bluuebunny/crossref_metadata_2025 huggingface dataset:
White Matter Hyperintensity and PET‐Based Amyloid Load Correlations: A Meta‐Analysis
Authors: Bauer Kacie , Malek‐Ahmadi Michael H.
Published: December 2022

Background

White matter hyperintensities (WMHs) are prevalent vascular pathologies that often co‐occur with amyloid plaque deposition in Alzheimer’s disease (AD). Previous research has shown that antemortem WMHs correlate well with post‐mortem findings of cerebral amyloid angiopathy (CAA). PET‐amyloid imaging is widely used to assess in‐vivo amyloid load, however the extent to which CAA‐binding of amyloid tracers contributes to global measures of amyloid load is unclear. The aim of this meta‐analysis was to determine the strength of the correlation between amyloid load and WMHs in AD subjects.

Method

Thirteen studies that reported either a correlation or regression coefficient between amyloid load and WMHs were included. Age, education level, sample size, correlation, study setting (community, clinic, Alzheimer’s Disease Neuroimaging Initiative [ADNI]), amyloid tracer type (florbetapir vs. Pittsburgh compound B [PiB]), and method of WMH quantification (visual vs. volumetric) were extracted. Random effects results were reported for the main and subgroup analyses. Between‐study heterogeneity was quantified using I2 with 95% confidence intervals.

Result

The overall correlation for amyloid load and WMH load was r=.25, 95% CI[.15, .35], p<.001; I2=80%, 95% CI[66%, 88%]. The combined effect size of community and clinic‐based studies (r =0.30) was larger than that of ADNI studies (r=0.21) and had substantially less heterogeneity (I2=67% vs. I2=86%). Florbetapir had a stronger correlation with WMHs (r=0.28) than PiB (r=0.20), with less heterogeneity (I2=71%, I2=87%). Visual methods of WMH quantification yielded a stronger correlation with amyloid load (r=0.38) than volumetric methods (r=0.20), however between‐study heterogeneity was similar for both methods (I2=80%, I2=82%).

Conclusion

WMHs correlate significantly with amyloid load, but this relationship is strongly influenced by amyloid tracer type and WMH quantification method. A high level of heterogeneity was noted for ADNI studies which further indicates the impact that methodologic and analytic techniques may have on a study’s findings. Although CAA‐related binding cannot be distinguished from parenchymal binding in amyloid‐PET studies, these results provide a general estimate of CAA’s contribution to PET‐based estimates of global amyloid load.
Carotid intima media thickening is associated with higher future amyloid‐ß burden
Authors: Baradaran Hediyeh
Published: December 2022

Background

Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid‐ß (Aß) burden. We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aß on 11C‐Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aß burden.

Method

We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5± 5.7 years) and an average of 9.6 years later at exam 8, and PiB imaging measuring Aß on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow‐up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aß in brain regions associated with Alzheimer’s disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors.

Result

Participants with higher mean ICA IMT had more Aß in the precuneus (beta ± standard error [SE]: 0.264 ± 0.12, p = 0.034) and the FLR regions (SE: 0.155 ± 0.071, p = 0.034), after adjusting for age, sex, and vascular risk factors. We did not find an association between any CCA IMT measures and Aß or progression of ICA or CCA IMT and Aß.

Conclusion

Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aß burden later in life. These findings support a link between vascular disease and AD/ADRD.
Discovery and validation of dominantly Inherited Alzheimer’s Disease mutations in populations from Latin America.
Authors: Llibre‐Guerra Jorge J , Takada Leonel Tadao , Verson Carmen Alaez , Burgute Bhagyashri , Nitrini Ricardo , Sosa‐Ortiz Ana Luisa , Castilhos Raphael Machado , Chaves Marcia L Fagundes , Ibarrola Mariana Longoria , Carrillo‐Sanchez Karol , Brucki Sonia Maria Dozzi , Flores‐Lagunes Luis Leonardo , Molina Carolina , Olivares Marcos Jimenez , Ziegemeier Ellen , Goate Alison M. , Cruchaga Carlos , Renton Alan E. , Fernandez Maria Victoria , Day Gregory S , McDade Eric , Bateman Randall J. , Karch Celeste M.
Published: December 2022

Background

More than 300 variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes have been reported to cause Dominantly Inherited Alzheimer Disease (DIAD). However, most of these reports come from non‐Hispanic whites and the full extent of DIAD remains understudied in Latin American (LatAm) countries. Here we describe five AD affected families from LatAm carrying novel DIAD variants.

Methods

Five novel variants in the presenilin1 (PSEN1) gene were identified in Brazilian (p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se and p.Ala275Thr) and Mexican families (p.Ile414Thr). To assign the likelihood of pathogenicity among these variants of unknown significance, we report pedigree information, frequency in control populations, in silico predictions, and cell‐based models.

Result

The mean age at onset in newly identified families was 43.5 years (range 36‐54). The novel variants were absent from gnomAD genome and exome databases. Two PSEN1 variants (p.Val103_Ser104delinsGly and p.Lys395Ile) showed segregation with the disease status; segregation studies were not possible in the other three families. Additionally, PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr produced Aβ profiles consistent with known AD pathogenic mutations (i.e. increased extracellular Aβ42/40); thus, we consider them as likely pathogenic. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation; therefore, PSEN1 p.Ile414Thr likely represents an AD risk factor or benign polymorphism.

