bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship of Neuropsychiatric Symptoms and ADRD Pathologies
Authors: Bacci Julia R. , Rudolph Marc D. , Mielke Michelle M. , Craft Suzanne , Bateman James R. , Lockhart Samuel N.
Published: January 2025

Background

Neuropsychiatric symptoms (NPS) in the Alzheimer’s Disease (AD) clinical spectrum are common, yet the pathological underpinnings are unclear. Prior research has been inconsistent, attributed in part to concomitant co‐pathologies. Additionally, prior modeling approaches have disregarded the distributional properties of right‐skewed NPS data and utilized predominantly racially homogenous cohorts. Thus, we examined the relationship between NPS and markers of vascular injury and neurodegeneration using generalized linear models (GLM) in a diverse community‐based sample. Of additional interest was whether these relationships differed by cognitive status or race.

Methods

We evaluated cross‐sectional relationships of brain white matter hyperintensity volume (WMHv) and plasma neurofilament light chain (pNfL) to NPS (NPI‐Q total severity scores) in 588 Wake Forest ADRC Clinical Core study participants. Analyses included participants with consensus diagnoses of cognitively unimpaired (CU; N = 348) and mild cognitive impairment (MCI; N = 240). WMHv and pNfL were log‐transformed prior to model entry. GLMs included age, sex, education, race, and cognitive status as covariates and pathologies as predictor variables. Secondary models included aforementioned covariates and pathology by (a) cognitive status and (b) race interaction terms to investigate how these associations differed.

Results

WMHv was not significantly associated with NPS (N = 561; β = 0.203; p = 0.053); further, we did not observe an interaction between cognitive status and WMHv (N = 561; β = ‐0.055; p = 0.800). However, a significant race by WMHv interaction on NPI‐Q was demonstrated (N = 561; β = ‐0.414; p = 0.016). In White participants, elevated WMHv was significantly related to elevated NPS (N = 434; β = 0.325; p = 0.006); whereas in Black/African American participants elevated WMHv was significantly related to lower NPS (N = 119; β = ‐0.239; p = 0.049). pNfL was not significantly associated with NPS (N = 506; β = 0.149; p = 0.576). A significant pNfL by cognitive status interaction on NPI‐Q was found (N = 506; β = ‐1.055; p = 0.029; Figure 2), where elevated pNfL was related to elevated NPS in MCI participants (N = 198; β = 1.656; p = 0.004) but not CU participants (N = 308; β = ‐0.316; p = 0.260). However, we did not observe an interaction between race and pNfL (N = 506; β = 0.185; p = 0.678).

Conclusion

Consistent with previous work we demonstrate associations of pNfL and WMHv with NPS. Future analyses with this cohort will examine additional biomarkers, including amyloid‐beta and tau measured in CSF, plasma, and PET.
Sleep in People with Dementia and Their Caregivers
Authors: Manning Carol A , Youngkin Anna E , Quigg Mark S
Published: January 2025

Background

There is mounting evidence that difficulties with sleep including insomnia, sleep quality, and sleep fragmentation contribute to Alzheimer’s disease risk including formation of beta‐amyloid. Disrupted sleep is common in people with dementia (PWD). Primary unpaid caregivers (CGs) of PWD may also have disrupted sleep as a result of their caregiving roles. It is clear that CGs experience CG burden, stress and depression. The interplay of CG‐PWD dyads and the impact of behavior, cognition and sleep in the PWD on the CG are relatively understudied.

Method

Eight dyads consisting of individuals diagnosed with Alzheimer’s Disease (AD) (PWD) and their CGs were recruited from the Virginia Alzheimer’s Disease Center (VADC) Clinical Cohort. Diagnosis of AD in the VADC cohort was made by team consensus using neuroimaging, biomarker, neurological and neuropsychological data. All participants had wrist actigraphy measured for 14 days and overnight polysomnography (PSG) done in a sleep lab. Dyad members were in separate rooms during PSG.

Dyads members independently completed the Montreal Cognitive Assessment 12, the Geriatric Depression Scale 13, Epworth Sleepiness Scale 14, and the Quality of Life in Alzheimer’s Disease scale 15 (QOL). CGs only completed the Preparedness for Caregiving Scale 16 and the Zarit Burden Interview and the Neuropsychiatric inventory.

Result

Neither activity nor rest over 14 days differed within dyads. Relative to PWD, CGs experienced shorter total sleep, lower sleep efficiency, and longer sleep onset. CG and PWD depression and QOL did not differ between dyad members. Importantly, poorer CG sleep was associated with higher CG burden and greater PWD neuropsychiatric symptoms but not with degree of cognitive impairment in the PWD.

Conclusion

Results suggest that sleep in CGs can be more impaired than the PWDs they are caring for even when sleeping separately. Importantly, behavioral disturbance may be more problematic than PWD cognitive impairment level in CG sleep. These may have implications for ability to care for the PWD potentially impacting nursing home placement. Furthermore, PWD sleep characteristics may impact longer‐term CG health and well‐being.
Sex Differences in Neuropsychiatric Symptoms Associated with Alzheimer’s Disease in Down Syndrome
Authors: Shaka Sophia E. , Krinsky‐McHale Sharon J. , Silverman Wayne , Pulsifer Margaret B. , Rosas H. Diana , Lai Florence , Lott Ira T. , Hom Christy L.
Published: January 2025

Background

Adults with Down syndrome (DS) have increased risk for developing Alzheimer’s disease (AD). Several studies have found that the onset of new neuropsychiatric and behavioral symptoms in DS is associated with AD progression. There is evidence in the neurotypical population that AD‐related apathy is more severe among males, while females display higher prevalence of depression, psychosis, and delusions. The current study investigates sex differences in AD‐related neuropsychiatric symptomology in adults with DS. It is hypothesized that men will have greater frequency or severity of AD‐related apathy compared to women while women will display more AD‐related depression.

