bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondria as Sensors of Amyloid‐Beta Toxicity and Regulators of Inflammation in Cerebrovascular Endothelial Cells
Authors: Parodi‐Rullan Rebecca M , Carey Ashley M , Fossati Silvia
Published: January 2025

Background

The blood‐brain barrier (BBB) is a crucial regulator of cerebral homeostasis and function. Cerebrovascular endothelial cells (EC) are important components of the BBB, and EC damage and/or dysfunction may result in defects in brain clearance and perfusion, microhemorrhages, inflammation, and neurodegeneration. In addition to EC damage resulting from the presence of amyloid‐beta (Aβ) in Alzheimer’s Disease (AD) and Cerebral Amyloid Angiopathy (CAA), the presence of cardiovascular risk factors (CVRF) may further exacerbate cerebrovascular function and neurodegeneration. Particularly, ECs may be the most susceptible to Aβ and CVRF damage leading to the initiation and/or perpetuation of an inflammatory cascade in neurodegenerative diseases. Brain ECs are highly dependent on glycolysis and their mitochondria have important roles as signaling organelles, sensing cellular damage and mediating downstream pathways such as inflammation. Here, we aim to understand the mechanistic nature of endothelial mitochondrial dysfunction and its elicited pathways in Aβ and mixed (Aβ+CVRF) vascular pathologies. Understanding the mechanisms by which the mitochondria may mediate EC inflammation could pave the way to new roads for therapeutic advancements in the field.

Method

Human brain microvascular ECs were challenged with Aβ, Homocysteine (Hcy, a CVRF), or the combination. Mitochondrial ultrastructure, metabolic function, and inflammatory cascades were assessed.

Result

The presence of Aβ, but not Hcy, increased mitochondrial ROS production (mtROS) and induced deficits in mitochondrial respiration concomitant with a decrease in mitochondrial ATP production. Deficits in mitochondrial respiration were accompanied by an increase in glycolytic ATP production and, to some extent, the expression of proteins involved in glycolytic regulation. Mitochondrial fragmentation, as an indicator of mitochondrial damage, was assessed ultrastructually and by the analysis of the expression of fission proteins. Markers of EC activation were assessed to link mitochondrial dysfunction to EC inflammation.

Conclusion

Deficits in mitochondrial function and metabolism were associated with Aβ but not Hcy, and accompanied by the release of mtROS, a mitochondria damage associated molecular patterns (mtDAMP). This, in turn, was associated to an increase in EC inflammatory markers and barrier permeability. Overall, our results reveal a novel role for mtDAMPs in vascular dysfunction in the presence of Aβ and/or Hcy.
Comprehensive Clinical and Neuropathological Analysis of Down Syndrome Over Seven Decades of Life
Authors: Sukreet Sonal , Goodwill Vanessa , Ngolab Jennifer , Kim H Y. , Leisher Solana , Salehi Sahar N , Rafii Michael , Hiniker Annie , Rissman Robert A.
Published: January 2025

Background

Individuals with Down Syndrome (DS) exhibit a unique aging profile and have early‐onset Alzheimer’s Disease (AD) due to a triplication of the amyloid precursor protein (APP) gene on chromosome 21.

Method

Here, we present a study of a 73‐year‐old non‐Hispanic White female with DS who underwent extensive clinical assessments for several decades. She had a cognitive and functional impairment consistent with DS and AD‐like symptoms. Post‐autopsy we did neuropathological and immunohistochemical analysis of the brain and retina.

Result

Neuropathological and immunohistochemical analysis of the brain and retina revealed age and disease‐related changes. Numerous senile plaques, neurofibrillary tangles, Lewy bodies, and cerebral amyloid angiopathy were found throughout cortical and subcortical regions of the brain. Additionally, aberrant TAR DNA‐protein (TDP) 43 accumulation was observed in the amygdala and hippocampus. Immunofluorescent analysis of retinal tissue revealed the presence of amyloid deposits and phosphorylated tau in the ganglion cell and inner plexiform layer of the retina. Whole‐genome sequencing identified two SNPs, rs2802292 and rs4977756 (p < 0.05), linked to longer lifespans.

Conclusion

This case report provides a comprehensive look into the clinical and neuropathological correlates of DS and documents unique clinical and pathological changes over 7 decades of life. We also explored hypotheses and potential mechanisms underlying increased lifespan in certain DS individuals despite progressive intellectual impairment and neurodegenerative pathologies.
Linkage analyses identifiy novel loci for Alzheimer’s disease in non‐Hispanic white families
Authors: Gomez Nicholas , Jean‐Francois Melissa , Hamilton‐Nelson Kara L. , Slifer Susan H. , Kunkle Brian W. , Cuccaro Michael L. , Martin Eden R. , Haines Jonathan L. , Reitz Christiane , Pericak‐Vance Margaret A , Vardarajan Badri N. , Beecham Gary
Published: January 2025

Background

Alzheimer disease (AD) is a progressive dementia with high heritability. While genome‐wide association studies have identified common variation associated with AD, most of these loci have effects too small to explain the segregation of disease within multiplex families. As such, these multiplex families likely harbor novel genetic variants with strong effects, and thus still play an important role in assessing the genetic etiology of AD.

Method

Linkage analyses were conducted on 670 individuals across 70 non‐Hispanic white (NHW) multiplex families for AD or mild cognitive impairment (MCI). A combination of genome wide array data and imputed data was used for the analyses. Rare variants, and low‐quality variants were excluded; remaining variants were LD pruned. Linkage analyses included both multipoint (MPT) and two‐point (2PT) approaches, with non‐parametric, parametric (affected only; AO), and parametric (age‐penetrance; AP) models. Primary analyses included (1) all AD+MCI individuals and (2) all AD+MCI individuals with age at onset 65 or lower (early‐onset AD). Sensitivity analyses included the same models but excluding MCI.