Conclusion

Our study provides further insights into the genetics of AD in LatAm by identifying novel DIAD pathogenic variants in Brazil and Mexico, two countries with distinct genetic admixtures. Expanding the families eligible to participate in observational and clinical trials of DIAD enhances the generalizability of diagnosis and treatment approaches.
How is semantic memory affected in Mild Cognitive Impairment?
Authors: Delage Emilie , Chasles Marie‐Joëlle , Cole Jessica , Rouleau Isabelle , Joubert Sven
Published: December 2022

Background

Mild cognitive impairment (MCI) is a condition considered by many as a transitional stage between healthy aging and Alzheimer’s disease. Although its diagnosis is typically based on the assessment of episodic memory, evidences show that impairment in semantic memory would be one of the first manifestations of cognitive impairment. This study aims to investigate how semantic memory is affected in MCI. Precisely, we will explore if core memory of common knowledge is impaired in MCI, and if the performance in semantic memory task vary with the modality of presentation of the stimuli (verbal vs visual).

Method

A group of healthy people aged between 60 and 90 years old (mean: 77.4 N = 43), and a age‐matched group meeting the criteria for MCI (N = 32), who have lived in Quebec (Canada) for at least 30 years, completed two neuropsychological tests evaluating the semantic memory of famous people, which have been proven to be the most sensible way to detect even subtle variation in semantic memory.

Result

Results indicate that performance in both tests is impaired in the MCI group, compared to the healthy elderly group. This means that the MCI group have more difficulty to name famous people (t (69) = 5,173, p < 0.01), as well as answer basic questions on them (ex: their profession, nationality, etc.), when presented from their picture (t (69) = 4.849, p < 0.01) or their name (t (65) = 3.488, p < 0.01), compared to healthy people of the same age. There was no difference between their performances when the stimuli was presented in the visual or verbal modality (t (30) = 0.928, p > 0.05).

Conclusion

This study demonstrates that semantic memory of famous people is impaired in MCI, and that impairment affects the capacity to name famous people as well as remembering facts about them. In addition, there are no difference if the stimuli are presented visually or verbally. This suggests that the impairment in semantic memory in MCI is due to a degradation of the memory, and is not modulated by other cognitive functions or modality.
High Cardiorespiratory Fitness Exerts a Neuroprotective Effect Against Obesity, Regardless of Lifestyle Modification
Authors: Pantiya Patcharapong , Thonusin Chanisa , Ongnok Benjamin , Chunchai Titikorn , Sumneang Natticha , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2022

Background

High cardiorespiratory fitness (CRF) and behavioral modification exert a neuroprotective effect in obese condition. However, the interplay between CRF, obesity, and behavioral modification has never been identified. Therefore, this study investigated whether high CRF level provides the neuroprotective effect in obese rats receiving either caloric restriction or exercise.

Method

Seven‐week‐old male Wistar rats were fed with either a normal diet (ND; n = 5) or a high‐fat diet (HFD; n = 25) to induce obesity for 12 weeks. At the end of week 12, baseline CRF was measured. The ND‐fed rats were continuously fed with a ND for an additional 16 weeks. The HFD‐fed rats were randomly assigned into 5 groups (n = 5/group) to receive either 1) a HFD without intervention for 16 weeks, 2) 40% caloric restriction for 6 weeks followed by an ad libitum ND for 10 weeks (short‐term caloric restriction followed by weight maintenance), 3) 40% caloric restriction for 16 weeks (long‐term caloric restriction), 4) a HFD plus an exercise for 6 weeks followed by a ND without exercise for 10 weeks (short‐term exercise followed by weight maintenance), or 5) a HFD plus an exercise for 16 weeks (long‐term exercise). At the end of interventions (week 28), CRF and cognitive function were determined. After that, the rats were euthanized for molecular studies in the brain.

Result

There was a significantly positive correlation between running distance at week 12 and week 28 (Figure A), indicating that CRF is highly intrinsic factor. When compared to the ND‐fed rats, CRF level was lower in the obese rats at week 12 (Figure B). At week 28, all types of behavioral modification significantly increased the CRF level in obese rats (Figure C). Interestingly, high baseline CRF level demonstrated a significant correlation with favorable brain profiles at follow‐up in obese rats, both with and without behavioral modification (Figure D).

Conclusion

Regardless of behavioral modification, high CRF exerts a neuroprotective effect against obesity. Hence, targeting on an enhancement of CRF may provide the better effective therapy for obesity‐induced neuronal impairment.
User‐centered design to examine interaction of people with MCI or dementia with smartwatches: the SAMi intervention study framework
Authors: Rong Eleonora , Köhler Stefanie , Bieber Gerald , Teipel Stefan , Goerss Doreen
Published: December 2022

Background

Assistive technologies show promising features to support people with cognitive impairment in daily life, e.g. mobile sensors for falls detection. But adoption of the rapidly evolving technologies is still limited in practice. We applied user‐centered design to investigate factors contributing or hindering successful interventions on smartwatches.

