis was concluded in August 2021. We calculated a measure of multidimensional poverty that includes seven dimensions and eleven indicators. Assessing Dementia 8 (AD8) and the Rowland Universal Dementia Assessment Scale (RUDAS) were used to measure dementia. Differences in level and depth of poverty between adults with no dementia and those with a score above the threshold for either AD8 or RUDAS, or for both AD8/RUDAS, and for comparing gender, age group and marital status were examined. Correlation analyses to assess overlap of dimensions of deprivation were carried out. Association between dementia and multidimensional poverty were investigated using multivariate regression model.

Result

Among 227 participants living in Soweto, South Africa, 151 adults were identified with dementia by the AD8 (66.5%), 64 by the RUDAS (28.2%) and 50 by both AD8 and RUDAS (22.0%). More men (32.1%) had no dementia compared to women (24.7%); and 20% of adults with dementia compared to 9.7% of those without dementia were found to be poor on four dimensions or more. The difference in multidimensional poverty index for k = 3 was 77.1% and 67.3% between adults with and without dementia. Education, health and employment were the main contributors of poverty. Multidimensional poverty was strongly associated with dementia as measured by AD8/RUDAS (adjusted OR 2.31, 95% CI 1.08‐4.95), with higher odds for older female (OR 2.03, 95% CI 1.00‐4.12) or those living in large households (OR 1.27, 95% CI 1.05‐1.53).

Conclusion

This study found that the prevalence and depth of poverty is higher among older adults with dementia. A lack of education, poor health and unemployment are major dimensions of poverty which was associated with higher risk of dementia. These findings suggest that early improvement in social determinants of health through targeted structural policies may prevent dementia later in life.
♣Public health policies, dementia care and support in LMICs
Authors: Karanja Wambui , Mutunga Elizabeth Kasimu , Timmons Fergus
Published: December 2022

Background

The World Health Organization (WHO) recommends that low‐and‐middle‐income countries (LMICs) develop national plans to formulate public health policies in response to dementia Across Africa, no country has developed a national dementia strategy to date. Although Kenya is in the process of developing a national dementia plan, much work remains to develop care pathways that meet the diverse needs of persons with dementia across the Kenyan population. In a study on perceptions and experiences of dementia and its care in rural Kenya, family caregivers reported negative experiences of disclosure of a diagnosis of dementia. They also reported limited and insufficient provision of information on dementia. The WHO Global dementia action plan has set the target of 75% of countries providing support and training programmes for carers and families of people with dementia by 2025.

Method

Alzheimer’s Society of Ireland (ASI) family caregiver training was developed to help caregivers respond to the needs of people with dementia more confidently by developing their caring skills. Though set for a population in Ireland, there are many similar challenges that caregivers in both Kenya and Ireland share. To avoid reinventing the wheel, we adopted the ASI caregiver training programme to be used in Kenya. We conducted a baseline survey to understand the needs of caregivers in Kenya before beginning course adaptation and training. . Due to COVID‐19, the training couldn’t be conducted in person and we conducted the training online with two goals:

• To provide quality online education to family caregivers to provide person centred care.

• To create peer support for caregivers.

We adopted and piloted 6 modules of the training. We used WhatsApp and Zoom to facilitate learning for caregivers, employing micro‐learning between weekly sessions.

Result

I will present the lessons learnt from culturally adapting a course for family caregivers in Kenya and providing online training for caregivers in Kenya.

Conclusion

There is an urgent need for more funding in LMICs to grow programs that provide support for caregivers and people with dementia.

Programs to build capacity for more people who provide training on dementia are essential to grow awareness and understanding.
Sex differences in risk for Alzheimer’s disease with extended maternal and paternal family history and vascular risk factors. The Cache County Study.
Authors: Vernon Elizabeth K. , Gonzalez Hector Leonardo , Schwartz Sarah , Rattinger Gail B. , Drewel Mikaela , Smith Ken Robert , DeBerard Scott , Kauwe John , Buhusi Mona , Tschanz JoAnn T
Published: December 2022

Background

Age, family history (FH), APOE status, and vascular factors are known risk factors for Alzheimer’s disease (AD). Sex differences in AD risk have been reported for some but not all of these factors. We examined sex differences in the association between FH and AD risk, studying the role of maternal/paternal lineage, parental longevity, and vascular factors in a population‐based cohort.

