bluuebunny/crossref_metadata_2025 huggingface dataset:
Type‐I interferon promotes tau pathology by potentiating seeded aggregation
Authors: Sanford Sophie Andrea Izumi , McEwan Will
Published: December 2023

Background

Recent work has implicated antiviral type‐I interferon (IFN) cytokines in Alzheimer’s disease (AD) and related tauopathies. Signatures of type‐I IFN‐driven gene expression are observed in the post‐mortem AD brain. Whilst the effects of type‐I IFN on β‐amyloid pathology have been previously investigated, its effects on tau pathology remain unclear.

Method

We examined the effects of type‐I IFN signalling on tau pathology ex vivo using primary neural culture models of seeded tau aggregation. In vivo, P301S‐tau transgenic mice were bred as homozygous knockout for the type‐I IFN receptor, Ifnar. Ifnar‐/‐ animals were compared with Ifnar+/+ for the extent of tau pathology by immunostaining.

Result

Treatment of neural cultures with polyI:C, a synthetic analogue of viral nucleic acids, evoked a potent cytokine response that enhanced seeded aggregation of tau. Type‐I IFN was the principal driver of this response, as Ifnar‐/‐ cultures were protected from the pro‐aggregant effects of polyI:C or exogenous type‐I IFN treatment. Pharmacological antagonists of IFN signalling prevented the effects of type‐I IFN. These effects of type‐I IFN were independent of microglia, as the phenotype remained when Iba1+ cells were pharmacologically depleted. Tau pathology was significantly reduced in aged Ifnar‐/‐ P301S‐tau mice relative to Ifnar+/+ P301S‐tau mice, consistent with IFN signalling driving tau pathology.

Conclusion

Our data shows a novel role for type‐I IFNs in the development of tau pathology both in vivo and ex vivo. This implicates the type‐I IFN response as a potential target for therapeutic intervention in AD and tauopathies.
The GSA KAER Toolkit: A Framework to Activate Primary Care in the Early Detection of Alzheimer’s Disease and Related Dementias
Authors: Tracy Karen K
Published: December 2023

The Gerontological Society of America (GSA) developed the KAER Toolkit to support primary care teams in increasing awareness of brain health in older adults, increase detection of cognitive impairment, initiate earlier diagnostic evaluations, and make referrals for supportive services for people with Alzheimer’s disease and related dementias (ADRD.)

The GSA KAER model identifies four steps which are essential for improving health‐related outcomes and well‐being for people living with ADRD and their families: Kickstart the Brain Health Conversation, Assess for Cognitive Impairment, Evaluate for Dementia, and Refer to Community Resources. The regularly updated evidence‐based tools and resources showcased in the toolkit were identified by consensus, gathering a diverse range of expert contributors and stakeholders to highlight best practices that research has shown to be most effective. The kit includes practical approaches which primary care teams can use to integrate these tools into their practice workflows.

The GSA program director for this initiative, who has shepherded its development and implementation since its inception, will provide insight into the framework’s development; its components, publications, supporting podcasts, and webinars; its wide‐ranging recognition, including by the National Institutes of Health and the National Alzheimer’s Project Act; and will review the projects to support its dissemination which have been funded by the Centers for Disease Control and Prevention. Finally, we will describe successful partnerships which the GSA has built with a number of large organizations, including the Alzheimer’s Association and the Gerontological Advanced Practice Nurses Association, who are now spreading awareness about it and facilitating training based on its principles in health systems across the United States.
Beyond Diagnosis: Compassionate Counseling, Effective Referrals
Authors: Raetz Jaqueline G.
Published: December 2023

Patients with Alzheimer’s disease and related dementias (ADRD) who receive an earlier diagnosis receive better care. To achieve system change to facilitate more timely and accurate diagnoses, primary care providers (PCPs) will need knowledge and confidence to compassionately counsel patients and families once a new diagnosis is made. Simply providing PCPs tools to make a diagnosis, without also giving them a clear path forward once they identify a new case, leads to resistance to practice change and poor care.

This presentation will outline an intervention built around training and tools for PCPs which meets that need. This intervention was pilot tested with 89 PCPs across the University of Washington’s Primary Care Network of clinics who found the intervention to be highly likely to change their practice (4.4 on 5‐point scale, SD 0.9). They particularly appreciated the guidance for how to provide compassionate counseling to newly diagnosed patients and their care partners.

Components of the training were 1) a set of validated serious‐illness communication principles which were adapted for use in ADRD, 2) concise information on how and when to make referrals to community resources and clinical dementia specialists, and 3) a structured checklist for giving guidance on key principles to cover in counseling a newly diagnosed patient.

This checklist was embedded in the electronic health record (EHR) and is concise enough to be easily implemented in the EHR of other healthcare systems. Highlights of the checklist include flags which indicate when a more urgent referral to a specialist is needed, a set of activating interventions which PCPs can implement to help patients with ADRD maintain brain health, and high‐quality referrals that PCPs can make to enable more supportive care. Such referrals include those with a national scope, such as Powerful Tools for Caregivers and the Alzheimer’s Association 24‐hour Help Line, and those with a more local focus as well.