Method

A total of 155 adults with DS from the Alzheimer’s Disease in Down Syndrome (ADDS) study (43.3% female, Mage = 50.26, SD = 7.20) received cognitive testing. Their care providers completed questionnaires that measured psychiatric and/or behavioral symptoms: the Neuropsychiatric Inventory Questionnaire (NPI‐Q), the Reiss Screen for Maladaptive Behavior (RSMB), and the Dementia Questionnaire for People with Learning Disabilities (DLD). AD clinical status was determined through consensus decisions by the research team based on cognitive and functional scores. 113 participants were classified as cognitively stable and 42 had possible/probable AD dementia. Participants with mild cognitive impairment or of uncertain clinical status were excluded.

Result

There were no significant main effects for sex on any of the measures examined. However, there was a significant interaction between sex and clinical status on the DLD Activity & Interest scale, adjusting for age, sex, and clinical status (F(4, 154) = 4.055, p = 0.46, η2 = 0.20). While cognitively stable men and women had similar scores on this scale, men with dementia had significantly greater problems in this area of functioning than women with dementia.

Conclusion

AD appears to affect men and women differently after the transition to dementia. Affected males engage in fewer activities and are less interested in their surroundings than females, suggesting greater apathy or withdrawal, despite the lack of sex differences in depressive symptomology during the preclinical and clinical stages of AD. Possible neurobiological reasons will be discussed as well as how individuals with DS and AD may need tailored support based on sex differences in psychiatric and behavioral symptoms.
Study of the irisin hormone on metabolism and mitochondrial dynamics in experimental models of Alzheimer’s disease
Authors: Fonseca Ariene Soares , Chauvet Mariana Gomes , Ferreira Sergio T , Lourenco Mychael V
Published: January 2025

Background

Age‐related decrease glucose utilization, coupled with insulin resistance, are key features of AD, resulting in reduced glucose utilization/catabolism and oxidative stress generation. Irisin, an exercise‐induced hormone promoting mitochondrial biogenesis in adipocytes via PGC‐1α, stimulates thermogenic pathways, increases energy expenditure and induces browning of adipose tissue. Further, irisin expression was shown to trigger neuroprotection in AD models.

Method

Here, we assessed whether irisin could prevent potential metabolic deficits induced by soluble Aβ oligomers (AβOs) in hippocampal slices and in C57BL/6 mice.

Result

Our results indicate that irisin produced only subtle changes in the metabolic profile without clearly altering the protein content associated with mitochondrial dynamics in the AβOs‐exposed hippocampus.

Conclusion

Our data suggest that other mechanisms may possibly contribute to the neuroprotective effects of irisin in AD models.
Lessons from Ten Years of Validation of Targets Identified by the Accelerating Medicines Partnership in Alzheimer’s Disease (AMP‐AD)
Authors: Ehrlich Michelle E.
Published: January 2025

Background

The Accelerating Medicines Partnership in Alzheimer’s Disease (AMP‐AD) is a public‐private partnership linking NIH, the FDA, pharmaceutical companies, and nonprofit organizations in an interactive, collaborative program utilizing transcriptomics, genomics, metagenomics, proteomics, and metabolomics to provide data for computational analysis, that, in turn, enables promising targets to be ranked by a combination of omic scores and druggability. This ranking informs the selection of targets for validation.

Method

Human postmortem samples were obtained from Mount Sinai, ROSMAP (Religious Orders Study and Rush Memory and Aging Project), Mayo Clinic (Florida), and Columbia University. The validation systems were mouse and fly models of AD pathology and human induced pluripotent stem cells (hiPSCs). Target genes were up‐ or down‐ regulated or mutated to determine whether AD‐related phenotypes were altered.

Result

Targets selected for validation by AMP‐AD included genes expressed in neurons (e.g., VGF, REST, ATP6V1A), microglia (e.g., BIN1, TYROBP, TREM2, SYK, MSN, INPP5D), or astrocytes (e.g., PLEXNB1, GJA1). As expected, phenotypes were improved by decreasing levels of proteins that are abnormally elevated in AD or by increasing the levels of proteins that are abnormally decreased in AD. Qualitative and quantitative variability in effects of target manipulation may be attributable to duration or stage of disease at the time of intervention, and/or to the cell type that expresses each target. AD‐related changes were used to predict therapeutic directionality, but up‐ and down‐regulation sometimes had similar effects. Plaque load changes did not reliably predict changes in other aspects of the phenotype. Paradoxically, manipulation of some targets (e.g., ABI3) caused amyloidosis and tauopathy to change in different directions.

Conclusion

Validation experiments in multiple systems support the AMP‐AD approach for selecting druggable targets for the treatment of AD. Future work will focus on validation of additional targets and close collaboration with the Target Enablement to Accelerate Therapy in AD (TREAT‐AD) Consortium to develop pharmacologic agents derived from these discoveries.
Unravelling the mechanisms of aducanumab on efficacy of Aß clearance by iPSC‐derived human microglia in 2D and 3D cell cultures
Authors: Lin Ada J. , Wendt Stefan , Brennan Declan , Nygaard Haakon B.
Published: January 2025

Background

Antibodies targeting amyloid beta (Aß) have recently been developed as promising treatments for Alzheimer’s Disease (AD). Aducanumab was the first to receive limited FDA approval in 2021 offering much needed new treatment options for AD patients. Aducanumab clears aggregated Aß in the brain, presumably through microglial phagocytosis, although the exact cellular and molecular mechanisms of its effect remain incompletely understood. We employed iPSC‐derived microglia in 2D and 3D cultures to study the mechanisms by which aducanumab facilitates Aß clearance in the brain.

