bluuebunny/crossref_metadata_2025 huggingface dataset:
A Haptoglobin (HP) Exon Deletion Polymorphism Alters the Effect of APOE Alleles on Alzheimer’s Disease in European‐Descent People with APOEε4
Authors: Bai Haimeng , Naj Adam C. , Leung Yuk Yee , Wang Li‐San , Schellenberg Gerard D. , Mayeux Richard , Pericak‐Vance Margaret A. , Farrer Lindsay A. , Dumitrescu Logan , Hohman Timothy J. , Kunkle Brian W. , Martin Eden R. , Haines Jonathan L. , Bush William S.
Published: December 2022

Background

Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE) – the strongest risk gene for sporadic Alzheimer’s disease (AD). The HP gene has two functional alleles, HP2 and HP1, which contains a two‐exon deletion that changes its protein structure conformation. We hypothesize that this structural variation is associated with AD.

Method

To investigate this, we imputed the HP genotypes for 12,403 cases and 11,699 normal controls from the Alzheimer’s Disease Genetics Consortium (ADGC), respectively within each cohort of 18 European‐descent cohorts, using a custom reference panel. We then evaluated the association between HP genotype and the AD status using logistic regression, adjusting for sex, age, and the first 3 principal components.

Result

The imputed HP1 frequency is 0.376. We found HP influences AD given an APOEε4 genetic context. In individuals with ≥1 APOEε4 allele (n=10,054), HP1 homozygotes attenuate the effect of the second APOE allele; both the protective effect of the ε2 allele and the risk effect of the ε4 allele are dramatically reduced (odds ratio, OR=0.92, p=0.415 of ε2 versus ε3, OR=1.09, p=0.415 of ε4 versus ε3). However, the HP2 allele accentuates the effect of the second APOE allele, both the protective effect of the ε2 allele and the risk effect of the ε4 allele (OR=0.80, p= 0.003 of ε2 versus ε3, OR=1.25, p=0.003 of ε4 versus ε3). This effect is even stronger in HP2 homozygotes (OR=0.64, p=0.003 of ε2 versus ε3, OR=1.55, p=0.003 of ε4 versus ε3). In addition, we analyzed time to AD diagnosis with a cox proportional hazard regression model within the more consistently examined National Alzheimer's Coordinating Center (NACC) cohorts (n=7,448). A cox model shows that HP2 alleles additively decrease the hazard of AD (hazard ratio=0.94, p=6.85e‐3).

Conclusion

HP impacts AD risk in people with APOEε4. Furthermore, this risk is different in people with APOEε24, APOEε34, and APOEε44 genotypes. Though the mechanism still awaits investigation, based on the current knowledge of HP function our results suggest a possible differential anti‐oxidative ability of HP proteins for distinct APOE proteins. As such, the HP protein may be an imminently translatable therapeutic target for AD in APOEε4 carriers.
African American Dementia Caregivers’ Perspectives on and Appraisal of Stress Associated with the Caregiving Role: A Qualitative Study
Authors: Block Laura M , Cotton Quinton , Seyyedmirza Paria , Chang Juliet , Gilmore‐Bykovskyi Andrea L
Published: December 2022

Background

African Americans are disproportionately impacted by Alzheimer’s disease and related dementias (ADRD), with family members providing the majority of support and care. Dementia caregivers often face high levels of stress and burden which contribute to poor physical and psychological health outcomes. African American dementia caregivers often face greater risk for stress and burden with discrepant evidence on whether this leads to worse outcomes compared to counterparts. Yet African American dementia caregivers remain under‐included in research designed to understand and ameliorate the stress and burden of caregiving. Our study aimed to understand African American dementia caregivers’ perspectives and appraisal of stressors surrounding caregiving and stressful events, such as hospitalization of the person with ADRD.

Methods

We harnessed qualitative interview data from the Stakeholders Understanding of Prevention Protection and Opportunities to Reduce HospiTalizations (SUPPORT) Study, a multi‐site study designed to determine family caregiver perspectives surrounding hospitalizations for people with ADRD residing in highly disadvantaged neighborhoods. Data from 30 dementia caregivers who self‐identified as African American were analyzed using thematic analysis.

Results

All participants described the presence of stressors and stressful events related to their life broadly and to dementia caregiving more specifically. However, there was great variation in the described degree of stressors in caregiver’s daily life. Caregivers experiencing a greater number, more recent, and more acute stressors described greater burden in their daily life. Long‐standing stressors, such as family conflict and financial hardship, sometimes ‘resurfaced’ with the proximity and role changes brought on by caregiving. Other individual and situational factors, such as one’s own health or status as a ‘sandwich caregiver,’ or the habits and preferences of the person with ADRD, could serve as contributors to overall stress. Few caregivers related stressors to long‐term outcomes, though some described strategies to seek formal mental health counseling.

Conclusions

African American dementia caregivers described a variety of acute and ongoing stressors that related not only to caregiving for the person with ADRD but also the caregiver’s personal health and their broader familial and neighborhood context, signaling the need for adaptive caregiver support interventions capable of addressing intervention targets across various stressors.
Different associations of varying types of Vitamin E and cognitive function in older adults with or without APOE Ɛ4 allele
Authors: Liu Xiaoran , Beck Todd , Dhana Klodian , Evans Denis A , Rajan Kumar B
Published: December 2022

Background

Different forms of vitamin E may have a different association with cognitive function, which might vary by the APOE E4 allele status. We aim to examine vitamin E from different sources and in varying forms and their relation to cognitive decline among those with and without the APOE E4 allele.