This innovative, pragmatic intervention provides PCPs with effective knowledge and confidence for counseling newly diagnosed patients, with the understanding that such counseling is an essential component of quality improvement initiatives to facilitate the identification of ADRD in the primary care setting.
Validation of Cerebrospinal Fluid Alpha‐synuclein Assay against Autopsy in Non‐Parkinson’s Disease Neurodegenerative Syndromes
Authors: Samudra Niyatee , Ljubenkov Peter A. , Rojas Julio C. , Staffaroni Adam M. , Wekselman Fattin , Jennifer Lamoureux , Grinberg Lea T. , Boxer Adam L. , VandeVrede Lawren
Published: December 2023

Background

Alpha‐synuclein (αSyn) is the underlying neuropathology in both Parkinson’s Disease (PD) and non‐PD neurodegenerative syndromes, e.g. dementia with Lewy bodies (DLB). Importantly, αSyn is also a common co‐pathology, especially in Alzheimer’s disease (AD), where autopsy studies reveal comorbid αSyn in >50% of cases. A seeded aggregation amplification (SAA) assay (SynTap) has been shown to be highly sensitive and specific for pathogenic αSyn seeds in patients with PD and DLB, with lower performance in amygdalar‐predominant Lewy Body disease (LBD). Here we evaluated the antemortem CSF performance of SynTap in patients with non‐PD syndromes, with specific attention to performance in brainstem‐predominant αSyn and patients with atypical PD, e.g. progressive supranuclear palsy Richardson’s syndrome (PSP‐RS, N = 6) and corticobasal syndrome (CBS, N = 11).

Method

Patients were evaluated through observational studies at the UCSF Alzheimer’s Disease Research Center and neuropathologic evaluation was performed by the Neurodegenerative Disease Brain Bank. Antemortem CSF samples were tested with SynTap. Operators were blinded to diagnosis, and all samples were run as a single batch. Sensitivity and specificity were compared, and clinical correlations were examined across pathological groups and clinical diagnoses, using antemortem clinical records.

Result

Overall, in 56 patients, SynTap was 59% sensitive and 96% specific for autopsy‐confirmed αSyn pathology of any type. SynTap had perfect performance for diffuse (4/4) and transitional (5/5) LBD, and correctly identified 3/3 cases where LBD was primary. Consistent with prior reports, sensitivity was low in amygdalar‐predominant LBD (6/14, 43%), and lower in brainstem‐predominant LBD (1/6, 17%). A false positive result was present in 1/27 cases (4%). In the PSP‐RS cohort, SynTap positively identified 1 case caused by diffuse LBD and AD, and was true negative in 5/5. Within CBS, SynTap positively identified 1/1 case with diffuse LBD co‐pathology, 1/2 cases with brainstem‐predominant LBD, but missed 1 case with amygdalar‐predominant LBD.

Conclusion

SynTap best identifies αSyn pathology in patients with diffuse and transitional LBD, though specificity is high in the entire cohort. The etiology of low sensitivity in amygdalar‐ and brainstem‐predominant LBD co‐pathology requires further elucidation. The test may aid diagnostically in atypical PD syndromes, but results should be carefully considered, given the possibility of co‐pathology.
Progress in imaging by α‐synuclein Positron Emission Tomography
Authors: Bennacef Idriss , Zeng Zhizhen , Miller Patricia J , Riffel Kerry , Purcell Mona L , Haley Hyking D , Meng Xiangjun , Yuchuan Wang , Roecker Anthony J , Shaw Anthony W , Stump Craig A , Mitchell Helen J , Tong Ling V , Fawaz Maria V , Drolet Robert E , Ma Lei M , Marcus Jacob , Li Wenping , Hostetler Eric D.
Published: December 2023

Background

Deposition of misfolded α‐synuclein (α‐Syn) aggregates in the human brain is one of the major hallmarks of synucleinopathies. Positron Emission Tomography imaging (PET) of α‐synuclein in Parkinson’s disease (PD) patients is highly desirable but remains elusive. An extensive PET radioligand discovery campaign was undertaken. Here, we present the in‐vitro and preclinical in‐vivo characterization of [3H]‐ and [11C]Compound S, representing an example of a promising PET radioligand for α‐Syn.

Method

Competition binding studies and autoradiographic studies were performed in cortexes of PD patients, healthy control, and Alzheimer’s disease (AD) patients brain tissue, and mid‐brain region of the aged A30P mouse using [3H]S. Brain PET experiments using [11C]S were carried out in a healthy non‐human primate (NHP) and the aged homozygote A30P mice.

Result

Compound S is a sub‐nanomolar affinity ligand to human and A30P mouse α‐Syn (Kd = 0.15 nM and 0.5 nM resp.). Lower affinity was observed in AD and healthy control brain tissues. [3H]S showed displaceable binding in PD brain cortex and A30P mid‐brain and brainstem, and little binding in AD and healthy control. In the NHP, [11C]S crosses the brain‐blood barrier and the uptake phase of [11C]S is followed by a washout. [11C]S PET studies in A30P mice showed higher uptake in the mid brain and brainstem regions, with standard uptake value ratios in those regions higher than 2.0.

Conclusion

Compound S is potent for α‐Syn in vitro, and PET imaging in the A30P mice showed an elevated signal in regions known to accumulate α‐Syn. This dataset suggests that the Compound S has promise towards imaging α‐Syn in PD patients.
Basal forebrain nuclei volume is associated with hematoencephalic barrier dysfunction in early Alzheimer’s disease
Authors: Lerch Ondrej , Martinkovic Lukas , Laczó Martina , Nedelska Zuzana , Hanzalová Jitka , Sheardova Katerina , Laczó Jan , Hort Jakub
Published: December 2023

Background

Hematoencephalic barrier (HEB) is a protective layer of cells that separates the circulatory system from the brain. Its dysfunction is one of the possible mechanisms leading to the development of Alzheimer’s disease (AD), a progressive neurodegenerative disease and a leading cause of dementia worldwide. The albumin quotient (QAlb), the ratio between cerebrospinal fluid (CSF) and serum albumin concentrations, is a frequently used measure of HEB breakdown. Elevated levels of QAlb were previously reported in early AD. Here we explored the relationship between QAlb and volumes of the hippocampus and entorhinal cortex (EC) subregions and basal forebrain (BF) nuclei, the brain structures affected early in the course of AD.

