bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired Microtubule Dynamics Are a Driver of Tau Phosphorylation
Authors: Parato Julie , Qu Xiaoyi , Richters Emily , Sproul Andrew , Bartolini Francesca
Published: December 2023

Background

The microtubule cytoskeleton is both stable and dynamic, and both states are necessary for normal neuronal function. Stable microtubules support long‐term structures like dendrites and axons, while dynamic microtubules promote synapse maintenance and are mostly composed of tyrosinated a‐tubulin, a condition that affects microtubule associated protein binding and motor protein recruitment. We have recently shown that human iPSC neurons carrying the familial AD APP London V717I mutation have impaired microtubule dynamics and significant increases in tubulin post‐translational modification (PTMs) associated with microtubule longevity. These changes result from decreased levels of the enzyme tubulin tyrosine ligase (TTL), which refreshes detyrosinated tubulin to its original, tyrosinated state. In human AD brains, TTL levels also decrease, while long‐lived microtubule PTMs increase. Here, we report that by compromising normal microtubule dynamics or by reducing TTL expression alone we can drive tau phosphorylation in rodent hippocampal neurons and explore the mechanisms by which this regulation occurs.

Method

Human cortical neurons derived from iPSC lines in which the London familial APP mutation V717I was knocked into one allele of the IMR90 control using CRISPR/Cas9, were used as a cellular model of familial AD. Inhibition of microtubule dynamics was performed with taxol or through lentiviral knockdown of TTL. Microtubule dynamics were measured by confocal time‐lapse microscopy in neurons expressing EB3‐EGFP, a protein that tracks the growing plus ends of microtubules. Immunoblotting was performed to measure protein levels.

Result

We found that in addition to increased levels of p262 tau, APP London neurons possess higher levels of active AMPK, a kinase that can phosphorylate serine 262 on tau and an important regulator of tau pathology in vitro and in vivo. We also demonstrate that decreasing microtubule dynamics with taxol or TTL silencing alone is sufficient to promote tau phosphorylation and that inhibition of AMPK or knockdown of its regulatory subunit can prevent it.

Conclusion

These findings demonstrate that reduced levels of TTL and loss of dynamic microtubules drive AMPK‐mediated tau phosphorylation and suggest that TTL‐dependent loss of dynamic microtubules may contribute to tau pathology in AD.
Understanding molecular and cellular mechanisms of APOE4‐mediated susceptibility to tau‐related cognitive impairments in the miBrain model
Authors: Forton‐Juarez Ana , Suhy Natalie , Goldman Camille , Mesentier‐Louro Louise A. , Rooklin Rikki , Blanchard Joel
Published: December 2023

Background

APOE4 is the strongest genetic risk factor for Alzheimer’s disease with Tau pathology, namely hyperphosphorylation (p‐Tau) and aggregation of Tau into neurofibrillary tangles (NFTs) being correlated with poor cognitive outcomes in AD. Instances of mild traumatic brain injury (TBI) have been associated with increased susceptibility to neurodegenerative diseases such as AD and related dementias. We hypothesize that human APOE4 carriers’ brains are more susceptible to increased tau pathology with instances of TBI further increasing the severity.

Method

Using the 3D multi‐cellular integrated human brain (miBrain) model, which recapitulates key brain tissues through the co‐culturing of all hiPSC‐derived major brain cell‐types, Tau pathology can be induced with treatment of Tau fibrils or by increasing endogenous phosphorylated Tau with methotrexate.

Result

APOE4/4 miBrain cultures exhibit increased Tau pathology compared to isogenic APOE3/3 miBrains. Combinatorial genetic mixing experiments revealed that the increase of Tau hyperphosphorylation is dependent on the presence of APOE4 microglia.

Conclusion

Data suggests that microglia facilitate the accumulation of p‐tau in APOE4 genetic backgrounds in an in vitro 3D model.
Dementia and Nutrition: A Multidisciplinary Massive Open Online Course for Health Care Professionals, Students and Non‐Professionals
Authors: Schüssler Sandra , Pleyer Brigitte Ursula , Ulbrich Eva , Maurer Lisa , Holasek Sandra , Staubmann Wolfgang , Hatz Manuela , Resinger Eva , Tatzer Verena , Fabianits Helga , Selzer‐Haslauer Ulrike , Roller‐Wirnsberger Regina , Horn Natalie Sofia , de Beaulieu Maurice Chales , Paletta Lucas , Zuschnegg Julia
Published: December 2023

Background

More than 55 million people worldwide have dementia. This number will increase in the future, causing strains on healthcare systems. In‐depth knowledge about dementia and its negative effects, such as nutritional problems, is necessary to pursue targeted prevention strategies and to provide adequate treatment and care. Therefore, the aim of the project was to develop a Massive Open Online Course (MOOC) on dementia and nutrition for the healthcare sector. Such MOOCs can reach many users and have proven effective for self‐directed continuous professional development.

Methods

The MOOC was developed for students and professionals in health care as well as for non‐professionals, like relatives of people with dementia, in German‐speaking countries as a joint project from 2021‐2022. Different disciplines (dietetics, nutritional scientists, nursing scientists, occupational therapists, speech and language therapists, nutritional geragogists, medical doctors, technological disciplines, social scientists) and institutions, like universities, developed the content of the MOOC based on design principles, international literature and expert knowledge. The online course was made available free of charge on the iMooX platform of the Technical University of Graz, Austria (https://imoox.at/mooc/).