Methods

We included 2,014 participants from the Chicago Health and Aging Project (62% African Americans, 63% female). Global cognition was assessed using a composite score of episodic memory, perceptual speed, and the MMSE. Diet was assessed by a 139‐item FFQ. APOE genotype was assessed by hME Sequenom mass‐array platform. Mixed models were adjusted for age, sex, education, smoking status, calorie intake, alcohol consumption, use of supplements, time since baseline, and the interaction term of time with each covariate.

Results

A higher dietary vitamin E was associated with slower cognitive decline. Those in the highest quintile of dietary vitamin E intake had 28% slower cognitive decline than the lowest quintile (β = 0.014, p = 0.02). A higher intake of dietary αlpha‐tocopherol was associated with slower cognitive decline in participants with APOE E4 allele, but not among those without. In participants with APOE E4 allele and in the highest quintile of alpha‐tocopherol intake had a 16.4% slower rate of global cognitive decline than those in the lowest quintile (β = 0.015, p = 0.0015). A higher intake of delta‐tocopherol was associated with a slower decline in individuals without the APOE E4 allele only. Among those without the APOE E4 allele and in the highest quintile, the rate of global cognitive decline was slower by 22% than the lowest quintile (β = 0.012, p = 0.0014). We found no significant associations between beta‐ and gamma‐tocopherol intakes and cognitive decline among those with and without the APOE E4 allele.

Conclusion

Our study found a positive association of alpha‐tocopherol with cognitive decline among those with the APOE E4 allele and delta‐tocopherol with the decline in those without the APOE E4 allele. Our findings suggest that different forms of vitamin E might have a different association with cognitive decline in older adults depending on their APOE E4 allele status.
Screening for MCI in the Swedish H70 Birth Cohort Study using digital automatic speech biomarker tests for cognition and a machine Learning classifier
Authors: Skoog Johan , Mallick Elisa , Bodin Timothy Hadarsson , Mina Mario , Linz Nicklas , Tröger Johannes , Skoog Ingmar
Published: December 2022

Background

Even if classic neuropsychological tests often have excellent psychometric properties to detect Mild Cognitive Impairment (MCI), they are not suitable for cost‐effective low‐burden screening at scale. Speech‐based digital biomarkers can be deployed in a highly automated fashion. We present the results of an MCI screening algorithm based on a digital Speech Biomarker for Cognition (SB‐C) in the Swedish H70 birth cohort study.

Method

We used a sample from the Swedish H70 Birth Cohort study (N = 404; 356 cognitively healthy (HC), 48 MCI). We automatically extract the SB‐C score and its subscores (executive function, memory, semantic memory, processing speed) from SVF and RAVLT speech recordings using ki:elements’ proprietary speech analysis pipeline including automatic speech recognition and feature extraction. We performed (1) inferential statistics comparing MCI and HC group based on the biomarker scores and (2) built a machine learning model to screen for MCI. For (1) we performed a non‐parametric Kruskal‐Wallis test to compare SB‐C scores of both HC and MCI groups to check for general feasibility. For (2), we trained a support vector machine model with class weights and leave‐one‐out cross validation to classify between MCI and HC using the SB‐C scores as input (overall score and the subscores).

Result

There was a group difference for the SB‐C aggregated cognition score between the groups (HC > MCI; χ2 = 45.9 (1), p <0.001; Figure 1), and also for the subscores (Table 2). To classify between MCI and HC, using a feature selection method, the best model was found for all the five biomarker scores selected with an Area Under Curve of 0.77 (Figure 2), a specificity of 0.77 and a sensitivity of 0.76 (Table 3).

Conclusion

We found that a machine learning‐based screening algorithm based on the SB‐C can detect probable MCI patients in representative population sample of older people using a speech biomarker read‐out.
Development of a Telehealth Intervention for People with Dementia: ROAD MAP (Recovery‐Oriented Approach to Dementia through Meaningful Activity Participation)
Authors: Garcia Lesley
Published: December 2022

Background

Given the success of recovery approaches for people living enduring mental illness who nevertheless experience the outcome of personal recovery despite ongoing clinical symptoms it is appropriate to consider applying this model to dementia. Additionally, telemedicine is increasingly seen as an effective and efficient means of health care delivery among this population (Rice et al., 2021). Leamy and colleagues identified the elements of CHIME (connectedness, hope and optimism, identity, meaning in life and empowerment) as the key features of successful recovery‐oriented approaches (Leamy et al., 2011). This research is postulating that enhancing CHIME in people with mild dementia through the use of a web‐based self‐management intervention tool will have health‐promoting outcomes for both the person living with mild dementia and their carer.

Method

The research design used in this intervention development process is participatory design (Young et al., 2020) based on systematic reviews, Agilie methodology in line with current best practice guidance on research with and for people living with dementia (Gove et al., 2018). Specifically, the intervention co‐design process will follow the guidance (Cathain et al., 2019) on the development and reporting (Duncan et al., 2020) of complex healthcare interventions.

Result

The development of a novel telehealth intervention that enhance markers of personal recovery, defined as CHIME, in people with mild dementia.