Method

92 participants, including 20 AD biomarker negative cognitively normal (CN), 42 AD biomarker positive with mild cognitive impairment (AD‐MCI) and 30 AD biomarker positive with mild dementia (AD‐DEM), from the Czech Brain Aging Study underwent structural MRI and CSF sampling. CSF levels of amyloid beta 1‐42, total tau, phosphorylated tau 181 and QAlb, as well as volumes of the hippocampal subregions (i.e., head, body and tail), anterolateral and posteromedial EC and BF nuclei were obtained. Associations between regional brain volumes, normalized to total intracranial volume, and QAlb were assessed using MANOVA controlled for gender and age.

Result

In the AD‐MCI group, volumes of the anterior and posterior parts of the nucleus basalis of Meynert (NBM), one of the BF nuclei, were positively associated with QAlb levels (β = 0.317 and 0.345, p = 0.045 and 0.029, respectively). There were no other significant associations of regional brain volumes with QAlb in CN, AD‐MCI or AD‐DEM groups. All measured volumes, except for BF nuclei of medial septum in AD‐DEM (p = 0.058), were smaller in AD‐MCI and AD‐DEM v.s. CN group (p<0.05). There were no differences in volumes between AD‐MCI and AD‐DEM groups. QAlb did not differ between groups.

Conclusion

Our results show that severity of HEB dysfunction is associated with increased volume of the NBM in individuals with AD‐MCI, suggesting a link between HEB dysfunction and early pathological changes in the BF nuclei.
Patterns and trajectories of multimorbidity prior to dementia: a UK Biobank study
Authors: Patel Raihaan , Mackay Clare , Griffanti Ludovica , Gillis Grace , Anatürk Melis , Suri Sana
Published: December 2023

Background

The co‐occurrence of multiple long term conditions (LTCs), termed multimorbidity, is a risk factor for dementia. However, we lack an understanding of how and when specific LTCs accumulate over time to impact dementia risk.

Method

338,270 individuals from the UK Biobank with linked electronic health records up to January 2022 were studied, excluding those with either a dementia diagnosis or age of latest follow up < 65 years. LTC diagnoses were derived using hospital episode statistics and GP records (age of diagnosis computed using month/year of birth and month/year of diagnosis). We performed an age‐stratified analysis in which we a) cluster individuals based on 43 non‐dementia LTCs diagnosed within age bins (0‐55, 55‐65, 65‐70 years), and b) compute risk of incident dementia using logistic regression with multimorbidity cluster as predictor and incident dementia as outcome. Diagnosis data was submitted to PCA, and the resulting factor scores were kMeans‐clustered. 6 clusters were derived per age bin.

Result

We named clusters based on the most prevalent LTCs within that cluster (Figure 1). Cardiometabolic, arthritis, gastrointestinal, and mixed clusters existed at all ages. Mental health and respiratory clusters were present exclusively in the younger age bin (0‐55) whereas hypertension and eye disorder clusters were exclusive to older ages (55‐65 and 65‐70). Across the lifespan, compared to being disease free, multimorbidity was significantly associated with incident dementia (OR>1). We also observed age‐specific multimorbidity preceding dementia onset. From 0‐55 years, being in the mixed cluster presented the highest dementia risk (OR = 5.13, 95% CI = [4.61, 5.73]). Being in the cardiometabolic cluster was associated with highest risk in 55‐65 (OR = 6.24 [5.48, 7.1]) and 65‐70 (OR = 6.99 [5.91, 8.27]) ranges. The most predictive trajectory of incident dementia involved the mixed cluster at 55, followed by the cardiometabolic clusters from 55‐65 and 65‐70. Table 1 displays the top 10 trajectories associated with dementia. All p‐values are bonferroni‐holmes corrected and < 0.01.

Conclusion

We present multimorbidity pathways linked to increased risk of dementia. We describe how and when diseases cluster together prior to dementia diagnosis.
Racial and Ethnic Differences in the Risk of Dementia under Hypothetical Blood‐Pressure‐Lowering Interventions: The Multi‐Ethnic Study of Atherosclerosis
Authors: Rojas‐Saunero Liliana Paloma , Fitzpatrick Annette L. , Swanson Sonja , Diez‐Roux Ana , Mayeda Elizabeth Rose , Jimenez Marcia Pescador
Published: December 2023

Background

Black and Latino people have a higher risk of Alzheimer’s disease and related dementias (ADRD) as well as ADRD comorbidities, including hypertension. Since hypertension is perhaps the most important modifiable vascular risk factor for the development of ADRD, we aimed to study whether sustained hypothetical interventions to reduce systolic blood pressure (SBP) would differentially change ADRD risk across racial/ethnic groups.

Method

We used 19 years of follow‐up data from the Multi‐Ethnic Study of Atherosclerosis. The study population included 6806 individuals between 44 and 84 years old, free of clinically recognized CVD and dementia diagnosis at baseline. We defined two sustained interventions on SBP based on continually maintaining SBP below (1) 120 mmHg and (2) 140 mmHg. We considered incident dementia diagnoses as outcome. We applied the parametric g‐formula to adjust for baseline and time‐varying confounding. Baseline covariates included sex, age, education level, income, health insurance, and clinical variables (e.g. diabetes). Time‐varying covariates included SBP, total cholesterol, low‐density lipoprotein, body mass index, health behaviors (e.g. alcohol use), myocardial infarction, stroke, and coronary heart disease diagnosis.