Results

The MOOC consists of 6 lessons which can be completed in a period of 6 weeks. The lessons include the following topics: (1) background information on dementia, like prevalence of dementia and costs; (2) risk factors for dementia, prevention and nutrition concepts; (3) impact of dementia on eating behaviors; (4) practical aspects of nutrition in dementia, like appetite stimulation; (5) activities of daily living & eating support; and (6) new technologies (e.g. robots, virtual reality) for prevention and support of eating problems. The content is delivered to the participants by means of videos and learning materials via various end devices. Each lesson ends with a quiz. Participants who answer at least 75% of the self‐assessment questions correctly receive a certificate.

Conclusion

The MOOC was successfully launched on January 17, 2023 (https://imoox.at/course/demern) and has already had more than 200 participants in the first round. In the future, an English‐language version is planned in order to further increase the number of people that can profit from the MOOC.
Cost of informal dementia care by US state, 2010‐2019
Authors: Lastuka Amy , Breshock Michael , Swart Vivianne , Dieleman Joseph L
Published: December 2023

Background

There are significant costs associated with dementia care throughout the world. These are expected to rise as populations age. Informal (unpaid) care represents a large fraction of these costs, although it is challenging to measure. In the United States, estimates of the cost of informal dementia care are dated and measured only at the national level. To fill this gap, we estimated the cost of informal care attributable to dementia through 2019 for each US state.

Method

The value of informal care is estimated as the replacement cost (cost of an equivalent number of hours of paid care) and opportunity cost (expected cost of forgone wages of the caregivers). We combine data from the Behavioral Risk Factor Surveillance System, the National Health and Aging Trends Study (NHATS), and the Health and Retirement Study to estimate caregiving hours at the state level from 2010‐2019. NHATS data are used to estimate the fraction of caregiving hours attributable to dementia.

Result

In 2019, the average annual per‐patient cost of informal care attributable to dementia was $42,271 ($37,338‐$47,898) using the replacement cost method and $19,769 ($15,711‐$25,029) using the opportunity cost method. These estimates imply a national cost of $207.2B ($183.1B‐$234.8B) or $96.9B ($77.0B‐$122.7B) per year, respectively. State‐level estimates show significant variation in informal caregiving hours per prevalent case of dementia. In 2019, the annual replacement cost of informal care provided per patient ranged from $15,885 ($13,941 ‐$17,979) in Nebraska to $71,438 ($63,155 ‐$80,316) in New Mexico. The opportunity cost had a larger spread in relative terms, ranging from $6,653 ($5,233‐$8,417) in Nebraska to $36,831 ($29,071‐$46,833) in Missouri. Co‐occurrence of diabetes mellitus prevalence is associated with more informal care hours for the average adult living with dementia, while average years of education of the caregiver is associated with fewer informal care hours.

Conclusion

The hours spent on informal care per prevalent case of dementia vary dramatically by state. This work adds to our understanding of health and demographic factors that are associated with hours of informal care, which can help policymakers plan for future increases in dementia prevalence and assess policy to support caregivers.
Effect of the combination of tetrahydrocannabinol and melatonin (IGC‐AD1) on blood pressure variability in patients with mild to moderate Alzheimer’s Disease
Authors: Silva‐García David , Gutierrez Evelyn , Sanchez Laura Tatiana , Arbelaez María Juanita , Tangarife Maria Alejandra , Delgado‐Murillo Laura , Rodriguez‐Soacha Diego , Shahnawaz Saadia S , Ghazaryan Varduhi , Naranjo Maria Paula , Venegas Margarita , Pujals Karen Y , De Jesus William Julio , Grimaldi Claudia , Lanctôt Krista L. , Hong L Elliot , Mukunda Ram
Published: December 2023

Background

Blood pressure (BP) variability (BPV) is a risk factor for Alzheimer’s disease (AD). Medications, such as atypical antipsychotics used to treat neuropsychiatric symptoms (NPS) common in AD, contribute to altering BP. Here we present preliminary data on the use of IGC‐AD1, a combination intervention of tetrahydrocannabinol (THC) and melatonin, on BP and BPV.

Method

Participants with hypertension (n = 12) and mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) were enrolled in a three‐Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, Cohort‐2 and Cohort‐3, one ml QD, BID, and TID of IGC‐AD1 were administered respectively for 14‐days with a minimum of 4‐days washout between Cohorts. For all Cohorts, BP was recorded daily. Coefficients of variation (CV), ∆DBP and ∆SBP (diastolic and systolic blood pressure) were calculated to assess SBP‐variability for each Cohort. A chi‐square was performed to verify whether the difference between controlled and uncontrolled SBP (>140mmHg in more than 20% of values per participant) was related to IGC‐AD1. SBP‐CV difference among Cohorts was determined with a one‐way ANOVA. The difference between active and placebo for each Cohort was assessed with independent t‐tests (dplr R‐Studio). BP‐associated adverse events (AEs) were evaluated daily.

Result

Variability measures fell within the normal range (∆DVP = 45.0±13.5 mmHg, ∆SBP = 66.44±22.9 mmHg, CV = 7.6±5.3 mmHg) for all three Cohorts. Cohort‐1 (mmHg): ∆SBP = 42.3±15.56, ∆DVP = 25.6±8.86, CV = 10.14±3.84; Cohort‐2 (mmHg): ∆SBP = 41.9±11.73, ∆DVP = 23±9.7, CV = 8.95±1.96; Cohort‐3 (mmHg): ∆SBP = 39.6±11.76, ∆DVP = 23.6±7.82, CV = 8.84±7.83. IGC‐AD1 had no statistically significant effect between controlled and uncontrolled SBP (X2(2) = 1.15, p = 0.562). There was no SBP‐CV mean‐difference among Cohorts (F (2,27) = 0.589, p = 0.562). No differences were detected between placebo and active (Cohort‐1: t(1.64) = 0.315, p = 0.788, Cohort‐2: t(1.31) = ‐0.225, p = 0.85, Cohort‐3: t(3.53) = 1.63, p = 0.188). While BP related AEs were reported, none were deemed, by the PI, to be associated with IGC‐AD1.