Methods

We previously presented data from qualitative studies which analyzed values and needs for assistive technologies. In this subsequent study, we included patients with MCI and dementia. To prevent participants from feeling overwhelmed, we accompanied participants during a test intervention (0). Patients’ reactions to the following two tasks delivered by the smartwatch were observed remotely via cameras: A) drinking some water, as a task related to nursing and B) circling bells on a worksheet, as an occupational task. We also implemented two different intervention‐intensities: 1) regular and 2) intensive, with respect to vibration, alarm sounds and instructions. User feedback was obtained with questionnaires. Here, we present data of the feasibility analysis after completion of n = 20 patient, randomly assigned to intensity level 1 or 2 (n = 10/10). All patients were confronted with both tasks in the respective intensity, repeated up to three times in case of failure.

Results

As result of discussions in interdisciplinary working groups, we decided for a “wizard‐of‐oz setting”, which means controlling the smartwatch manually by a smartphone used as remote control. Systematic debriefing revealed obstacles in all study phases. On user side the problem of varying use of glasses and hearing aids couldn’t be overcome. On the technical side pairing problems (connection of phone and watch), automatically reduced brightness of smartwatch display and complicated maintenance of hardware were critical problems. Patients were committed to give feedback and felt not stressed due to the study. Still, filling in the questionnaires with Likert scales was challenging for many participants due to alternation of positively and negatively worded items.

Conclusion

Studying effects of smartwatch‐based interventions in patients with cognitive decline with user‐centered design requires intensive interdisciplinary work. Comparison of the video‐taped, observed behavior with self‐reported behaviors in questionnaires might elucidate chances and limits of user‐centered approaches and will be our next objective.
Lipidome Profiling of APOE4 AD brains implicated unresolved neuroinflammation involving polyunsaturated fatty acid metabolism
Authors: Asante Isaac , Ebright Brandon , Wang Shaowei , Poblete Roy , Arvanitakis Zoe , Bennett David A , Louie Stan G , Yassine Hussein N.
Published: December 2022

Background

The Apolipoprotein E4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, eicosanoids play a prominent role in neurodegeneration.

Method

This study compared measures of the eicosanoid lipidome from patients with AD dementia compared to age and sex‐matched controls with no cognitive impairment (NCI), stratified by APOE genotypes using postmortem brain tissues from the Religious Order Study (n = 42).

Result

Targeted lipidomic analysis by mass spectrometry of the dorsolateral prefrontal cortex demonstrated lower levels of omega‐3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA), and DHA‐derived neuroprotectin D1 (NPD‐1) in persons with lower global cognitive function, independent of age, sex and education years. APOE4 was associated with greater pro‐inflammatory lipids (e.g., PGD2, PGE2, 12‐HHT, LTB4 and 5‐HETE) and pro‐resolving lipids (eg. lipoxins, resolvins and EETs) in patients with dementia (Figure 1). Pathway analysis implicates greater activation of calcium dependent phospholipase A2 (cPLA2), 5‐lipoxygenase (5‐LOX) and soluble epoxide hydrolase (sEH) underlying the observed lipidomic profile.

Conclusion

These results confirm a chronic state of unresolved inflammation in the AD dementia brain that is accentuated in carriers of the APOE4 allele and identify novel therapeutic targets.
Brain Controllability of Cognitive Control Networks is Associated with Executive Functions in Older Adults
Authors: Tang Rongxiang , Elman Jeremy A. , Franz Carol E , Hagler Donald J. , Puckett Olivia K. , Kremen William S.
Published: December 2022

Background

Executive functions encompass effortful top‐down cognitive processes crucial for daily functioning. They are particularly vulnerable to aging in older adults and are often affected early in the course of Alzheimer’s disease. However, the neural mechanisms underlying aging‐related decline in executive functions are not well understood. Modal controllability is a structural metric quantifying the ease at which brain regions can move the brain into difficult‐to‐reach states with substantial effort to support diverse cognitive processes. The emphasis on effortful state transitions bears strong similarity to the definition of executive functions as effortful cognitive processes, rendering modal controllability as a putative neural substrate of executive function. Controllability has been associated with cognitive performance in younger populations, but no studies have examined controllability in older adults or its association with executive function over time.

Method

We used diffusion MRI (dMRI) data from community‐dwelling men ages 56‐70 (N=264 Time 2, N=104 Both Time 1 & 2) in the Vietnam Era Twin Study of Aging (VETSA).We performed whole‐brain deterministic fiber tracking on dMRI data to reconstruct white matter streamlines, which were then used to build structural connectivity matrices. Network‐level modal controllability of two cognitive control networks (multiple demand system and control network) were computed from connectivity matrices. An executive function factor score was computed based on six well‐established neuropsychological tasks: Stroop, Trail Making Test, Category Switching, Letter‐Number Sequencing, Reading Span, and Digit Span.

Results

In cross‐sectional analyses controlling for age, health status, ethnicity, and young adult general cognitive ability, modal controllability of cognitive control networks was positively associated with executive function at Time 2. Change in controllability from Time 1 to Time 2 (∼6 years) was positively associated with change in executive function over the same period.