Method

iPSC‐derived microglia were studied in both 2D and 3D environments. Microglia plated in 2D were treated with pHrodo conjugated oligomeric Aß42 and aducanumab and imaged live for 24 hours to monitor short term changes. Cells and supernatant were collected for ELISA afterwards. For 3D cell culture, neurospheres were formed from iPSC‐derived neuronal progenitor cells, which grew to consist of mature neurons and astrocytes. Microglia were added to the neurospheres and infiltrated into the 3D tissue, followed by longer Aß and aducanumab treatment. Both the neurospheres and the surrounding 2D microglia were imaged afterwards, and the supernatant was collected for Aß ELISA.

Result

Live imaging 2D microglia over 24 hours indicated that microglia treated with aducanumab have significantly higher levels of phagocytosed Aß and at a faster rate. Intriguingly, immunostaining for fibrillar Aß revealed that aducanumab decreased the amount of highly aggregated intracellular Aß. In the neurospheres, microglia are the primary cell type phagocytosing Aß. Aducanumab did not cause a significant reduction of Aß in the 3D tissue but prevented the formation of larger Aß aggregates, which may in turn facilitate microglia mediated Aß clearance.

Conclusion

Aducanumab acutely increases the ability of iPSC‐derived microglia to phagocytose Aß and may also prevent Aß aggregation. 3D neurospheres can be used to study more functional impacts of aducanumab on neuronal function. Further analysis of phagocytosed Aß using biochemical techniques after anti‐Aß antibody treatment will help to determine the precise molecular mechanisms of its effects.
MIAMI‐AD (Methylation in Aging and Methylation in AD): an integrative knowledgebase that facilitates explorations of DNA methylation across sex, aging, and Alzheimer’s disease
Authors: Wang Lily , Lukacsovich David , O'Shea Deirdre , Huang Hanchen , Zhang Wei , Young Juan I , Chen X. Steven , Dietrich Sven‐Thorsten , Kunkle Brian W. , Martin Eden R.
Published: January 2025

Background

Alzheimer’s disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur in each sex.

Method

We created the MIAMI‐AD, a comprehensive database containing manually curated summary statistics from 97 published tables in 37 studies, all of which included at least 100 participants. There are four main sections: Genome‐wide Query, Gene Query, CpG Query, and Epigenetic Clock Query.

Result

MIAMI‐AD enables easy browsing, querying, and downloading DNAm associations at multiple levels – at individual CpG, gene, genomic regions, or genome‐wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI‐AD facilitates our understanding of age‐associated CpGs in AD and in revealing sex‐specific DNAm differences in AD.

Conclusion

MIAMI‐AD (https://miami‐ad.org/) facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD. This open‐access resource is freely available to the research community, and all the underlying data can be downloaded.
Neuronal mTORC1 is required for acute Aβ‐induced cognitive dysfunction
Authors: Hussong Stacy A , Williams Kylie M , Galvan Veronica
Published: January 2025

Background

Previous studies have found that mechanistic target of rapamycin complex 1 (mTORC1) activity is significantly increased in Alzheimer’s disease (AD) patients and mouse models of AD. Additionally, inhibition of mTORC1 with systemic rapamycin treatment ameliorates AD‐like phenotypes in several AD mouse models. However, the specific contribution of neuronal mTORC1 signaling in driving AD phenotypes has not yet been explored. In this study, we use an innovative neuron‐specific knockdown mTORC1 mouse model to determine whether neuronal mTORC1 signaling contributes to cognitive dysfunction in response to acute amyloid β (Aβ) exposure.

Methods

For these experiments, we used an innovative mouse model that expresses an inducible, neuron‐specific Cre recombinase in Raptorff/fl mice. Raptor is a required component of mTORC1, thereby this Cre‐lox system results in a neuronal mTORC1 knockdown mouse. Cre expression was induced at 6 months of age. To create Aβ1‐42 oligomers, Aβ1‐42 was reconsitituted in a 10% DMSO in PBS solution (220µM) and incubated at 37°C for 48 hours. Littermate control (wildtype, Cre non‐transgenic) and neuronal mTORC1 knockdown mice were given a single intraventricular injection of vehicle (10% DMSO in PBS) or oligomerized Aβ1‐42 (5µL of 220µM Aβ1‐42) to acutely induce AD‐like cognitive deficits. Cognitive behavior was assessed by Y‐maze and contextual fear conditioning 7‐10 days after acute Aβ1‐42 exposure.

Results

Wildtype control mice acutely exposed to Aβ1‐42 had significantly impaired spatial working memory (Y‐maze, p<0.01) as well as significant deficits in contextual memory (fear conditioning, p<0.05). However, we found that mice with reduced neuronal mTORC1 signaling injected with Aβ1‐42 did not exhibit cognitive deficits in either spatial working memory or contextual memory as compared to vehicle‐treated wildtype controls. Furthermore, we found that mice with reduced mTORC1 signaling acutely exposed to Aβ1‐42 had significantly improved cognitive outcomes as compared to Aβ‐injected, wildtype, control mice (Y‐maze, p<0.05; fear conditioning, p<0.05).

