bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential associations of amyloid and tau (from PET) with brain volumes (from MRI) by cognitive status
Authors: Woodworth Davis C. , Corrada Maria M. , Kawas Claudia H. , Sajjadi S. Ahmad
Published: December 2022

Background

Alzheimer’s disease pathology (AD) is an important cause of neurodegeneration and brain atrophy. Non‐AD mechanisms can also cause neurodegeneration alone or in conjunction with AD. Harboring combination of AD and non‐AD pathologies leads to greater cognitive impairment and dementia. Here, we examined the hypothesis that the association of amyloid and tau burden from positron emission tomography (PET) with brain volumes from magnetic resonance imaging (MRI) is weaker in those with dementia compared to those with mild cognitive impairment (MCI) or normal cognition.

Method

We used data from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had either florbetapir amyloid PET (N=1320) of flortaucipir tau PET (N=833, 535 of whom had both). We examined the association between volumes of brain structures (FreeSurfer‐v7) and standardized uptake value ratios (SUVr) for amyloid (summary cortical region, normalized to whole cerebellum) and tau (meta‐temporal region, normalized to inferior cerebellar gray matter) separately, using linear regressions adjusting for age, sex, and education. We report results in overall groups and by cognitive status (normal, MCI, dementia). We display semi‐partial correlations (sr, thresholded at Puncorrected<0.05), as measures of effect size.

Result

Table‐1 summarizes participant characteristics. The effect of amyloid on brain volumes was modest in the overall cohort, with associations strongest for inferior/middle temporal, inferior parietal, entorhinal, hippocampus, and amygdala regions (sr∼‐0.2, P<0.001 all). In those with dementia, however, there were no distinct associations between amyloid and brain atrophy (Figure‐1). For tau, associations in the overall cohort were similarly strongest for inferior/middle temporal, inferior parietal, entorhinal, hippocampus, and amygdala regions (sr∼‐0.3, P<0.001 all). In those with dementia, associations remained strong for inferior/middle temporal regions (sr∼‐0.3, P<0.001) but tau was not associated with hippocampus volumes (left, sr=‐0.05, P=0.6; right, sr= ‐0.12, P=0.14, Figure‐2); this divergence is further highlighted in select regions (inferior temporal and hippocampus) in Figure‐3.

Conclusion

We found that the relationship between amyloid and tau burden and atrophy was stronger in the overall cohort than in participants with dementia. This was particularly the case for medial temporal lobe structures. The effect of non‐AD pathologies on medial temporal lobe atrophy is a potential explanation for the observed results.
Preparation and qualification of soluble amyloid beta oligomers for use in bioanalytic assays supporting Alzheimer’s disease therapeutics
Authors: Cline Erika N. , Vanderstichele Hugo Marcel , Johnson Derrick , Abdeen Sanofar Jainul , McDermott Paul , Cruse James , Viola Kirsten L. , Dean Robert A , Jerecic Jasna
Published: December 2022

Background

Soluble amyloid beta oligomers (sAβOs) accumulate early in Alzheimer’s disease (AD) and trigger AD‐related neuropathologies and impairments in memory. sAβO structures contributing to the neurotoxic effects remain ill‐defined due to their low concentration, instability, and heterogeneity, impeding the effective design and use of sAβO reference standards in bioanalytic assays for use in clinical trials. At present, no assays for sAβOs are available with proven robustness and clinical performance, due to absence of well‐characterized critical raw materials (antibodies, reference materials for preparation of sAβO calibrators) and quality control specimens.

Method

We have used amyloid‐derived diffusible ligands (ADDLs), a synthetic model preparation commonly used in the literature (Stine et al. 2003), as a sAβO standard integrated into different assays designs developed on the Mesoscale Discovery (MSD) technology. As proof‐of‐concept, we have utilized these ADDL assays to study the specificity and selectivity of antibodies targeted against sAβOs.

Result

Optimization of ADDL coating, stabilization of coated materials, and long‐term plate stability indicated that ADDL‐coated plates provided a suitable platform to assess the performance of sAβO‐targeting antibodies.

Prior to coating, ADDL preparations were tested for reproducible SDS‐stable size distribution and immunoreactivity using SDS‐PAGE with silver stain and Western immunoblotting. The native size distribution (SEC) and globular conformation (AFM) of ADDLs and their ability to bind neuronal synapses in culture (ICC) and subsequently elicit AD‐related pathologies has been well reported in the literature. ADDLs were coated onto 96‐well MSD plates and the ADDL‐coated plates were stored at 4 °C for long‐term use; plate stability was confirmed up to one year. Biotinylated and non‐biotinylated sAβO‐targeting antibodies with variable selectivity towards monomeric or oligomeric Aβ species were used for comparative binding analysis. Additional sAβO preparations, including low concentration ADDL preparations and commercially available sAβOs were used to further understand the selectivity and specificity of the panel of sAβO‐targeting antibodies.

Conclusion

Qualified sAβO preparations (ADDLs) can be used as tools for coating plates to determine specificity and selectivity of sAβO‐targeting antibodies. Other expected uses are: (i) calibrator in immunoassays; or (ii) to screen for the presence of sAβO auto‐antibodies in biological fluids.
Improving movement confidence of people with dementia using gaming
Authors: Astell Arlene J. , Dove Erica
Published: December 2022

Background

People living with dementia face increased risk of falls due to balance impairment and falling‐related psychological factors, such as fear of falling and lack of confidence. Improving movement confidence could improve balance and impact fall risk. This study set out to examine movement confidence of people living with dementia while playing a digital bowling game.