Conclusion

Preliminary data indicate that IGC‐AD1, a cannabis‐based formulation, in trials to treat NPS did not statistically affect BP or BPV in a MAD study indicating that it may not contribute as a risk factor for AD; warranting a larger placebo‐controlled trial.
A finger prick collection method for detecting blood biomarkers of neurodegeneration – a pilot study (DROP‐AD)
Authors: Huber Hanna , Montoliu‐Gaya Laia , Blennow Kaj , Zetterberg Henrik , Rovira Mercè Boada , Jeromin Andreas , Arús Xavier Morató , Ashton Nicholas J.
Published: December 2023

Background

Plasma biomarkers have proven to indicate developing cerebral pathologies and injury that underpin neurodegenerative disorders in a non‐invasive manner. However, the measurement of certain blood biomarkers requires on‐site sampling with strict, time‐limited and temperature dependant processing protocols. To further facilitate the usefulness of blood biomarkers, methods for remote and/or unsupervised sample collection would greatly increase the utility as a screening and monitoring tool in secondary care and therapeutic trials.

This pilot study investigated a novel method to quantify neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated tau (p‐tau) in capillary dry blood spots (DBScapillary) and venous dry blood spots (DBSvenous).

Methods

We included 77 memory clinic participants from ACE Alzheimer Center Barcelona. DBScapillary, DBSvenous, and EDTA plasma as well as neuropsychological measures were obtained from each participant. A subset (n = 23) had cerebrospinal fluid (CSF) biomarkers. Capillary whole blood was obtained by a macro lancet needle from the left index finger. A total of 65µL of capillary and venous blood were spotted and dried on Noviplex DBS cards, which were shipped overnight without temperature control or cooling to Gothenburg, Sweden. Samples were extracted from DBScapillary and DBSvenous cards, and NfL, GFAP, p‐tau181, and, in a subset (n = 11), p‐tau217 were measured by single molecular array (Simoa). Statistical analysis included Pearson correlation between DBS and EDTA plasma.

Results

DBScapillary GFAP (r = 0.7180, p<0.0001), and NfL (r = 0.6967, p<0.0001) correlated highly with their counterparts in EDTA plasma. We also demonstrated that DBScapillary p‐tau217 (r = 0.8955, p = 0.0002), but not DBScapillary p‐tau181 (r = 0.0132, p = 0.9447) correlated with the same measures in EDTA plasma, likewise DBSvenous GFAP (r = 0.7614, p<0.0001), NfL (r = 0.7701, p<0.0001), p‐tau217 (r = 0.9625, p<0.0001) and p‐tau181 (r = 0.6619, p<0.0001). Moreover, DBScapillary GFAP and DBSvenous GFAP, NfL and p‐tau181 correlated with MMSE, CDR and amyloid status (all p<0.05).

Conclusion

This pilot study demonstrates the potential of remote collection and quantification of GFAP, NfL, p‐tau217 and p‐tau181 without low‐temperature storage/transportation or centrifugation (DBSvenous). Our data also suggests that this may be possible from a simple finger prick collection, including p‐tau217. We speculate that this simple, self‐executable method of blood collection would facilitate regular monitoring of patients with suspected neurological conditions.
Sensitivity of individual and composite test scores from the Cogstate Brief Battery to mild cognitive impairment and dementia due to Alzheimer’s disease
Authors: Maruff Paul , Lim Yen Ying , White Josh , Edgar Chris J.
Published: December 2023

Background

The Cogstate Brief Battery (CBB) is a computerized cognitive test battery found to detect and confirm cognitive deficits related to Alzheimer’s Disease (AD). As the clinical AD and normative samples used to understand the sensitivity of the CBB to AD have been relatively small and varied in terms of selection criteria, it is important to examine the ability of all CBB measures, and potential composites, to discriminate adults with mild cognitive impairment (MCI) and dementia due to AD from carefully selected cognitively unimpaired (CU) adults.

Method

All speed and accuracy measures from the CBB were examined and both theoretically and statistically derived composites were created, from a sample of 4969 CU adults and 185 adults who met clinical criteria for MCI (clinical dementia rating, CDR = 0.5) or dementia (CDR > 0.5) due to AD.

Result

Individual CBB measures of learning and working memory showed high discriminability for AD‐related cognitive impairment for CDR 0.5 (AUCs ∼ 82‐.85), and CDR > 0.5 (AUCs ∼ .90‐.95). There was also high discrimination ability for theoretically derived CBB composite measures, particularly for the Learning and Working Memory (LWM) composite measure (CDR 0.5 AUC = .83, CDR > 0.5 AUC = .97). Various statistically derived linear composite measures showed discrimination abilities similar to the LWM composite.

Conclusion

In older adults, the CBB is an effective instrument for objectively discriminating cognitive impairment due to MCI or AD‐dementia from unimpaired cognition, with the LWM composite being a near‐optimal linear CBB composite for that purpose.
The modifying effects of cardiovascular risk factors on the relationship between lifetime discrimination and cognitive function: Study of Healthy Aging in African Americans (STAR)
Authors: George Kristen M , Gilsanz Paola , Peterson Rachel , Barnes Lisa L. , Glymour M. Maria , Decarli Charles , Whitmer Rachel A. , Mungas Dan M. , Mayeda Elizabeth Rose
Published: December 2023

Background

Discrimination is a root cause of health inequities contributing to the excess burden of cognitive impairment among Black Americans. Using the Study of Healthy Aging in African Americans (STAR) we examined whether the effect of lifetime discrimination on late‐life cognitive decline was magnified by early adulthood cardiovascular risk factors.

