bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel 3D imaging method to establish baseline amyloid‐beta plaque load and analyze compound efficacy in pre‐clinical Alzheimer’s disease animal models
Authors: Ferron Gianna , Linehan Stefan T , Ragan Tim , Elk Kevin J , Garceau Dylan , Sasner Michael
Published: December 2023

Background

Amyloid‐beta (Aβ) plaque deposition in the brain represents a significant hallmark of Alzheimer’s Disease (AD). Standard laboratory approaches assessing Aβ lack the ability to pair high‐throughput whole‐organ imaging with region‐specific quantitation, and often require tissue homogenization. To analyze changes in Aβ spatiotemporally, we developed a novel Serial Two‐Photon Plus (STP2) pipeline to quantify plaque progression and depression as a function of brain region, resulting in indexed brain sections for secondary analysis using MALDI HiPLEX‐IHC with imaging mass spectrometry (IMS).

Method

Plaques in the well characterized 5XFAD mouse model of AD were labeled with Methoxy‐X04, an Aβ plaque‐specific compound, prior to transcardial perfusion and whole‐brain excision. The STP2 platform uses a TissueCyte system to produce high‐resolution multi‐channel datasets, yielding 3D models of each brain. The Allen Mouse Brain Common Coordinate Framework (CCFv3) was registered to each brain, and our automated pipeline quantified plaque load and density per brain region. Select resulting sections were analyzed using AmberGen MALDI HiPLEX‐IHC and Bruker Daltonics IMS for Aβ42, pTau, GFAP, GLUT1, MBP, NeuN, NF‐L, PVALB, SNCA and SYN‐I.

Result

Quantifying baseload plaque distribution in the 5XFAD model at 2, 3, 4, and 6‐months revealed significant changes in density of Aβ plaques both spatially and temporally. STP2 imaging, combined with CCFv3 mapping and secondary proteomic analysis allows for targeted evaluation of compound treatment on the Aβ plaques.

Conclusion

The STP2 pipeline produces translational high‐throughput pre‐clinical AD data with enhanced sensitivity and precision, with resulting sections remaining in‐tact for further secondary analysis of spatial proteomics and pharmacodynamics in the brain.
Effects of Exergaming in Cognitive Functions for People with MCI and dementia. A systematic review and meta‐analysis
Authors: Chan Joyce YC , Chan Aaron TC , Tsoi Kelvin KF
Published: December 2023

Background

Cognitive decline is one of the initial symptoms of older adults with mild cognitive impairment (MCI) and dementia. Physical activity has been found to be able to prevent cognitive decline in older adults with MCI and dementia. Exergaming is a form of technology‐driven physical activity which is suggested for older adults. However, it is still unclear whether exergaming is able to help older adults with MCI and dementia to prevent deterioration of cognitive functions. Therefore, we performed a systematic review and meta‐analysis to examine the effect of exergaming on cognitive functions in older adults with MCI and dementia.

Method

A systematic literature search was conducted via OVID databases. Studies recruited older adults with MCI or dementia, and examined the effect of an exergaming intervention and compared with a non‐exergaming group were included. Both randomized controlled trails and quasi‐experimental studies were eligible. The outcomes were global cognition and verbal memory. All outcomes were measured by using standard cognitive assessment tools. The effects were pooled by meta‐analysis.

Result

Nine studies involving 497 older adults with MCI or dementia were included. The mean age ranged from 67 to 84, and the percentage of male ranged from 27% to 72%. Seven studies were RCT; two studies were with quasi‐experimental design. Older adults who received exergaming showed better global cognition than the control group (SMD = 0.32, 95% CI = 0.1 to 0.54). For memory functions, older adults who received exergaming showed better verbal memory than the control group (SMD = 0.85, 95% CI = 0.63 to 1.67). In subgroup analysis, older adults who received exergaming showed better global cognition than the usual care group (SMD = 0.44, 95% CI = 0.19 to 0.69), and comparable performance with the traditional exercise group.

Conclusion

Exergaming was demonstrated to be a potential psychosocial intervention to prevent cognitive and memory decline in older adults with MCI and dementia. Exergaming can capture behavioral data that may be able to further understand the change in the cognitive abilities of older adults at risk. However, the number of studies was small, further investigation of the effect of exergaming is suggested.
Natural cubic splines for the analysis of Alzheimer’s trials
Authors: Donohue Michael C. , Langford Oliver , Insel Philip S. , van Dyck Christopher H , Petersen Ronald C. , Craft Suzanne , Raman Rema , Sims John R. , Sperling Reisa A. , Aisen Paul S. S
Published: December 2023

Background

Mixed model repeated measures (MMRM) is the most common analysis approach in clinical trials for Alzheimer’s disease. The model treats time as a categorical variable, which can be problematic when assessments occur off‐schedule, as including off‐schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. Since MMRM entails a mean parameter for each group and visit, the model can be inefficient for longer trials of Preclinical Alzheimer’s. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time.

Method

We use model selection techniques to compare the predictive value of spline models to slope models, MMRM, and models that assume a proportional treatment effect using data from several completed trials. These trials include the ADCS trial of donepezil in MCI, trials of intranasal insulin and a fyn kinase inhibitor in mild Alzheimer’s dementia, and the A4 trial of solanezumab in Preclinical Alzheimer’s. Simulation studies assess the power and Type I error of these models for trials in Preclinical Alzheimer’s, MCI, and mild dementia.