Conclusion

Neuronal mTORC1 is required for acute Aβ‐induced cognitive dysfunction. Therefore, reduction of mTORC1 signaling in neurons with systemic rapamycin treatment contributes to the amelioration of Aβ‐induced cognitive dysfunction in AD mouse models.
In vivo TurboID labeling for paired proteomic and transcriptomic profiling of neurons and astrocytes
Authors: Ramelow Christina C , Xiao Hailian , Cheng Lihong , Kumar Prateek , Dammer Eric B. , Sampson Maureen , Nelson Ruth S , Malepati Sneha , Quo Qi , Bagchi Pritha , Duong Duc M , Seyfried Nicholas T , Sloan Steven A , Rangaraju Srikant
Published: January 2025

Background

Our group has developed the innovative proximity labeling cell‐type specific in vivo biotinylation of proteins (CIBOP) approach to quantify cell‐specific in vivo proteomic and transcriptomic signatures that may lead to identify novel therapeutic targets for Alzheimer’s disease (AD) pathogenesis. CIBOP uses TurboID, a biotin ligase, selectively expressed in the cell type of interest using a conditional Cre/lox genetic strategy to label the cytosolic proteome. Using mass spectrometry (MS)‐based proteomics, we have found that TurboID biotinylates many RNA‐binding and ribosomal proteins. We extended the CIBOP approach to obtain representative cell type‐specific transcriptomes and proteomes.

Method

We crossed cell‐specific Cre lines (astrocytic: Aldh1l1‐Cre‐ert2 and neuronal: Camk2a‐Cre‐ert2) and Rosa26TurboID/wt floxed mice for cell‐specific proteomic labeling (astrocyte‐CIBOP and neuron‐CIBOP). CIBOP and control (Cre‐only) mice received tamoxifen, followed by biotin‐containing water. While maintaining RNA‐protein interactions, cortical tissue was lysed, biotinylated proteins were enriched via streptavidin beads, and RNA and proteins were eluted. Immunofluorescent microscopy (IF), biochemical assays, MS‐based proteomics, and RNA‐sequencing were completed to confirm cell‐specific molecular profiling. Concordance analysis of paired proteomes and transcriptomes from CIBOP mouse brains was conducted.

Result

Western blot analysis of the cortex confirmed biotinylation of the cellular proteome of CIBOP mice when compared to controls. Cell‐type specificity was further validated by IF images showing that biotin‐labeled proteins colocalized with corresponding astrocytic (e.g., GFAP and NDRG2) or neuronal markers (e.g., MAP2 and beta‐tubulin‐3). RNA gel electrophoresis displayed high levels of RNA from CIBOP brain streptavidin pulldowns and low RNA yield from control pulldowns. MS‐based proteomics and RNA‐sequencing analysis showed upregulation of astrocytic proteins (e.g., Hepacam, Glu, Aqp4, Plpp3) and genes (e.g., Sox9, Aqp4, Gfap, Apoe) from astrocyte‐CIBOP brain. In contrast, upregulation of neuronal proteins (e.g., Map2, Ncam1, Mapt) and genes (e.g., Pdyn, Tmem130, Ptpn7) was observed in neuron‐CIBOP brain samples, confirming specificity.

Conclusion

Together, these results validate the CIBOP approach to capturing the cortical Aldh1l1‐positive astrocytic and Camk2a‐positive neuronal proteome and transcriptome. Our innovative in vivo cell type‐specific and native‐state dual‐omics approach provides complementary transcriptomic and proteomic information that can extend to AD models to investigate disease mechanisms, discover new biomarkers, and identify therapeutic targets.
Family history of AD and memory problems associated with worse subjective memory, not objective memory, in cognitively normal individuals
Authors: Hou Mingzhu , Jagust William J. , Chen Xi
Published: January 2025

Background

Family history of Alzheimer’s disease (AD) or undiagnosed memory problems is linked to an increased risk of dementia. Subjective memory complaints are also more common among individuals with positive family history, which could be indicative of heightened awareness of memory deficits in these people. Here, we conducted an online study in cognitively normal individuals across the lifespan and aimed to examine whether the presence of family history is linked to worse objective memory performance that mediates the lower subjective memory in these individuals.

Method

Participants’ objective memory was measured online by an object‐scene‐pair memory task that assessed their memory in different domains. Here we focused on the d prime (ZHit‐ZFA) for the object‐scene pairs, while other measures yielded similar results. Participants’ subjective memory was assessed by Memory Functioning Questionnaire (MFQ). We focused on the two most commonly used measures from this questionnaire, the general question and the frequency of forgetting subscale, as the primary measures of subjective memory. Participants’ family history was based on self‐report information using a comprehensive family history questionnaire. Family history positivity was defined as any family member having been diagnosed with AD or having undiagnosed memory problems.

Results

Among 273 participants (aged 22‐70 yrs), 71.4% reported no family history (N = 195). In the 78 reports of positive family history, 14.7% was parent only (N = 40), 1.1% was sibling only (N = 3), 9.9% was other family member only (N = 27), 2.6% was parent & another member (N = 7); 0.4% was parent & sibling & another member (N = 1) (Fig.1). Individuals with family history reported having more memory problems (general, p = .032; Fig.2a) and more often forgetting (frequency of forgetting, p = .004; Fig.2b), after controlling for age and gender, despite having equivalent objective memory performance (p = .295; Fig.2c). These associations remained significant while further controlling for actual memory performance in the same model (Fig.3).

Conclusion

Our findings suggest that, contrary to our hypothesis, family history of AD and memory problems is associated with worse subjective memory, but not objective memory, in cognitively normal individuals. Low subjective memory in people with family history may reflect their general worry about dementia that is not based on actual cognition.
Psychological profiles associated with cortical thickness changes in middle‐aged adults
Authors: Bartrés‐Faz David , Demnitz‐King Harriet , Cabello‐Toscano María , Vaqué‐Alcázar Lídia , Saunders Rob , Cattaneo Gabriele , Bargalló Núria , Tormos‐Muñoz Josep M. , Sánchez Javier Solana , Pascual‐Leone Alvaro , Marchant Natalie L.
Published: January 2025

Background

Psychological factors such as repetitive negative thinking, proneness to experience distress, and perceived stress are associated with increased risk of neurodegeneration and clinical dementia, whereas having a sense of life‐purpose, self‐reflection, and dispositional mindfulness may be protective. However, whether combinations of these risk and protective factors may inform distinct psychological profiles, which may be differential associated with age‐related health outcomes is currently unknown.