Method

STAR enrolled long‐term Kaiser Permanente Northern California members ages 50+ who identify as Black/African American. In early adulthood, participants completed Multiphasic Health Check‐ups (MHC; 1964‐1985) where systolic blood pressure (BP), total cholesterol, and body mass index (BMI) were assessed. A latent class analysis identified groups based on responses to the Major Experiences of Discrimination Scale and gender. Standardized z‐scores for executive function (EF) and verbal episodic memory (VEM) were measured over 3 waves (2018‐2022) using the Spanish and English Neuropsychological Assessment Scales. Linear mixed models with random intercepts and slopes associated latent class with cognitive decline adjusting for age at MHC, age at baseline cognitive assessment, education, and assessment mode (in‐person/telephone). Separate models tested class*cardiovascular risk factor interactions.

Result

Participants (n = 646) averaged 27.7(SD = 7.3) years of age at MHC and 68.5(SD = 8.8) at baseline cognitive assessment (Table 1). Four latent classes were identified: men reporting widespread discrimination (Class‐1men; 12%), women reporting widespread discrimination (Class‐2women; 22%), men and women reporting unfair police treatment (Class‐3police; 17%), and men and women reporting little/no discrimination (Class‐4no_discimination; 49%). Using Class‐4no_discimination as reference, those in Class‐2women had significantly higher baseline EF (β(95% CI):0.18(0.03,0.34)) while Class‐1men (β:0.04(‐0.15,0.23)) and Class‐3police (β:‐0.08(‐0.25,0.09)) did not differ (Figure 1). Class‐2women (β:0.17(0.00,0.33)) had higher baseline VEM compared to Class‐4no_discrimination while Class‐1men (β:‐0.40(‐0.60,‐0.19)) and Class‐3police (β:‐0.27(‐0.46,‐0.09)) had significantly lower (Figure 1). There were no differences in rate of decline. There was a systolic BP*class interaction (p = 0.04) where 5 mm Hg higher systolic BP in early adulthood was associated with worse EF for Class‐3police (β:‐0.07(‐0.12,‐0.02)) compared to Class‐4no_discrimination while Class‐1men and Class‐2women did not differ (Figure 2). This pattern was similar for VEM but non‐significant (interaction p = 0.07). We found no interactions with total cholesterol or BMI.

Conclusion

For Black Americans, discriminatory experiences may differentially impact late‐life cognition, and elevated systolic BP in early adulthood may exacerbate this harm.
Pneumonia‐induced cerebrovascular dysfunction: potential contributions to dementia
Authors: Chaney Samantha D , McAdams Lauren H , Gwin Meredith S , Bauman Allison J. , Stevens Troy T , Lin Mike , Nelson Amy R.
Published: December 2023

Background

Many survivors of lung injury, including bacterial pneumonia and COVID‐19, suffer from incident dementia. Patients who have had pneumonia and other infections are at a higher risk for developing Alzheimer’s disease and related dementias (ADRD) (Chu et al., BBI, 2022, Sipila et al., Lancet Infec Dis, 2021, Girard et al., J Gen Intern Med, 2018). There is growing appreciation and strong evidence that neurovascular uncoupling, cerebral blood flow reductions and dysregulation, and breakdown of the blood‐brain barrier (BBB), including the loss of pericytes, are early events in the ADRD pathophysiological cascade. Furthermore, astrocytes and microglia are activated in the ADRD brain and can also disrupt cerebrovascular health and impact cognition. Because these are key events in ADRD, we aimed to determine the effects of bacterial pneumonia on the cerebrovascular system.

Method

C57BL/6J mice were intratracheally infected with P. aeruginosa PA103 (ExoU and ExoT competent, 2.5×105 CFU) was introduced as a virulent bacterial strain for 24 or 48 hours. In addition, ΔPcrV (PA103ΔPcrV, 2.5×107 CFU), a mutant lacking a functional Type III secretion system was used for control. Following transcardial perfusion, brains were snap frozen in OCT and serially sectioned. Next, we performed immunofluorescence staining for CD13 (pericytes), lectin (endothelial cells), IgG (BBB leakage), Gfap (reactive astrocytes), and Iba1 (microglia).

Result

Significant BBB leakage of IgG was detected in both cortex and hippocampus 48 hours post‐infection with PA103 compared to ΔPcrV. Significant activation of astrocytes and microglia was detected 48 hours post‐PA103 infection compared to ΔPcrV. Pericyte coverage was unchanged in cortex and hippocampus both 24‐ and 48‐hours post‐infection with PA103 compared to ΔPcrV.

Conclusion

Here we have shown that bacterial pneumonia causes BBB breakdown and gliosis in young mice. Because BBB breakdown and gliosis are early events in many neurodegenerative diseases leading to cognitive dysfunction, understanding how pneumonia can accelerate these events is extremely timely and important. Future studies should focus on the mechanism(s) by which pneumonia causes cerebrovascular dysfunction and how this may increase ADRD.
Effects of Alzheimer’s disease genetic risk on brain morphometric development in three multiple‐ancestry pediatric datasets
Authors: Vogel Jacob W , Schultz Laura M , Larsen Bart , Seidlitz Jakob , Al‐Sharif Noor B , Barzilay Ran , Cieslak Matthew , Covitz Sydney , Gur Raquel E , Gur Ruben C , Huguet Guillaume , La Joie Renaud , McMillan Corey T , Nilsson Nathalie I.V. , Poline Jean‐Baptiste , Ruparel Kosha , Shinohara Russell T. , Wisse Laura EM , Wolf Daniel , Wolk David A. , Alexander‐Bloch Aaron , Almasy Laura , Satterthwaite Theodore
Published: December 2023