Method

Sixty‐six people (34F/32M) with dementia (mean MoCA 12.7/30), completed a formal balance measure (mini‐BEST or Sharpened Romberg) before and after participating in a 20‐session (2x per week) digital bowling game. Samples of video recordings of the bowling sessions were analysed by two raters, using a coding scheme developed to examine movement confidence.

Result

Formal balance measures confirmed that the majority of participants were substantially impaired in several domains, including reactive postural control (mini‐BEST) and balance with eyes open (Sharpened Romberg). By contrast movement confidence during game play started at a high level in several domains such as optimal walking and fluency of motion and remained high throughout.

Conclusion

Movement confidence can be observed when people with dementia are playing a physical game and contrasts with their performance on formal measures. This may be due to game playing focusing attention onto the game activity, whereas formal assessment focuses on completing the specific movements under assessment. The results highlight the potential of exergames to improve movement confidence and target balance to reduce fall risk of people living with dementia.
Alzheimer‐like biomarker heterogeneity in a preclinical elderly birth cohort: Insight46
Authors: Garcia Mar Estarellas , Young Alexandra L. , Keuss Sarah E , Alexander Daniel C. , Schott Jonathan M
Published: December 2022

Background

Two main complexities of Alzheimer’s Disease (AD) arise from pathological changes (such as amyloid accumulation) occurring a decade or more before symptom onset, and AD being a highly heterogeneous disease with various clinical subtypes. Subtype and Stage Inference (SuStaIn), a data‐driven modelling technique, has been previously applied to ADNI to better understand AD. Here we apply SuStaIn to Insight46, a sub‐study of the British 1946 Birth Cohort to detect different trajectories of preclinical neurodegeneration.

Method

SuStaIn was applied to cross‐sectional MRI, amyloid PET, plasma biomarkers, and cognition (Preclinical Alzheimer Cognitive Composite [PACC]) from 466 study members (Table 1). 376 Amyloid‐negative individuals (computed as Lane et al. 2019) were designated as controls. SuStaIn subtypes were also estimated in ADNI (N=789; Tables 1 and 2) for comparison. T‐tests and Chi‐squared tests were used to assess subtype differences in baseline APOE, amyloid status, white matter hyperintensity volume (WMHV), and rates of change in whole brain, ventricular and hippocampal volume calculated using the boundary shift integral.

Result

Figure 1 shows three subtypes uncovered by SuStaIn: ‘Typical’, ‘Subcortical’ and ‘Cortical’. The ‘Typical’ subtype appears to reflect a typical AD progression pattern, with early involvement of Aβ40/42 ratio and Neurofilament light (NFL), followed by the PACC and finally, plasma tau. MRI volumetric changes appear later. Both ‘Subcortical’ and ‘Cortical’ subtypes are characterised by earlier abnormality in MRI volumes.

Figure 2 shows that subjects assigned to the ‘Cortical’ subtype had significantly higher WMHV than the other two subtypes (p‐value < 0.002). No other significant differences in baseline characteristics were found.

Figure 3 shows ‘Typical’ subtype has significantly higher rates of ventricular expansion and whole brain atrophy compared with ‘Subcortical’ subtype (p‐values = 0.001).

Conclusion

This study reveals three different subtypes (‘Typical’, ‘Subcortical’ and ‘Cortical’) of presumed neurodegeneration in an elderly, preclinical cohort; these are consistent with those found in AD patient cohorts, e.g. ADNI, meaning that these methods may have utility in population based cohorts. These results suggest that SuStaIn may be helpful in determining different subtypes of neurodegeneration at a very early stage with implications for recruitment to, and powering of, clinical trials.
Progranulin upregulation by antisense oligonucleotides targeting regRNAs for treatment of FTD‐GRN
Authors: Aydemir Yeliz Yuva , Abdullatif Ali Al , Ramaswami Gokul , Golczer Gabriel , Akerberg Brynn , Weinstein Jenna , Nishi Yuichi , Pai Rutuja , Cohick Evan , Matthews Bryan , Liu Yuting , Giagtzoglou Nikolaos , Bumcrot David , Sehgal Alfica
Published: December 2022

Background

Heterozygous mutations in progranulin (GRN) gene leading to progranulin protein (PGRN) haploinsufficieny are the major genetic cause of GRN‐related frontotemporal dementia (FTD‐GRN)1, 2 and 3. Decreased levels of PGRN disrupt lysosome homeostasis, cause aberrant microglia activation and neuronal cell death resulting in progressive behavioral changes, language deficits and memory impairment4. We hypothesize that upregulation of PGRN in both neuronal cells and microglia would be effective for treating FTD‐GRN patients.

Method

Regulatory RNAs (regRNAs) are a class of noncoding RNAs that modulate gene transcription. We have developed an RNA Actuating Platform (RAPTM) that identified regRNAs and enables tunable upregulation of genes by specific targeting of regRNAs with antisense oligonucleotides (ASOs).

Result

Our platform identified shared GRN regRNAs in human iPSC‐derived neuron and microglia like cells (iMGLs). ASOs targeting shared regRNAs were screened in a human neuroblastoma cell line to identify lead ASOs that upregulate GRN at least 2‐fold. We showed that the lead ASOs upregulate GRN in both human iPSC‐derived neurons and iMGL cells. Moreover, this level of GRN upregulation was sufficient to rescue staurosporine‐induced toxicity in FTD‐GRN patient iPSC‐derived neurons.