Method

We included 742 middle‐aged (mean age 51.4 (SD:7.0), 51.1% women) healthy individuals from the Barcelona Brain Health Initiative. All participants underwent a psychological assessment of individual risk and protective factors based on previous literature (Figure 1). An initial 3T MRI was acquired for all participants, with follow‐up MRIs conducted for 533 participants (average follow‐up 2.3 years). Latent profile analysis (LPA) was used to identify statistically distinct psychological profiles from risk and protective factors and MRIs were automatically processed with FreeSurfer v6.0 (maps p < 0.05, corrected for family‐wise error).

Result

LPA revealed a 3‐profile solution: Profile 1 (n = 190, 25.6%) was characterized by lower levels of positive or protective psychological factors; Profile 2 included individuals showing higher negative or psychological risk factors (n = 149, 20.1%); and Profile 3 reported high protective and moderately low risk factors (n = 403, 50.3%; Figure 1). Age‐, gender‐, and education‐adjusted results revealed that compared to Profile 3, individuals in Profile 1 exhibited accelerated cortical thinning in the inferior and middle temporal areas, including regions within the AD cortical thinning signature. In models additionally adjusted for anxiety and depressive symptoms, Profile 1 also exhibited greater cortical thinning over time in the inferior temporal lobe region compared to Profile 2 (Figure 2A and B).

Conclusion

Using a person‐centered approach to identify statistically distinct psychological profiles we found that already in middle‐age, those with lower levels of protective factors (Profile 1) exhibit accelerated cortical atrophy. This emphasizes the need for comprehensive psychological assessments in dementia prevention research, including the assessment of ‘protective’ factors in addition to the more commonly assessed ‘risk’ factors.
Evolution of BPSD and psychotropic drug therapy in patients with dementia
Authors: Pullia Rosanna , Rogani Sara , Bianco Maria Giovanna , Taverni Irene , Pardini Noemi , Maltese Leonarda , Giusti Andrea , Calsolaro Valeria , Virdis Agostino
Published: January 2025

Background

Despite being off‐label, antipsychotics and antidepressants are widely prescribed to manage Behavioural and Psychological Symptoms of Dementia (BPSD). Aim of our study was to assess the evolution of BPSD and psychoactive pharmacological therapy in older patients with dementia.

Method

In this retrospective observational study, outpatients with dementia underwent a Comprehensive Geriatric Assessment (ADL, IADL, CFS and CIRS), at baseline, 6‐month and 12‐month follow‐up visits. Additionally, cognitive impairment (MMSE) and severity of BPSD (NPI) were determined.

Result

266 patients (mean age 82.69 ± 10.19; 69.58% female) were enrolled; 169 underwent a 6‐month follow‐up and 111 had a 12‐month follow‐up. We observed a progressive decline in MMSE [18.89 (±5.02), 17.69 (±5.72), 17.25 (±5.70); p<0.001], ADL [5 (±3), 4 (±3), 4 (±3); p<0.001], and CFS [5.44 (± 1.23), 5.67 (±1.78), 5.77 (±1.15): p<0.001]. No differences were found in the prescription of antipsychotics over 12 months. However, there was a notable increase in Trazodone prescription between baseline and 6‐month follow‐up (18.42% at baseline, 31.55% at six months, p>0.001), with consistent prescription rate at 12 months (32.43%). Among the neuropsychiatric symptoms (anxiety, agitation, sleep disturbances), there was a significant increase in agitation at the 6‐month follow‐up compared to baseline (p = 0.026). The prescription of antidepressants significantly increased between baseline and 6‐month follow‐up (p = 0.003), without a significant increase in symptoms like depression, anxiety, or eating behaviour disorders. Patients taking antidepressants at baseline were mostly female (p = 0.043), didn’t significantly differ in age and NPI scores both at baseline and six months, but showed lower frailty levels compared to non‐users (p = 0.009), higher prevalence of anxiety (p = 0.015), appetite disturbance (p = 0.017) and depression (p = 0.034). Antidepressants were more frequently taken by women (p = 0.03) and linked to clear depressive symptoms both at 6‐month (p<0.001) and 12‐month follow‐up (p = 0.025), with higher burden of psychiatric symptoms observed at six months and baseline.

Conclusion

In older patients with dementia, BPSD gradually increased, together with functional and cognitive decline over 12 months. Managing agitation led to an increased prescription of trazodone, while antidepressant medications were used in follow‐ups for depressive symptoms; more importantly, prescription of antipsychotics did not increase, aligning with recommendations regarding their safety profile.
Pathological patterns of TDP‐43 in LATE, Alzheimer’s Disease and FTLD‐TDP
Authors: Tomé Sandra O. , Gawor Klara , Vandenberghe Rik , Nelson Peter T , Thal Dietmar Rudolf
Published: January 2025

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) has been recently recognized as a cause of dementia in the elderly. LATE and Alzheimer’s disease (AD) share similar clinical presentations, and their neuropathological changes—LATE‐NC and ADNC—commonly co‐occur in the brains of individuals with dementia. Frontotemporal degeneration (FTLD‐TDP) represents another group of TDP‐43‐associated neurodegenerative diseases. Still, the morphological and molecular features of TDP‐43 lesions in different diseases remain under‐researched. Here, we investigated distinct TDP‐43 lesions and immunoreactive species in cases of AD with LATE‐NC, pure LATE (ABC score < 1), and FTLD‐TDP.