Result

The spline model with ADAS‐Cog version effect attained the best predictive value for the trials in mild dementia. The proportional model was preferred for the trial in MCI, but the proportional effect assumption was violated, and the treatment effect estimate was in the wrong direction. Considering that the spline with two degrees of freedom and version effect provide fits that are similar to MMRM in Figure 1, we concluded that two degrees of freedom appear to be sufficient to capture enough of the general trend to assess the treatment effect. AIC results from the A4 Study will be considered and included after the study is completed in Spring 2023.

Conclusion

The spline model is shown to have better predictive value and precision in real datasets and has better power and Type I error control in a variety of simulation scenarios.
Statistical innovations in the API ADAD Colombia trial: a randomized, double‐blind, placebo‐controlled, parallel‐group study in cognitively unimpaired PSEN1 E280A mutation carriers evaluating efficacy and safety of crenezumab
Authors: Hu Nan , Mackey Howard , Doody Rachelle S. , Lopera Francisco , Tariot Pierre N. , Reiman Eric M. , Thomas Ronald G. , Langbaum Jessica B. , Sink Kaycee M.
Published: December 2023

Background

A number of extended families in Colombia with early‐onset ADAD have a PSEN1 mutation at codon 280 (E280A), comprise the largest ADAD kindred in the world. Trial participants have been treated with crenezumab (an experimental anti‐amyloid monoclonal antibody) or placebo. Topline results were presented in August, 2022 at AAIC. Although the trial did not demonstrate a statistically significant clinical benefit in either of its co‐primary endpoints, multiple statistical innovations were incorporated into this trial.

Method

The API ADAD Colombia trial is a randomized, double‐blind, placebo‐controlled, parallel‐group phase 2b study evaluating the efficacy, safety, and tolerability of crenezumab in cognitively unimpaired ADAD PSEN1 E280A mutation carriers in Colombia (NCT01998841). Due to under enrollment and concerns with the sensitivity of the primary endpoint, the protocol was amended mid‐trial to change from 260 weeks of treatment to a common‐close design whereby treatment continued in the double‐blind portion until the last enrolled participant received 260 weeks of treatment. Because of the change in trial design and power considerations, the primary analysis was adapted from a traditional mixed model with repeated measures (MMRM) based analysis to a random coefficient regression model (RCRM) based analysis. To quantitatively examine the adequacy of the RCRM assumptions, a robust variance estimator (Huber 1967; White 1982) was prespecified as a sensitivity analysis to calculate the standard errors and p‐values of the co‐primary endpoints. This study used a type‐I‐error‐controlled statistical procedure to identify and elevate the Free and Cued Selective Reminding Test (FCSRT) cueing index to a co‐primary endpoint. To comprehensively assess the crenezumab effect across primary and secondary endpoints, the prespecified relative reduction point estimates along with the bootstrapped 95% confidence intervals were generated.

Result

Innovative statistical methods in this trial will be presented.

Conclusion

Although the API Colombia study did not meet its co‐primary endpoints, statistical learnings from this trial can benefit development of future AD trials. To further maximize the value of this unique trial dataset, participant‐level data will be made publicly available, including clinical, imaging, and biomarker data.

Funding: NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer’s Foundation. FlorbetapirPET was partly supported by Avid and Lilly.
Alternative Endpoints and Models for AD Prevention Trials
Authors: Wang Guoqiao , Li Yan , Xiong Chengjie , McDade Eric , Bateman Randall J.
Published: December 2023

Background

There are several challenges for AD prevention trials. First, the subtle cognitive change in asymptomatic disease stages requires large sample sizes, e.g. 400‐500/arm for two phase 3 confirmatory trials, or 800‐900/arm for a single phase 3 confirmatory trial, using the traditional MMRM. Second, large, international trials may necessitate the use of different tracers for imaging biomarker assessment due to global availability issues, however, statistical models that harmonize tracer differences within clinical trials are still lacking. Third, primary prevention trials using time to event endpoint demands even larger sample sizes, e.g., 1650/arm for TRAILBLAZER‐ALZ 3 with time‐to‐first‐conversion from CDR global 0 to >0 as the outcome. The percentage slowing relative to placebo decline (e.g., lecanemab led to 27% slowing at 18 months) is a popular concept to describe treatment effect. Instead of estimating the absolute difference using MMRM, we proposed to model this percentage treatment effect directly using the percentage or proportional MMRM (pMMRM). pMMRM can harmonize assessments from different tracers by converting the absolute difference into a shared proportional treatment effect across tracers. When using time‐to‐conversion as the primary outcome, instead of using a single event, Cox proportional hazards models for recurrent events can capture the treatment effect after the first event, where a recurrent event is defined as any increment over the previous visit in CDR global.

Method

We first demonstrated that disease modifying treatment effects are essentially proportional retreatment effects. Then, we evaluated the power advantage of pMMRM over MMRM and Cox recurrent events model over single event model through simulations. Finally, we demonstrated how to harmonize data from different tracers using pMMRM.

Result

Figure 1 demonstrates that disease modifying treatment effects are like proportional treatment effects, leading to diverged disease progression trajectories and increased absolute differences. Figure 2 shows the power comparison between MMRM and pMMRM. pMMRM led to a power increase up to 30% over MMRM.