Furthermore, we identified mouse Grn regRNA‐targeting ASOs that upregulate Grn transcription 2.5‐fold in mouse neuroblastoma cell lines and primary neurons. We tested these ASOs for efficacy in an FTD‐GRN mouse model (Grn+/tm1.1Far
)5 by intracerebroventricular injection. Grn upregulation is observed across disease‐relevant brain regions, including cortex in the Grn haploinsufficient mice.

Conclusion

Here, we describe the development of oligonucleotide drug candidates that target regRNAs to upregulate GRN expression as a therapeutic approach for FTD‐GRN. We believe that our strategy will restore secreted and lysosomal PGRN levels in both microglia and neurons thereby decreasing neuroinflammation and neurotoxicity. We are developing these oligonucleotides as a disease modifying treatment for patients with FTD‐GRN.
Ante mortem imaging of cortical microstructure relates to post mortem locus coeruleus hypopigmentation in autopsy‐confirmed Alzheimer’s disease
Authors: Torso Mario , Ridgway Gerard R , Hardingham Ian , Chance Steven A ,   National Alzheimer’s Coordinating Center,   for The Alzhemer's Disease Neuroimaging Initiative
Published: December 2022

Background

Several lines of evidence indicate that Locus Coeruleus (LC) abnormalities occur early in Alzheimer’s disease and are linked to tau pathology. However, the mechanisms underlying alterations in LC structure and function, and their contributions to pathogenesis and disease progression remain unclear. We investigate ante mortem cortical microstructural changes in patients with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC), stratified by Locus Coeruleus hypopigmentation (LCh).

Method

Participants with intermediate or severe ADNC and ante mortem MRI were obtained from the National Alzheimer's Coordinating Center (NACC; n=29) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=6). Participants were grouped by LCh severity (15 with none/mild and 20 moderate/severe).

Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures, at whole‐brain and regional levels: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).

Clinical, demographic and MRI data were used to characterize groups. Group differences in diffusion metrics were tested with a linear model, adjusting for age, interval between scan and date of death, site‐ID, number of dMRI images, and diffusion b‐value, with false discovery rate correction (pFDR<0.05).

Result

The more severe LCh group was significantly younger; no significant differences were detected for cortical or hippocampal volumes, cortical thickness, CDR or MMSE. At whole‐brain level, more severe LCh exhibited significantly higher PerpPD and ParlPD. The regional investigation revealed a widespread pattern of higher PerpPD, while ParlPD showed significantly higher values mainly in parieto‐occipital regions (Figure1).

Conclusion

Together, these findings suggest that LCh severity might contribute to different patterns of cortical microstructural changes in individuals with the same ADNC severity. The more severe LCh group was significantly younger, consistent with the idea that noradrenergic hyperactivity in a more impaired LC might accelerate the spreading of AD neuropathology due to an influence of noradrenergic projections (Weinshenker, 2018). Cortical microstructural measures from dMRI could help stratify patients in clinical trials based on patterns linked to noradrenergic dysfunction, supporting pharmacological treatment focused on hyperactivities of the noradrenergic system.
Cardiac function and neuropathological substrates on MRI across age span: A Cross‐Cohort Collaboration (CCC)
Authors: Yaqub Amber , Wolters Frank J. , Collaboration Cross‐Cohort
Published: December 2022

Background

Cardiac dysfunction has been linked to an increased risk of dementia. However, the underlying pathophysiological substrates remain largely unspecified due to considerable heterogeneity in prior studies. We aggregated data from seven community‐based studies within the Cross‐Cohort Collaboration, to study the association between cardiac function and brain health.

Methods

Participants from all cohorts underwent echocardiography to assess systolic function (left ventricular ejection fraction (LVEF)) and diastolic function (EA‐ratio, deceleration time (DT)). High‐resolution brain MRI was performed to compute volumes of total brain (TBV), gray matter, white matter, hippocampus, and white matter hyperintensities (WMH). We used multivariable linear regression models to determine the association of echocardiographic measures and clinical heart failure with brain volumes, pooling the results using random‐effects meta‐analysis.

Results

Among 10,307 individuals (median age: 62.5 years [54.7 – 70.5]; 54.9% women), moderate to severe systolic function was associated with lower total brain volume (beta per 1‐SD decrease: ‐0.18; 95%CI [‐0.32 ‐ ‐0.04], I2=36%), most profound for white matter and hippocampal volumes. Impaired relaxation in the diastolic phase was associated with smaller total brain volumes (‐0.10; 95%CI [‐0.16 ‐ ‐0.04], I2=2%), again driven by white matter and the hippocampi. Restrictive diastolic function similarly predisposed to lower hippocampal volume (‐0.16; 95%CI [‐0.31 ‐ ‐0.01], I2=0%). Diastolic dysfunction, but not systolic function, was associated with higher volume of WMH (0.03; 95%CI [0.01‐0.05]; I2=0% for DT). Of 8055 participants with clinical data, 277 (3.4%) had heart failure, which was related to all lower brain volumes. These results were consistent across cohorts. In stratified analyses, higher LVEF was associated with higher TBV, from age 50‐59 years onwards up until the oldest age category (80+ years), including larger hippocampi (0.04; 95%CI [0.00‐0.08]; I2=0%) for those aged between 50‐59 years.