Conclusion

It is intended that this systematic development process will enhance knowledge of the methodology of development of useful and acceptable telehealth tools for people living with this condition. Involvement of stakeholders in the co‐development process will be invaluable with regard to usability and acceptability, and hopefully limit wasting of research resources as a consequence.
Proposal of a stepwise approach for CSF biomarkers testing for Alzheimer's Disease in middle‐ and low‐income countries
Authors: Bicalho Maria Aparecida Camargos , Hansen Erika de Oliveira , Dias Natália Silva , Miranda Millena Figueiredo , Miranda Mariana Figueiredo , Costa Giulia , Barbosa Izabela , Burgos Ivonne Carolina Bolaños , Romano‐Silva Marco Aurelo , Viana Bernardo de Mattos
Published: December 2022

Background

The incidence and prevalence of dementia are increasing, mainly in low‐ and middle‐income countries. Alzheimer's disease (AD) accounts for the majority of cases. Thus, cost‐effective techniques with lower cost are necessary for scaling up the number of tested individuals in these countries for research and clinical use. Luminex (Millipore xMap®) is a semi‐automated test that can analyze CSF biomarkers with a cost per sample of one fourth of ELISA’s kits.

Method

We performed a cross‐sectional, case‐control study. After consent, 35 older adults were submitted to clinical and neuropsychological assessment, and then to a lumbar puncture. Based on clinical and neuropsychological assessment, seven patients had a diagnosis of AD’s dementia (McKhann criteria), 17 of amnestic mild cognitive impairment (MCI) (DSM‐5 criteria) and 11 without objective cognitive impairment. CSF biomarkers concentrations were measured by INNOTEST® (ELISA) and Millipore xMap®. Both techniques were compared and the accuracy of the latter was assessed.

Result

Millipore xMap® measurements showed a robust accuracy for all biomarkers, with AUC of 0.808 for t‐Tau, 0.935 for p‐Tau and 0.952 for Aβ42 compared to ELISA as the reference test. The Aβ42 showed a great sensibility (100%) and the ratio p‐tau/Aβ42 a good specificity (0,944). So, we propose a stepwise approach for the diagnosis of AD based on CSF biomarkers. A patient with a cognitive assessment suggestive of AD (MCI or initial dementia) could be initially assessed for CSF biomarkers with a more affordable test, such as Luminex. If there is a need of a confirmation due low pretest probability or the need of a more specific test for a high‐cost treatment, researchers and clinicians could order an ELISA test in the same CSF sample or additional molecular neuroimaging techniques. For patients with a high pretest probability, Luminex has excellent accuracy and can define biological diagnosis.

Conclusion

The use of Millipore xMap® as the first step in a stepwise approach for the assessment of suspected AD in middle‐ and low‐income countries cases is promising, considering its accuracy and lower cost per sample. Still, the implementation of the proposed approach in this study should be replicated in larger and different samples.
Diagnostic Utility of Brain MRI Volumetry in Comparing Traumatic Brain Injury, Alzheimer Disease and Behavioral Variant Frontotemporal Dementia
Authors: Raji Cyrus A. , Meysami Somayeh , Porter Verna R. , Merrill David A. , Mendez Mario F.
Published: December 2022

Background

Application of brain MRI with volumetric quantification can improve delineation of various neurocognitive disorders.

Method

We utilized 136 participants from previously defined cohorts of traumatic brain injury (TBI; n=40) [1], early (EOAD; n=45) and late onset Alzheimer disease (LOAD; n=31) [2] as well as of behavioral variant frontotemporal dementia (bvFTD; n=20). Participants had brain MRI including 3D T1 sequences amendable to volumetric quantification. Scans were analyzed with an FDA cleared software program, Neuroreader[3] to measure regional brain volumes. At the time of analysis, Mini‐Mental State Exam (MMSE) scores were available on majority of participants (n=125). One‐way ANOVA compared mean age, MMSE, and brain volumes across all four groups with Bonferroni correction for multiple comparisons. All brain volumes were corrected for total intracranial volume (TIV). Discriminant analysis was done with leave‐one‐out cross validation on measured brain volumes to determine diagnostic delineation across groups. Automated linear regression identified predictive features from these quantified structures.

Result

Participant demographics and MMSE scores are shown in Table 1. With respect to age, LOAD was the oldest compared to other groups (p<.001). There were no statistically significant differences in sex (p=.58) with women comprising 54.4% of the entire sample. EOAD and LOAD had the lowest MMSE scores compared to TBI (p=.04 for EOAD and p=.01 for LOAD). Regional volume difference across groups showed lowest hippocampal volumes in LOAD (p=.005), low white matter volume in TBI (p=.007), lower parietal lobe volumes in EOAD (p<.01), and lower frontal lobe volumes in bvFTD (p<.001). Regional volume differences resulted in a correct classification of 89%, 79.4% after cross validation. Predictive features included caudate, amygdala, frontal, parietal, temporal lobar and total white matter volumes.

Conclusion

We identified the diagnostic utility of regional volumetric differences across multiple neurodegenerative and non‐neurodegenerative disorders. The lower parietal lobe volumes in EOAD and lower hippocampal volumes in LOAD and well as frontal atrophy of bvFTD reflect the known anatomical distribution of pathology in those conditions[4]. The white matter volume loss in TBI is a previously demonstrated feature of that condition[5]. Brain MRI volumetry may therefore be beneficial in clinical practice.
The relationship of soluble p‐tau isoforms with brain amyloid and tau deposition in sporadic AD
Authors: Barthélemy Nicolas R. , Saef Benjamin A. , Li Yan , Gordon Brian A. , He Yingxin , Horie Kanta , Sato Chihiro , Ovod Vitaliy , Benzinger Tammie L.S. , Morris John C. , Bateman Randall J. , Schindler Suzanne E.
Published: December 2022

Background

Hyperphosphorylated tau isoforms (p‐tau) in cerebrospinal fluid (CSF) and plasma represent promising measures to monitor Alzheimer disease (AD) pathological changes. Brain amyloid deposition precedes tau aggregation and associated clinical decline by two decades. Several CSF and plasma p‐tau isoforms have been described as potential surrogates for tau Positron Emission Tomography (PET) imaging, but p‐tau isoforms have a strong association with amyloid PET, and increase without tau pathology. In this study, we investigated the relationship between multiple CSF p‐tau isoforms and brain imaging measures in the Knight ADRC cohort.