Conclusion

Findings suggest that a putative mechanism of cognitive aging may involve the controllability of structural networks in supporting brain functional dynamics necessary for cognition. In particular, the longitudinal association suggests that structural network changes in controllability may be a key mechanism underlying aging‐related decline in executive function. A next step will be to how such changes are related to risk for mild cognitive impairment and Alzheimer’s dementia.
Baseline hippocampal vascular reactivity predicts conversion to mild cognitive impairment: an analysis of the SPRINT‐MIND study
Authors: Aslanyan Vahan , Ortega Nancy E , Williamson Jeff D. , Mack Wendy J , Pa Judy
Published: December 2022

Background

Alzheimer’s disease (AD) is characterized by gradual decline to mild cognitive impairment (MCI) and dementia. Vascular risk factors contribute to cognitive decline suggesting that maintaining cerebrovascular health could slow disease progression. Vascular reactivity, a measure of blood vessel elasticity and arterial stiffness, provides a quantitative neurobiological measure of cerebrovascular health. In the present study, we hypothesized that higher hippocampal and whole‐brain gray matter vascular reactivity would be associated with lower rate of conversion to MCI.

Method

518 participants enrolled in Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT‐MIND) study were selected for the current analyses. Participant structural MRI and vascular reactivity measures were included in the current analyses. Vascular reactivity was derived from a 16‐second breath‐holding BOLD fMRI scan. MCI conversion was determined by an expert panel from cognitive assessments. Cox proportional hazards model was used to test if disease progression was associated with hippocampal or whole‐brain gray matter vascular reactivity adjusting for age, sex, education, and treatment assignment (intensive vs. mild BP control). Entorhinal cortex and parahippocampal gyrus control regions were also tested.

Result

Participant demographics are presented in Table 1. Median follow‐up was 5.36 years (IQR=2.11), median time‐to‐MCI was 2.04 years (IQR=0.46). Hippocampal vascular reactivity was significantly associated with conversion to MCI (hazard ratio (HR)=0.52 per 1% ΔCBF/1mm Hg CO2, 95% confidence interval (CI):(0.21,0.84)); this association did not differ by treatment group. Hippocampal volumes were also significantly associated with conversion to MCI (HR=0.58 per 1cm3, 95% CI:(0.36, 0.92)), but there was no correlation between vascular reactivity and volume, and hippocampal volumes did not confound the relationship between vascular reactivity and conversion. Whole‐brain gray matter vascular reactivity was associated with conversion to MCI (HR=0.60 per 1% ΔCBF/1mm Hg CO2, 95% CI:(0.42,0.86)). There were no associations between the control regions and conversion (HR(entorhinal cortex)=0.9 per 1% ΔCBF/1mm Hg CO2, 95% CI: (0.75,1.08); HR(parahippocampus)=0.96 per 1% ΔCBF/1mm Hg CO2, 95% CI: (0.90,1.01)).

Conclusion

Baseline hippocampal and whole‐brain gray matter vascular reactivity is associated with MCI progression, such that those with more vessel elasticity and less arterial stiffness converted to MCI at a significantly lower rate.
Effects of Histone Deacetylase Inhibitors on Different Memory Domains in an Animal Model of Aging and Alzheimer’s Disease
Authors: McClarty Bryan , Dong Hongxin
Published: December 2022

Background

Histone deacetylases (HDACs) have been involved in regulation of memory and previous work from our group and others have shown promising beneficial effects of HDAC inhibitors (HDACis) in aging and neurodegenerative disorders, including Alzheimer’s disease. However, currently, there are no reports on cross comparison of none‐selective and selective HDACis for their beneficial effects on memory and AD‐like pathologies in both aging and AD models.

Method

In this study, 3‐, 12‐, and 18‐months of age WT and APP/PS1 mice were administered a broad acting HDACi valproic acid (VPA), and two selective Class 1 HDACis entinostat (MS‐275, targeting HDAC 1 and 3) and tacedinaline (CI‐994, targeting HDAC 1, 2 and 3) for 30 days. After HDACi administration, mice underwent three memory tests: the novel object recognition (NOR) for executive memory, Y‐maze for short‐term working memory, and Morris water maze (MWM) for long‐term spatial reference memory (n = 8‐10). After memory assessment, mouse prefrontal cortex and hippocampus were collected for biochemical studies.

Result

We found a decrease in executive memory, and long‐term spatial reference memory in WT mice at 18 months of age and, severe memory deficits of three memory domains in APP/PS1 mice at 12‐ and 18‐months of age, and most importantly, we found an age and genotype interaction in the severity of executive and long‐term spatial reference memory deficits in APP/PS1 mice. Both MS‐275 and CI‐994 rescued executive memory, and short‐term spatial reference memory, however, only CI‐994 was sufficient to rescue long‐term spatial reference memory in APP/PS1 mice. We also found a decrease in H3K9ac in APP/PS1 mice with aging at the gene promoters related to memory and synaptic plasticity, however, only CI‐994 rescued H3K9ac levels in APP/PS1 mice.