Conclusion

Cardiac dysfunction is associated with brain imaging markers of neurodegeneration in community‐dwelling individuals from midlife to late‐life. Preservation of cardiac function may be an additional target to promote cognitively healthy ageing.
Motoric Cognitive Risk Syndrome and Cognition: The Influence of Depression
Authors: Aliberti João Paulo Quessada , Serraglio Ana Beatriz dos S , Suemoto Claudia Kimie , Aliberti Marlon Juliano Romero
Published: December 2022

Background

Motoric Cognitive Risk (MCR) syndrome is a practical tool used to identify independent people at risk of developing dementia. Although mood disorders and MCR relates, whether depression changes the association of MCR with cognition remains uncertain. We estimated the associations of MCR with cognitive performance and impairment in people aged ≥50 years and examined whether depression modifies the relationship between these conditions.

Method

Cross‐sectional analysis comprising participants without dementia or physical disability of the Brazilian Longitudinal Study of Aging (ELSI‐Brazil), a nationally representative sample. MCR syndrome was defined as presence of memory complaints and slow gait (one standard deviation below age‐ and sex‐specific gait speed means). Depression was assessed through the 8‐item Center for Epidemiologic Studies Depression Scale (CES‐D). We estimated the associations of MCR with global cognition, orientation, memory, and verbal fluency z‐scores, using linear regressions adjusted for sociodemographic, clinical, and lifestyle factors. The relationship of MCR with cognitive impairment was examined using logistic regressions. We explored interactions between MCR and depression for cognition.

Result

We evaluated 7,131 participants (mean age 62±9 years; 53% women). Individuals with MCR (7% of the sample) had poorer scores for global cognitive performance than those without the syndrome (β = ‐0.29; 95%CI = ‐0.42 to ‐0.17). Participants with MCR were also associated with 2‐fold odds of cognitive impairment compared to those without the syndrome (39% vs. 19%; aOR = 1.93; 95%CI = 1.44 to 2.71). However, depression modified the relationship between MCR and cognitive impairment in people aged 50 to 64 years, with a p‐value for interaction = 0.02 (Figure 1). In middle‐aged adults without depression, MCR was not associated with cognitive impairment. In contrast, in middle‐aged adults with depression, MCR was associated with almost 3‐fold odds of cognitive impairment (aOR = 2.70; 95%CI = 1.60 to 4.40).

Conclusion

MCR syndrome was associated with worse cognitive performance. Among middle‐aged adults, MCR was related to cognitive impairment only in those with depression. Depression evaluation alongside MCR may help clinicians identify individuals who are more likely to experience cognitive impairment. Future studies should test the impact of treating depression on those with MCR.
Comparative characterization of 5XFAD and hAbetaSAA mouse models of familial AD
Authors: Elk Kevin J , Garceau Dylan , Oblak Adrian L , Pandey Ravi S , Carter Gregory W , Ferron Gianna , Linehan Stefan T , Ragan Tim , Little Gabriela , Williams Sean‐Paul , Rizzo Stacey J Sukoff , Lin Sherry , Datta Sandeep Robert , Sasner Michael
Published: December 2022

Background

The failure of most clinical Alzheimer’s disease (AD) trials has been partially attributed to the lack of translatability of current AD mouse models to human patients. A recently developed model of familial AD (fAD), expressing Swedish, Arctic and Austrian mutations in App (hAbetaSAA), has been shown to be a useful amyloidogenic model which recapitulates many aspects of human AD, including plaque distribution and microglial transcriptional changes. Our aim is to further characterize the hAbetaSAA model and compare it to the widely used 5xFAD transgenic model.

Method

Motion Sequencing (MoSeq) software was used to model the underlying structure of spontaneous behaviors recorded in an open field in hAbetaSAA and 5xFAD mice longitudinally from 10 to 18 months of age. Aged hAbetaSAA and 5xFAD brain tissue was used for spatial transcriptomic/proteomic profiling, performed by Nanostring’s GeoMx®, which allowed for quantification of gene and protein expression in plaque‐associated and non‐plaque‐associated regions of interest. A fluorophore‐conjugated amyloid antibody (Methoxy‐X04) was administered to cohorts of hAbetaSAA and 5xFAD prior to harvest at various ages. An additional fluorophore‐conjugated antibody (lectin Dylight®594) was administered to 19‐month‐old cohorts permitting visualization of cerebral amyloid angiopathy (CAA). Whole brains were sectioned/imaged using Serial Two‐Photon Tomography on the TissueCyte (TissueVision), creating indexed tissue sections and high‐resolution 3D models of each brain. Subsequent rounds of staining permitted characterization of disease‐associated microglia (DAM) and dystrophic neurites. An independent cohort was evaluated for EEG telemetry.

Result

MoSeq revealed divergent behaviors of 5xFAD and hAbetaSAA mice suggesting differences in behavioral phenotypes of these two models. Preliminary GeoMx data shows upregulation of DAM genes localized to plaques in hAbetaSAA homozygotes as identified by RNA‐seq; correlating 5xFAD data is in progress. Further assessments of bulk RNA‐Seq, amyloid distribution, CAA burden and cortical EEG spectral analysis are underway.

Conclusion

Comparison of hAbetaSAA and 5xFAD using innovative modes of assessment showcase hAbetaSAA as an amyloidogenic mouse model of fAD that aligns more closely with human than 5xFAD. This model is available for preclinical research with no licensing restrictions and is devoid of artifacts related to transgenic overexpression, positioning it as an improved mouse model for studying fAD mutations.
Prognostic value of regional tau PET measures in Alzheimer’s Disease
Authors: Tunali Ilke , Svaldi Diana , Kotari Vikas , Collins Emily C. , Shcherbinin Sergey , Initiative Disease Neuroimaging
Published: December 2022

Background

Recent findings (Ossenkoppele et al, JAMA Neurology, 2021; Pontecorvo et al, Brain, 2019) suggest that tau‐positron emission tomography (PET) may better predict cognitive change in AD compared to amyloid‐PET and MRI‐based cortical thickness. However, the relationship between region‐based standardized uptake value ratio (SUVR) metrics and cognitive change in terms of prognostic value is not clearly understood. In this study, we evaluated the potential utility of region‐based tau‐PET metrics to stratify patients by cognitive decline risk and amyloid status in the brain.