Result

Mean age was 62.1 (SD = 10.2), 52.9% were female, 38.5% (2617) self‐identified as White, 27.8% (1890) as Black, 21.9% (1495) as Latino and 11.8% (804) as Chinese American. The observed 19‐year risk for dementia was 8.6%. Compared to no specified intervention, maintaining SBP below 120 mmHg was associated with an overall dementia risk reduction of about 5% in the full study population (risk ratio (RR): 0.95, 95%CI: 0.88, 1.02). The estimated RRs for this same comparison were: 0.95(95%CI: 0.87, 1.03) for White participants, 0.93 for Black participants (95%CI: 0.81,1.06), 0.92 for Latino participants (95%CI:0.81, 1.09), and 1.15 for Chinese American participants (95%CI: 0.74,1.63) (Table 1). Of note, the proportion of participants who would have had to have been intervened differed by race/ethnicity, where 92% Black participants, 82% of White and Chinese American, and 86% of Latino participants would have had to have been intervened to maintain SBP below 120 mmHg.

Conclusion

Our results highlight a heterogenous effect that should be considered for implementation of blood pressure control strategies.
Mobile Toolbox: Remote, unsupervised longitudinal assessment of a diverse cohort in the UCSF Brain Health Registry
Authors: Landavazo Bernard , Camacho Monica R , Kaat Aaron J. , Hosseinian Zahra , Gershon Richard C. , Weiner Michael S. W. , Nosheny Rachel L
Published: December 2023

Background

A critical need in the AD field is development and validation of efficient, scalable cognitive assessments to identify older adults with cognitive impairment. The Mobile Toolbox (MTB), a novel suite of app‐based cognitive assessments, was developed to address this need. The goal of this study was to assess the feasibility, usability, compliance, longitudinal retention, and validity of MTB assessment in a large, ethnoculturally and educationally diverse cohort in a remote, unsupervised setting.

Method

Participants were recruited from the UCSF Brain Health Registry (BHR), an online study. BHR participants were invited by email, screened for eligibility (English fluency and access to a compatible smartphone), and provided online instructions for MTB app download. All participants could complete a baseline administration. A subset was invited to a longitudinal study, in which they complete MTB assessments at a short‐term timepoint (day 7, 14, or 21; study arms sequentially assigned), and then at 6‐month intervals. Enrollment goals were N = 800 with equal distribution across 10‐year age bands (ages 18‐80+); 60% with <16 years of education; 10% non‐Latinx Black, 15% Latinx, and 5% non‐White other ethnocultural identity.

Result

Over a 5‐month period, 48,110 BHR participants were invited to the study. Of those, 8287 (17%) expressed interest, 3554 (7%) completed baseline assessment, and 1327 (3%) were assigned to the longitudinal study. Participants submitted 1205 help tickets asking for email support to complete MTB. The baseline and longitudinal cohorts underrepresented Black individuals and younger age bands, despite targeted recruitment efforts (Table 1). Longitudinal completion rates were 59.0% for the short‐term timeline and 55.2% for the 6‐month timepoint, and varied by ethnocultural group (Figure 1). Compared to those invited, those who enrolled in the longitudinal study were older, had higher education, and were more likely to identify as female non‐Latinx White (p<0.05).

Conclusion

Results demonstrate feasibility and usability of remote, unsupervised MTB assessment. Underrepresented populations were less likely to enrolled and to complete assessments at baseline and longitudinally, emphasizing the need to develop more inclusive recruitment and engagement efforts. This approach can be scaled up to efficiently assess cognition in many research, clinical trial, and healthcare settings.
Risk of Mild Behavioral Impairment: the role of gender and APOE allele carrier status
Authors: Mortby Moyra E , Ismail Zahinoor , Kiely Kim M , Fischer Corinne E. , Anstey Kaarin J.
Published: December 2023

Background

Gender differences in dementia and dementia‐related neuropsychiatric symptoms are well described. Similarly, the Apolipoprotein E (APOE) ε4 allele is a well‐known predictor of Alzheimer’s disease. However, their impact on the clinical manifestation of Mild Behavioral Impairment (MBI) remains unclear. Using data from the Australian population‐based PATH Through Life Study we explored the associations between gender and APOE ε4 carrier status with MBI. We hypothesized that MBI likelihood would be greater in males and ε4 carriers.

Method

1316 dementia‐free participants (48% female; aged 72‐79) were included. Gender was self‐reported (female/male). Participants were classified as APOE ε4+ if they carried at least one ε4 allele (APOE ε4/ε4, ε2/ε4, ε3/ε4). MBI was approximated using a previously published transformation algorithm, which utilizes items from the Neuropsychiatric Inventory assessed at a single study visit. Binomial logistic regression was used to examine the role of gender and APOE ε4 carrier status, and their interaction, on predicting MBI status, while controlling for self‐reported years of education.

Result

Of the 1316 participants, 339 (25.8%) were APOE ε4+ and 445 (34%) had MBI symptoms. A higher proportion of APOE ε4+ carriers (χ2 (1) = 5.99, p = .014) and men (χ2 (1) = 4.59, p = .032) were in the MBI group compared to the non‐MBI group. Binomial logistic regression showed APOE ε4 carrier status (OR = 1.58, 95% CI: 1.063‐2.344) and male gender (OR = 1.45, 95% CI: 1.093‐1.925) were associated with a greater likelihood of MBI. Male gender was also associated with a 2‐fold greater likelihood of having symptoms of the Decreased Motivation (OR = 2.08, 95% CI: 1.13‐3.86) and Impulse Dyscontrol (OR = 2.16, 95% CI: 1.54‐3.03) domains. No interaction effects were found between gender and APOE ε4 carrier status for MBI or any of its domains.