Method

We analyzed 10 p‐tau isoforms by mass spectrometry in 1932 CSF samples (1173 participants). Associated data includes 1250 amyloid PET and 442 tau PET scans, as well as CSF Aβ42/Aβ40 by immunoassay for all samples. We measured phosphorylation occupancies (ptau/tau) at T111, T153, T175, T181, S199, S202, T205, S208, T217 and T231, together with corresponding p‐tau and tau concentrations. We compared the accuracy of CSF p‐tau isoforms in predicting amyloid PET and tau PET status stratified according to amyloid PET, tau PET and/or Clinical Dementia Rating (CDR) status.

Results

PT217/T217 best‐predicted abnormal amyloid PET (AUROC=0.980) or CSF Aβ42/Aβ40 (AUC=0.954). PT217/T217 predicted brain amyloidosis in asymptomatic and symptomatic participants with similar accuracy (AUC=0.979 and 0.986 respectively) and was correlated with amyloid PET centiloid and CSF Aβ42/Aβ40 (Spearman R=0.73 and ‐0.76, p<0.0001). Notably, the correlation between pT217/T217 and amyloid PET centiloid was higher in amyloid PET(+)/tau PET(‐) compared to amyloid PET(+)/tau‐PET(+) (R=0.77, p<0.0001 versus 0.16, p=0.007). PT205/T205 and pT217/T217 better predicted tau PET positivity in amyloid PET(+)positive participants (AUC=0.908 and 0.866). These markers were also associated with tau PET signal in tau PET(+) participants (R=0.53 and 0.55 p<0.0001). Other p‐tau isoforms also predicted amyloidosis, except for T175, S199, S202 and T205. Only pT205/T205 and pT217/T217 were correlated with tau‐PET in tau PET(+) participants.

Conclusion

These results suggest that tau hyperphosphorylation, notably at T217, is more strongly associated with brain amyloid burden than tau deposition in tau PET(‐) individuals. After tau PET becomes positive, p‐tau217 and p‐tau205 are correlated with tau burden. Soluble p‐tau are markers of both amyloid and tau aggregation in the AD brain.
Therapeutic Efficacy of the Murine Precursor to PBD‐C06: a Novel CDC‐Mutant Anti‐pGlu3Aβ mAb
Authors: Bathini Praveen , Grenon Martine , Papavergi Maria‐Giusy , Price Brittani R. , Schroeder Maren K. , Kleinschmidt Martin , Rahfeld Jens‐Ulrich , Schilling Stephan , Lemere Cynthia A.
Published: December 2022

Background

Pyroglutamate‐3Aβ (pGlu3Aβ) is a toxic N‐terminally truncated and modified form of Aβ that leads to faster aggregation and seeding of plaques, making it an important target in Alzheimer’s disease. Anti‐amyloid antibodies, e.g., bapineuzumab, are associated with Amyloid‐Related Imaging Abnormalities (ARIA) involving vasogenic edema and microhemorrhages in AD patients, especially in ApoE4 carriers. Previously, we demonstrated reductions in plaques and cognitive deficits using an anti‐pGlu3Ab mAb, 07/2a. Here, we tested a novel CDC‐mutant version (07/2a‐k, murine precursor to PBD‐C06) to avoid C1q activation to reduce vascular‐related inflammation associated with anti‐amyloid antibodies.

Method

To estimate an effective therapeutic dose, 12 mo‐old APP/PS1dE9 mice were treated weekly (i.p.) for 5 weeks with 150, 300 or 600 µg 07/2a‐k or IgG2a (n=10‐12/group). General Ab and pGlu3Aβ levels were quantified by ELISA and immunohistochemistry. Next, 16 mo‐old APP/PS1dE9; hApoE4 mice were treated weekly (i.p.) for 15 weeks with 350 µg of 07/2a‐k, 3D6‐L (a murine analog of bapineuzumab), or IgG2a, while hApoE4 mice were treated with PBS (n=10‐13 mice/group). Subsequently, cognitive testing was performed over 3 weeks using the Spatial Novelty Y Maze (SNYM), Novel Object Recognition (NOR), and the Barnes Maze followed by euthanasia.

Result

Five weekly treatments with 07/2a‐k in the dosing study did not alter general and pGlu3 Aβ biochemical levels; however, hippocampal pGlu3Aβ plaques were significantly reduced (300 µg, p<0.0005; 600 µg, p<0.005). In the therapeutic study, 3D6‐L reduced Aβx‐42 levels (p<0.009) by ELISA but not Abx‐40 levels. 07/2a‐k did not significantly alter Aβx‐42 or Abx‐40 levels. Both antibodies improved performance in the NOR test (07/2a‐k, p<0.05; 3D6‐L, p=0.05) and showed a non‐significant trend for improvement in the SNYM and Barnes maze compared to IgG2a controls. Macro‐hemorrhages were visible in 33% of 3D6‐L treated mice but not in 07/2a‐k treated mice.