Result

We identified three primary linkage regions (HLOD > 3). For the MPT‐parametric‐AO model (AD+MCI) we identified chromosome 5q33 (HLOD = 3.017; 149MB‐156MB). A region on 8p11‐p21 (20MB‐37MB) was identified using the MPT‐parametric‐AO model (AD and early‐onset models; HLOD = 3.09, 3.27). Finally, chromosome 14q22‐24 (57MB‐70MB) was identified using the MPT‐parametric‐AP model (AD+MCI; HLOD = 3.56). The 5q33 region contains IL12B and ADAM19 genes. IL12B is an inflammatory cytokine that has been associated with amyloid burden and AD affection status. ADAM19 has been associated with AD progression and has functional links to APP. The 8p locus houses the CLU locus, first identified in large AD GWAS, while the 14q locus is near the PSEN1 gene. Further analyses of whole genome sequence data in these regions are ongoing.

Conclusion

These analyses highlighted three regions and several genes connected with Alzheimer’s disease. These new loci, along with the established loci identified, may give more insight into the causes of AD for multiplex families.
Progranulin acts in lysosomes to promote neuronal survival and growth
Authors: Kaplelach Azariah K , Hall Justin A , Davis Skylar E. , Roth Jonathan R , Aljabi Qays , Hakim Ahmad R. , Savell Katherine , Day Jeremy J , Arrant Andrew E.
Published: January 2025

Progranulin is a secreted pro‐protein that is necessary for maintaining lysosomal function and exerts anti‐inflammatory and neurotrophic effects in the brain. Loss‐of‐function GRN mutations, most of which cause progranulin haploinsufficiency, are a major autosomal dominant cause of frontotemporal dementia (FTD). Other GRN variants are associated with risk for FTD, Alzheimer’s disease (AD) and Parkinson’s disease. A common AD‐ and FTD‐associated GRN variant is also associated with mild reduction of progranulin levels. Thus, loss of progranulin’s lysosomal, anti‐inflammatory, and/or neurotrophic effects may underlie the association of GRN with neurodegenerative disease. Restoring progranulin is a promising treatment strategy for people with GRN mutations and perhaps for a broader group of patients. Understanding progranulin’s mechanism of action could enable design of optimal progranulin‐based therapies. Progranulin is constitutively secreted and can interact with several signaling receptors before being taken up and trafficked to lysosomes. It is not clear if progranulin’s anti‐inflammatory and neurotrophic effects are mediated by extracellular signaling or actions in lysosomes. To distinguish between these mechanisms, we developed lentiviral vectors expressing human progranulin (PGRN) fused to the transmembrane domain and cytosolic tail of LAMP‐1 (L‐PGRN). We used these vectors in mixed primary neuron/astrocyte cultures to test the hypothesis that progranulin’s neurotrophic effects are mediated in lysosomes. L‐PGRN was not secreted, but was trafficked to lysosomes, cleaved into granulins, and able to normalize lysosomal enzyme activity in Grn–/– neurons. L‐PGRN mimicked the protective effects of PGRN against NMDA excitotoxicity in primary cortical neurons. Delivery of L‐PGRN with neuron‐specific vectors confirmed that this effect was mediated directly in neuronal lysosomes. Further investigation revealed that L‐PGRN blocked the contribution of autophagy to excitotoxic cell death. L‐PGRN was also as effective as PGRN at promoting dendritic outgrowth in primary hippocampal neurons. A neuron‐specific L‐PGRN vector failed to promote neuronal outgrowth, but an astrocyte‐specific L‐PGRN vector promoted neuronal outgrowth similarly to the non‐specific L‐PGRN vector. Progranulin may therefore promote dendritic outgrowth through a non‐cell–autonomous mechanism involving astrocytes. We are currently investigating how progranulin may act in astrocytic lysosomes to change reactive and/or neurotrophic phenotypes.
Multi‐ancestry Genome‐wide Gene‐Vascular Risk Factors Interaction Analyses in Alzheimer’s Disease
Authors: Lee Annie J. , Cui Zuoqiao , Song Zhengwei , Reyes‐Dumeyer Dolly , De Jager Philip L. , Bennett David A. , Schneider Julie A. , Menon Vilas , Wang Yanling , Lantigua Rafael A. , Medrano Martin , Mejia Diones Rivera , Jiménez‐Velázquez Ivonne Z. , Kukull Walter A. , Biber Sarah A , Brickman Adam M. , Tosto Giuseppe , Kizil Caghan , Farrer Lindsay A. , Mez Jesse , Chung Jaeyoon , Vardarajan Badri N. , Mayeux Richard
Published: January 2025

Background

Cardio and cerebrovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and clinical Alzheimer’s Disease (AD), and over 70% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with a burden score of hypertension, diabetes, heart disease, and body mass index (BMI) by altering the normal astroglial‐vascular mechanisms that underly amyloid clearance. Stroke, defined by history of a clinical stroke or brain imaging, is a moderately robust risk factor for AD and dementia. The goal here was to identify genes that interact with CVRFs, incorporating stroke as an additional factor, on AD in multi‐ethnic cohorts.