Conclusion

The current study found that in dementia‐free older adults both male gender and APOE ε4+ status increased the risk of having MBI. However, no cumulative/interaction effect between gender and APOE ε4 carrier status was found, suggesting that being both male and APOE ε4+ does not further increase the risk of MBI. These results provide novel and valuable insight into the connection between gender, APOE ε4 carrier status and MBI.
Single‐domain antibody‐based non‐invasive in vivo imaging of α‐synuclein or tau pathology
Authors: Jiang Yixiang
Published: December 2023

Background

Synucleinopathies and tauopathies are characterized by progressive deposition of α‐synuclein (α‐syn) and tau proteins, respectively. These diseases have been linked to proteins mutations or excess α‐syn gene, indicating prominent roles of these proteins in their etiology and pathogenesis. Consequently, being able to non‐invasively image these aggregates would allow early and accurate diagnosis to facilitate clinical trials on drugs targeting these lesions and eventually for prophylactic therapies. Recently, several dye‐based imaging probes with selectivity for tau aggregates have been developed but suitable imaging biomarkers for synucleinopathies are still unavailable. However, these β‐sheet binders bind to different amyloids and thereby lack specificity. Compared to β‐sheet dyes, single domain antibodies (sdAbs), found in camelids and a few other species, are highly specific and their small size allows better brain entry and distribution than whole antibodies.

Method

To develop anti‐α‐syn or anti‐tau sdAbs, we immunized llamas with α‐syn and tau preparations, respectively. Phage display libraries were generated from peripheral blood mononuclear cells and screened for binding to α‐syn or tau proteins using various assays, resulting in prototype sdAbs deemed promising for in vivo imaging. Subsequently, these anti‐α‐syn or anti‐tau sdAbs were labeled with a near‐infrared tag and injected intravenously in synucleinopathy, tauopathy or control mice, followed by imaging in an In Vivo Imaging System (IVIS). Subsequently, brains were extracted for tissue analysis.

Result

Intravenous injection of labeled anti‐α‐syn or anti‐tau sdAbs resulted in strong in vivo brain signal detected through the intact head in synucleinopathy and tauopathy mice, respectively, but not in control mice. Notably, anti‐α‐syn sdAbs did not give signal in tauopathy mice and vice versa. The in vivo brain signal correlated strongly with insoluble, soluble, and phospho‐antigen within the brain. Postmortem analysis revealed extensive co‐localization of the sdAb imaging probe with α‐syn or tau aggregates within neurons in the endosomal‐lysosomal system, indicating their interaction in these degradation pathways.

Conclusion

These anti‐α‐syn or anti‐tau sdAb probes allow non‐invasive and specific in vivo imaging of α‐synuclein vs tau pathology in mice, with brain signals correlating strongly with lesion burden. These small antibody derivatives have great potential for in vivo diagnosis of these diseases.
The Black Experience of COVID‐19. What is next for Clinical Psychologists in Alzheimer’s Disease research post‐pandemic?
Authors: Browne Laurel Y , Cedeno Jeffrey A , White Payton Gabrielle , Cesar Oliver , Azad Dishari Zaman , Tosto Giuseppe , Osorio Ricardo S , Bubu Omonigho Michael M
Published: December 2023

Background

COVID‐19’s emergence in 2020 altered the dynamics of societal norms leading to a new reality of increased mortality, financial strain, and psychopathology. Individuals with dementia, older adults, and marginalized racial/ethnic communities were identified as vulnerable to being disproportionately impacted by the COVID‐19 pandemic. The unequal overrepresentation of non‐White communities in Covid‐19 infections and deaths demonstrated that the pandemic widened pre‐existing healthcare inequalities and did not impact all racial groups equally. In Louisiana, the Black community made up 76.9% of COVID‐19 cases and accounted for 70.6% of the total deaths, but only comprised 31% of the total population (Tirupathi et al., 2020). Research showed that the racial disparities experienced due to systemic racism resulted in more African Americans suffering from increased stress, anxiety, and depression. The existing literature led to the following research question: What are the Clinical implications of COVID‐19 on older adults in the Black community in Alzheimer’s Disease & related dementia research?

Method

Databases such as Pubmed, Google Scholar, and APA PsycNet were used. Keywords included COVID‐19, African/Black Americans, older adults, dementia, and racial health disparities. Articles were used to identify themes, identify risk factors in the Black community, and methods to improve them.

Results

The results from the literature review revealed that COVID‐19 impacted older adults (65 +), affecting their activity level, sleep quality & well‐being. Contracting the disease was associated with experiencing cognitive deficits even into the recovery phase. Unfortunately, COVID‐19 disproportionately impacted older, ethnically diverse individuals. In particular, COVID‐19’s high infection rate and impact on Black mental health put older African Americans at risk for AD & related dementias. The findings elucidate that the risk of long‐term COVID‐19, AD, and related dementias need to be studied, particularly among older adults in the Black community.