Conclusion

Treatment with the 3D6‐L mAb, a murine analog of bapineuzumab, lowered cerebral Aβ levels and improved cognition but induced macro‐hemorrhages in aged APP/PS1dE9;hApoE4 mice, while treatment with 07/2a‐k, the precursor to PBD‐C06, did not alter general Ab levels but improved cognition in the absence of macro‐hemorrhages. Further analyses are underway to quantify cerebral pGlu3Ab levels, plaques, CAA, microhemorrhages and gliosis. (NIH 1RF1AG058657‐CAL)
Screening for Memory Concerns at the Well‐Woman Visit
Authors: Joyce Jillian L. , Caes Dorota , Chapman Silvia , Gottesman Reena T. , Haque Hoosna , Manly Jennifer J , Waltrip Leah H. , Rizer Sandra , Marder Karen , Rosser Mary L. , Cosentino Stephanie
Published: December 2022

Background

Routine healthcare visits offer the opportunity to screen older adults for cognitive changes that accompany the earliest clinical stages of Alzheimer’s disease (AD) including Mild Cognitive Impairment (MCI) and Subjective Cognitive Decline (SCD). It is well‐established that women are at increased risk for AD and that many women see their gynecologist as their primary care doctor. Given this unique relationship, the Women’s Preventive Services Initiative and the American College of Obstetrics and Gynecology now advocate for integrated care of women at all ages. Memory screening of older women should be paramount in this effort. Research is needed to determine which screening tools are most effective and practical. Here we assess the feasibility and utility of a subjective memory screener at the well‐woman visit.

Method

Women aged 60 and above completed a 5‐item screener at their well‐woman visit at the Columbia University Integrated Women’s Health Center (Table 1). Women who endorsed any item were considered to have a positive screen and were given the option to pursue clinical evaluation for memory concerns through the Division of Aging and Dementia.

Result

Only 8 of 354 women declined to complete the screener. Of the completed screeners, 16% (n = 56) were positive. The most frequently endorsed item was difficulty with memory or thinking compared to others the same age (8%, n = 28) (See Table 1). 44% (n = 24) of women with positive screens pursued referral, and six have been seen to date. One woman was diagnosed with MCI. Clinical impressions of the remainder were unremarkable. All six cases had family history of dementia or memory problems.

Conclusion

The well‐woman visit provides a key opportunity to routinely screen older women for early indicators of AD and treatable causes of cognitive impairment. Preliminary results support the feasibility and value of such screening as part of a comprehensive well‐woman program. Early identification of women experiencing SCD will enable investigation into the cause of their memory concerns, and longitudinal monitoring of cognitive change. Future work should evaluate the added value of an objective cognitive screen to complement SCD screening and identify women who may benefit from further evaluation.
Diabetes is related to cognition but not plasma amyloid‐β 42/40 in an African American cohort
Authors: Ennis Gilda E. , Bouges Shenikqua , Zuelsdorff Megan , Van Hulle Carol A. , Jonaitis Erin M. , Koscik Rebecca Langhough , Lambrou Nickolas H. , Salazar Hector , Carter Fabu P , James Taryn T. , Johnson Adrienne L. , Fischer Barbara L. , Kirmess Kris , Holubasch Mary S. , Meyer Matthew R. , Venkatesh Venky , West Tim , Verghese Philip B. , Yarasheski Kevin E. , Chin Nathaniel A. , Asthana Sanjay , Carlsson Cynthia M. , Johnson Sterling C. , Bendlin Barbara B. , Gleason Carey E.
Published: December 2022

Background

The prevalence of clinical Alzheimer’s disease (AD) and type 2 diabetes is higher in African Americans (AA) relative to non‐Hispanic White Americans. Although diabetes is a risk factor for Alzheimer’s clinical syndrome, it is unclear whether diabetes associates with amyloid‐β, a pathological hallmark of AD. We investigated whether diabetic status was associated with age‐related decline in plasma amyloid‐β (Aβ) 42/40 ratio and cognition in a predominantly dementia‐free AA cohort.

Method

Participants (N=314) were middle‐aged and older adults (Table 1) enrolled in the African Americans Fighting Alzheimer’s in Midlife cohort. EDTA plasma was collected at 1‐8 visits for Aβ 42/40 quantification using immunoprecipitation mass spectrometry (C2N Diagnostics, St. Louis, MO). 52% had >1 plasma Aβ 42/40 measurements over an average interval of 4.9 years (SD=3). Recall (immediate and delayed) and executive functioning were assessed using Rey’s Auditory Verbal Learning Test and Trails B, respectively. Diabetic status was determined from clinician‐report, self‐report, self‐report of antidiabetic medication use or fasting glucose ≥126 mg/dL. Cognitive data from the first of 1‐6 visits and diabetic status were obtained at the same visit as baseline plasma Aβ 42/40 for 96% of participants. Linear mixed‐effects models tested diabetic status as a moderator of age‐related decline in plasma Aβ 42/40 ratio and cognition. If age x diabetic status was not significant, diabetic status was tested without the interaction. Covariates included APOE4 carrier status and sex, and education was included when cognition was the outcome.

Results

Diabetic status did not significantly moderate age‐related decline in plasma Aβ 42/40 (β=0.0001, p=.21) or predict average plasma Aβ 42/40 ratio (β=‐0.001, p=.22). Diabetes was also not significantly related to aging‐associated decline in cognition but was a significant predictor of worse average Trails B scores (Table 2). Results from a cognitively unimpaired subsample (n=261) revealed a similar pattern.