Conclusion

Alternative models such as pMMRM or Cox recurrent event models can yield greater power and pMMRM can harmonize assessment from different tracers, which may help enable global prevention trials in AD with disease modifying drug effects.
Correlation between vestibular dysfunction with worse cognitive outcomes in the elderly
Authors: Ribeiro Marlon Bruno Nunes , Mancini Patricia Cotta , Bicalho Maria Aparecida Camargo
Published: December 2023

Background

the vestibular system has neural connections from the vestibular nucleus to limbic and cortical areas, involved in both cognition and spatial orientation. The superior vestibular cortex consists of a network that interacts with other sensory systems, such as visual, sensorimotor, motor and cognition. Studies have found structural changes in the brain of patients with persistent perceptual postural dizziness (PPPD) when compared to controls, particularly in visual, vestibular and limbic areas, including a decrease in gray matter volume and turnover, a decrease in blood flow to the cortex region.

Method

cross‐sectional, observational and analytical study. The sample consisted of 50 elderly people, of both sexes, aged between 60 and 86 years. Elderly individuals with vestibular dysfunction confirmed by Vestibular Evoked Myogenic Potential (VEMP) and Video Head Impulse Test (v‐HIT) tests were included. Balance and the impact of dizziness on quality of life were evaluated through tests and vestibular scales. Cognition, functioning and depression were assessed in a quiet room using tests and scales. Univariate analysis was performed using the Spearman test. Variables that presented correlation ≤ 0.2 were selected for multivariate analysis by linear regression. A significance level of 5% was adopted (p< 0.05).

Result

there was a correlation between vestibular dysfunction and imbalance with the results of neuropsychological assessment (p = 0.000), depressive symptoms (p = 0.001) and functionality (p = 0.002).

Conclusion

in this present study, a correlation was found between vestibular dysfunction and imbalance with the worst clinical and functional indices, worse functionality, depressive symptoms and in visuospatial function skills, executive functions and praxis.
Cardiac Autonomic Function of older adults with mild cognitive impairment during eyes‐closed resting state
Authors: Rosales‐Lagarde Alejandra , Mateos‐Salgado Erik Leonardo , Rodríguez‐Torres Erika E. , de Montis Arango , Domínguez‐Aguilar Ramiro , Santana‐Garduño Hazael , Sánchez‐González Sonia Arely
Published: December 2023

Background

A different autonomic function would be expected between older adults with mild cognitive impairment (MCI) versus a control group (CTRL), having older adults with MCI a higher rate of risk factors than CTRL subjects. These risk factors consist in diseases (arterial hypertension and diabetes) and traumatic events (cranioencephalic trauma), among others.

Method

The cardiac autonomic function was evaluated through high frequency (HF) (or Respiratory Sinus Arrhythmia, RSA) and low frequency (LF) of heart rate variability. The electroencephalogram (EEG) (19 derivations) and the electrocardiogram (ECG) of 8 subjects: 4 with MCI and 4 CTRL (ages: 66.75 ± 3 and 70.5 ± 6 years; education: 9.5 ± 0.8 and 10.25 ± 4 years, respectively), were registered during eyes‐closed resting condition for 5 minutes. From each group, 3/4 MCI and 2/4 of CTRL subjects had risk factors. After verifying subjects were in the eyes closed resting state by the EEG, free artifact segments of the ECG with a mean duration of 3:18 ± 1 were analyzed.

Result

No statistically significant differences were found between both groups in the values of HF and LF expressed in natural logarithm.

Conclusion

A larger sample and a more unequal proportion of risk factors must be considered to evaluate the relationship between MCI and autonomic cardiac function.
Synergistic contributions of vascular risk factors and APOE ε4 carriage to cognitive performance in middle‐aged adults enrolled in the Healthy Brain Project
Authors: Rosenich Emily , Norfolk Maya , Buckley Rachel F. , Lim Yen Ying
Published: December 2023

Background

Midlife vascular risk factors (VRFs) and APOE ε4 carriage are individually associated with poor cognitive performance and increased dementia risk. However, the extent to which VRFs interact with APOE ε4 carriage to influence cognition in midlife remains unclear. This study aimed to investigate interactions between VRFs and APOE status on cognitive performance in cognitively normal (CN) middle‐aged adults.

Method

CN adults aged 40‐70 enrolled in the Healthy Brain Project with ≥75% complete baseline data on five VRFs and APOE status were included (N = 1610; 546 ε4 carriers). Cardiovascular risk was operationalized by assessing history of hypertension, hypercholesterolemia, diabetes mellitus, body mass index (BMI) ≥25, and current cigarette smoking. Participants were categorized into low (0) or high vascular risk groups (≥1 VRF) determined via median split. Analyses of covariance (ANCOVAs) investigated interactions between VRF group × APOE status on attention and memory composites (derived from the Cogstate Brief Battery), controlling for age, sex, education, ethnicity, and depressive/anxiety symptoms. Linear regression analyses explored contributions of individual VRFs on memory in ε4 carriers and non‐carriers.