Method

We performed immunohistochemistry in paraffin‐embedded tissue from the hippocampus, amygdala, temporal and frontal cortices of 22 non‐demented cases, 24 AD cases with comorbid LATE‐NC, 9 pure LATE and 22 FTLD‐TDP cases (subtypes A‐C). We semiquantitatively assessed the severity of neuronal cytoplasmic inclusions and dystrophic neurites using antibodies against different TDP‐43 epitopes: pS409/pS403, pS403/pS404 and non‐phosphorylated C‐ and N‐terminal TDP‐43. We also assessed general neuropathological parameters among the groups.

Result

LATE cases were older at death and exhibited lower neuronal density in the hippocampus compared to the remaining groups, supporting the hypothesis of a slower disease course in LATE compared to AD. AD and LATE did not differ in LATE‐NC stages.

Morphologically, pure LATE cases showed higher severity levels of hippocampal dystrophic neurites compared to AD with LATE‐NC and FTLD‐TDP cases. The severity of neuronal cytoplasmic inclusions was similar among groups. AD cases showed an overall predominance of pS409/pS410 TDP‐43 species, however LATE and FTLD‐TDP cases showed no significant differences in burden of all TDP‐43 species except N‐terminal TDP‐43, which showed lower severity in all groups. LATE cases also exhibited decreased burdens of TDP‐43 species in the frontal cortex compared to FTLD‐TDP.

Conclusion

These results suggest that TDP‐43 assumes distinct patterns of immunoreactivity in dementia, especially in the hippocampus. LATE and FTLD‐TDP cases showed a similar, but non‐identical patterns of TDP‐43 immunoreactive species, patterns which were different in turn from LATE‐NC in ADNC. These data may also support the concept of LATE as a separate disease with high burdens of different TDP‐43 species restricted to the limbic system in the absence of moderate‐high ADNC.
Ten‐word Test:An Effective Tool to Differential Mild Cognitive Impairment from Subjective Cognitive Decline
Authors: Ren Hua , Dong LI , Liu Tiejun , Wang Ziqi
Published: January 2025

Background

Identifying the transition from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) is crucial for delaying the progression of dementia and enabling early intervention. In clinical practice, there are many deficiencies in the scale tools used to identify the two. We wanted to evaluate the application of the 10‐word test in identifying SCD and MCI.

Methods

A total of 62 MCI and 203 SCD subjects were assessed and underwent multiple neuropsychological assessment, including the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐cog), Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment‐B (MOCA‐B), and Activities of Daily Living scale (ADL). We performed a statistical analysis on these assessments results.

Results

Neuropsychological assessment results of the MCI and SCD groups indicated significant differences in the scores of the ten‐word test (P< 0.001, figure 1), with the MCI group scoring higher. When the cut‐off value for the ten‐word test was set at 3.15, the sensitivity for differentiating MCI from SCD was 87%, and specificity was 61% (AUC 0.777, P< 0.001, figure 2). DeLong’s test revealed no statistically significant difference in the ability of the ten‐word test to distinguish between MCI and SCD compared to the total score of ADAS‐Cog (AUC 0.833) and MMSE (AUC 0.784) (P > 0.05), but a significant difference was observed when compared to MOCA (AUC 0.973, P < 0.001). In the population with an education level of ≤ 9 years, the optimal cut‐off value for the ten‐word test was 3.15, with a sensitivity of 91% and specificity of 45% (AUC = 0.674, P = 0.030, figure 3). In the population with an education level of > 9 years, the optimal cut‐off value was 3.63, with a sensitivity of 79% and specificity of 71% (AUC = 0.785, P < 0.001, figure 3).

Conclusion

Memory impairment is the most common complaint in MCI and SCD. The 10‐word immediate recall test from the ADAS‐cog may objectively reflect the short‐term memory level of subjects, with its simplicity and quick administration. It serves as an effective and convenient tool for rapid identification of mild cognitive impairment.
In vivo amyloid and tau metabolism in human brain tissue
Authors: Aslanyan Aram , Mukherjee Soumya , Dulewicz Maciej , Coyle Reid , He Yingxin , Sato Chihiro , Ghoshal Nupur , Ge Junyue , Moncur Eleanor , Koutarapu Srinivas , Camporesi Elena , Thorne Lewis , Toma Ahmed , Schwetye Katherine , Roberts Kaleigh F , Watkins Laurence , Elbert Donald L. , Bateman Randall J. , Hanrieder Jörg , Paterson Ross W.
Published: January 2025

Background

Knowledge of the chemical composition of amyloid plaques and tau tangles at the earlier stages of Alzheimer’s disease (AD) pathology is sparse. This is due to limited access to human brain during life and at the earlier stages of AD pathophysiology and technical limitations in quantifying amyloid and tau species at a subcellular level. Understanding the chemical composition of plaques and tangles, how rapidly they grow and what factors drive growth is important for developing and refining therapeutics. We access in vivo cortical brain biopsy samples from individuals undergoing surgery, aiming to provide detailed characterisation of pathology with spatial and temporal resolution.