Conclusion

In a predominantly dementia‐free AA cohort, diabetes was unrelated to plasma Aβ 42/40 but was related to worse Trails B performance. Poor Trails B performance has been linked in previous studies to cerebrovascular dysfunction. Determining mechanisms, vascular and AD pathological pathways, that link diabetes to increased dementia risk in AAs warrants further investigation.
Inhibition of calcium‐dependent phospholipase A2 improves blood‐brain barrier integrity in ApoE4 carrying mice
Authors: Kerman Bilal E. , Duro Marlon Vincent V. , Maria Naomi Sta. , Liu Xiaodan , Wang Shaowei , Van Valkenburgh Juno S. , Chen Kai , Jacobs Russell E. , Yassine Hussein N.
Published: December 2022

Background

Blood‐brain barrier (BBB) is essential for neural health and function. Degradation of BBB is observed in Alzheimer’s disease (AD) and is more pronounced in individuals carrying the apolipoprotein E4 (ApoE4) allele, which is a major genetic risk factor for AD. ApoE4 increases the activation of calcium‐dependent phospholipase A2 (cPLA2), which is linked to BBB function. Here, we asked if cPLA2 inhibition in ApoE4 carrying mice could repair BBB integrity and if the changes could be observed in vivo by dynamic contrast‐enhanced MRI (DCE‐MRI).

Method

16‐month‐old ApoE4 targeted replacement (ApoE4‐TR) mice were divided into a control group treated with vehicle (n=4) and an experimental group treated with a cPLA2 inhibitor ASB‐14780 (n=4). All imaging was performed using a 7T MRI scanner. DCE‐MRI protocol involved acquisition of baseline images (5min), mice receiving a bolus of gadolinium diethylenetriaminepentaacetic acid (Gd‐DTPA, 0.3mmol/kg, i.v.)) and followed by post‐bolus scans for 20min. Regions of interest (ROIs), such as the hippocampus and isocortex, were manually defined using T2‐weighted (FSE) anatomical scans in ImageJ. Volume transfer constants (KTrans) of the contrast agent uptake were calculated for each subject from the dynamic DCE‐MRI scan using the Patlak model on the Rocketship software (MATLAB).

Result

KTrans values for the isocortex and the hippocampus were calculated for two animals from the control group and three animals from the experimental group. The mean KTrans value in the hippocampus region was 60% lower for the mice treated with cPLA2 inhibitor than controls (p=0.056), 0.0459 ± 0.0168 min‐1 and 0.117 ± 0.030 min‐1 respectively. Similarly, the mean KTrans value in the isocortex for the treated mice was 50% lower than the controls (p=0.89), 0.0554 ± 0.018 min‐1 and 0.110 ± 0.028 min‐1 respectively.

Conclusion

We observed that cPLA2 inhibition decreased KTrans values implying increased BBB function. Thus, cPLA2 inhibition can be a possible therapeutic path towards reversing some of the damage to the brain due to AD. Currently, we are validating this observation with larger sample sizes and by analyzing the brains of these mice for changes in molecular signatures of BBB.
Agitation in Cognitive Disorders: Use of the National Alzheimer’s Coordinating Center Uniform Data Set (NACC‐UDS) to Evaluate the International Psychogeriatric Association Definition.
Authors: Sano Mary , Zhu Carolyn W , Neugroschl Judith A. , Grossman Hillel , Schimming Corbett , Aloysi Amy
Published: December 2022

Background

The consensus‐based definition of agitation by the International Psychogeriatric Association (IPA) has not been evaluated in community‐based samples who are not preselected for behavioral disturbances. Here we use a well‐characterized cohort of community‐dwelling older individuals with cognitive impairment to assess the IPA criteria associated with agitation to validate the construction of this diagnostic entity

Method

We used the National Alzheimer Coordinating Center Unified Data Set (NACC‐UDS) to select a cognitively impaired cohort across etiological diagnoses, excluding those with a primary psychiatric etiology (IPA criteria A). We used this dataset to evaluate the IPA consensus‐based provisional definition of agitation in cognitive impairment. We used clinician diagnosis of agitation as a gold standard in those with MCI and dementia and the Neuropsychiatric Inventory–Questionnaire (NPI‐Q) algorithm to define agitation symptoms (IPA Criteria B); Standardized assessments of function (including Functional Assessment Scale and CDR Sum of Boxes) were used to assess excess social/functional disability (IPA Criteria C). We examined patterns of psychiatric comorbidities to determine if they were consistent with IPA criteria (IPA Criteria D).

Result

We identified a cognitively impaired cohort (N = 19,424), across multiple etiologies (AD = 73.7%, FTLD = 9.7%, LBD = 6.8% and vascular brain injury = 3.5%). Mean (SD) age was 72.7 (10.1) years, 77.0% were non‐Hispanic White, 11.1% non‐Hispanic Black, 8.3% Hispanic, with an average of 14.7(3.7) years of education. Mean (SD) MMSE = 22.0(6.4), FAQ = 12.7(9.5), and GDS = 2.8(2.8). Clinician judgement of agitation was present in 15.7% of the sample. Those with agitation were younger, more likely to be male, had slightly lower educational levels and were more likely to be from under‐represented groups. 38.6% had agitation by NPI algorithm, with high agreement with clinician judgement. More than 84% of those with clinician judgment of agitation and 74% of those meeting the NPI algorithm demonstrated excess social/functional disability. Psychiatric comorbidities were present in 38% of the sample without evidence of agitation, and were higher in those with agitation (56% to 82%, depending on agitation definition).