Conclusion

Covid‐19 exacerbated historical health inequities in marginalized communities and their psychological well‐being. This research highlights the importance of clinical psychologists advocating for health equity in Alzheimer’s and related dementia research to mitigate the adverse effects of the COVID‐19 pandemic. Dismantling structural barriers, increasing cultural education, and representation in clinical trials are the next steps to advocating against health disparities.
Strengthening subject recruitment and retention of the older Black population in Alzheimer’s Disease and related dementias studies through community outreach
Authors: White Payton Gabrielle , Azad Dishari Zaman , Petersen Karyn , Browne Laurel Y , Cedeno Jeffrey A , Cesar Oliver , Jean‐Louis Girardin A , Osorio Ricardo S , Bubu Omonigho
Published: December 2023

Background

Representation in dementia research is extremely important in creating effective prevention methods, interventions, and treatments across all populations (Lennon et. al 2022; Barnes 2022). One of the main goals set by the National Institute on Aging (NIA) for the years 2020‐2025, is to disseminate information to several outlets including older adult‐support organizations about research and interventions. The NYU Healthy Brain Aging and Sleep Center (HBASC) has successfully built relationships with community organizations in an effort to contribute to meeting the NIA’s goal using the PEACE method. We evaluated pre‐post subject retention rate, after instigation of PEACE.

Method

In 2019, HBASC began recruitment for a longitudinal study focusing on sleep and Alzheimer’s Disease (AD) in healthy older Blacks (ages 60‐75 years) in the New York Metropolitan Area using community outreach/education as a method of recruitment (i.e. partnering with senior recreation centers, local churches, etc.). Study team members implemented the PEACE method in their outreach efforts. Team members practiced Patience, when accommodating organizations’ needs and requests, Empathy, for the members of the communities they were working in, Appreciation, for the organizations’ aid in reaching the community, Cultural competence, when planning or participating in community events, and prioritized Educating the community, on AD and other related dementias before recruitment.

Result

Within the first year of recruitment, ∼77% vs. ∼23% of subjects were successfully recruited from the community favoring the PEACE method. When the PEACE method was successfully executed, the study team gained the trust of members of the community and retained ∼ 70% of subjects recruited from the community. Older Blacks trusted the HBASC study team because the PEACE method demonstrates dedication to the community. This in turn increases the likelihood of follow‐up response in longitudinal ADRD studies.

Conclusion

Collaborating directly with community organizations, is an efficient method not only of recruitment, but also retention of older Black subjects in ADRD studies. Collaborations with well‐known trusted community partners can establish a strong relationship between the Black community and research.
Supporting ADRD care partners from historically and currently underserved communities
Authors: Dawson Walter D , Gelmon Sherril B
Published: December 2023

Supports for people living Alzheimer’s disease and related dementias (ADRD) and their care partners in the US remain limited. Historically and currently underserved populations in health care experience particularly stark disparities in accessing ADRD‐specific care and supports. To inform enhanced outreach and supports for underserved populations in ADRD care, and to better understand how state and federal policies can help support this goal, a study was conducted to gather insights from the perspectives of individuals with lived experience as care partners, with an emphasis on communities historically and currently underrepresented in ADRD research, for whom culturally appropriate services for people living with ADRD may be non‐existent or difficult to access.

The study population focused on care partners of people living with ADRD who identify with historically and currently underserved communities including Black, Indigenous, Asian, and Latinx Americans in the Portland, Oregon region. Recruitment strategies for potential focus group participants were developed in collaboration with leaders of Portland‐area community‐based organizations that provide ADRD care and supports. Focus groups were convened with care partners from these four communities, along with one focus group with individuals who identified with other communities.

ADRD care partners across all populations reported a need for additional supports to help them manage care‐related activities. The specific needs and supports identified varied across populations. The findings also indicate widespread unmet care partner needs across all populations, including more information on ADRD, financial and psychological supports, in‐home care, and respite services. While many care partners were generally satisfied with their clinical care and research involvement, nearly all identified potential areas for further supports, suggesting an opportunity for coproduced supports, services, and policies.

Innovative approaches to service delivery and policy development should be pursued in order to better support care partners of people living with ADRD. US policymakers could coproduce policies through direct collaboration with care partners, researchers, and clinicians by co‐designing and implementing policies focusing on improving the care partner experience. In moving toward equitable service provision, offering specific and unique supports for care partners from underserved communities who may have difficulties accessing culturally appropriate services must be a priority.
The association of hyperglycemia and kidney dysfunction with cognitive impairment in community‐dwelling older adults in Taiwan
Authors: You Ying‐Shu , Chen Jen‐Hau , Chiou Jeng‐Min , Chen Ta‐Fu , Chen Yen‐Ching
Published: December 2023

Background

Diabetes was considered one of the risk factors for dementia. However, one‐third of diabetic patients also suffer from kidney disease. It remains unclear the intercorrelation between blood sugar and kidney function that affects the occurrence of mild cognitive impairment for people with normal blood sugar levels. This study aimed to explore the relationship between hyperglycemia and kidney dysfunction (KD) on cognitive impairment in older adults.

Method

This is an eight‐year cohort study (2011‐2019). A total of 509 non‐demented older adults were recruited from the elderly health checkup program at baseline (2011‐2013) with three biannual follow‐ups. Global and domain‐specific (memory, attention, executive function, and language) cognition were assessed by the Taiwanese version of Montreal Cognitive Assessment (MoCA‐T) and a battery of neuropsychological tests, respectively. MCI was defined as a MoCA‐T score of 22 or 23. Hyperglycemia was defined as fasting blood glucose greater than 100 mg/dL. KD was defined as having either glomerular filtration rate < 60 ml/min/1.73 m2 or proteinuria. The generalized linear mixed model was utilized to examine the effects of hyperglycemia and KD on cognitive performance.