Method

We collected in vivo brain biopsies with matched ventricular and lumbar cerebrospinal fluid samples from individuals with suspected Normal Pressure Hydrocephalus (NPH) undergoing ventriculoperitoneal shunt surgery. All participants were labelled with intravenous 13C6 Leucine as per Stable Isotope Labelling Kinetics protocol. We used immunohistochemistry, immunoprecipitation‐mass spectrometry (IP‐MS) and Matrix Assisted Laser Desorption Ionization (MALDI) mass spectrometry‐based imaging (MSI) to characterise amyloid and tau and their common post‐translational modifications. We calculate the tracer‐to‐tracee ratio of labelled to unlabelled amyloid and tau to determine rate of pathological accumulation of these proteins. Using a 2‐compartment model we establish the half‐life of tau in brain tissue.

Result

We collected cortical brain biopsies from individuals with suspected NPH (n = 6), labelled between 4.25 hours to 133 days prior to surgery; 4 out of 6 individuals had amyloid plaques (range 1‐25 plaques/mm2). These individuals had mild cognitive impairment. Cored plaques showed characteristic localization of Aβ1‐40 and Aβ 3pE‐40 in the core while x‐42 species including 1‐42, 4‐42 and 3pE‐42 showed a more homogenous distribution across both plaque core and diffuse/immature plaque periphery (Figure 1, 2). We did not detect incorporation of labelled amyloid in any subject using IP‐MS or MALDI. We detected labelled tau in brain homogenate as early as 4.25 hours after label administration. The half‐life of tau in human brain was calculated to be 26.85 days.

Conclusion

Our study provides the first detailed chemical characterisation of AD pathology in living human brain giving insights into plaque composition, age and tau dynamics.
Contributions of heavy metal exposure to late‐onset Alzheimer’s disease
Authors: Kotredes Kevin P , Minaeva Olga , Pandey Ravi S , Moncaster Juliet A , Lamb Bruce T. , Carter Gregory W , Goldstein Lee E , Howell Gareth R
Published: January 2025

Background

Late‐onset Alzheimer’s disease (LOAD) is the leading cause of dementia and a major contributor to increased mortality. Recent human datasets have revealed many LOAD genetic risk factors that are correlated with the degree of AD burden. Further, the complexity and heterogeneity of LOAD appears to be promoted by interactions between genetics and environmental factors such as diet, sedentary behavior, and exposure to toxicants, like lead (Pb), cadmium (Cd), and arsenic (As). While the neurotoxicants‐LOAD association is known, the molecular mechanisms modulated by these gene‐environmental interactions are unknown. Here we test the hypothesis that heavy metal exposure induces cerebrovascular deficits, neuroinflammation, and brain biometal dyshomeostasis which exacerbate AD‐associated brain pathologies in next‐generation mouse models of LOAD. Examination of these gene‐environmental (“exposome”) interactions provides essential insight into the heterogeneity observed in human disease and may uncover potentially modifiable mechanisms that mediate AD pathogenesis.

Method

Young and aged mice from novel polygenic strains expressing LOAD risk alleles (APOE4, Trem2, APP, Mthfr, Abca7) were exposed to heavy metal toxicants in drinking water. Toxicants and endogenous biometals were assayed by ICP‐mass spectrometry in the brain, blood, and urine. Transcriptional profiling of brains revealed specific changes in human‐aligned, LOAD‐related gene expression networks indicating mechanisms of disease progression. Neuropathology was evaluated with LOAD‐relevant phenotypes, including amyloid burden, glial activity, and neuron loss.

Result

Neurotoxicants were detected in all tissue samples collected. Pb, Cd, and As accumulated in the brain and altered expression of LOAD‐relevant genes in a toxicant‐specific manner, including a decrease in Vgf and an increase in App. Reduced VGF expression has been observed and reported in all four independent AMP‐AD studies and nominated as a key therapeutic target in each and APP encodes amyloid precursor protein (APP) from which the Aβ peptides are generated.

Conclusion

Pb, Cd, and As exposure is common, especially in disadvantaged populations (urban, rural), raising concern about LOAD risk disparities, socioeconomic/racial inequities, and environmental justice. These experiments provide critical feedback related to the impact of the “exposome” in the aging, disease progression, and gene expression of novel preclinical LOAD models. Collectively these data suggest a direct effect of neurotoxicant exposure related to LOAD progression.
Prioritization of polygenic combinations for LOAD mouse models from ensemble machine learning on cross‐species transcriptomic signatures
Authors: Cary Gregory A. , Pandey Ravi S , Uyar Asli , Spruce Catrina , Haber Annat , Carter Gregory W ,   The IU‐JAX‐PITT MODEL‐AD Center
Published: January 2025

Background

The genetic etiology of late‐onset Alzheimer’s disease (LOAD) is complex, with over 75 identified loci contributing to disease risk. Recent efforts of the MODEL‐AD consortia have yielded several dozen mouse strains harboring variation designed to model LOAD risk alleles. Given the complex genetic architecture of LOAD, developing animal models that combine multiple risk alleles is likely essential to improving the fidelity of these models to human disease. However, it is not clear which combinations of risk alleles are optimal for modeling disease features in mice. In this study we utilize transcriptome data from existing strains to prioritize which variants should be combined in future model development.

Method

We estimated the effects of genetic variants and environmental perturbations on gene expression using multiple linear regression. The computed gene‐level effects were used as features in separate regression models fit to changes in human transcriptomes from AMP‐AD cohorts and previously described disease subtypes. To mitigate multicollinearity and allow for non‐linear relationships, we employed both regularized linear models (LASSO, SVM) and non‐linear models (Random Forest, Neural Network). Variable importance was extracted from the fit models for each regression analysis. We evaluated the importance of each feature (e.g. genetic variant) across models in an ensemble approach.