Method

We conducted a genome‐wide gene‐CVRF score interaction analysis for AD, in 7,939 AD patients and 9,631 controls from eight multi‐ethnic cohorts of non‐Hispanic Whites, African Americans, and Hispanics including ADNI, NACC, NOMAS, WHICAP, EFIGA, and ROSMAP. A CVRF score was created from the first principal component of history of clinical stroke, hypertension, diabetes, and heart disease, and measured BMI. Gene‐based interaction test was performed with the adaptive gene‐environment interaction test. Results were summarized using a meta‐analysis. We investigated the association of pathological AD, amyloid‐β, or brain infarcts with gene expression and protein expression from the frontal cortex in ROSMAP using a generalized linear model. Age, sex, and the first three principal components were adjusted in the models.

Result

The interaction of CVRF score with FMNL2 on AD (p = 1.02E‐05) was identified and additional genes were identified to interact with CVRF score, including SLC22A14 (p = 1.44E‐06), AMMECR1L (p = 2.74E‐06), PRG3 (p = 2.76E‐06), CFAP99 (p = 5.22E‐06), ADPGK‐AS1 (p = 8.58E‐06) and BRINP1 (p = 6.29E‐06). ADPGK‐AS1 and FMNL2 gene expressions were associated with pathological AD (p = 0.004 and p = 0.0002). FMNL2 and BRINP1 gene expressions were higher in the brains of patients with brain infarcts (p = 0.025 and p = 0.006). BRINP1 protein expression was associated with pathological AD (p = 0.0002) and was higher in the brains of patients with brain infarcts (p = 0.022).

Conclusion

We identified novel candidate genes that interact with CVRFs on AD in multi‐ethnic cohorts. Understanding the interplay between genes, CVRFs, and AD has the potential to reveal novel molecular targets for prevention and treatment for AD.
Carbonic Anhydrase Inhibitors rescue microvascular impairment and neuroinflammation in 3xTg AD mice
Authors: Canepa Elisa , Lemon Nicole L , Alves Micaelly , Vazquez‐Torres Rafael , Abyaneh Maryam H. , Fossati Silvia
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized‐ at both early and late stages‐ by neurovascular impairment. In AD, dysfunctional cerebral microvasculature is accompanied by an inflammatory response, contributing to Aβ and tau accumulation, brain cell stress and death, impaired clearance of metabolic waste, BBB permeability, and ultimately leading to neuronal demise and cognitive impairment. We previously showed that Aβ peptides induce mitochondrial dysregulation and caspase‐mediated apoptosis in brain cells, including endothelial, glial, and smooth muscle cells. Moreover, we found FDA‐approved carbonic anhydrase inhibitors (CAIs), acetazolamide (ATZ) and methazolamide (MTZ), clinically used for non‐AD related conditions, effectively rescue these pathological events, and ameliorate cognitive impairment, brain amyloidosis, and vascular and glial fitness, in an AD/CAA (Cerebral Amyloid Angiopathy) in vivo model. We unveiled a mitochondrial isoform, Carbonic Anhydrase (CA‐VB), as a major player in Aβ‐mediated toxicity, with increased CA‐VB levels in AD/CAA mouse and human brains.

Method

3xTg mice express three familial AD mutations: Swedish APP mutation (KM670/671NL), PSEN1 M146V mutation, and MAPT P301L mutation. Following 10 month‐CAI‐diet, mice were sacrificed at 16 months of age,. Brains were harvested and processed for biochemical and immunohistochemistry analysis.

Result

CAIs ameliorate cognitive dysfunction, and significantly reduce hippocampal and cortical Aβ deposition and Thioflavin S positive deposits in 3xTg mice. Specifically in the hippocampus, CAIs rescue OXPHOS complexes dysregulated expression, reduce mitochondrial CA‐VB expression, and prevent caspase‐3 activation. In hippocampus and cortex, 3xTg present loss of PDGFRβ (microvascular marker) and increased gliosis (GFAP and IBA1), which are rescued by CAIs.

Conclusion

CAIs show positive behavioral outcomes in 16‐month‐old 3xTg mice, and reduce brain amyloidosis, compared to untreated animals. In the hippocampus, CAIs foster microvascular health and reduce inflammatory state, and in the cortex, MTZ decreases microgliosis, unveiling cell specific CAI effects underlying Aβ deposition reduction observed in both areas. This work points to CAIs as a potential therapeutic strategy to treat brain microvascular impairment and neuroinflammation, preventing mitochondria‐mediated cell stress and death.
Astrocytic induction of triglyceride lipolysis in AD‐associated pathology and neuroinflammation
Authors: Zimmer Till S , Barnett Daniel , Orr Adam L , Orr Anna G.
Published: January 2025

Background

Multiple AD risk genes are implicated in lipid metabolism, and plasma and brain lipid levels are altered in AD. Astrocytes are enriched in key lipid‐related factors and are likely contributors to altered lipid homeostasis in AD. We hypothesize that APP/Aβ‐related pathology and neuroimmune factors modulate astrocytic gene transcription that promote maladaptive changes in lipid pathways, including aberrant astrocytic production and release of lipids that could affect Aβ pathology and neuronal deficits.

Method

To investigate the effects of APP/Aβ and neuroinflammation on astrocytic lipid metabolism, we used homozygous mutant APP knock‐in mice (APPSAA‐KI) that have progressive Aβ proteinopathy and gliosis, as well as mice injected systemically with lipopolysaccharide (LPS) to induce acute neuroinflammatory responses. Astrocyte‐specific analyses were performed in vivo by either FACS‐sorting astrocytes for downstream lipidomic profiling or by ribosome‐tagging astrocytes in mouse models (Ribotag) for astrocyte‐specific RNA sequencing. We also performed lipidomic, RNA, and protein‐based analyses in primary murine astrocytes stimulated with oligomeric Aβ (oAβ) or interleukin‐1 (IL‐1α/β).