Result

A significant VRF group × APOE status interaction was observed for memory (p = .04), but attention was lower in those at high vascular risk, regardless of APOE ε4 status (Table 1, Figure 1A and 1B). For memory, APOE ε4 carriers with high vascular risk demonstrated worse performance compared to ε4 carriers and non‐carriers with low vascular risk (Figure 1A and 1B). Linear regression analyses revealed that BMI ≥25 and hypercholesterolemia were significantly associated with worse memory performance in ε4 carriers only (Table 2).

Conclusion

In CN middle‐aged adults, vascular risk significantly modified associations between APOE status and memory performance, such that ε4 carriers with high vascular risk demonstrated the lowest memory performance. More specifically, higher BMI and hypercholesterolemia were significantly associated with lower observed memory performance within this group. Results suggest that middle‐aged ε4 carriers with vascular risk factors may be an important sub‐group to target within lifestyle prevention trials to reduce future risk of cognitive impairment and decline.
Hearing impairment is associated with cognitive decline, brain atrophy and tau pathology
Authors: Yu Jin‐Tai
Published: December 2023

Background

The association between hearing impairment and Alzheimer’s disease (AD) and the mechanisms involved remain unclear.

Methods

Survival analyses were performed in 66,577 participants from the UK Biobank to investigate whether hearing impairment is associated with an increased risk of AD. The association of hearing status with cognitive function, brain structure and CSF proteins were explored in cross‐sectional, longitudinal, and mediation analyses across the UK Biobank (n = 165,550), Chinese Alzheimer’s Biomarker and Lifestyle (CABLE, n = 867), and Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 802).

Results

Hearing impairment was associated with an increased risk of AD over 11 years of follow‐up (HR 1.80, 95%CI 1.50‐2.15). Poor hearing status was associated with worse cognitive function in cross‐sectional and longitudinal studies. Moreover, hearing impairment was significantly related to lower volume of the temporal cortex, hippocampus, amygdala, inferior parietal lobe, precuneus and orbitofrontal cortex, to lower integrity of white matter tracts, and to a higher level of CSF tau protein. Mediation analyses showed that brain structure and CSF tau partly mediated the association between hearing impairment and cognitive decline.

Conclusion

Hearing impairment is a risk factor for AD, and is associated with brain structure, tau pathology, and cognitive decline.
Dementia is an auditory brain disorder
Authors: Warren Jason D , Hardy Chris JD , Johnson Jeremy , Jiang Jessica , Bamiou Doris‐Eva
Published: December 2023

Background

While impaired hearing has emerged as a major potentiating factor for dementia, the basis for this relationship has not been defined. Most studies have emphasised the role of peripheral hearing loss. However, we hear with our brains: natural listening places immense computational demands on neural circuitry, and the neural networks pre‐eminently targeted by major dementias are essential for decoding and responding appropriately to the auditory environment. Auditory brain dysfunction is therefore predicted both to contribute importantly to hearing impairment in Alzheimer’s and other dementias and to be integral to the expression of neurodegenerative pathologies. Here I present an overview of evidence that speaks to this hypothesis.

Methods

In a series of linked experiments, we have assessed aspects of auditory cognition – the processes whereby the brain perceives, interprets and acts upon sounds ‐ in patient cohorts with Alzheimer’s disease and major syndromes of frontotemporal dementia, relative to healthy older individuals. We designed novel psychoacoustic tests to assess aspects of auditory scene analysis (the ‘cocktail party effect’ and localisation of sounds in space), comprehension of acoustically degraded speech and the processing of semantic and emotional information in sound in cognitively impaired people. Neuroanatomical mechanisms were assessed using voxel‐based morphometry and functional MRI.

Results

Across experiments, after taking peripheral hearing function and general cognitive performance into account, patients with Alzheimer’s disease and frontotemporal dementias showed characteristic ‘auditory phenotypes’ or profiles of auditory cognitive impairment. Alzheimer’s disease is associated with impaired auditory scene analysis, linked to atrophy and dysfunction of temporo‐parietal cortical regions in the core ‘default mode network’ targeted by Alzheimer pathology. Frontotemporal dementia syndromes produce distinct impairments of auditory feature analysis, sound recognition and emotional valuation.

Conclusions

Auditory brain dysfunction plays a key role in everyday hearing impairment and reflects core pathophysiology in major dementias. These findings raise the exciting prospect that auditory cognitive measures might be used in the early diagnosis of dementia, in guiding novel hearing interventions and as dynamic markers of therapeutic response in the dawning era of disease modification.
A genetic and proteomic approach to understanding neuropsychiatric symptoms in ADRD
Authors: Wingo Thomas S. , Liu Yue , Gerasimov Ekaterina S , Vattathil Selina , Wynne Meghan E , Faundez Victor , Liu Jiaqi , Bennett David A. A , Seyfried Nicholas T , Levey Allan I. , Wingo Aliza P.
Published: December 2023

Background

Three lines of epidemiologic evidence link several psychiatric disorders to ADRD. First, experiencing schizophrenia or a mood/anxiety disorder in early/mid‐adulthood increases the risk of developing dementia by 6‐folds. Second, approximately 80% of ADRD patients experience neuropsychiatric symptoms (NPS), including depression, apathy, anxiety, irritability, agitation, delusions, and hallucinations. Third, these NPS overlap with symptoms of schizophrenia and mood/anxiety disorders. Given these observations, this study focuses on the question of whether these psychiatric disorders and ADRD have shared pathophysiology, which may underlie the manifestation of NPS in ADRD