Methods

3677 participants (59% female) of the Cache County Memory Study [mean(SD) age = 75.75(7.11) years] were studied. FH of AD and health information were obtained from self‐report or Medicare claims and death certificates via data linkage through the Utah Population Database. AD cases were determined via clinical examination and Medicare claims and non‐cases via clinical examination or negative cognitive screenings.

Results

Multivariate logistic regression models (covarying age, education, and APOE) found that individuals with a first‐ degree relative with AD was associated with a 58% and 66% increased risk of AD in males and females, respectively. In males, APOE Ɛ4 carriers with a history of exceptional maternal longevity (survival age 87+) had 3‐times the risk of AD than males with neither risk factor (OR = 3.15, p interaction p = .020). Males with both exceptional maternal and paternal longevity (survival age 87+) had an 11%
reduced
risk of AD (OR = 0.894, interaction p = .041). A history of both maternal and paternal lineages of AD was associated with a 46%
lower
risk (OR = 0.544) at trend level significance (interaction p = .054). In females, maternal lineage of AD was associated with a 56% increased risk of AD (OR = 1.56; p = .005). Females with a history of congestive heart failure and paternal lineage of AD had twice the AD‐risk (OR = 2.26, interaction p = .013) compared to females with neither risk factor. Parental exceptional longevity was not associated with AD risk in females.

Conclusion

Risk for AD associated with family history varies by sex, maternal and paternal lineage of AD and exceptional parental longevity. Elucidating mechanisms and modifiable lifestyle factors underlying sex differences may facilitate developing primary AD prevention strategies.
Role of the activated microglia in hippocampal synaptic plasticity alteration in in vitro inflammatory models
Authors: Piccioni Gaia , Mango Dalila , Nisticò Robert
Published: December 2022

Background

Microglia cells are primary players in neuroinflammation, which plays a key role in the pathogenesis of Alzheimer's disease (AD). Under pathological inflammatory conditions, microglia activation leads to synaptic alterations thereby influencing the progression of AD. Increased activation of microglial colony stimulating factor 1 receptor (CSF1R) can lead to pathological microglia activation in experimental models of AD (Olmos‐Alonso et al., 2016). Using electrophysiological and immunohistochemical analysis, we investigated hippocampal synaptic transmission and plasticity in experimental models of neuroinflammation. We then tested whether pharmacological manipulation of microglia activation could restore the observed neuroplasticity alterations.

Method

C57BL6/J mices of both sexes aged between 30‐ and 40‐days were used. Employing electrophysiological approaches (field and whole cell patch clamp), we recorded in area CA1 in response to stimulation of Schaffer collaterals. We evaluated Long‐Term Potentiation (LTP) induced by theta‐burst stimulation measuring field Excitatory Post‐Synaptic Potentials (fEPSPs) 1 hour after tetanization. We also investigated paired‐pulse ratio (PPR) and spontaneous EPSCs (sEPSCs). Two in vitro inflammatory models were obtained applying Lipopolysaccharide (LPS) (10 μg/ml) or Aβ 1‐42 oligomers (200 nM). As a control, we tested the effect of scrambled Aβ 1‐42. To inhibit the activation of microglia we used Pexidartinib (PLX‐3397) (10μM) and Minocycline (500 nM). For immunohistochemical experiments free‐floating sections were incubated with primary antibodies overnight at 4°C followed by Alexa‐conjugated secondary antibody and DAPI for 2 hours at room temperature in the dark. VGLUT1, Iba1 and CD68 were used as synaptic marker in a triple staining to study pathological pruning and its reversal by PLX‐3397.

Result

Both inflammatory models induced LTP impairment, that was restored by application of a no‐specific blocker, Minocycline, or a specific inhibitor of activated microglia, PLX‐3397.Using whole cell patch clamp recordings, we observed that Aβ produces a reduction in glutamatergic transmission, evaluated as amplitude or frequency of sEPSCs and PPR, that is prevented by PLX‐3397. The data were confirmed using imaging studies, by which count of CA1 microglia and spine remodeling were evaluated.