Result

Lipidomics in acutely sorted cortical astrocytes from APPSAA‐KI or LPS‐injected mice revealed decreased levels of triglycerides and cholesterol esters. In LPS‐injected mice, cortical astrocytes also had increased expression of enzymes involved in lipolysis, most notably adipose triglyceride lipase (Atgl), the principal triglyceride hydrolase. Similarly, primary astrocytes had increased levels of triglyceride lipolysis upon IL‐1α/β or oAβ stimulation, leading to increased liberation of free fatty acids (FFAs) in an NF‐κB and ERK1/2‐dependent manner. Astrocytic FFAs generated from triglyceride lipolysis were not used for energy production via β‐oxidation but instead utilized by astrocytes to produce prostaglandins (PGE2) and to facilitate secretion of extracellular vesicular bodies (EVB). Inhibiting ATGL decreased PGE2 production, revealing an essential role of astrocyte triglyceride lipolysis in neuroinflammatory processes.

Conclusion

Our findings suggest that Aβ pathology and neuroinflammatory factors cause astrocytic triglyceride lipolysis, a process that liberates fatty acids to be utilized for various potentially pathogenic cascades in disease. We conclude that amyloid pathology and neuroimmune factors converge to alter astrocytic lipid‐related gene transcription and lipid‐based signaling.
Mild Behavioral Impairment in individuals with subjective cognitive decline and mild cognitive impairment in Southern Brazil
Authors: Souza Victória Tizeli , da Mota Simone Sieben , Paz Gabriela Raquel Rivas , De Marchi Bruno De Oliveira , Carvalho Guilherme Da Silva , De Souza Haniel Bispo , Beltrami Lucas Bastos , Santos Rhaná Carolina , Carnevalli Sarah Vitoria Bristot , de Albuquerque Ana Letícia Amorim , de Paula Leonardo Martins , Giordani Manuella Edler Zandoná , Borelli Wyllians Vendramini , Carello‐Collar Giovanna , Chaves Marcia L Fagundes , Zimmer Eduardo R. , Castilhos Raphael Machado
Published: January 2025

Background

Mild Behavioral Impairment (MBI) is a construct developed to capture neuropsychiatric symptoms in individuals in early stages of neurodegenerative diseases. The assessment of MBI in individuals with preclinical cognitive manifestations in Brazil is still quite limited. The aim of this study is to evaluate the MBI‐Checklist (MBI‐C) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) in the Brazilian Subjective Cognitive Decline (BRASCODE) cohort in southern Brazil.

Method

BRASCODE cohort is currently following cognitive unimpaired individuals with > 60 years with cognitive complaints and without severe clinical or neuropsychiatric illness. In this analysis we included the individuals evaluated in the 12 months follow‐up. We performed the following scales: MBI‐C (participant and informant), Neuropsychiatric Inventory–Questionnaire (NPI‐Q), Memory Complaint Scale (MCS) (participant and informant), Geriatric Anxiety Inventory (GAI), Geriatric Depression Scale (GDS), and Mini Mental State Examination (MMSE). A correlation analysis was conducted among these variables.

Result

Until December 2023, 47 individuals performed the 12‐month evaluation. Table 1 described the characteristics of the participants. The MBI‐C of the patient and informant had medians (IQR) of 3(0.75‐6) and 3(1‐9), respectively. The MBI‐C‐informant showed a strong positive correlation with the NPI (p‐value<0.0001, rho = 0.827) and also correlated with the SCD‐informant (p‐value = 0.006, rho = 0.404). The MBI‐C‐patient correlated positively with GDS (p‐value<0.0001, rho = 0.604) and with GAI (p‐value = 0.049, rho = 0.314), and negatively with their education (p‐value = 0.009, rho ‐0.387), but it was not with NPI, MCS‐patient and MCS‐informant Particularly, MBI‐C of the participant and informant did not correlate.

Conclusion

Our partial analyses showed that informant perceptions of neuropsychiatric and memory manifestations were correlated in participants with SCD and MCI. In addition, MBI‐C of the participants was correlated with anxiety and depression symptoms. Studies with a larger sample size may provide additional information about MBI in individuals with SCD and MCI.
Orexin/hypocretin modulation of neuroinflammation in a rodent model: implications for age‐related cognitive decline
Authors: Frick Marla A , Somera Brandy Lynn , Woodruff Jennifer L. , Reagan Lawrence P. , Fadel Jim R.
Published: January 2025

Background

The orexin/hypocretin neuropeptide system, primarily found in the lateral hypothalamus and perifornical region, modulates sleep, wakefulness, appetite, and cognitive function. One region with dense orexinergic projections is the basal forebrain (BF), which is the major source of acetylcholine in the neocortex and limbic structures such as the hippocampus. The basal forebrain cholinergic system mediates cognition and dysfunction is one of the key hallmarks of Alzheimer’s disease. We have previously shown significant reductions in orexin signaling and orexinergic innervation of cholinergic cells within the BF of aged rodents. Loss of orexin impairs cholinergic neurotransmission and cognitive function, but the mechanisms responsible for such deficits remain poorly understood. Recent evidence suggests neuroinflammation as a contributing factor to the pathogenesis of Alzheimer’s disease. It has been suggested that orexin may be neuroprotective, and we hypothesize that the age‐related loss of orexin neurons diminishes the brain’s anti‐inflammatory response, leading to basal forebrain cholinergic dysfunction.