Conclusion

Agitation ranges between 15 and 38% in those with cognitive impairment. The pattern of excess disability and presence of comorbid psychiatric symptoms in this well characterized dataset is consistent with IPA published criteria.
Simulations and Experiments Reveal Diverse APOE States that Inform their Pathogenicity
Authors: Levine Zachary
Published: December 2022

Background

Mutations to the lipid transport protein Apolipoprotein E (APOE) can dramatically increase the risk of developing late‐onset Alzheimer’s Disease (AD) by up to 15‐fold, however a molecular description of why some isoforms are protective while others are pathological has remained elusive. We hypothesize that individual APOE isoforms sample distinct conformational landscapes that are modulated by the presence of lipids, and that these landscapes contain co‐existing pathological and protective states.

Method

To test this hypothesis, we carried out a combination of molecular dynamics (MD) simulations and single‐molecule FRET (smFRET) experiments to highlight the conformational heterogeneity of human APOE isoforms, thereby informing states that differentially traffic lipids into neurons.

Result

Our data suggests that there is no single pathological or protective APOE conformation, but rather a broad spectrum of protective and susceptible conformations that impact disease and memory impairment.

Conclusion

Biophysical studies are powerful tools that can inform the molecular mechanisms driving Alzheimer’s Disease and help bridge the gap between genetic associations (e.g. APOE status) and clinical phenotypes such as amyloid buildup or memory impairment.
Pooling CSF Measurements Across Multiple Cohorts in the Preclinical Alzheimer's Consortium
Authors: Lokhande Vishnu Suresh , Wang Jiangxia , Soldan Anja , Pettigrew Corinne , Moghekar Abhay , Morris John C. , Fagan Anne M. , Schindler Suzanne E. , Xiong Chengjie , Albert Marilyn S. , Johnson Sterling C. , Singh Vikas
Published: December 2022

Background

Studies focused on understanding cerebrospinal fluid (CSF) biomarkers of presymptomatic disease processes in Alzheimer’s disease (AD) are restricted by sample sizes that lack statistical power to investigate subtle effects of interest pertaining to risk. Pooling data across cohorts may be effective to identify early trends in CSF biomarkers to subsequent neurodegeneration and cognitive decline. Unfortunately, different instruments, preanalytics and workflows at each site lead to unique challenges when analysis of a pooled dataset is undertaken. We report initial findings from harmonized pooling of CSF measurements (cross‐sectional) across three preclinical AD studies at different institutions on a combined cohort size of N=733.

Method

CSF measurements were contributed from three studies: Adult Children Study (ACS), Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD). For harmonization, ACS was the reference site to which the CSF measurements from WRAP and BIOCARD were transformed using our domain adaptation algorithm (affine transformation to align covariate‐matched distributions under a distributional discrepancy measure). Parameters are optimized using Stochastic Gradient Descent in PyTorch.

Result

a) Figure 1 shows each CSF measure as a function of age for each study (using the first CSF timepoint). The trend lines as age progress are preserved in the harmonized pooled data (Figures1‐ 2). b) Figure 3 shows each CSF measure before/after harmonization. c) Figure 4 includes scatter plots of CSF measures before/after harmonization using a categorical coding for APOE e4 status. We see that the shape of the distribution for each measure is preserved.

Conclusion

These results show the feasibility of aligning CSF values from different cohorts and assay platforms (Lumipulse G1200 assay in ACS and Biocard and Roche Elecsys in WRAP). Mathematically rigorous schemes for analysis of pooled datasets based on modern developments in machine learning are facilitating AD research. We have shown that deploying such ideas for harmonizing/pooling CSF measures across preclinical AD studies appears viable. Our ongoing investigations are focused on understanding and quantifying the degree of improvements such schemes may offer for downstream statistical analysis tasks such as longitudinal trajectories of these measures as a function of demographic variables and risk factors.
Optimizing early detection of beta‐amyloid accumulation with PET using spatial extent
Authors: Farrell Michelle E. , Thibault Emma G. , Becker Alex , Price Julie C , Schultz Aaron P. , Properzi Michael J , Buckley Rachel F. , Jacobs Heidi I.L. , Hanseeuw Bernard , Sperling Reisa A. , Johnson Keith A.
Published: December 2022

Background

As clinical trials shift towards prevention, there has been increasing interest in improving early detection of beta‐amyloid (Aβ), below standard global PET positivity thresholds. While many studies have demonstrated that some regions appear more vulnerable to the earliest deposits, those regions have varied widely across studies. We sought to develop more flexible metrics for identifying subthreshold individuals at risk for progression to global Aβ positivity by evaluating a wide range of early regional targets and expanding our measurement beyond tracer retention (DVR/SUVR) to include spatial extent.

Method

269 clinically‐normal older adults were included from the Harvard Aging Brain Study, focusing on 150 initially globally PIB‐ adults with longitudinal PET. Region‐specific positivity thresholds were computed using iterative longitudinal two‐level linear mixed effect models that identified the cutoff beyond which local accumulation significantly increases over time. Next, we identified all regions significantly predictive of future global accumulation in initially PIB‐ adults and generated 3 aggregate masks at liberal (p<.05), moderate (p<.001) and conservative a‐levels (Bonferroni p<.0007). DVR and spatial extent (number of elevated ROIs) were computed in each mask. Receiver operator characteristic (ROC) curve analysis determined sensitivity/specificity of each metric to predict future global positivity. External validation was performed using globally florbetapir‐negative (FBP‐) healthy controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=211).