Methods

We analyzed a subgroup of N=100 symptomatic (24 MCI and 76 AD) subjects from the ADNI database that had longitudinal cognitive scores and flortaucipir and florbetapir scans acquired within ±6 months of baseline cognitive scores. We quantified tau burden using global MUBADA SUVR (Devous et al, JNM, 2018) and AAL atlas‐based temporal and parietal regions using a modified cerebellar gray matter reference region (Pontecorvo et al, Brain, 2017). For every global and region‐based tau SUVR, patients were dichotomized into tau groups of high (T+) and low (T‐) by using a series of thresholds (1.15‐1.45). For all identified tau groups, average Mini‐Mental State Exam (MMSE) score, average MUBADA SUVR, percentage of amyloid‐positive individuals and change in 13‐item Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog13) scores were assessed. Signal‐to‐noise ratios (SNRs) and mean annual cognitive changes were measured using ADAS‐Cog13 scores that were obtained in a 2‐to‐3‐year period per patient.

Results

For every global and region‐based flortaucipir measure, an increase in SUVR threshold resulted in lower average MMSE score, larger average global tau burden, higher percentage of amyloid‐positive patients and increased mean cognitive decline for patients in T+ group. SUVR thresholds that identified subgroups with high percentage (≥90%) of amyloid‐positive (Table 1) and high (>1) SNRs (Table 2), were observed to be lower for brain regions identified later in the tau pathologic cascade: inferior temporal (1.45), lateral temporal (1.35), lateral parietal (1.20).

Conclusions

Region‐based tau‐PET analysis showed that utilizing temporal and parietal SUVR values could help stratify patients by risk of cognitive decline and amyloid status. Clinical trial eligibility algorithms based on region‐based tau metrics, might enable enrolling patients into customized AD trials.
The association of the of late‐life onset psychotic symptoms with incident cognitive impairment in a cognitively normal sample.
Authors: Creese Byron , Aarsland Dag , Ballard Clive G , Brooker Helen , Corbett Anne , Ismail Zahinoor
Published: December 2022

Background

Previous research suggests around 5–10% of cognitively normal older people report some degree of psychotic experiences as measured in the Mild Behavioral Impairment framework. Such late‐onset symptoms potentially confer a relatively high risk for neurodegenerative disease so there is a need for studies examining their clinical correlates prior to dementia onset. We compared the relationship between psychotic symptoms and progression to cognitive impairment in a large community‐dwelling sample of adults over 50.

Method

5,085 participants were drawn from the PROTECT study. These individuals had no reported neurological diseases (including MCI), psychotic disorders or cognitive impairment as rated by the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE). Cognitive impairment was operationalised as a score of >3.3 on the IQCODE. Participants were followed up for a maximum of 5 years. IQCODE scores were taken every. Survival until ‘cognitive impairment’ (i.e. IQCODE >3.3) was the primary outcome. At baseline participants were dichotomised into those scoring >0 on any of the 5 items pertaining to psychosis on the Mild Behavioral Impairment Checklist (‘MBI‐psychosis’ group) and those scoring 0 on all 5 items (‘no symptoms’ group). Survival until IQCODE >3.3 was assessed in a Cox proportional hazards model (adjusting for age, gender, education and mental health diagnoses). The frequency of other medical conditions and Instrumental Activities of Daily Living (IADL) impairment was also compared between the two groups.

Result

There were 429 (8%) participants in the MBI‐psychosis group (72% men) and 4,656 in the no symptom group (72% men). The mean age was 63 (SD: 6.9). MBI‐psychosis was associated with a 3‐fold (95% CI: 2.4‐3.6, p<0.0001) higher risk of cognitive impairment relative to the no symptom group. There were modestly higher proportions of the following conditions in the MBI‐psychosis group compared with the no symptoms group (p<0.05): heart disease (9%, 6%), high blood pressure (33%, 27%), high cholesterol (30%, 25%), hypothyroidism (11%, 7%), arthritis (26%, 21%). There was no difference in IADL impairments.

Conclusion

Relatively mild psychotic symptoms that emerge in later are associated with an increased risk of cognitive decline, suggesting that these symptoms in the cognitive normal population may be of clinical significance.
Association of apolipoprotein E in peripheral blood and in vivo Alzheimer’s disease pathologies in nondemented older adults
Authors: Byun Min Soo , Yi Dahyun , Ahn Hyejin , Kim Min Jung , Jung Joon Hyung , Jung Gi Jung , Lee Jun‐Young , Kim Yu Kyeong , Lee Yun‐Sang , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: December 2022

Background

Previous studies reported the link between apolipoprotein E (apoE) in peripheral blood and risk of Alzheimer’s disease (AD) dementia. However, underlying mechanism for this link remains unclear. We investigated whether serum apoE concentration is associated with in vivo AD pathologies in nondemented older adults.