Method

Lentivirus mediated expression of Preproorexin antisense or sense was administered into the lateral hypothalamus of young adult (3 months; antisense) and aged (22‐26 months; sense), male and female Fisher 344/Brown Norway F1 hybrid rats. Three weeks later, a neuroinflammatory response was induced with an acute lipopolysaccharide (1 mg, intraperitoneal) challenge. 6 hours later, brains were removed and bilaterally dissected with one hemisphere post‐fixed in 4% paraformaldehyde for immunohistochemical analysis and one hemisphere frozen for cytokine analysis.

Result

Lentivirus efficacy was verified using immunohistochemistry for GFP expression and changes in orexin expression within the lateral hypothalamus and terminal regions. There was no significant difference in total Iba‐1 in the basal forebrain, but there was a shift in activation state towards an activated, pro‐inflammatory, “M1” phenotype in the orexin antisense treated rats. In addition, there was an increase in IL‐6 and TNF‐alpha in the prefrontal cortex of orexin antisense treated male rats.

Conclusion

Loss of orexin expression in aging may facilitate neuroinflammatory processes in key regions, such as the basal forebrain and prefrontal cortex, and thereby contribute to neurodegeneration and cognitive decline.

Acknowledgements: Supported by NIH R01 AG050518 and 2RF1 AG050518. Karly Pikel provided technical assistance.
Standardizing Care for Agitation in Alzheimer’ Dementia: Results from a Randomized Controlled Trial of an Integrated Care Pathway versus Usual Care ‐The StaN trial
Authors: Kumar Sanjeev , Burhan Amer M. , Chu Li , Colman Sarah , Davies Simon , Derkach Peter , Elmi Sarah , Gerretsen Philip , Graff‐Guerrero Ariel , Hussain Maria , Ismail Zahinoor , Kim Donna , Krisman Linda , Ma Clement , Moghabghab Rola , Mulsant Benoit H. , Nair Vasavan , Pollock Bruce G. , Rej Soham , Rostas Aviva , Streiner David , Van Bussel Lisa , Rajji Tarek K. ,   StaN Study Group
Published: January 2025

Background

Adherence to treatment guidelines for agitation in dementia is suboptimal and inconsistent. We designed an Integrated Care Pathway (ICP) that standardized behavioral and pharmacological interventions for agitation in dementia, and evaluated it against treatment‐as‐usual (TAU). The two primary hypotheses were that, compared to TAU, the ICP would result in (1) lower agitation and (2) lower rates of polypharmacy at study end.

Method

The Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) trial (ClinicalTrials.gov # NCT03672201) was conducted at five academically affiliated inpatient units (Inpatient) and seven long‐term‐care homes (LTCHs). Participants with agitation related to Alzheimer’s dementia were randomized 1:1 to receive the ICP or TAU for 12 weeks. Primary outcomes were: (1) Cohen Mansfield Agitation Inventory (CMAI) completed at weeks 3, 8, and 12 (primary), and (2) polypharmacy defined as using more than one psychotropic medication assessed at weeks 1, 3, 4, 6, 8, 10, and 12 (primary) post‐randomization. Linear mixed effect models and generalized estimating equations were used to test our hypotheses controlling for age, gender, and stage of dementia. The study was powered for Inpatient and LTCH settings separately.

Result

185 participants were randomized: 93 in Inpatient (46 ICP: 47 TAU; females = 32 (34.4%); mean (standard deviation [SD]) age = 75.0 (8.4) years), and 92 in LTCH (46 ICP: 46 TAU; women = 63 (68.5%); mean (SD) age = 85.9 (7.6) years). There were no significant time*group interactions for the CMAI scores for Inpatient (F4, 297.9 = 0.8, p = 0.53) or LTCH (F4, 297.3 = 1.1, p = 0.36) and no significant differences at week‐12 (Inpatient: ICP‐TAU adjusted difference = 0.025; 95% Confidence Interval (CI): ‐0.410, 0.460; LTCH: ICP‐TAU adjusted difference = ‐0.214; 95%CI: ‐0.699, 0.270). However, there were significant time*group interactions for polypharmacy for both Inpatient (χ27 = 18.6, p = 0.01) and LTCH (Χ27 = 22.9, p = 0.002). Differences were not significant at week‐12 (Inpatient: ICP‐TAU adjusted difference = 0.15; 95%CI: ‐0.11, 0.40; LTCH: ICP‐TAU adjusted difference = 0.33; 95%CI: ‐0.06, 0.72), the ICP group had lower rates of polypharmacy than TAU group at weeks 3, 4, and 6 on Inpatient, and week 3 in LTCH.

Conclusion

Standardizing care for agitation in dementia may result in less polypharmacy without affecting efficacy. Future studies should assess the ICP in broader community and outpatient settings.
Brain and Blood Transcriptome‐Wide Association Studies Identify Three Novel Genes Associated with Cognitive Resilience
Authors: Mews Makaela , Naj Adam C. , Below Jennifer Elizabeth , Dumitrescu Logan C. , Hohman Timothy J. , Griswold Anthony J. , Bush William S.
Published: January 2025

Background

While there are numerous genome‐wide association studies (GWAS) assessing the genetic basis of Alzheimer’s disease (AD), there are far fewer studies examining genetic factors for cognitive and global resilience to AD neuropathology. By focusing on a gene‐level rather than a single‐variant basis, transcriptome‐wide association studies (TWAS) have increased statistical power relative to GWAS and can assess the role of genetically regulated gene expression in AD resilience. We leveraged the largest available cis‐eQTL meta‐analysis summary statistics from brain tissue (MetaBrain Brain‐Cortex; N = 2,547) and whole blood (eQTLGen; N = 31,684) and applied them to the largest cognitive and global resilience to AD neuropathology summary statistics from Dumitrescu et al. 2020 (N = 5,108; Cognitively Unimpaired(CU) = 3,820) to identify novel resilience genes using the OTTERS TWAS pipeline.