Result

The top mouse features prioritized by the different regression models were largely similar. Moreover, similar features were also prioritized across the different human cohorts. The top mouse features included a humanized Aβ and variants in SPI1, ABCA7, Epha1, and Sorl1. Intriguingly there were distinct sets of strains prioritized for different disease sub‐types. Looking across cohorts there were generally a typical (i.e. inflammatory) sub‐type and a non‐inflammatory sub‐type. The inflammatory subtypes prioritized similar features to the overall cohorts, while the priorities for non‐inflmmatory subtypes included Cd2ap, Shc2, and Mtmr4.

Conclusion

We identified consistent predictions regarding which mouse factors are most influential in modeling disease across model classes and human cohorts. Ensembling the models was a useful approach for feature selection. These priorities informed the selection of mouse strains to breed in the development of polygenic LOAD mouse models by the IU‐JAX‐PITT MODEL‐AD center.
Large‐scale Genome‐wide Investigation of Short Tandem Repeats Associated with Alzheimer’s Disease Risk
Authors: Küçükali Fahri , Sleegers Kristel ,   EADB
Published: January 2025

Background

Classical genome‐wide association studies (GWAS) of Alzheimer’s disease (AD), which successfully identified over 75 risk loci to date, are limited to the content of the imputation panels that typically do not cover all types of genetic variation, e.g., tandem repeats encompassing >55% of human genome. Recent advances in the imputation panels with short tandem repeats (STRs; repeated motifs of 1‐6 bp in tandem, accounting for 10% of all repetitive elements) pave the way for large‐scale STR GWAS opportunities for complex diseases with substantial missing heritability such as AD. In this study, we investigated the contribution of STRs to AD risk.

Method

We leveraged a publicly available STR imputation reference panel to impute over 440,000 multiallelic STRs in the European Alzheimer & Dementia Biobank (EADB) core cohort of 20,301 AD cases and 21,839 controls. After converting multiallelic STRs and applying filters of imputation quality score (R2≥0.3) and minor allele counts (≥20), imputed dosages from ∼2.35 million biallelic STRs were included in GWAS where the results were adjusted for the first 20 genetic principal components and genotyping center. We ran conditional analyses to determine independent risk loci driven by STRs. Furthermore, we constructed brain expression and splicing STR (eSTR & sSTR) catalogues for accurate mapping of non‐coding STRs to prioritized risk genes.

Result

We identified 410 significant biallelic STR associations at P<1 × 10‐5, of which 194 were passing the stringent genome‐wide significant threshold, originating from 50 risk loci. ∼8% of the associations were rare (minor allele frequency <1%), while ∼10% of them were positioned outside of previously identified AD GWAS loci. One of these new association peaks was positioned near the promoter of a novel candidate gene, which was prioritized also by the eSTRs regulating the expression of this gene in the locus.

Conclusion

Our first biallelic STR GWAS results demonstrate the power of our approach, and together with the complementary subsequent analyses (e.g., multiallelic length‐based STR GWAS method, conditional analyses, e/sSTR integration analyses, and additional replication and meta‐analyses), it has the potential to unravel and characterize AD‐associated STRs, towards a full characterization of all types of understudied genetic variation for AD in the future.
Biological pathway‐based Alzheimer’s Disease polygenic risk score and proteinopathy
Authors: Katsumata Yuriko , Wu Xian , Aung Khine Zin , Tsuchiya Inori , Shade Lincoln MP , Karanth Shama D , Gauthreaux Kathryn , Mock Charles , Kukull Walter A. , Abner Erin L. , Nelson Peter T , Fardo David W.
Published: January 2025

Background

We recently reported genetic associations with dementia‐related proteinopathies. Using multidimensional generalized partial credit modeling, we constructed three continuous latent variables, corresponding to TDP‐43, Aβ/Tau, and a‐synuclein related neuropathology endophenotype scores.

Method

Participant data were drawn from the National Alzheimer’s Coordinating Center (NACC) neuropathology (NP) data (from the September 2023 data freeze) linked to Alzheimer’s Disease Genetics Consortium (ADGC) genotype data. ADGC genotype data were imputed by TOPMed Imputation Server (https://imputation.biodatacatalyst.nhlbi.nih.gov/). The AD summary statistics were obtained from GWAS Catalog (https://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90027001‐GCST90028000/GCST90027158/) created by Bellenguez et al. We calculated biological pathway‐based PRS by Gene Ontology (GO) terms listed for Homo sapiens from Ensembl (http://www.ensembl.org/biomart/martview/) with the subset of retained SNPs based on r2 = 0.1 with a physical distance threshold of 250 kb and p‐value < 0.0001 using PRSice‐2 (https://www.prsice.info/). We then estimated the associations between each of the PRS scores and each of the three latent proteinopathy scores adjusting for age at death, sex, the top three principal components, and the two non‐outcome latent scores than the outcome. We adjusted the p‐values using the Bonferroni correction.

Result

The total 19,596,813 single nucleotide variants (SNVs) or short indels were overlapped in ADGC imputed genotype and the GWAS summary statistics. We extracted 1,850 biological process, 542 molecular function, and 405 cellular component GO terms that were constructed of 5 or more SNVs. The AD PRSs in “membrane” cellular component and “protein binding” molecular function were strongly associated with the Ab/Tau pathology related latent score (Bonferroni corrected p‐value = 1.7 × 10‐6 and 0.00011, respectively). There was no biological pathway‐based AD PRS associated with TDP‐43 and α‐synuclein pathology‐related latent scores.

Conclusion

The biological pathway‐based AD PRSs were associated with only Aβ/Tau pathway related latent proteinopathy score. We will explore PRSs for other diseases that are potentially related to AD etiology including Parkinson’s disease linked to α‐synuclein pathology, amyotrophic lateral sclerosis (ASL) with TDP‐43 aggregation, cardiovascular diseases, cardiovascular risk factors, and psychiatric diseases.