Method

A total 437 nondemented older adults were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. All participants underwent comprehensive evaluation including clinical assessment, blood sampling, as well as 11C‐PiB PET and MRI. A subset of participants (N=130) also underwent 18F‐AV1451 PET for measurement of brain tau pathologies. All participants were divided into low, middle, and high apoE concentration tertile groups (i.e., T1, T2, and T3).

Result

There were no significant differences in demographic and clinical variables except the frequency of female and rate of apoE ε4 allele (APOE4) positivity; the lower serum apoE was associated with fewer female (40.1%, 61.6%, and 67.8% for T1, T2, and T3, respectively) and higher APOE4 positivity rate (34.3%, 25.2%, and 16.8%). In terms of AD biomarker, Aβ positivity rate showed significant negative association with serum apoE (40.1%, 31.8%, and 24.8%), which remained significant after adjustment of covariates including age, sex, and diagnosis. In addition, reduced AD‐signature region volume, a neurodegeneration biomarker of AD, was significantly associated with lower serum apoE after controlling the same covariates. With regard to tau biomarker, positivity rate of global tau deposition showed significant negative association with serum apoE level (56.8%, 50%, and 20%) after adjustment of covariates. When we additively controlled the effect of APOE4 positivity, the associations between low serum apoE and greater neurodegeneration and tau positivity remained significant, whereas the association between apoE and Aβ positivity did not reach statistical significance.

Conclusion

In the present study, low serum apoE was associated with greater burden of in vivo AD pathologies and such association appears even independent of APOE4 carrier status in regard of tau deposition and neurodegeneration. The finding suggests a potential role of serum apoE as a surrogate marker for in vivo AD pathologies in nondemented older adults.
Cognitive resilience polygenic risk score sensitive to preclinical disease changes
Authors: Eissman Jaclyn M. , Khan Omair A. , Liu Dandan , Petyuk Vladislav A , Gifford Katherine A. , Dumitrescu Logan , Jefferson Angela L. , Hohman Timothy J.
Published: December 2022

Background

Alzheimer’s disease (AD) polygenic risk scores (PRS) are often derived from case/control GWAS, which are typically not sensitive to preclinical disease changes, limiting their clinical utility. To overcome this pitfall, we built and evaluated the performance of multiple PRS of AD‐related endophenotypes, including resilience to cognitive impairment in the presence of amyloid.

Method

Four PRS were derived from GWAS of baseline memory, memory decline, cognitive resilience (Dumitrescu et al., 2021), and AD (Kunkle et al. 2019). PRS were built in an independent cohort that was free of dementia, the Vanderbilt Memory and Aging Project (N=255). We used linkage disequilibrium clumping on TOPMed‐imputed genotypes, and a threshold of P=0.01. We ran linear models with baseline memory score as the outcome, and baseline age, sex, and PRS as predictors. Linear mixed effects models, with identical predictors, were used when longitudinal memory was the outcome, letting individual slope and intercept vary. Finally, we tested a CSF Aβ42‐by‐PRS interaction term to assess if PRS modified associations between amyloid and cognition. Sensitivity analyses excluded APOE from PRS calculations.

Result

As expected, the baseline memory PRS related to baseline memory (β=0.12, P=0.04), and the memory decline PRS related to longitudinal memory (β=0.04, P=0.001). Without APOE, the baseline memory PRS and the memory decline PRS results attenuated. The AD PRS related to both baseline memory (β=‐0.19, P=0.002) and longitudinal memory (β=‐0.03, P=0.01), but results attenuated without APOE. The resilience PRS did not have a main effect on baseline or longitudinal memory. However, interestingly, the resilience PRS interacted with CSF Aβ42 on baseline memory (β=‐0.001, P=0.02; Figure 1), whereby the resilience PRS related to memory among amyloid‐positive individuals (β=0.44, P=0.01) but not amyloid‐negative individuals (β=0.06, P=0.46). No other PRS was predictive of memory among amyloid‐positive individuals, and resilience PRS results remained consistent without APOE.

Conclusion

Our results demonstrate that a resilience PRS appears to be predictive of individual cognitive performance downstream of amyloidosis. Future work is needed to replicate this finding, but our preliminary findings highlight the potential utility of resilience PRS for predicting individual risk for AD‐related cognitive impairment during the preclinical stages of disease.
Type 2 diabetes mellitus and obesity impact AD‐related pathology through overlapping and independent pathways
Authors: Yu Yang Yang , Nowell Joseph , Edison Paul
Published: December 2022

Background

It is proposed that neuronal damage in diabetes is related to hyperglycaemia and insulin resistance, whilst inflammation and subsequent oxidative stress affects cognitive function in obesity. We investigated whether obesity and diabetes present distinct neuropathological features of neurodegeneration.

Methods

To compare amyloid, tau and cerebral glucose metabolism, we processed 1973 available PET scans for 18F‐AV‐45, 18F‐flortaucipir and 18F‐fludeoxyglucose (FDG) from 971 participants with diabetes (n=194), obesity (n=377) and without diabetes or obesity (n=400) from the Alzheimer’s Disease Neuroimaging Initiative dataset. Independent t‐tests and multivariate analysis were used for regions of interest (ROIs) analysis in participant groups with diabetes vs non‐diabetic/non‐obese and obesity vs non‐diabetic/non‐obese. This was conducted across different cognitive subgroups, namely Alzheimer’s disease, mild cognitive impairment or normal cognition. Amyloid positive and negative subjects were evaluated separately. Voxel‐wise analysis using SPM was also conducted for these groups.