Background

Few prior studies have investigated whether genetic risk for Alzheimer’s disease (AD) can manifest through altered neurodevelopment of AD‐vulnerable brain regions. This pre‐registered study tests the effects of AD polygenic risk on morphometric neurodevelopment across 3 large datasets totaling 8,364 youths aged 3‐22 (Table 1)

Method

Polygenic risk score (PRS) was calculated using PRS‐CS software, with summary scores from Kunkle et al. (2021) for African ancestry individuals (AA) and Jansen et al. (2019) for European ancestry individuals (EA). For EA only, PRS were calculated with (PRS‐APOE+) and without (PRS‐APOE‐) the APOE locus included. All individuals had T1‐weighted MRI processed with FreeSurfer that passed quality assessment checks. ComBAT was used to harmonize sites within‐cohort. Primary analyses investigated effects of PRS, age and their interaction on bilateral hippocampal volume and AD MetaROI cortical thickness using generalized additive models. Age interactions were not evaluated in ABCD due to limited age range. Exploratory analysis examined effects of age and PRS on cortical thickness, volume, surface area and subcortical volume across Desikan‐Killiany regions, adjusting for multiple comparisons (FDR). For exploratory analyses only, ABCD was split into training and test sets. All analyses were conducted for EA and AA separately; sex, total intracranial volume, image quality (Euler number) and ten genetic principal components were included as model covariates.

Result

Table 1 summarizes primary results. Hippocampal volume increased with age in 3/6 datasets, while MetaROI thickness decreased with age in all datasets. Surprisingly, increased PRS was associated with larger hippocampi in three datasets. In one dataset only, greater PRS was associated with increased metaROI thickness (Fig 1). 2/3 AA datasets showed age*PRS interactions on hippocampal volume, but in opposite directions. An age*PRS interaction on metaROI thickness was found in one dataset (Fig. 2A‐C). For exploratory analyses, no regions survived multiple comparisons for any contrast in 5/6 datasets; APOE only PRS was associated with larger supramarginal surface area in one dataset (Fig 2E). Effects were not correlated across studies (Fig 2D)

Conclusion

This large, pre‐registered study provides little evidence that AD genetic risk manifests during pediatric brain morphometric development.
Targeted plasma eQTL and pQTL to identify potential novel biomarkers for Alzheimer’s Disease in African Americans
Authors: Reddy Joseph S. , Badillo Vanessa M. Colon , Jin Jianli , Lincoln Sarah J. , Ho Charlotte C.G. , Crook Julia E. , Wang Xue , Malphrus Kimberly G. , Nguyen Thuy , Polanco Jean M Marrero , Tamvaka Nicole , Lucas John A. , Graff‐Radford Neill R , Ertekin‐Taner Nilufer , Carrasquillo Minerva M.
Published: December 2023

Background

Given the overlap of symptoms between Alzheimer’s disease (AD) and other dementias, it is essential to develop widely accessible biomarkers that will ensure an accurate diagnosis of AD to enable its proper treatment. African Americans (AA) are twice more likely to develop AD than non‐Hispanic whites (NHW) and yet they remain underrepresented in AD research. The few studies conducted in AA suggest that there are different factors that influence AD in this population; therefore, it is possible that different biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study we are testing the hypothesis that genetic variants that show association with AD‐risk in AA and with plasma levels of transcript and proteins may serve as AD biomarkers which are more accessible and less costly than cerebrospinal fluid or neuroimaging biomarkers.

Methods

In 189 AD cases and 183 cognitively unimpaired (CU) AA participants of the Florida Consortium of African American Alzheimer’s Disease Studies (FCA3DS), we performed targeted DNA sequencing of 10 AD‐associated loci. Genetic variants were tested for association with plasma transcripts and plasma total tau protein levels previously measured in this cohort using a nanoString® custom panel (Reddy J, et al. 2022) and Simoa assays (Deniz K, et al. 2021), respectively. In receiver operating characteristic (ROC) analyses, the most significant expression/protein quantitative trait loci (eQTL/pQTL) were added sequentially to a base model that included only age and sex to identify eQTL/pQTL that improved the accuracy to correctly classify AD cases vs. CU.

Results

Of the 5112 variants identified in the targeted sequencing, 71 were nominally associated (p<0.05) with plasma transcript/protein levels and with AD‐risk. ROC analysis of age, sex, eQTL/pQTL in APOE, ABCA7, AKAP9, EPHA1, SORL1, and TLR4, and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE‐ɛ4 dosage achieved 77.6% area under the curve (AUC) to discriminate AD vs. CU, a 19.9% improvement over a model that only included age and sex.

Conclusions

Plasma transcript levels and eQTL/pQTL are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.
Quantifying associations of four major proteinopathies with grey matter atrophy: an imaging‐pathology study
Authors: Phillips Jeffrey S , Robinson John L. , Cousins Katheryn A Q , Das Sandhitsu R. , Yushkevich Paul A. , Wolk David A. , Lee Eddie B , McMillan Corey T , Trojanowski John Q , Grossman Murray , Irwin David J.
Published: December 2023

Background

Gross atrophy observed on MRI provides a clinically useful marker of possible neurodegenerative disease. However, autopsy studies of polypathology suggest atrophy is likely driven not by a single proteinopathy but also co‐pathologies. We hypothesized that in a clinically heterogeneous autopsy sample, amyloid‐β, tau, α‐synuclein, and TDP‐43, would co‐occur within regions, and that co‐pathologies would have independent associations with grey matter atrophy.