Result

Regional variations in measurement reliability were detected (Fig1) and accounted for by employing accumulation‐based regional positivity thresholds. A broad set of ROIs were identified as potential early targets based on prediction of global accumulation, encompassing bilateral cingulate, medial frontal/parietal cortices and left‐lateralized lateral frontal/parietal/temporal cortices (Fig2). ROC analyses demonstrated that spatial extent outperformed DVR in predicting progression to global PIB+ within 3 years (Fig3), with 82% sensitivity and 97% and 98.5% specificity, respectively, for the two larger aggregate masks. External validation in ADNI (Fig4) again demonstrated the superior performance of spatial extent (SE=100%, SP=91.6%) in predicting progression to global positivity within 3 years.

Conclusion

Our findings demonstrate that due to a high level of heterogeneity in early Aβ deposition, measures of spatial extent across a broad set of neocortical regions are more sensitive to detect early Aβ than traditional DVR/SUVR.
Impact of amyloid PET in the clinical care of US Veterans in a Tertiary Memory Disorders Clinic
Authors: Vives‐Rodriguez Ana , Schiloski Kylie A , Marin Anna , Wang Ryan , Hajos Gabor P , Powsner Rachel , DeCaro Renee , Budson Andrew , Turk Katherine W
Published: December 2022

Background

Prior studies assessing the clinical impact of amyloid PET have been limited to assessments before and after the scan. We aim to characterize the impact of amyloid PET in a veterans population with cognitive decline by comparing differences in clinical management within two years of follow‐up.

Methods

The current retrospective observational study includes all patients seen for an initial evaluation for cognitive complaints in the Memory Disorders Clinic at the VA Boston Healthcare System from October 2016 to January 2020. Clinical impact outcomes within two years of follow‐up were compared between patients with and without an aPET scan. Poisson regressions, negative binomial regressions, and binomial logistic regression were used for the analysis. Age, cognitive syndrome, follow‐up time, clinical diagnosis after initial evaluation and MoCA scores were used as covariates. Additionally, propensity score matching was performed to balance confounders between the two groups. To further understand the clinical impact outcomes in the aPET group, multiple regressions were performed within the group.

Results

Five‐hundred‐sixty‐five veterans were included in the analysis. Thirty‐five percent of patients underwent aPET imaging in addition to routine diagnostic workup. The study was positive in 72 patients (36.56%). Having an aPET, in addition to the usual diagnostic workup, was associated with a longer follow‐up time, and a higher diagnostic variability at follow‐up. We did not find an association between aPET use and the number of additional diagnostic studies ordered, early cholinesterase inhibitors prescription, or referrals to social work, research and clinical trials. When analyzing the same clinical utility outcomes within the group with an aPET, we found that a positive result was associated with fewer additional diagnostic tests, less diagnostic variability at follow up visits, more cholinesterase inhibitors prescription, and more research referrals.

Conclusions

In medically complex populations, aPET positivity might be lower than prior studies have described, used more to “rule out” than confirm the diagnosis of Alzheimer’s disease. This lower positivity rate results in less robust differences in classically explored clinical impact variables when comparing patients with and without an aPET.
Translational potential of JAX humanized‐APOE mice: Building the foundation for translational validity by applying human clinical trial principles
Authors: Wiegand Jean‐Paul L. , Skopp Stacy M , Brinton Roberta Diaz
Published: December 2022

Background

The 4th isoform of apolipoprotein E is the most prevalent genetic risk factor for Alzheimerʼs Disease (AD) and transgenic APOE animal models are widely used. However, APOE4’s penetrance is only ∼50‐60% and many studies do not use sufficient sample sizes to account for this.

Method

To address knowledge gaps regarding APOE penetrance and advance translatability of JAX humanized APOE (hAPOE) mouse models, we utilized a translational animal data management system recapitulating core aspects of human clinical trials: unique mouse IDs linked to all tissue samples and analytic outcomes. Transgenic C57BL/6J mice carrying hAPOE alleles (hAPOEe3/3, hAPOEe3/4 or hAPOEe4/4) were bred and longitudinally tracked for identification and analysis of susceptible and resilient subpopulations through population‐level studies on monthly weights (N = 1129 mice, N = 13262 weights), clinical observations (N = 2754 mice), and survival rates (N = 559 mice not utilized in studies).

Result

Colony‐wide analyses showed few differences, potentially leading to incorrect conclusions of minimal allelic effects. In this study, sub‐populations of hAPOEe4/4 mice exhibit divergent weight trajectories beginning at 15mo. Moreover, hAPOEe4/4 females displayed aberrations in fur barbering trajectories. The clinical observation of dermatitis was also noted more often in hAPOEe4/4 mice compared to hAPOEe3/3. Accordingly, hAPOEe4/4 animals, especially females, exhibit reduced survival rates, potentially due to divergent trajectories of susceptibility and resilience.

Conclusion

The present study identified distinct subpopulations of hAPOE mice exhibiting clear susceptible vs. resilient phenotypes within longitudinal data. Therefore, results from cross‐sectional studies of hAPOE mice with small, average cohorts will be highly variable. Future studies selecting cohorts based on clinical observations such as weight and phenotypic indicator trajectory will advance translatability to human APOE4‐AD.

Acknowledgements: Research supported by T32AG061897, R01AG057931, RF1AG059093, and Center for Innovation in Brain Science (CIBS) to RDB.