Results

For diabetes, higher amyloid uptake was found in the medial temporal regions in the cognitively normal diabetic group compared to the cognitively normal (non‐diabetic/non‐obese) group. This was also found in the amyloid positive mild cognitively impaired diabetic groups compared to mild cognitively impaired (non‐diabetic/non‐obese) group. Similarly, higher amyloid deposition was seen in the hippocampus of the cognitively normal obese group compared to the cognitively normal (non‐diabetic/non‐obese) group.

Additionally, higher tau uptake was found in the whole brain (global brain value), frontal, parietal and occipital lobes for cognitively normal diabetic and obese groups, compared to cognitively normal (non‐diabetic/non‐obese) groups. Higher tau was further found in the temporal lobe and anterior cingulate of AD obesity participants compared to the AD (non‐diabetic/non‐obese) participants.

Discrete cerebral glucose metabolic patterns were found in diabetes and obesity. In the diabetic groups, reduced FDG uptake was found in mild cognitively impaired participants (whole brain, frontal, parietal and occipital lobes) and amyloid positive AD participants (occipital lobe) compared to non‐diabetic/non‐obese participants. In contrast, increased FDG uptake was mainly found in amyloid negative obese participants.

Conclusions

Glucose hypometabolism in diabetic participants in contrast to hypermetabolism in obese participants implies that different pathological processes of neurodegeneration occur in these two conditions. This suggests that these two conditions require different therapeutic strategies to prevent neurodegeneration.
DNA methylation of mitochondrial DNA shows variation in human brain.
Authors: Wheildon Greg , Smith Adam R. , Soanes Darren , Southern Francesca , Devall Mathew , Moore Karen , O'Neill Paul , Troakes Claire , Lunnon Katie
Published: December 2022

Background

There is growing evidence for the role of DNA methylation in regulating the transcription of mitochondrial genes, particularly in neurodegenerative disorders characterized by mitochondrial dysfunction including Alzheimer’s disease (AD). However, to date, a cross‐comparative analysis of the mitochondrial DNA methylome in neurodegenerative disorders has yet to be undertaken.

Method

Here, we present an interrogation of the mitochondrial DNA methylome at single base resolution, using pyrosequencing, across different types of neurodegenerative disorders. We performed a targeted study design to investigate the D‐Loop methylation of the mtDNA in the entorhinal cortex (EC) for a pilot cohort of 26 AD, 22 Dementia with Lewy bodies (DLB) and 26 control samples, matched as closely as possible for age and sex. This research forms the basis of a larger study which will compare D‐Loop methylation in several brain regions including the EC, superior temporal gyrus and cerebellum in AD, DLB, Vascular dementia, Huntington’s (HD) and Parkinson’s disease (PD) samples. The striatum and substantia nigra, will also be analyzed in the HD and PD samples respectively.

Result

We have identified DNA methylation differences at the D‐Loop in different neurodegenerative diseases. In particular, we have found two statistically significant sites that show a decrease in percentage methylation of approximately 4% and 3% in the EC of the DLB brain samples compared to controls.

Conclusion

We have discovered differences in DNA methylation across the mitochondrial genome between different types of neurodegenerative disorders in human brain samples using pyrosequencing. Moving forward we will take this approach and expand into the larger cohort to further investigate the role of mitochondrial epigenetic mechanisms in neurodegenerative disorders.
Bulk and single cell transcriptomic analysis of different dementia types in human hippocampus
Authors: Olayinka Oluwatosin A , Hu Junming , O'Neill Nicholas K , Wong Melissa , Rickner Hannah , Simkin Irene , Stein Thor D. , Wolozin Benjamin , Zhang Xiaoling , Farrer Lindsay A.
Published: December 2022

Background

Alzheimer’s disease (AD) is characterized by cognitive deterioration and extracellular amyloid beta deposits and neurofibrillary tangles in the brain. These may occur in tandem with markers of Lewy body (LB) and vascular dementia (VaD). Studying bulk and single‐cell expression profiles for these disorders may identify factors shared between and unique to AD and other dementias.

Method

Bulk RNA‐sequencing was performed using 210 human postmortem hippocampal region samples obtained from brains donated to the BU Alzheimer Disease Research Center. After quality checks (QC), 191 samples classified as AD+LB (n=43), AD+VaD (n=54), AD alone (n=73), and controls (n=17) were included in the study. Analysis of expression differences between each of these AD groups and controls was performed using limma software with models including covariates for age, sex, RNA quality, plate, and two surrogate variables to adjust for unknown variation. Weighted gene co‐expression network analysis (WGCNA) was used to identify clusters of co‐expressed genes. Additionally, high quality single‐nuclei RNA sequencing data (snRNA‐seq) was obtained from 8 of the 210 hippocampal samples with an average of 6000 cells detected per sample and 1800 genes per cell after QC. This snRNA‐seq data was integrated with the bulk data using Scissor to identify cell populations positively and negatively associated with AD.

Result

481 genes were differentially expressed between AD cases and controls. Upregulated genes in AD subjects were enriched for cilia function and morphological development and downregulated genes in AD subjects were enriched for mitochondrial energy production. A WGCNA module strongly associated with ciliary function was found to be overrepresented in AD (and especially AD+VaD) samples compared to controls. Multiple brain cell types were detected from our snRNA‐seq data. Of these, a subpopulation of ependymal cells related to the ciliary WGCNA module was positively associated with AD status.