Conclusion

Our results suggest that selective HDACis could rescue memory function in APP/PS1 mice, and HDAC2 may be an important modulator for hippocampal dependent memory. We are continuing our investigation of changes of specific HDAC and histone acetylation marks on genes related to memory and synaptic plasticity in the hippocampus, but also in the PFC to identify regional specific of HDAC modulation across aging and AD.
Association of DNA methylation from the temporal cortex and cerebellum with AD‐related neuropathology and biochemistry
Authors: Oatman Stephanie R , Allen Mariet , Quicksall Zachary , Reddy Joseph S. , Carrasquillo Minerva M. , Wang Xue , Liu Chia‐Chen , Yamazaki Yu , Nguyen Thuy , Heckman Michael G. , Martens Yuka A , Zhao Na , DeTure Michael , Murray Melissa E. , Kanekiyo Takahisa , Dickson Dennis W. , Bu Guojun , Ertekin‐Taner Nilufer
Published: December 2022

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often measured by Thal phase and Braak stage, respectively. Frequently, Aβ also deposits in the brain vasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. Assessment of these and related endophenotypes can reveal biological insights into the phenotypic variability in AD. We hypothesize that, amongst AD patients, severity of neuropathology and brain levels of AD‐related proteins are influenced by variation in DNA methylation (DNAm), the identification of which may uncover biological pathways for AD pathogenesis. To test this, we performed epigenome‐wide association studies (EWAS) using DNAm from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathology measures (Braak, Thal, and CAA) and brain levels of five proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).

Methods

DNAm from autopsy‐confirmed AD cases available through the Mayo Clinic Brain Bank was measured by reduced representation bisulfite sequencing (RRBS) from 471 brain samples, 200 of which had both TCX and CER measures. Bisulfite converted reads were sequenced on the Illumina High Seq4000 and quality filtered. Neuropathology scoring was performed by an experienced neuropathologist. TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Individual CpG methylation ratios were tested for association with each neuropathological and biochemical measure using the R package CpGassoc.

Results

We identified multiple epigenome‐wide significant CpGs unique to each AD‐related measure. Comparisons between the TCX and CER revealed region specific CpG associations. The effects of sex, age at death, APOE genotype, and presence of genetic variants for each significant CpG association were also identified.

Conclusions

Although all neuropathological and biochemical measures tested reflect core AD pathologies, our results demonstrate unique associations of epigenetic factors with these individual phenotypes, suggesting that their variability may be governed by distinct epigenetic processes. Discovery of DNAm changes that underlie specific neuropathological or biochemical outcomes can enhance our understanding of AD pathophysiology and may lead to the identification of novel gene or pathway targets for the different facets of this complex condition.
APOE‐targeted epigenome therapy for late onset Alzheimer’s disease
Authors: Kantor Boris , Rittiner Joseph , Nicholls Peter J , Chiba‐Falek Ornit
Published: December 2022

Background

There is an urgent need to refocus Alzheimer’s disease (AD) drug discovery on new targets and shifting the paradigm of AD DRUG DEVELOPMENT towards precision medicine. Apolipoprotein E gene (APOE) is the strongest and most reproduceable genetic risk factor for late‐onset Alzheimer’s disease (LOAD), and thus holds promise as a potential therapeutics target for LOAD. In this study we developed an epigenome therapy platform to reduce APOE expression generally and APOEe4 specifically by targeted modification of the epigenome landscape within APOE locus.

Methods

Our gene therapy strategy is based on CRISPR/deactivated (d)Cas9 editing technology fused with an effector molecule and delivered by lentiviral (LV) vehicle. Our gRNAs were designed to target regulatory elements in the APOE promoter and in exon 4 overlapping the SNP that define the APOEe4 allele. We evaluated our epigenome therapy platform in vitro using human hiPSC‐derived neurons and in vivo by stereotactic injection of reporter gene into the hippocampus of mice.

Results

The LV dCas9‐repressor vector showed decreased APOE‐mRNA and protein overall levels in hiPSC‐derived neuronal model. To specifically target the APOEe4 allele we utilized the VRER‐dCas9 protein. Evaluation of the system specificity showed a reduction in APOE‐mRNA levels in the hiPSC‐derived neurons with the e4 allele while there was no effect in the isogeneic hiPSC‐derived neurons homozygous for the e3 allele. Moving onto in vivo studies in mice administration of LV dCas9‐repressor vector and the GFP reporter gene into the hippocampus showed 50‐70% decrease in GFP expression demonstrating promising preliminary data. Collectively, our results provided in vitro and in vivo proof‐of‐concept for the utility and efficacy of the APOE‐targeted epigenome therapy.

Conclusions

Our epigenome therapy strategy for fine‐tuning of APOE expression based on dCas9 technology is translational toward the development of a therapeutics approach to prevent and/or delay LOAD onset. Furthermore, the technology offers the opportunity to refine the platform for the development of gene‐specific and even allele‐ and cell‐type‐ specific therapies, and by that enables the advancement of strategies for precision medicine in LOAD.
Non‐specific elevation of plasma phosphorylated tau181 during neurological illnesses affecting consciousness
Authors: Thanapornsangsuth Poosanu , Ongphichetmetha Tatchaporn , Hemachudha Thiravat
Published: December 2022

Background

Phosphorylated tau (p‐tau)181 has become a promising blood‐based biomarker for Alzheimer’s disease (AD), however, most prospective diagnostic studies excluded participants with other neurological illnesses. We studied the agreement of plasma p‐tau181 and cerebrospinal fluid (CSF) markers, according to AT(N) framework to evaluate the practicality of implementing blood‐based AD diagnosis.