Method

T1‐weighted antemortem MRI was available in 121 patients with postmortem ordinal pathology ratings (0 = none; 1 = mild; 2 = intermediate; 3 = severe). Primary neuropathologic diagnoses included Alzheimer’s disease (AD; n = 52), amyotrophic lateral sclerosis (n = 2), frontotemporal lobar degeneration due to tau (n = 29) and TDP‐43 (n = 22), and Lewy body disease (16). Regional volumes were expressed as W‐scores adjusting for age, sex, and intracranial volume for 10 regions spanning the limbic system, neocortex, and subcortex. We used mixed effects models with a random intercept per patient to regress W‐scores on ordinal pathology ratings.

Result

Amyloid‐β and tau co‐occurred in all regions, reflecting the prevalence of AD neuropathologic change (Fig. 2, top). Alpha‐synuclein and TDP‐43 pathology were highest in amygdala, anterior cingulate, entorhinal cortex, and hippocampus, where they frequently co‐occurred with amyloid‐β and tau. Neocortical regions including middle frontal, angular, and superior/middle temporal cortex had intermediate rates of co‐pathology, while thalamus, striatum, and globus pallidus had the lowest polypathologic burden (Fig. 2, bottom). Ordinal measures of tau [F(3,1073) = 24.1, p<0.001], TDP‐43 [F(3,1073) = 13.7, p<0.001], and ‐synuclein [F(3,1073) = 4.3, p<0.005] burden were inversely associated with regional volumes, but amyloid‐ [F(3,1073) = 1.8, p>0.15] was not. An increase in ordinal tau scoring by one unit was associated with a mean reduction of ‐0.29 in regional W‐score; for TDP‐43, a decrease of ‐0.51; and for α‐synuclein, a decrease of ‐0.16.

Conclusion

Mixed proteinopathies were common at the regional level in limbic and neocortical structures. Using blinded ordinal pathology scoring, TDP‐43 was associated with greater atrophy than tau; α‐synuclein had a smaller but significant association. Amyloid‐β was not associated with atrophy when adjusting for tau. Results suggest co‐pathologies have a measurable effect on observed brain atrophy.
Sleep health and subjective cognitive decline in the Vanderbilt Memory and Aging Project
Authors: Full Kelsie M , Gogniat Marissa A. , Pechman Kimberly R. , Hohman Timothy J. , Jefferson Angela L. , Gifford Katherine A.
Published: December 2023

Background

Identifying modifiable risk factors for Alzheimer’s disease (AD) and related dementias (ADRD) may reveal critical evidence for early prevention. It is commonly believed that poor sleep is an early symptom of neurodegeneration and ADRD. However, distinct neurobiological processes occur during sleep, and dysfunction of these processes may also contribute to AD pathogenesis. Less is known about poor sleep and associations with subjective cognitive decline (SCD), a clinical symptom occurring before overt cognitive impairment due to early pathological AD. This study investigated associations between objective and self‐reported measures of sleep health and SCD in a community‐based cohort of older adults.

Method

Participants from the Vanderbilt Memory and Aging Project (n = 220; 74±7 years; 34% female) completed 7‐days of wrist actigraphy and self‐report measures for SCD [Everyday Cognition Scale (ECog)] and sleep quality [Pittsburgh Sleep Quality Index (PSQI)]. Actigraphy data was processed to estimate average nightly sleep duration, sleep efficiency, and wake after sleep onset. Linear regressions related objective and self‐report sleep health measures with total ECog score adjusting for age, sex, race/ethnicity, education, body mass index, depressive symptoms, Framingham cardiovascular risk score, and apolipoprotein E‐e4 carrier status.

Result

In main effect models, longer sleep duration was associated with greater SCD (b = 0.05, p<0.01). In models adjusted for age, sex, race/ethnicity, and education, higher PSQI (indicative of poorer sleep quality) was associated with greater SCD (b = 1.06, p = 0.01); however, the association was no longer statistically significant in the fully adjusted model. No associations were observed between sleep efficiency or wake after sleep onset and SCD.

Conclusion

In this community cohort of older adults, longer nightly sleep duration and self‐reported poor sleep quality were linked with higher SCD. Findings could suggest that abnormal sleep duration and poor sleep quality increase the earliest clinical symptoms of AD. Further investigations are needed to evaluate the potential pathways connecting sleep health to ADRD development.
Mini‐Cog acceptance and conversion rate in Medicare beneficiaries in the primary care
Authors: Saxena Saket , Factora Ronan , Hashmi Ardeshir , Wang Mary , Jones Robert
Published: December 2023

Background

Assessing patients for cognitive impairment is a required element of Medicare’s Annual Wellness Visit (AWV). Variability exist in the type of cognitive assessment methods used to assess patients for cognitive impairment during such visits. Paper and pencil tests such as the Mini‐Cog are commonly used in such visits, as they are easy to administer and interpret. Our study aims to assess acceptance of Mini‐Cog use in primary care and conversion of Mini‐Cog from normal to abnormal in the older adults visiting primary care for repeat AWV.

Methods

Cleveland Clinic implanted Mini‐Cog as a cognitive screening tool in Primary Care Institute in 2019. Inclusion criteria were Age 65+, AWV, no preexisting diagnosis of dementia, normal Mini‐Cog in previous year. Since this process was established, primary care providers were educated about use of Mini‐Cog by internal continuous quality improvement (CQI) platform. Use of Mini‐Cog in AWV within the Primary Care Institute was registered during the study period from January 2021 ‐ December 2022. The number of repeated tests, the rates of conversion of normal (3‐5) to abnormal (0‐2) and the total proportion of abnormal scores overall were recorded.