Method

We modified the OTTERS approach (Dai et al. 2023) to only include genes with concordant effect size directions across the five TWAS methods it implements. We used the 1000 Genomes high‐coverage dataset as a LD reference, and characterized genes as novel by excluding regions that overlapped a 1MB window around the previously identified GWAS hits from the GWAS catalog. We also validated our hits using one‐tailed T‐tests applied to RNA‐seq expression data from an independent NHW whole‐blood dataset (MAGENTA: AD = 119; Controls = 117) and a partially independent brain RNA microarray dataset called KRONOSII that was curated for high AD pathology and low secondary pathology (AD = 168; Controls = 177).

Result

Within blood, we identified and validated one gene (LCLAT1, p = 1.97e‐10) where the expression was positively associated with cognitive resilience in a CU subset and we confirmed AD cases had significantly lower expression relative to controls. Within brain, we identified and validated two genes that were negatively associated with all resilience phenotypes (SNX7, p = 8.05e‐08) or resilience using CU subsets (FAM117B, p = 2.34e‐13) and we validated AD cases had significantly higher expression relative to controls. Notably, SNX7 is a member of the sorting nexin protein family which have been implicated in APP trafficking and degradation.

Conclusion

By combining multiple large scale eQTL summary statistics with resiliency GWAS results, we have identified multiple new gene associations to cognitive and global resilience to AD.
FKBP51: A Promising Therapeutic Target for Tauopathies
Authors: Gebru Niat T , Guergues Jennifer , Stevens Stanley M. , Gulick Danielle , Blair Laura J.
Published: January 2025

Background

Tau accumulation, a hallmark of Alzheimer’s disease, fuels cognitive decline and neuronal death. Our team identified FKBP51, a stabilizer of neurotoxic tau oligomers. Notably, FKBP51 levels increase with age and further in AD brains, where it is found associated with pathological tau. FKBP51 has also been linked to vulnerability in excitatory neurons in the AD brain and poorer cognitive stability. In mice, the absence of FKBP51 has been shown to be protective from stress‐induced deficits. Recognizing this critical role, we are now developing methods to lower FKBP51 and understand the detailed molecular effects of its removal.

Method

We designed and synthesized locked‐nucleic acid (LNA) GapmeR ASOs targeting conserved regions in FKBP5, the gene that encodes FKBP51. The ASOs were tested in cultured cells and the brains of wild‐type mice. We also performed proteomic profiling of aged FKBP51 KO mice compared to young and aged wild‐type controls using a trapped ion mobility spectrometry (TIMS)‐QTOF instrument (timsTOF Pro, Bruker).

Result

LNA GapmeR ASOs significantly lowered FKBP51 levels using less than10 nM doses with no signs of toxicity. In vivo, greater than 25% reductions of FKBP51 were found in the initial studies. Proteomic profiling revealed preservation of specific proteins and pathways in a young‐like state in mice lacking FKBP51.

Conclusion

ASOs targeting FKBP51 show promise as a potential therapeutic avenue for reducing tau. The silencing of FKBP51 long‐term may directly reduce tau phosphorylation and aggregation, and indirectly protect neurons from tau‐mediated damage. Further optimization in vivo will commence shortly, followed by assessments in tau transgenic mice.
Identification of genetically driven Therapeutic Targets for Alzheimer’s disease
Authors: Goate Alison M. , Marcora Edoardo , Cruchaga Carlos
Published: January 2025

Therapeutics against targets supported by human genetics are more than twice as likely to make it to the clinic as an FDA approved drug. In 2012 the National Institute on Aging in response to the U.S. congressional initiative established the Alzheimer’s Disease Sequencing Project (ADSP), a large‐scale genetics effort to further our fundamental understanding of Alzheimer disease and related disorders (ADRD) with the goal to accelerate the development of effective treatments for ADRD. The ADSP has used genome‐wide association studies (GWAS) of SNP array data and whole genome sequencing to identify more than one hundred loci associated with Alzheimer’s disease (AD) risk. Post GWAS analyses has identified candidate causal genes for a good proportion of these loci. We integrated human genetics and functional genomics to identify the cell types, genes and pathways that may modulate AD risk. Induced pluripotent stem cells and multi‐OMICs were used to validate the impact of risk alleles and genes on AD relevant phenotypes in vitro and in vivo. Functional genomics has implicated myeloid cells including microglia and other macrophages in AD risk. Pathway‐based analyses demonstrate that efferocytosis is a disease risk hub and that TREM2 signaling is implicated by multiple risk genes. Immunotherapies targeting TREM2, MS4A4A, MS4A6A are under development. Progress toward developing therapies to these and other targets will be reviewed. Immunotherapies, gene‐based and small molecule approaches are being developed to target TREM2 signaling, APOE biology and other aspects of macrophage/microglial function such as efferocytosis.
Exploring the Impact of Race, African Ancestry, and APOE4 on Sex Differences in Amyloid Pathology and Cognitive Outcomes in an Admixed Population‐Based Neuropathological Sample
Authors: Raya Maison Abu , Paes Vitor Ribeiro , Leite Renata Elaine Paraizo , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Nitrini Ricardo , Suemoto Claudia Kimie , Grinberg Lea T.
Published: January 2025

Background

Prior research investigating sex and racial differences in amyloid pathology burden has yielded inconsistent findings. We examined the impact of sex and other confounding factors on neuritic plaque burden and cognitive outcomes.