Method

Plasma and CSF were simultaneously collected in subjects presenting with alteration of consciousness to the King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Plasma p‐tau181 was measured using the single‐molecule array. CSF biomarkers were classified according to the AT(N) framework.

Result

Among 69 participants enrolled in the study, the median (IQR) age was 57 (28.5‐75) years, 32 (46.4%) were male, and 4 (5.8%) had AD. Plasma p‐tau181 yielded area under the curve (AUC) of 0.86, although its correlation with CSF p‐tau181 was relatively weak (Rho=0.42, p<0.001). Based on the Youden’s index, the optimal cut‐off point showed sensitivity, specificity, and overall agreement of 0.75, 0.85, and 0.84, respectively. Among subjects with negative CSF biomarkers of AD, plasma p‐tau181 was elevated beyond the usual cut‐offpoint derived from our memory clinic patients undergoing positron emission tomography in many, resulting in a poor specificity of 0.65.

Conclusion

Plasma p‐tau181 showed inadequate performance for diagnosing AD in patients with other neurological illnesses and warrant great caution if used.
Becoming physically active or maintaining physical activity during midlife is associated with biomarkers of amyloid‐beta, microglia, and temporal lobe integrity
Authors: Akinci Muge , Deulofeu Carme , Palpatzis Eleni , Peña‐Gomez Cleofé , Fuentes‐Julian Sherezade , Operto Grégory , Garcia Marina , Milà‐Alomà Marta , Shekari Mahnaz , Kollmorgen Gwendlyn , Suridjan Ivonne , Wild Norbert , Blennow Kaj , Zetterberg Henrik , Gispert Juan Domingo , Suárez‐Calvet Marc , Sánchez‐Benavides Gonzalo , Grau‐Rivera Oriol , Arenaza‐Urquijo Eider M
Published: December 2022

Background

Physical activity (PA) has a beneficial effect on brain health in older age. Whether and how changes in PA during midlife are linked to brain health later in life remains understudied. In adults at risk for Alzheimer’s disease (AD), we investigated the change in PA during midlife in relation to biomarkers of AD pathology, microglia, and brain integrity.

Methods

A questionnaire investigating the minutes of PA per week was administered to 273 cognitively unimpaired participants at baseline and after a follow‐up of 4.1 (±0.8) years. The change in PA minutes/week between the two time points was calculated. Participants were classified in groups based on their activity levels at the two time points (active≥150 minutes, inactive<150 minutes): (1) maintained‐PA groups: active/active, inactive/inactive and (2) changing‐PA groups: inactive/active, active/inactive. During the follow‐up, participants had available CSF amyloid‐β42/40, phosphorylated‐tau and sTREM‐2 measured using either the exploratory Roche NeuroToolKit or the Elecsys® immunoassays, amyloid PET, and structural MRI (AD signature [medial temporal lobe structures] thickness and hippocampal volume). We conducted multiple regression analyses with AD, microglia, and brain integrity biomarkers as outcome measurements and the change in PA minutes between the two time points as predictor, to assess dose‐dependent effects within the whole group, and maintained‐PA and changing‐PA groups separately. Furthermore, we investigated the associations of maintenance and change in activity status (PA groups) on the outcome measurements. All models were adjusted by age, sex, APOE‐ε4 status, education, and time interval between baseline and follow‐up.

Results

The associations observed were group‐specific: increased minutes of PA was associated with greater AD signature thickness in the active/active group (p = 0.05) and greater hippocampal volume in the inactive/active group (p = 0.046). In the maintained‐PA groups, being active/active predicted higher CSF amyloid‐β42/40 (p = 0.024). In the changing‐PA groups, decreased minutes of PA predicted higher sTREM2 (p = 0.036) and brain amyloid‐β burden (p = 0.021). Additionally, the active/inactive group showed higher sTREM2 (p = 0.033) and brain amyloid‐β burden (p = 0.013).

Conclusions

Our results suggest that becoming or staying physically active during midlife is associated with lower amyloidosis, microglia activation, and preserved temporal lobe integrity. The results further suggest a dose‐dependent effect of PA on brain health.
Microglial proteins Iba1 and TSPO (PBR) are differentially altered in the temporal cortex and cerebellum according to Braak stage
Authors: Garland Emma F , Dennett Oliver , Hartnell Iain James , Nicoll James AR , Bottlaender Michel , Boche Delphine
Published: December 2022

Background

Microglia are the resident immune cells in the brain and contribute to the neuropathology of Alzheimer’s disease (AD) by mechanisms not completely known. Iba1 is a microglial marker associated with homeostatic and motility functions. Whereas TSPO (PBR) is a marker of the mitochondrial membrane in microglia, macrophages and endothelial cells and is proposed to be associated with the activated subtype of microglia.

Method

To assess both Iba1 and PBR, we retrieved human temporal cortex and cerebellum samples from 57 cases at different stages of the disease, based on the Braak staging (Group 0‐II n=19, Group III‐IV n=20, Group V‐VI n=18), using immunohistochemical analysis. Additionally, a V‐Plex Mesoscale Discovery (MSD) analysis was performed to assess the inflammatory environment.