Results

Total number of Mini‐Cog during the study period was 46094 out of which 2843 (6.2%) were abnormal.16644 were repeat tests and out of these 507 were abnormal suggesting a 3% conversion rate when testing was repeated on previously normal subjects. An upward trend and 1.7 fold increase was observed in the total number of tests on year to year basis (2021 vs 2022). (Figure 1)

Conclusion

Currently, variability exists in the type of cognitive assessments methods used during the AWV in primary care. Consistent use of Mini‐Cog combined with CQI over the period of two years have shown to increase usability and acceptance within Primary Care community. As the repeat assessment have increase over period of time; now we have the opportunity to identify a narrow subset of converted patient (3%) who could benefit from urgent comprehensive cognitive assessment to confirm a diagnosis of dementia and can subsequently close examination of the risk factors that could have contributed to measurable cognitive decline.
GM‐CSF reduces amylin amyloid, inhibits pancreatic apoptosis, and sustains lowered blood glucose levels in the hIAPP mouse model of Type 2 diabetes mellitus, a known risk factor for Alzheimer’s disease
Authors: Wang Athena Ching‐Jung , Boyd Timothy D. , Adame Vanesa , Potter Huntington
Published: December 2023

Background

People with Type II diabetes mellitus (T2D) are at higher risk for developing Alzheimer’s disease (AD). T2D is characterized histopathologically by accumulation of pancreatic amyloid deposits comprised primarily of self‐aggregating amylin/human islet amyloid polypeptide (hIAPP). Amylin is implicated in both T2D and AD pathogenesis, and in T2D patients, pancreatic amyloid deposition occurs before and induces islet β‐cell apoptosis.

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) has demonstrated anti‐apoptotic, neuroprotective, neurotrophic, immunomodulatory, and regenerative effects in several neuronal injury models. We discovered that GM‐CSF treatment rapidly reduced cerebral amyloidosis and reversed cognitive impairment in transgenic AD models (Boyd et al, 2010), which led to the initiation and successful completion of a Phase 2 clinical trial (NCT01409915) using sargramostim (rhuGM‐CSF) in mild‐to‐moderate AD participants (Potter et al., 2021). Thus, we hypothesized the GM‐CSF might also reduce amyloid, prevent pancreatic apoptosis, and thereby reduce blood glucose in the hIAPP mouse model of T2D.

Method

We investigated GM‐CSF treatment effects in hIAPP mice (Jackson strain Tg(Ins2‐IAPP)RHFSoel), which accumulate amylin amyloid in pancreatic islets. Hemizygous mice received daily subcutaneous injections (5 days/week for 23 total injections) of either recombinant murine GM‐CSF (5 µg/day or ∼167 µg/kg) or sterile saline, and were then euthanized, perfused according to CU Anschutz OLAR regulations, and pancreatic tissues obtained and processed for histopathology. Contrastingly, homozygous mice received 15 total injections and were monitored for 45 days post‐treatment, before euthanizing and perfusion procedures. In homozygous mice, blood glucose levels were measured 3 days/week (weeks 2‐4) and at 45 days post‐treatment. Unpaired t‐tests were used to determine significant differences (p<0.05) between treatment groups.

Result

In pancreas of male GM‐CSF‐treated hemizygous mice (n = 9), Thioflavin‐S staining revealed significantly less pancreatic amyloid (p = 0.0140) and Caspase‐3 immunohistochemistry showed significantly less apoptosis (p = 0.0057), compared to the saline‐treated group (n = 7). In homozygous mice, GM‐CSF‐treated male (n = 5) and female (n = 3) mice showed significantly reduced blood glucose from baseline levels, which treatment effects were sustained 45 days post‐treatment (p<0.001 female, p = 0.0002 combined M/F), whereas saline treatments (n = 5 male; n = 3 female) had no effect.

Conclusion

These preliminary data suggest therapeutic potential for GM‐CSF to prevent or treat T2D, and thereby reduce AD risk.
The Asian Cohort for Alzheimer’s Disease pilot study at University of California San Francisco: A focus on recruitment of Chinese American older adults
Authors: Qian James , Tee Boon Lead , Tzuang Marian , Lieu Kevin , Mei Diana , Rosen Howard J. , Lanata Serggio , Wang Li‐San , Chow Tiffany W , Jun Gyungah R , Park Van Ta , Consortium ACAD
Published: December 2023

Background

Asian American and Canadian (ASAC) populations have long been under‐represented in Alzheimer’s disease (AD) research. The Asian Cohort for Alzheimer’s Disease (ACAD) is the first large US and Canada cohort to study genetic and non‐genetic AD risk factors specifically for older ASAC persons. The University of California San Francisco (UCSF) is one of ACAD’s largest recruitment sites for Chinese American participants.

Method

The UCSF ACAD team has adopted a collaborative multifaceted approach to outreach, recruitment, and data collection including a) recruitment from community partners, social media platforms, clinic referrals, CARE (a research recruitment registry for Asian Americans, Native Hawaiians, and Pacific Islanders), and other ongoing studies (e.g., UCSF’s Alzheimer’s Disease Research Center); b) coordination of multilingual and culturally appropriate outreach events with multiple San Francisco Bay Area community organizations that serve the Chinese American community; c) pilot of ACAD’s data collection packet and procedures in two testing modes (in‐person, on‐line) and three spoken languages (Cantonese, English, Mandarin).