Method

To investigate whether there is a shared genetic and molecular basis between the psychiatric conditions (major depressive disorder [MDD], bipolar disorder [BD], neuroticism, anxiety, PTSD, schizophrenia, and alcoholism) and ADRD (AD, Lewy body dementia [LBD], ALS, Parkinson’s disease [PD]), we performed three analyses. First, we examined genetic correlations between a psychiatric disorder and an ADRD using GWAS results in each condition and LDSC regression. Second, to identify causal genes and proteins for each of these brain conditions, we integrated each GWAS results with human brain proteomes (n = 722) using multiple independent state‐of‐the‐art integration approaches (PWAS, Mendelian randomization, colocalization analysis). Third, we examined protein‐protein interactions (PPIs) between a psychiatric causal protein and an ADRD causal protein using BIOGRID database.

Result

From LDSC regression, we found 7 pairs of a psychiatric condition and an ADRD having significant genetic correlations, suggesting a shared genetic diathesis between these psychiatric conditions (MDD, BD, neuroticism, anxiety, PTSD, alcoholism) and ADRD (AD, LBD, ALS). Furthermore, among the causal proteins we identified for each condition, 30% of the ADRD causal proteins (13 of 42) were also causal proteins in the psychiatric conditions, highlighting a shared pathophysiology. Moreover, we found 2.6‐folds more PPIs between a psychiatric causal protein and an ADRD causal protein than by chance (p = 0.003, 120 PPIs).

Conclusion

Together, these 3 levels of novel evidence highlight a shared genetic and molecular basis between several psychiatric conditions and ADRD, which may underlie the pathophysiology of NPS in ADRD. The 13 shared causal proteins are promising targets for further validation in NPS in ADRD and towards the goal of developing effective therapeutics for NPS.
Facilitating the use of the target product profile in academic research
Authors: Ibnidris Aliaa , Streffer Johannes , Rea Mike , Gold Michael , Bot Sjaak , Teipel Stefan , Gardiol Alex , Boccardi Marina
Published: December 2023

Background

Target product profiles (TPP) were first defined by industry and supported by FDA to address user needs and guide communication in all phases of drug development. However, heterogeneity in practical use hurdles uptake in academic research. Our study aims to facilitate uptake by outlining a reference template to be adapted to dementia research.

Methods

We conducted a systematic review to extract structural characteristics, along with differences and commonalities across TPPs used in different product development (e.g., drugs vs diagnostics). We included data from peer‐reviewed publications on TPPs
content
(i.e., developing, revising, or mentioning a TPP),
product
type (drug, diagnostics, vaccine, medical device, other),
disease category
(infectious, non‐infectious diseases),
specific disease
, TPP
features
of the target profile, and
levels of compliance
for each feature.

Results

327 of 1297 identified records were eligible for full‐text review. Preliminary data extraction from 20 papers shows that:
Content
: 45% (n = 9) developed a new TPP, 10% (n = 2) revised a predefined TPP; 45% only mentioned TPPs (n = 9).
Product
: of the nine papers that developed a new TPP, 77.8% (n = 7) were for drug and 22.2% (n = 2) for diagnostics development.
Disease category
: 70% (n = 14) used TPPs in infectious diseases while 30% (n = 6) were in non‐infectious diseases. So far, no publication reported using TPPs in dementia. TPP
features
for different product types from the 11 publications that developed or revised TPPs: 39 features were extracted from TPPs for diagnostic development, 11 of which (28%) were in common. We extracted 35 features from TPPs for drug development, 9 of which (27.5%) were in common.
Levels of compliance
ranged between one (n = 5, 45.5%) to two (n = 5, 45.5%) levels, corresponding to conservative and optimistic levels. One (9%) did not report targeted levels of compliance.

Conclusion

TPPs are not frequently used by academic researchers. Despite being a useful tool enhancing product development, its considerable heterogeneity in structure renders its adaptation challenging. Completing data extraction and comparing the outcome with opinion leader’s assessment and formal guidance (e.g., from WHO) will facilitate drawing a comprehensive picture of common TPP features to derive a consistent and comprehensive template and facilitate its use in academic dementia research.
Relationship between metabolic disease and Alzheimer’s disease
Authors: Arvanitakis Zoe
Published: December 2023

Background

Diabetes is an enormous and growing global public health problem, associated with poor health outcomes including dementia. Mechanisms underlying the relationship of diabetes to dementia are less well understood.

Methods

We leveraged several large, ongoing community‐based cohorts of older women and men with and without diabetes, taking part in longitudinal, clinical‐pathologic studies of aging at the Rush Alzheimer’s Disease Center. Participants undergo annual clinical evaluations including detailed neuropsychological testing, and brain autopsy at time of death. We examined the relation of diabetes and related clinical variables (e.g., medications, body mass index [BMI], hypertension), and blood and brain biomarkers of insulin resistance and other measures (e.g., epigenetics), to brain outcomes. Level and change in global cognition and five cognitive domains were based on neuropsychological tests, and dementia status was classified. Postmortem human brain specimens of deceased persons were systematically evaluated for neuropathology, including neurodegenerative (e.g., Alzheimer’s disease [AD]) and cerebrovascular disease (e.g., infarcts).