Result

There was a significant increase in PBR percentage load (P<0.001) across the Braak stages in the temporal cortex (average load 0.93%) but not in the cerebellum (average load 0.76%). Conversely, there was a significant increase in cerebellar Iba1 load (average load 0.96%, P=0.012) but not in the temporal cortex (average load 1.12%). Furthermore, it was observed that Iba1 forms clusters, putatively around amyloid plaques, whereas this phenomenon was not seen with the PBR marker. The only significant inflammatory molecule was the cytokine IL15 in the temporal cortex (P=0.024), which increased across all Braak stages. However, when the MSD data was correlated with the Iba1 and PBR markers it showed that GM‐CSF was significantly correlated with PBR in the temporal cortex (P<0.0099) and IL‐16 was significantly correlated with Iba1 in the cerebellum (P<0.0012).

Conclusion

This emphasises the outcome that, in AD, PBR may contribute to inflammation in the temporal cortex and Iba1 may be correlated to inflammation in the cerebellum. The findings indicate that TSPO relates to microglial activation in the brain which is Braak‐stage specific and consequently supports the use of TSPO ligands for positron emission tomography (PET) imaging of Alzheimer’s disease‐relevant microglial activity in vivo. Moreover, the absence of an increase in PBR load in the cerebellum could qualify this structure as a reference region for PET quantification.
The impact of social health on global cognition and cognitive domains: An individual participant level data meta‐analysis of longitudinal cohort studies of cognitive ageing
Authors: Samtani Suraj , Mahalingam Saly , Lam Ben C. P. , Lipnicki Darren M. , Costa Erico , Xiao Shifu , Guerchet Maëlenn , Preux Pierre‐Marie , Skoog Ingmar , Scarmeas Nikolaos , Kim Ki Woong , Riedel‐Heller Steffi G. , Hamid Tengku Aizan , Numbers Katya T. , Ganguli Mary , Crowe Michael G , Ng Tze Pin , Sachdev Perminder S. , Brodaty Henry ,   Cohort Studies of Memory in an International Consortium (COSMIC) and Social Health And Reserve in the Dementia patient journal (SHARED) consortium
Published: December 2022

Background

The Social Health and Reserve in the Dementia patient journey (SHARED) project is an international collaboration investigating the association between social health and cognitive function. We conducted an individual participant‐level meta‐analysis of the associations between social health variables and cognitive function (global cognition, memory, language, and executive function).

Method

We obtained individual participant level data (N = 38,641, mean age = 70.5 years, 58.49% female) from 13 longitudinal cohort studies of ageing (12 studies from the COSMIC consortium and the English Longitudinal Study of Ageing). Linear mixed models examined the impact of social health factors, namely relationship status, cohabitation, interactions with friends/family, community group engagement, perceived social support, loneliness, and having a confidante, on global cognition and cognitive domains (memory, language, and executive function).

Result

After controlling for age, sex, and education, we found significant associations between social health variables and slower cognitive decline over time (Mean follow up = 4.99 years, SD = 3.71 years). Compared to being single, being in a relationship was associated with slower decline in global cognition (b = 0.0132, 95% CI: 0.0044, 0.0220), and language (b = 0.0180, 95CI%: 0.0015, 0.0346). Living with others was associated with slower decline in global cognition (b = 0.0089, 95% CI: 0.0039, 0.0139), and memory (b = 0.0155, 95%CI: 0.0031, 0.0279). Compared to never interacting with friends/family, weekly interactions were associated with slower decline in global cognition (b = 0.0178, 95% CI: 0.0021, 0.0335) and memory (b = 0.0198, 95% CI: 0.0094, 0.0302). Other social variables (community group engagement, loneliness and having a confidante) were not associated with cognitive decline.

Conclusion

Good social health (specifically, being in a relationship, living with others, and interactions with friends/family) was associated with slower cognitive decline. Further research is required to investigate the causal pathways from social health to cognitive health.
Shared genetic components between brain regions identify potential therapeutic targets for Alzheimer’s disease by integrative proteomic analysis
Authors: Liu Andi , Manuel Astrid M. , Dai Yulin , Fernandes Brisa S. , Enduru Nitesh , Jia Peilin , Zhao Zhongming
Published: December 2022

Background

Genome‐wide association studies (GWAS) have identified >30 genetic loci associated with Alzheimer’s disease (AD). However, how those variants impact protein expression in different brain regions remain elusive. Large‐scale quantitative proteomic datasets of AD postmortem brain tissues have become available with the breakthrough of high‐throughput mass spectrometry‐based technologies. Thus, we utilized these datasets to understand brain region‐specific molecular pathways underlying AD pathogenesis and their potential drug targets.

Method

We extended our multi‐omics network‐based tool, Edge‐Weighted Dense Module Search of GWAS (EW_dmGWAS), to integrate genetic variants with brain region‐specific proteomic profiles. We performed this analysis by leveraging publicly available AD GWAS statistics of 472,868 individuals (Schwartzentruber et al., 2021) and protein expression profiles covering 190 parahippocampal gyrus (PHG) samples from the Mount Sinai Brain Bank (MSBB) and 192 dorsolateral prefrontal cortex (DLPFC) samples from the Religious Orders Study and Memory and Aging Project (ROSMAP). The resulting modules were evaluated using a scale‐free network index. We highlighted key overlapped genes between region‐specific top module genes (TMGs) and further examined region‐specific differentially co‐expressed genes to identify investigational AD drug targets. Gene set enrichment analyses were performed to assess the functions and cell‐type‐specificity of region‐specific TMGs.