Result

The prevalence of MCI was 9.4% at baseline. Hyperglycemia [adjusted odds ratio (aOR) = 1.91] and KD (aOR = 1.98) were significantly associated with the risk of MCI over eight years after adjusting for covariates, respectively. In addition, hyperglycemia and KD were significantly associated with poor performance of logical memory (β:‐0.51 to ‐0.01), executive function (β:‐0.25 to ‐0.003), attention (β:‐0.07 to ‐0.03), and verbal fluency (β:‐0.08 to ‐0.005). Hyperglycemia and KD was associated with an increased risk of MCI participants aged less than 75 years (aOR = 2.19–2.21) and in APOE ε4 non‐carriers (aOR = 2.02–2.15).

Conclusion

Our finding indicated that poor glycemic control and kidney function were associated with an increased risk of MCI or poor performance of cognitive domains in older adults. Cognitive impairment may be reversible through optimal management of glycemia and kidney disease; interventions (e.g., self‐management education, dietary restriction, and sufficient physical activity, etc.) at the early stage will be helpful to prevent dementia.
Plasma oligomer βeta‐amyloid and white matter microstructural integrity in cognitively normal older adults according to cerebral amyloid deposition
Authors: Wang Sheng‐Min , Lim Hyun Kook
Published: December 2023

Background

Multimer detection system‐oligomeric amyloid‐ß (MDS‐OAß) measures plasma OAß level, which is associated with earlier pathology of Alzheimer’s disease (AD). Previous studies showed that plasma levels of MDS‐OAβ were higher in patients with dementia due to AD than in cognitive normal older adults (CN), and they correlated well with conventional AD biomarkers including standardized uptake value ratio (SUVR) of Pittsburgh compound B (PiB) and CSF level of Aβ42, p‐Tau, and t‐Tau. However, no previous study investigated MDS‐OAβ difference in CN with or without cerebral Aβ burden. In addition, associations among MDS‐OAß, cerebral Aß deposition, aberrance of white matter integrity, and cortical thickness in CN is not elucidated.

Method

We studied 34 CN with amyloid‐PET negative and 23 CN with amyloid‐PET positive results who received MDS‐OAβ, structural MRI, and diffusion tensor imaging (DTI).

Result

Amyloid‐PET positive group showed higher MDS‐OAß level than amyloid‐PET negative group, but two groups did not differ in WM integrity or cortical thickness. MDS‐OAβ level was significantly higher in amyloid‐PET positive group than in amyloid‐PET negative group. MDS‐OAβ positive group had significantly higher cerebral AB deposition, or mean global SUVR values, than MDS‐OAβ negative group. There was a positive correlation between MDS‐OAβ level and PET‐SUVR. In terms of DTI analysis, MDS‐OAβ positive group had significantly lower FA in the left forceps minor of corpus callosum and right superior longitudinal fasciculus than in lower MDS‐OAβ negative group. In addition, the FA values were negatively correlated with MDS‐OAβ level (figure 1). MDS‐OAB positive group showed a significant reduction in the cortical thickness in the left fusiform when compared with the MDS‐OAB negative group

Conclusion

Plasma MDS‐OAβ value might reflect cerebral amyloid status and global cerebral Aß retention in CN. We elucidated toxic role of OAβ by showing that the plasma OAβ value were associated with decrement of WM microstructural integrity in the early pathological process of AD. Cortical thickness did not differ according to cerebral Aβ burden but rather was associated with higher plasma OAβ level. Thus, MDS‐OAβ value might reflect earlier, and different, pathology than cerebral Aß retention measured using amyloid PET scan in CN with AD continuum.
The Mobile Toolbox for assessing cognition in older adults: associations with standardized cognitive testing and amyloid and tau PET
Authors: Jutten Roos J. , Burling Jessa , Campbell Emily C , Roy Chloe , Properzi Michael J , Amariglio Rebecca E. , Marshall Gad A , Johnson Keith A. , Sperling Reisa A. , Papp Kathryn V. , Rentz Dorene M.
Published: December 2023

Background

Remote, smartphone‐based cognitive assessments such as the Mobile Toolbox (MTB) can improve our ability to detect subtle, yet meaningful cognitive changes that are affected early on by Alzheimer’s disease (AD) pathology. The goal of our study was to investigate which MTB tests are sensitive to subtle cognitive deficits due to early amyloid and tau deposition.

Method

The MTB will be administered to N = 100 clinically normal (CN) older adults who have retrospective and prospective clinical, cognitive and AD biomarker data from three well‐characterized prospective cohort‐studies of CN older adults: the Harvard Aging Brain Study and the affiliated Subjective Cognitive Decline and Instrumental Activities of Daily Living cohorts. The MTB includes six measures of fluid cognition, including episodic memory (Picture Sequence Memory and Face‐Name Associations), executive functions (Dimensional Change Card Sort, Flanker), working memory (Memory for Sequence), processing speed (Number‐Symbol Match), and two measures of crystallized cognition (Spelling and Vocabulary). Using confirmatory factor analysis, MTB baseline data will be used to determine which MTB tests are most strongly associated with established clinical assessments (i.e., measures included in the Preclinical Alzheimer’s Cognitive Composite‐5 [PACC5]) as well as amyloid and tau biomarkers on positron emission tomography (PET) imaging.

Result

Preliminary MTB data was available on 15 participants (age 74.3±8.2, 63% female, 16.6±2.9 years of education, MMSE 29±1.5). Table 1 shows exploratory correlation analyses, revealing that both MTB crystallized measures were associated with education but not age or sex. As expected, worse performance on MTB memory measures were associated with lower PACC5 scores, and greater amyloid and tau burden, albeit at trend‐level. Executive function and processing speed measures were not related to amyloid but did show associations with entorhinal tau.