Result

As of January 2023, UCSF has enrolled 121 participants, 116 (95.87%) of whom have completed their visits since we began enrollment in July 2021. Out of the 116 participants, 80 (68.97%) were co‐enrolled with other ongoing studies, 21 (18.10%) were recruited from outreach events in the community, and 15 (12.93%) participated in ACAD through CARE registry, clinic referrals, or social media platforms. The age of our cohort ranges from 60‐90 years (m = 70.45 years). Most of the participants were females (72.4%) and had a college or graduate level education (68.97%). Approximately 50% of the participants completed the study in Mandarin, 32.76% in English, and 17.24% in Cantonese. Nearly two‐thirds of the participants completed their visits virtually. Consensus diagnoses were fully reviewed on 106 participants, including 61 cognitively normal controls, 16 with subjective cognitive complaints, 23 with mild cognitive impairments, and 6 with AD diagnosis.

Conclusion

ACAD aims to enhance the representation of ASAC communities in AD research. The use of culturally and linguistically tailored approaches has and will continue to assist us in outreach, recruitment, and data collection efforts as we aim to expand our sample size and collect longitudinal data.
A multi‐site study of Alzheimer’s disease neuroimaging and cognitive biomarkers in 2819 cognitively normal individuals
Authors: Xie Long , Das Sandhitsu R. , Wisse Laura EM , Lyu Xueying , McGrew Emily , de Flores Robin , Gibson Eli , Yushkevich Paul A. , Wolk David A. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Developing effective Alzheimer’s disease (AD) biomarkers in cognitively normal (CN) individuals is crucial. Prior studies have identified neuroimaging and cognitive measures that are sensitive to preclinical AD. However, the generalizability of these biomarkers in large, multi‐site cohorts and their power to predict disease progression remain unclear. Structural MRI, tau PET and standardized cognitive tests of 2819 CN adults were pooled from three studies to investigate the power of these measures in discriminating β‐amyloid positivity (A+/‐) and predicting disease progression.

Methods

T1‐weighted MRI and cognitive data of 2819 CN (A‐/A+: 1180/1540, Table 2) individuals from ADNI, HABS and A4 were included. Baseline medial temporal lobe structural measures were extracted from MRI (complete list in Table 1). For participants with prospective longitudinal MRI or cognitive measures (4.5 years), annualized change rate of each measurement was estimated. ANCOVA and receiver operating characteristic analyses were used to test biomarker differences between A+/A‐. In 563 CN with cross‐sectional tau PET available, stepwise linear mixed effect modeling was performed to identify the subset of baseline cross‐sectional biomarkers (tau, MRI and cognition) that yields the optimal model (smallest Akaike information criterion) in predicting longitudinal atrophy and cognitive decline. The area under the curve (AUC) of each model in discriminating the first (fast) and last (slow progressors) tertiles of each longitudinal measurement was reported.

Results

Significant differences between A+/A‐ (Table 2) were observed in cross‐sectional tau (most significant), cross‐sectional and longitudinal cognitive, as well as longitudinal structural MRI measures. When predicting disease progression with baseline measures (Figure 1‐a), tau (selected in all the models) and cognitive biomarkers were included in the most predictive models while MRI biomarkers did not provide additional information. The selected biomarkers can identify fast versus slow progressors with AUCs ranging from 0.63‐0.78 (Figure 1‐b).

Conclusions

The results demonstrated that both cross‐sectional (tau PET and cognition) and longitudinal biomarkers (MRI and cognition) are sensitive to amyloid status in CN. In addition, baseline tau PET and cognitive measures provide complementary information in predicting disease progression regardless of amyloid status. This indicates that these biomarkers may have important utility in preclinical AD clinical trials and normal aging studies.
Investigation of IL1RAP in vascular endothelial and microglia interactions
Authors: Fisher Elizabeth S , Tubbesing Kate , Bertucci Taylor , Stevens Katherine , TCW Julia , Goate Alison , Temple Sally
Published: December 2023

Background

Approximately 84% of Alzheimer’s Disease (AD) patients have cerebrovascular pathology. It remains unclear if vascular damage is causative or a result of disease progression. Blood‐brain barrier breakdown can be induced by inflammation, which is increased in aging and AD. IL1β is a cytokine upregulated in patients with AD and in mouse models of the disease. Released IL1β interacts with IL1R1, which relies on its obligate co‐receptor, IL1RAP, for signaling. A genome wide association study identified a SNP in IL1RAP with increased incidence of AD and higher rates of amyloid accumulation. This IL1RAP variant exerts independent, additive effects with APOE44. These findings suggest IL1RAP could play an important role in AD and vascular damage.

Method

Human induced pluripotent stem cells (iPSCs) isogenic for the APOE33 or APOE44 allele were differentiated into vascular endothelial cells (ECs) or microglia. Differentiated cells were treated with inflammatory factors then subjected to several assays relevant to AD‐pathological changes. For ECs, barrier properties were assessed via trans‐endothelial resistance measurements and by immunohistochemistry for junctional proteins. For microglia, the ability to phagocytose Aβ was assessed. Both ECs and microglia were examined for inflammatory factor gene expression and protein secretion via ELISA. IL1RAP was overexpressed and knocked down in both APOE33 and APOE44 ECs, and changes were assessed by select assays described above.

Results

APOE44 iPSC‐ECs exhibited disrupted barrier properties compared to ECs derived from APOE33 cells. Different inflammatory stimuli have differential effects on the EC response, including the level of upregulation of the EC‐specific inflammatory gene E‐selectin. On‐going experiments will determine if there is a modifying effect of overexpression or KD of IL1RAP in ECs and microglia in these assays, and notably, if there is a different response depending on APOE allele.

Conclusion

APOE alleles alter the functional properties of human iPSC‐ECs and microglia and their responses to inflammatory challenges. In the future, we will determine if interactions between microglia and ECs are altered by APOE genotype and how altering IL1RAP levels modifies the observed changes. These experiments will help establish the role of microglia‐EC interactions in inflammatory reactions, and how these may contribute to the development or progression of AD.