Results

Diabetes, present in 15‐20% of our cohorts, is associated a two‐fold increased risk of dementia and relates to cognitive decline (particularly in some cognitive domains more than others), and these observations are found in both Black and White participants. Some diabetes‐related clinical variables (e.g., BMI) are associated with faster cognitive decline, while others such as medications (metformin) are associated with slower cognitive decline. Regarding human postmortem neuropathologic outcomes, diabetes is associated with cerebrovascular pathologies, and small subcortical infarcts in particular. But, while we have not found clear associations of diabetes with neurodegenerative pathologies such as AD, some brain molecular markers in the insulin signaling pathway (AKT1) are associated with AD (including amyloid‐beta and tau tangles) and cognition (memory). Recently, using blood and brain specimens, we show that genome‐wide 5‐hydroxymethylcytosine profiling uncovers epigenetic features and biologic pathways related to nucleotide sugar metabolism linking diabetes to diabetes‐associated AD.

Conclusion

Diabetes is a potentially‐modifiable risk factor for dementia and cognitive decline. Clinical, neuropathologic, and epigenetic factors are at play in the underlying mechanisms. A better understanding of mechanisms will inform future research and offer opportunities for precision medicine and dementia prevention (supported by NIH: R01NS084965, RF1AG059621, RF1AG074549, R01AG022018, P30AG10161, P30AG072975, R01AG15819, R01AG17917).
The role of the blood‐brain barrier in brain insulin signaling
Authors: Calon Frederic
Published: December 2023

Background

Defects in central response to insulin is suspected to play a role in AD. However, to act on the brain, pancreas‐secreted insulin must interact first with the blood‐brain barrier (BBB). The insulin receptor (INSR) consists in 2 insulin‐binding extracellular α chains, either short (INSRα‐A) or long (INSRα‐B) isoforms, as well as 2 intracellular β‐chains (INSRβ) containing auto‐phosphorylation sites. The aim of the present study was to better understand the role of INSR located on the BBB in AD.

Method

We used microvessel‐enriched brain samples from individuals classified as Controls, MCI or AD and from 3xTg‐AD mice from different ages. In situ cerebral perfusion was used to directly assess the interaction between circulating insulin and the BBB.

Results

We first show that INSR in human and mouse brains are concentrated in blood microvessels, with INSRα‐B being almost absent from the parenchymal fractions. Lower levels of INSRα‐B were observed in microvessel extracts from the parietal cortex of AD persons, associated with cognitive decline. The resulting shift toward a higher INSRα‐A:INSRα‐B ratio is consistent with insulin resistance situated on the BBB. Intracarotid infusion of insulin induced a rapid phosphorylation of INSRβ retrieved from cerebrovascular extracts, but not from parenchymal extracts of the mouse brain. In the 3xTg‐AD mouse model of AD neuropathology, lower levels of cerebrovascular INSRα‐B were observed whereas activation of INSRβ was blunted upon intracarotid administration of insulin. Finally, we provide some insights on a possible association between BACE1 activation and the reduction of cerebrovascular INSR.

Conclusion

Overall, data gathered from postmortem AD brains and an animal model of AD neuropathology suggest that brain insulin resistance in AD may occur at the level of INSR located on microvessels. These results also indicate that INSR and its downstream signaling within endothelial cells of the BBB are systemically accessible drug targets in AD.
Effect modification of the association between BMI and cognition in India
Authors: Nichols Emma , Deal Jennifer A , Gross Alden L. , Lee Jinkook
Published: December 2023

Background

High body‐mass index in midlife is an established risk factor for poor cognition and dementia. While most evidence supporting the association between high BMI and dementia comes from high‐income countries, 60% of global dementia cases are expected to be in low‐ and middle‐income countries by 2050. Existing evidence from India suggests higher BMI is associated with better cognition and lower odds of dementia. We sought to replicate these findings and investigate effect modification by age, rurality, and education to better contextualize results.

Method

We used cross‐sectional data from the Longitudinal Aging Study in India (N = 57,164). We used weighted linear regression models to assess associations between latent cognitive functioning, estimated from confirmatory factor analysis models, and BMI category. We compared unadjusted models to models controlling for age, sex, rurality, state, literacy, education, per capita consumption quintile, parental education, smoking, and depressive symptoms. We investigated effect modification by age, rurality, and education.

Result

Compared to unadjusted models, estimated associations from multivariable models were substantially attenuated but remained statistically significant. Underweight BMI was associated with lower cognitive scores and overweight and obesity were associated with higher cognitive scores (underweight = ‐0.16 SD units [‐0.18‐ ‐0.14]; overweight = 0.10 [0.09‐0.12]; obese = 0.13 [0.11‐0.16]). For participants in urban settings or with higher educational attainment, associations between cognition and overweight and obesity were smaller and not statistically significant for those with tertiary education. A global ANOVA test for effect modification was statistically significant for rurality (p<0.01), trending towards significance for education (p = 0.09), but not significant for age category (p = 0.31).