Conclusion

While preliminary, these findings suggest that the MTB may help elucidate the subtle cognitive deficits that are associated with early AD pathology. In addition to memory measures, the MTB fluid measures capture various aspects of cognitive function that are also relevant to preclinical AD. Data collection is ongoing, and next steps include examining which (combination of) MTB measures are most sensitive for detecting emerging AD pathology and to track cognitive change over time.
Clinical phenotype of the A431E mutation in PSEN1 arising as a founder effect from the Mexican State of Jalisco
Authors: Sánchez González Victor J. , Orozco Maribel , Figuera‐Villanueva Luis Eduardo , Matute Esmeralda , Ringman John M
Published: December 2023

Background

Autosomal dominant Alzheimer’s disease (ADAD) is a rare subtype of AD in which the disease is caused by mutations in the PSEN1, APP, or PSEN2 genes which are essentially fully penetrant. Mutations in PSEN1 are most common and several populations have been described within which the same causative variant appears to have arisen from a common founder. The study of such populations allows for an increased sensitivity for identification of genetic and non‐genetic variables affecting phenotype and for studying the effects of interventions.

Methods

We summarize 20 years of work characterizing the population with ADAD due to the A431E mutation in PSEN1.

Results

Nine families with 60 members with ADAD due to the A431E PSEN1 mutation were originally reported by investigators in Mexico City in 2006 (Yescas et al). They noted a mean age of onset of 40 years and 1 of 13 probands had spastic paraparesis (SP). All probands hailed from the Los Altos region of Jalisco State and all affected persons shared the same CA and GT dinucleotide microsatellite alleles surrounding the PSEN1 gene, suggesting a common origin of the haplotype. U.S. Investigators then reported an additional 15 families with the A431E variant. Mean age of onset was 39.5 years and 9/20 probands (45%) had SP. In 2020 Dumois‐Petersen et al, reported their experience of 46 index patients in Guadalajara from families in which 560 persons were identified to be at 50% risk of inheriting the mutation. Mean age of onset of 42.5 years with at least a moderate degree of leg spasticity being present in 77% in the first 2 years of symptoms. Memory loss was ubiquitous with language deficits ultimately being present in 82%, depression in 53%, delusions in 30%, Parkinsonism in 28%, cerebellar dysfunction in 23%, and seizures in 15%.

Conclusions

Combined efforts in the U.S. and Mexico have allowed the identification of more than 100 superficially distinct families with the A431E PSEN1 mutation and an estimated number of 1,260 identifiable at‐risk persons, providing an attractive target for both mutation‐specific genetic interventions and for anti‐AD therapy in general.

P30AG066530, U01AG051218, R01AG062007, R01AG069013
A single dose of lipopolysaccharide injection exacerbates synaptic engulfment by microglia, and dendritic spine loss in high‐fat diet‐induced obese rats
Authors: Chinchapo Thirathada , Chunchai Titikorn , Pintana Hiranya , Ongnok Benjamin , Pantiya Patcharapong , Jinawong Kewarin , Arunsak Busarin , Janjek Sornram , Kerdphoo Sasiwan , Apaijai Nattayaporn , Pratchayasakul Wasana , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

Diet‐induced obesity can lead to develop endotoxemia and cognitive decline (1). A previous study in Alzheimer’s disease model demonstrated that an increase in the colocalization of C1q, a classical complement protein, and microglia occurred, when those microglia increased synaptic engulfment, resulting in increased synaptic‐pruning process and synaptic loss (2). However, the effects of lipopolysaccharide (LPS) as endotoxin on peripheral inflammation, blood‐brain barrier(BBB) integrity, brain oxidative stress, synaptic engulfment by microglia, synaptic plasticity, and cognitive function in high‐fat diet‐induced obese rats have never been investigated.

Method

Sixteen male Wistar rats were randomly assigned to receive either a normal diet (ND, n = 8) or the high‐fat diet (HFD, n = 8) for 12 weeks. All animals in each dietary group were subsequently assigned into 2 subgroups (n = 4 /subgroup) to receive either a single dose of vehicle (1 ml of 0.9% normal saline solution, intraperitoneal (i.p.) injection, or LPS (0.5 mg/kg, i.p.). After the injections for 12‐16 hours, all animals were measured for cognitive function and the blood was collected. Then, animals were sacrificed, and their brains and spleens were obtained for further investigation.

Result

All HFD‐fed rats exhibited peripheral inflammation as indicated by increased spleen IL‐1β protein levels, BBB disruption as indicated by the reduction of hippocampal claudia‐5 protein levels, and increased brain oxidative stress as indicated by the increased brain malondialdehyde levels (p<0.05, Figure 1). Interestingly, LPS‐treated ND‐fed rats and vehicle‐treated HFD‐fed rats equally impaired microglial function by increasing synaptic engulfment as indicated by the increase in C1q colocalized in microglia and the decreased dendritic spine density (p<0.05, Figure 1). The results demonstrated that these parameters were aggravated in LPS‐treated HFD‐fed rats. Lastly, all HFD‐fed rats decreased the preference index of novel object location and recognition test suggesting long‐term HFD consumption caused cognitive decline (p<0.05, Figure 1).

Conclusion

Long‐term HFD consumption, but not LPS alone, caused cognitive decline by increasing peripheral inflammation, disrupting BBB integrity, increasing brain oxidative stress, increasing synaptic engulfment by microglia, and decreasing synaptic plasticity. Microglia are susceptible to impair their function in response to LPS, which potentially worsen brain pathologies in obese condition.