Method

This study included 1,857 individuals, with post‐mortem brain tissues, from the Biobank for Aging Studies of the University of São Paulo Medical School, collected from 2004‐2023. In a subset of subjects, global ancestry was analyzed dichotomously, using a 2% cutoff for African Ancestry (AFR), first quartile of the AFR distribution. We employed multinomial logistic regression and general linear models to explore the associations of sex, reported race (White versus Black and Brown groups combined), AFR, and APOE4 genotype on CERAD scores and cognitive outcomes measured by Clinical Dementia Rating Scale Sum of Boxes(CDR‐SOB) while adjusting for age at death and education.

Result

Women (48% of the sample) were older than men (76.8±12.3 yo versus 71.4±12.3 yo, p<0.001). Men had higher educational attainment with a mean(SD) of 5.5(4.2) years and 3.9(3.9) years in women, (p<0.001). Dementia prevalence was higher in women (31% vs.18.5%, p<0.001). The sample was predominantly white (64.7%), followed by black (23.1%), and Asian (2.2%). 76.7% of men and 76.5% of women had AFR+ (p = 0.96). Women had higher odds of ‘Frequent’ CERAD scores with OR(95%CI) = 2.3(1.42‐3.72), p<0.001) Table 1 (Frequent‐Sparse or None) model 2. Black race was associated with lower odds of ‘Moderate’ CERAD scores compared to whites. A significant three‐way interaction among sex, APOE4, and race showed that Black men without APOE4 had lower odds of ‘Moderate’ and ‘Frequent’ CERAD scores (Table 1). Similar trends were found with Sex*APOE4*AFR. Testing the association of CERAD scores with cognitive outcomes, higher CERAD scores were associated with lower CDR‐SOB (P<0.001), and sex moderated this effect showing that women with ‘Moderate’ CERAD scores had worse cognitive outcomes than men (Figure 1). Notably, black race (Figure 2), but not AFR (Figure 3), modified the interaction between sex and CERAD on cognitive outcomes.

Conclusion

Women exhibited increased susceptibility to amyloid pathology, resulting in more pronounced cognitive impairment, suggesting that sex‐specific genetic, biological, and sociocultural factors may play a role in women’s higher AD vulnerability.
Storyteller: Normative data for the brief, remote, unsupervised automated speech‐based AD/MCI clinical trial screening measure
Authors: Skirrow Caroline , Meepegama Udeepa , Ropacki Michael T. , Weston Jack , Fristed Emil
Published: January 2025

Background

Storyteller, a brief self‐administered test that uses speech analysis to measure cognitive functioning, has demonstrated ability to predict Mild Cognitive Impairment (MCI) and mild Alzheimer’s disease (AD). The test is being implemented globally in Sponsor clinical trials, ADNI, and Sites for pre‐screening and will be used across heterogeneous populations. Normative data for Storyteller exists and is important for contextualising test performance, but has not been previously published.

Method

US residents aged 50+ were recruited into the AMYWEB study (NCT05298501). Participants completed a remote assessment via web application on their own personal devices, including screening and demographic questionnaires, the Patient Health Questionnaire‐8 (PHQ8), and Storyteller. Participants’ spoken responses were recorded, automatically transcribed and analysed to obtain a measure of proportional recall, “G‐match”, that leveraged two immediate and one delayed story recall conditions. Linear regression examined the influence of age, education, and sex on G‐match. Z‐scores were calculated to determine normative task performance ranges.

Result

679 participants (381 females, 298 males; age range 50‐84, mean 59.52) were recruited after excluding individuals with incomplete submissions, history of mild cognitive impairment (MCI), dementia or stroke and PHQ‐8≥10. The sample was demographically diverse, with residents across 49 US states and representation from minoritized groups (n = 115 overall: Black or African American n = 66; Hispanic or Latino/a n = 28; Asian n = 22; Native American or Alaska Native n = 18; Pacific Islander n = 4)). Assessments were completed across a range of common devices and browsers. Z‐scores identified score bands across different performance ranges (Fig 1). Regression analyses showed no significant age‐related change (β = ‐0.07, p = 0.21), but revealed higher scores for more educated participants (β = 0.80, p<0.001) and lower scores in males (β = ‐3.00, p<0.001).

Conclusion

Storyteller’s remote, unsupervised completion across a diverse U.S. sample generated valuable normative data, allowing contextualization of how impaired recruited samples are within AD/MCI clinical trials and in the broader population. Although G‐match showed no meaningful decline with age, the current findings replicate research showing a protective effect of education on cognitive function, and modestly better performance by women for story recall tasks.
Indian‐enriched genetic variants are associated with cognitive function
Authors: Abu‐Amara Hasan , Zhao Wei , Li Zheng , Leung Yuk Yee , Schellenberg Gerard D. , Wang Li‐San , Moorjani Priya , Dey A.B , Dey Sharmistha , Zhou Xiang , Gross Alden L. , Lee Jinkook , Kardia Sharon L R , Smith Jennifer A
Published: January 2025

Background

The prevalence of dementia in India is approximately 7.4% among those aged 60 years and older, yet little is known about genetic risk factors for dementia in this population. Examining genetic variants at higher frequency in India than other ancestries (i.e., Indian enriched variants) presents an opportunity to detect genetic effects which might be unique to the Indian population and/or underpowered for detection in other ancestral groups. We examined associations between Indian‐enriched variants and cognitive outcomes in 2680 older adults from the Longitudinal Aging Study in India ‐ Diagnostic Assessment of Dementia (LASI‐DAD) to identify potentially novel variants that may influence cognitive aging and dementia.