Result

The EW_dmGWAS analyses prioritized 52 TMGs from PHG and 58 TMGs from DLPFC. The TMGs in both regions were found to be enriched in excitatory neurons through cell‐type‐specific enrichment analysis (combined p‐value = 0.03 in PHG; combined p‐value = 0.09 in DLPFC). We found four key overlapped genes with high genetic risk (gene‐level FDR < 0.05), CLU, PICALM, PRRC2A, and NDUFS3. In addition, the differentially co‐expressed drug target analysis pinpointed three potentially drug‐targetable genes, APP, SNCA, and VCAM1, in PHG but none in DLPFC. Additional enrichment analyses of TMGs revealed region‐specific biological processes and drug signatures, including disulfiram in PHG (‐log2FDR = 9.5).

Conclusion

Our network‐based analyses of PHG and DLPFC proteomic profiles prioritized potential key shared genetic factors, which were further proved to play possible roles in the excitatory neurons in AD pathology. Our drug signature analyses validated three known investigational drugs targets, suggesting our findings might serve as a repurposing strategy for AD.
Delays in access to an Alzheimer’s treatment for individuals dually eligible for Medicare and Medicaid in the U.S.
Authors: Mattke Soeren , Jun Hankyung , Chu Samantha , Hanson Mark
Published: December 2022

Background

Prior research has predicted substantial wait times for access to a disease‐modifying Alzheimer’s treatment because of the combination of a highly prevalent disease and a complex diagnostic process. Access could be particularly limited for individuals dually eligible for Medicare and Medicaid in the U.S. in some states. Medicaid programs cover Medicare cost‐sharing requirements for their indigent members, but under the so‐called “lesser of” policy, states may elect to pay only up to the Medicaid rate which is typically less than the Medicare rate. In states with that policy, providers will only receive the lower Medicaid rate, which is known to reduce appointment availability. We estimate the effect of the policy on wait times.

Method

We use a Markov model to predict wait times for dually eligible and regular Medicare beneficiaries. Counts of both groups by age, sex and states came from Census data and Medicare enrollment records, specifics of each state’s Medicaid policy from published data and inquiries to states, and prevalence and incidence data as well as price elasticity of supply from published data.

Result

At total of 35 states and the District of Columbia have a “lesser of” policy and pay less than the Medicare rate for elective specialty care. The average wait time for dually eligibles is between 5.9 and 48.5 months with an average of 17.5 compared to between 3.6 and 42.5 with an average of 13.8 for regular Medicare beneficiaries in those states. Conversely, wait times are indistinguishable in states without that policy, as Figure 1 illustrates. As Figure 2 shows, the difference means that duals have a 30.3% higher average wait times than regular Medicare beneficiaries with a range of 61.2% in DC and 1.2% in Georgia.

Conclusion

The “lesser of” policy is likely to reduce access for the socio‐economically disadvantaged group of dually eligibles, who also suffer from a higher disease burden. The delays would translate into avoidable disease progression and mortality, raising concerns about health equity.
Ubiquitin‐proteasome system dysfunction induced by Alzheimer's disease‐linked Ab oligomers
Authors: Cozachenco Danielle , Ribeiro Felipe Campos , Fortuna Juliana , Lourenco Mychael V. , De Felice Fernanda G. , Ferreira Sergio T.
Published: December 2022

Background

Brain accumulation of the amyloid‐β peptide (Aβ) is a pathological hallmark of Alzheimer’s disease (AD). Considerable evidence indicates that soluble Ab oligomers (AβOs) cause synapse failure/loss and cognitive decline in AD. Evidence further indicates that the ubiquitin‐proteasome system (UPS) is inhibited in AD brains, likely leading to impaired synaptic plasticity and memory. However, the mechanisms underlying UPS dysfunction in AD remain to be elucidated

Method

Here, we investigated proteasome activity in primary hippocampal cultures and in isolated hippocampal synaptosomes from mice that received an intracerebroventricular (i.c.v.) infusion of AβOs. We further investigated the possible protective actions of UCH‐L1, an enzyme that enhances proteasome‐mediated degradation of target proteins, against the impact of AβOs on hippocampal neurons and memory.

Result

Exposure to AβOs resulted in decreased proteasome activity in primary hippocampal cultures and in isolated hippocampal synaptosomes. Synaptosomes isolated from the hippocampi of AβO‐infused mice were also inhibited compared to hippocampal synaptosomes from control, vehicle‐infused mice. Treatment with exogenous recombinant UCH‐L1 prevented oxidative stress in AβO‐exposed hippocampal neurons and memory deficit in AβO‐infused mice.

Conclusion

These results indicate that AβOs inhibit the proteasome, notably at synapses, and suggest that boosting proteasomal proteolysis prevents AβO‐induced neuronal damage and memory deficit.