Conclusion

Our results demonstrate a functional role of activated microglia in synaptic plasticity alteration that occurs in neuroinflammation suggesting CSF1R as new pharmacological target for AD treatment.
The Specialist Dementia Care Program: Describing and evaluating a novel model of care for people with severe and intractable behaviors in Australia.
Authors: Morris Thomas , Atee Mustafa , Alford Marie
Published: December 2022

Background

A small proportion of people living with dementia experience very severe and intractable behaviors that cannot be supported by mainstream aged care. As a result, this population often rotates between acute, mental health, and aged care settings, and is at increased risk of inappropriate psychotropic prescribing and hospitalization. This led the Australian Government to announce in 2016 the funding for 35 Specialist Dementia Care Program Units (SDCPUs) across Australia.

SDCPUs are purpose built, cottage‐like units staffed by specialist multidisciplinary teams who provide person‐centered care for people with very severe and intractable behaviors and psychological symptoms of dementia (BPSD). SDCPUs aim to reduce BPSD, improve quality of life, reduce inappropriate prescribing, and ultimately successfully transition residents to mainstream care within 12 months. As of January 2022, 10 SDCPUs were operational in 6 of 8 states and territories of Australia.

Method

Eligibility criteria for admission to SDCPUs include: (1) a diagnosis of dementia; (2) evidence of very severe BPSD (e.g., physical aggression); (3) evidence that the behaviors are enduring (i.e., have lasted at least 3 months); and (4) evidence of intractability to adequate trials of treatment (e.g., nonpharmacological interventions). This session will describe and discuss this assessment process required to access SDCPUs in Australia, the design features and model of care required of their operation, as well as learnings from the first two years of their operation.

Result

This session will also present the first longitudinal results of the impact of SDCPUs on resident behavior and wellbeing. Specifically, we will present the clinical outcomes of 37 residents from two SDCPUs, including BPSD, quality of life, activities of daily living, mood, prescribed psychotropics, rates of hospitalization, and successful transition into mainstream aged care.

Conclusion

We will discuss these findings in the context of feasible and effective emerging models of care for BPSD support worldwide.
Rare Genetic Risk in Progressive Supranuclear Palsy
Authors: Chang Timothy , Wang Hui , Lee Wan‐Ping , Kumar Urvashi , Leung Yuk Yee , Dickson Dennis W. , Dalgard Clifton L. , Wang Li‐San , Schellenberg Gerard D. , Geschwind Daniel H.
Published: December 2022

Background

Genetic risk in common variants have been identified for Progressive Supranuclear Palsy (PSP), but common variants only account for a portion of disease heritability. A proportion of the remaining disease heritability is likely contributed by rare variants identifiable via sequencing. Leveraging whole‐genome sequencing of 1719 PSP cases and 2940 controls from the Alzheimer’s Disease Sequencing Project, we detected single nucleotide variants (SNVs), insertion/deletions (INDELs), and copy number variants (CNVs). Note that all samples are non‐Hispanic whites with identity by descent (IBD) >0.25, and no outlier is >6 standard deviation in the principal component analysis. We conducted association analysis for variants, genes and gene sets to identify rare genetic risk for PSP.

Method

After quality control (variants and genotypes notated PASS by the calling algorithms), we detected 85,228,234 rare SNVs/INDELs and 163,987 rare CNVs (minor allele frequency (MAF) < 1%). For rare SNVs/INDELs, the Sequence Kernel Association Test Optimized was performed to identify rare genetic PSP risk from protein truncating variants (PTV) and damaging missense variants (MAF<0.01%) in both protein coding genes and gene sets that were previously associated with PSP based on protein co‐expression networks. For rare CNVs, a permutation‐based association test implemented in Plink was performed to identify CNVs associated with PSP.

Result

Combining protein truncating variants (PTV) and damaging missense variants, we identified one genome‐wide significant gene, FBXO38 (FDR = 0.0003, OR = 1.78). We also found enrichment of PTVs and damaging missense variants in genes comprising the C2 module, a neuronal module previously identified in post mortem PSP brain (FDR = 0.0016). For CNV analysis, there were 17 significant deletions and 2 significant duplications that were associated with PSP (Padjust < 0.05). The deletion (18:58488230‐58488489) in ALPK2, which has been identified as an Alzheimer’s Disease risk gene, was the only CNV that conferred a higher‐risk for PSP. Particularly, one deletion (17:46009357‐46009595) was in linkage disequilibrium with MAPT H2 haplotype which has been associated various neurodegenerative diseases including PSP.

Conclusion

We identified several new genes and a protein co‐expression network in which risk variants were associated with PSP. These genes and pathways provide potential candidate drug targets for future investigation.