Conclusion

Counter to findings in high‐income settings, but consistent with prior findings in India, high BMI was associated with higher cognitive performance. Lack of evidence for effect modification by age and the association between low BMI (underweight) and lower cognition, indicate reverse causation due to weight loss in early disease stages is unlikely to explain results. Instead, strong attenuation of effects with confounder control and effect modification by rurality and education indicate that associations could be due to the clustering of access to fat‐enriched foods with other factors that are beneficial for health, such as higher education and access to healthcare.
Carnosine supplementation improves delayed recall: a systematic review and meta‐analysis
Authors: Bell Simon M , Hariharan Rohit , Laud Peter , Majid Arshad , Courten Barbora
Published: December 2023

Background

Carnosine is a histidine‐containing dipeptide found in human muscle tissue and other organs like the brain. Data in rodents and humans indicate that administration of exogenous carnosine improved cognitive performance. However, RCTs results RCTs vary.

Methods

We searched OVID Medline, Medline, EBM Reviews, Embase, and Cumulative Index to Nursing and Allied Health Literature databases from 1/1/1965 to 1/6/2022 for all RCT of carnosine and other histidine‐containing dipeptides. 2653 abstracts were screened, identifying ninety‐four full‐text articles which were assessed for eligibility. 11 articles reporting use of carnosine supplementation were meta‐analysed. The random effects model has been applied using the DerSimonian‐Laird method.

Results

Carnosine treatment significantly increased performance on Wechsler Memory Scale (WMS) ‐2 Delayed recall (Z = 3.28, p<0.01). Treatment with carnosine had no effect on Alzheimer’s Disease Assessment Scale‐Cognitive (Weighted mean difference (WMD) (95% CI) = ‐0.2 (‐1.1, 0.7), P = 0.65, I2 = 0%), Mini‐Mental State Examination (WMD (95% CI) = 0.7 (‐0.2, 1.5), P = 0.14, I2 = 42%), The Wechsler Adult Intelligence Scale (WAIS) Digit span Backward (95% CI) = 0.1 (‐0.3, 0.5), P = 0.51, I2 = 0%), WAIS digit span Forward (WMD (95% CI) = 0.0 (‐0.3, 0.4), P = 0.85, I2 = 33%) and the WMS‐1 Immediate recall (WMD (95% CI) = 0.7 (‐0.2, 1.5), P = 0.11, I2 = 0%). The effect on delayed recall remained in subgroup meta‐analysis performed on studies of patients without mild cognitive impairment (MCI), and in those without MCI where average age in the study was above 65.

Conclusions

Carnosine supplementation improved scores on the Delayed recall examination, a neuropsychological test affected early in Alzheimer’s disease. Further studies are needed in people with early cognitive impairment with longer follow‐up duration and standardisation of carnosine doses to delineate the true effect.
INVOKE‐2: Phase 2 trial of a TREM2 mAb in Early AD
Authors: Romano Gary , Mayorga Arthur , Simmons Adam , Burgess Brady , Grundman Michael , Gao Jinjing
Published: December 2023

AL002 is an investigational, humanized monoclonal antibody that targets triggering receptor on myeloid cells 2 (TREM2) and is currently under development for the treatment of early Alzheimer’s disease. The INVOKE‐2 trial is an ongoing global Phase 2 randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of AL002 in participants with early Alzheimer’s disease. This presentation will provide an update on AL002 clinical development.
Symptomatic Alzheimer’s Disease Therapy Utilization in 3 National Cohorts
Authors: DiBello Julia R , Zhong Wenjun , Ma Jiemin , Goto Daisuke , Liu Xinyue
Published: December 2023

Background

Although the positive results of the first disease modifying therapies is anticipated to moderately slow disease progression, significant need remains for cognitive enhancers to address AD symptoms and improve quality of life. Despite potential benefits of current treatments, the literature suggests that a large percentage (40‐60%) of AD patients do not use symptomatic treatments for AD and treatment patterns may have considerable geographic variation.

Method

Patients with AD (ICD‐10 code G30 or READ code for AD) in 2018‐2019, with ≥1‐year baseline period before index date (first AD diagnosis date during 2018‐2019) and ≥1‐year follow‐up after the index date were selected from the US Humana Research Database (Humana) and the UK Clinical Practice Research Datalink GOLD (CPRD). Patients with an AD diagnosis during the baseline period were excluded. Within the Japan Medical Data Vision (MDV) database, an ICD‐10 code for AD (G30) was required prior to/on the same date as the first provider visit with an associated prescription for a specified AD medication during the 2018‐2020 study period (defined as the index date). Patients with AD medication visits ≤6 months before the index date were excluded. Percentages of patients initiating donepezil, rivastigmine, galantamine, and memantine, median time on first therapy, and use of a second therapy were calculated.

Result

AD therapy was initiated by 35,459, 8,901, and 51,115, patients in the US, UK, and Japan, respectively. Sixty‐three percent were female, in the US and UK, and 59% in Japan; mean age ranged from 81‐82 years. Donepezil was used most frequently (69%, 61%, and 50%), followed by memantine monotherapy (19%, 28%, and 22%) in the US, UK, and Japan, respectively. Median time on first therapy was 213, 334, and 111 days, and a second treatment was used by 30%, 12%, and 10%, respectively.