Conclusion

Our results suggest that different sets of co‐expressed genes in hippocampus distinguish AD brains with and without pathological hallmarks related to other forms of dementia, and brains without AD pathology. This study also provides preliminary evidence for the involvement of ependymal cell populations in AD
The Relationship of Alzheimer’s Disease, Stroke and Ancestry in the Puerto Rican Alzheimer Disease Population.
Authors: Feliciano‐Astacio Briseida E. , Beecham Gary W. , Hamilton‐Nelson Kara L. , Silva‐Vergara Concepcion , Contreras Maricarmen , Mena Pedro Ramon , Adams Larry D. , Acosta Heriberto , Feliciano Nereida I , Lopez Alexandra , Cuccaro Michael L. , Vance Jeffery M. , Pericak‐Vance Margaret A.
Published: December 2022

Background

The Puerto Rico Alzheimer and Related Dementias Initiatives (PRADI) patient cohort was developed to investigate AD and the associated genetics factors in the Puerto Rican population. PRADI recruitment was a snowball sampling, with both island‐wide geographic distribution, and extensions of the PR communities in the continental US. A prior analysis suggested that stroke is a contributing factor to AD in the PR population. In this study we further evaluated the association between stroke and AD, while considering also age, gender, and ancestry.

Method

We assessed 1063 elderly PR individuals for dementia and obtained a medical history. Affection status or mild cognitive impairment was established using standard AD clinical criteria (NINCDS‐ADRDA). Medical history was obtained by a self‐report or informant report. The global ancestry was assessed through the ADMIXTURE program. Differences between affected and cognitively unimpaired (CU) individuals were initially evaluated using a chi‐square test (for age, gender, global ancestry, and stroke) and a t‐test for the age at the exam time. Follow‐up analyses on stroke were performed using logistic regression with age‐at‐exam, gender, and global ancestry proportions as covariates in the model. Initially we assess how stroke is associated with AD, while accounting for age, sex, and global ancestry analysis without APOE, results on the first table. The first table is the model without APOE. Then a second tab turns it around and looks at what factors are associated with Stroke, in the context of AD.

Result

In the PRADI population stroke is associated with an increased risk of AD dementia (p=0.012); this association persists even after accounting for APOE dosage (p=0.017). Additionally, age, gender and APOE dosage were all also associated with increased AD risk (p <0.05) (table 1). AD correlated with Stroke (p=0.013). Gender was also associated with stroke, with females having a decreased risk of stroke (p=0.0021). APOE dosage and ancestry proportions measured through ADMIXTURE approach were not associated with stroke (table 2).

Conclusion

Stroke was independently associated to AD after controlling for APOE dosage. In contrast, age and gender were associated with stroke whereas global ancestry and APOE dosage were not.
Granulocyte‐Macrophage Colony‐Stimulating Factor Reduces Two Major Pathological Hallmarks of Alzheimer’s Disease and Astrogliosis in the TgF344‐AD Rat Model
Authors: Ahmed Md. Mahiuddin , Wang Athena Ching‐Jung , Boyd Timothy D. , Solano D. Adriana , Vielle Anne , Markham Neil , Coughlan Christina M , Chial Heidi J , Vergara M. Natalia , Potter Huntington
Published: December 2022

Background

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), a hematopoietic growth factor and the innate immune system modulator, has shown therapeutic and neuroprotective effects in animal models of Alzheimer’s disease (AD), Parkinson’s disease, Down syndrome, stroke, and normal aging. Recently, Potter et al. (2021) published the results of a Phase2 clinical trial in mild‐to‐moderate AD subjects showing that recombinant human GM‐CSF (sargramostim) treatment shifted both MMSE scores and plasma biomarkers of neurodegeneration toward normal. Cohen et al. (2013) developed a transgenic rat model (TgF344‐AD) that expresses the Swedish mutant human APP (APPsw) and mutant human presenilin 1 (PSEN1 deltaE9) genes that cause familial AD. In addition to cerebral amyloidosis, neuronal loss, and cognitive deficits, TgF344‐AD rats also show age‐dependent tauopathy including overexpression of phosphorylated tau and neurofibrillary tangle formation, which are not present in mouse models of AD. To evaluate the potential ability of GM‐CSF to reverse and/or prevent the full range of AD pathology, we treated ∼20‐month‐old TgF344‐AD rats with GM‐CSF or saline, and investigated AD pathology in the brain and retina. We also analyzed biomarkers in plasma using MSD and SIMOA neuroinflammation panels.

Method

TgF344‐AD rats were injected subcutaneously with GM‐CSF (83.3ug/kg/day; 5days/week) or with saline (200ul/day) for 24 injections total over 32 days. On day 32, blood samples were collected, plasma samples were used for biomarkers assays, and brain and retinal tissues were processed for immunohistochemistry and immunoblotting.

Result

TgF344‐AD rats treated with GM‐CSF showed a significant reduction in amyloid plaque deposition in the cortex and a strong trend towards reduced plaque deposition in the hippocampal CA region compared to saline‐treated TgF344‐AD rats. We also observed a trend of reduced phosphorylated tau expression in the cortex and hippocampal region in GM‐CSF‐treated TgF344‐AD rats. In addition, GM‐CSF treatment significantly reduced astrogliosis in the CA1 and dentate gyrus/hilus regions of TgF344‐AD rats.

Conclusion

Although experiments are ongoing, our findings indicate that GM‐CSF treatment rescues two major pathological hallmarks of AD and neuroinflammation (astrogliosis) in TgF344‐AD rats. Our results suggest that GM‐CSF/sargramostim/Leukine® may be a potential therapeutic not only for reducing amyloidosis, but also for reducing levels of hyperphosphorylated tau and other relevant pathological manifestations of AD.