Conclusion

In contemporary cohorts of US, UK, and Japanese individuals newly initiating symptomatic AD therapy, donepezil was the most frequently used therapy followed by memantine monotherapy. Time on first therapy was relatively short (<1 year) and the majority of patients did not utilize a second therapy. These results underscore the unmet need for additional therapies to alleviate the significant burden of AD.
The relationship between ApoE4 and lipid dysregulation in glia of the PS19 mouse model of tauopathy
Authors: Litvinchuk Alexandra
Published: December 2023

Background

Apolipoprotein E4 (apoE), the major lipoprotein in the brain, plays an essential role in brain`s lipid homeostasis; furthermore, the presence of the apoE4 allele is the strongest genetic risk factor for developing late‐onset AD compared to most common apoE3 and protective apoE2 alleles. Recent studies in iPSC microglia and astrocytes demonstrate that apoE modulates cholesterol dysfunction and inflammatory responses in an isoform‐specific fashion. However, it is not known if lipid accumulation in glia mediates toxic effects in vivo in the context of tauopathy and neurodegeneration.

Method

In this work we used the combination unbiased lipidomics coupled with immunostainings to dissect the role of apoE and apoE isoforms in glial lipid metabolism of tauopathy P301S tau transgenic mice with a targeted replacement of murine apoE with human ApoE4, ApoE3, or ApoE KO. We further treated the P301S/ApoE4 mice with the LXR agonist GW3965 to test if promoting cholesterol efflux in P301S mice would reduce tau pathology and neurodegeneration in this model.

Results

By performing unbiased lipidomic analysis of forebrain samples, we demonstrate that P301S/ApoE KI mice accumulate significant amounts of specific cholesteryl esters, oxidized sterols and endolysosomal BMP lipids in an ApoE‐isoform and Tau‐dependent manner. We further show that microglia from aged 9.5 months old P301S/ApoE4 mice accumulate significant amounts of neutral BODIPY‐positive lipid inclusions within lysosomes. Next, we demonstrate that the oral administration of the LXR agonist GW3965 for 3 months significantly reduces p‐tau‐positive AT8 immunostaining in cortex and hippocampus, protects from associated brain neurodegeneration, and improves nesting behavior in 9.5 months old P301S/ApoE4 mice. Using bulk RNA sequencing and immunostaining, we show that LXR agonist diet induces changes in cholesterol biosynthesis and metabolism that result in a significant reduction of neuroinflammatory responses in aged P301S/ApoE4 mice. Lastly, using unbiased lipidomics of forebrain tissues we demonstrate that P301S/ApoE4 mice on LXR diet exhibit significantly lower levels of cholesterol esters when compared to tau transgenic animals on control diet.

Conclusions

Together, we demonstrate that ApoE4 promotes lipid accumulation in glia in the setting of tauopathy and that reducing the accumulation of these lipids by LXR activation is neuroprotective.
COVID‐19 Infection and Dementia: Analyses of time‐varying risk, subtypes, and subpopulations from the UK Biobank
Authors: Cao Yaying , Feng Chengwu , Chen Jing , Liu Yunman , Sheng Aili , Li Shuai , Hu Yonghua , Yuan Changzheng , Xie Junqing , Zong Geng
Published: December 2023

Background

Although COVID‐19 patients were suggested to experience worse cognitive outcomes, there is a paucity of evidence on time‐varying risk of dementia, especially the subtypes, as well as among critical subpopulations.

Method

Out of over 50,000 individuals from a general population in the UK Biobank, SARS‐COV‐2 infected patients between March 1, 2020, and July 31, 2021 and maximally 5:1 propensity score matched contemporary non‐infected individuals were selected, with baseline dementia cases excluded. Matching was done on demographic characteristics, lifestyle, and comorbidities. Dementia was captured according to primary care, inpatient records, and death registry, with the follow‐up ending at the earliest of outcome occurrence, death, or August 31, 2021. Associations were evaluated using time‐varying hazard ratios (HRs) and odds ratios (ORs).

Result

With a mean age of 65.0 years for 18,032 COVID‐19 patients and 83,008 controls, participants were followed for a median of 247 (IQR: 204‐305) days and 255 dementia cases occurred, including 90 Alzheimer’s disease (AD) cases and 42 vascular dementia cases. Compared with matched controls, COVID‐19 infection was associated with increased risks of dementia during the acute phase (first 30 days), with HRs (95% CIs) being 12.77 (6.77, 24.08) for all‐cause dementia, 9.21 (2.77, 30.59) for AD, 5.53 (1.69, 18.11) for vascular dementia, and 25.35 (8.74, 73.56) for other dementia. Dementia risk declined drastically after COVID‐19 infection and sustained for all‐cause dementia, vascular dementia, and other dementia, while became non‐significant for AD. Among those not hospitalized during the acute phase, elevated dementia risk in the follow‐up remained for all‐cause dementia, vascular dementia, and other dementia, with ORs being 1.82, 4.55, and 1.64, respectively. Among most of the subpopulations classified by demographic characteristics, APOE genotype, and comorbidities (except for those with baseline chronic obstructive pulmonary diseases), COVID‐19 infection was associated with an elevated all‐cause dementia risk and no modification effect was detected.

Conclusion

Declined yet sustained elevated dementia risk since COVID‐19 infection was found, with differential trends for dementia subtypes. Increased dementia risk from COVID‐19 infection also applied for the non‐hospitalized during the acute phase and most subpopulations. The potential dementia risk associated with Omicron variants warrants further evaluation.