Method

Using whole‐genome sequence (WGS) data, we identified 4.8M Indian‐enriched variants, including 4.2M rare variants (0.2%<MAFLASI‐DAD < 5%, and MAFLASI‐DAD/MAFEA>5; and 600K common variants (MAFLASI‐DAD≥5%, and MAFLASI‐DAD /MAFEA>3). We conducted single‐variant association tests for all Indian‐enriched variants with the Hindi Mental State Exam (HMSE) score, a general cognitive function score, and five cognitive domain scores. Given the potential for heterogeneity between sexes, we also added variant‐by‐sex interaction terms to test the joint effects of variants and variant‐by‐sex interactions. In all analyses, we controlled for age, sex, state, education, literacy, rural/urban status, the first 10 genetic principal components, and genetic relatedness.

Result

At 5% false discovery rate, 11 variants were associated with one or more cognitive outcomes, including rs118075114, an intronic variant of CA12 that is in a known risk locus for Alzheimer’s disease in European ancestry. Joint models identified an additional 17 variants with a sex‐specific association with HMSE score (11 in females and 6 in males). Although the identified variants are rarely reported in the literature, partly because they are almost absent in European populations and elsewhere, several of the loci have been associated with neuropsychiatric traits and dementia risk factors such as diabetes, blood pressure, and coronary artery disease.

Conclusion

These results demonstrate the potential of LASI‐DAD WGS to identify Indian‐enriched variants that are associated with cognition at older ages. Future studies are warranted to replicate and understand the functional relevance of the identified variants.
Differential relations between depressive symptoms and everyday function in older adults using multiple modes of functional assessment
Authors: Halberstadter Kimberly , Kaplan Marina , Mckniff Moira , Holmqvist Sophia L. , Tassoni Molly B. , Simone Stephanie M. , Giovannetti Tania
Published: January 2025

Background

The impact of depressive symptoms on everyday function in older adults remains poorly understood. Depression may decrease motivation, impair cognition, and/or bias self‐reports of functional ability. The present study examined relations between depressive symptoms and everyday function as measured by self‐report, informant‐report, and an objective performance‐based measure which evaluates functional/cognitive capacity but requires only minimal motivation.

Method

88 community dwelling older adults with normal cognition or mild cognitive impairment completed the Geriatric Depression Scale (GDS‐15), tests of cognitive abilities, and the performance‐based Naturalistic Action Test (NAT), which requires preparation of a breakfast and lunch using real objects presented on a table. Video recordings of the NAT were scored for completion time and errors. Participants and their study partners also completed the Instrumental Activities of Daily Living – Compensation (IADL‐C) Questionnaire, which evaluates the ability to perform a range of everyday tasks in daily life. A Spearman correlation matrix was used to assess associations among measures.

Result

GDS‐15 scores were significantly associated with both questionnaires (participant IADL‐C: r = .369, p < .001; informant IADL‐C: r = .265, p = .022) but did not correlate with NAT scores. Global cognitive composite scores were negatively correlated with self‐reported IADL‐C scores (r = ‐.320, p = .003) and NAT scores (completion time: r = ‐.376, p < .001; errors: r = ‐.349, p < .001), but did not correlate with informant‐reported IADL‐C scores. Ancillary analyses showed the two questionnaire measures were significantly correlated (self‐report x informant‐report IADL‐C, r = .362, p = .002) but did not correlate significantly with NAT scores, and the GDS‐15 did not correlate with the cognitive composite.

Conclusion

Among community dwelling older adults, depressive symptoms were associated with participant‐reported and informant‐reported everyday function, but not with performance‐based tasks or cognitive abilities. The pattern of correlates suggests that depressive symptoms may affect function in everyday contexts by decreasing motivation to engage in daily activities without altering cognitive capacity to perform everyday tasks. Future research should investigate relations among specific depressive symptoms, such as apathy, and multiple measures of everyday function.
Role of TDP‐43 in dysregulation of cholesterol metabolism and implications for AD
Authors: Kabra Khushbu , Bradshaw Elizabeth M
Published: January 2025

Background

Lipid dysregulation is a known feature of Alzheimer’s Disease. Importantly, alterations in lipids pathways affect immune responses in cells like microglia, which have been shown to accumulate cholesterol in both aging and neurodegeneration. Recently, the presence of TDP‐43 inclusions has been linked to increased severity of cognitive impairment in AD patients. While TDP‐43 inclusions are associated primarily with ALS, their presence has been observed in around 57% AD patients. The link between TDP‐43, cholesterol dyshomeostasis and defects in immune responses in the context of AD is yet to be uncovered.

Method

Microglia: Peripheral blood mononuclear cells (PBMCs) are isolated and microbead separation is used to further purify monocytes. These monocytes are cultured with a cytokine cocktail for 10‐14 days to induce differentiation into MDMi (monocyte derived microglia). N = 17 Knockdown screen: Lentivirus mediated shRNA knockdown is used to reduce expression of various genes implicated in AD and ALS, including TREM2, CD33 and TARDBP in MDMi. Functional assays: Cholesterol uptake is measured by using a fluorescence microplate reader and lipid droplets are stained using LipidTox. Gene expression is measured using Fluidigm.

Result

TARDBP knockdown resulted in the most significant downregulation of several cholesterol metabolism associated genes, including ABCG1, NPC1, CYP27A1, LXR and SREBP1/2, which are involved in cholesterol uptake, storage and synthesis. The TARDBP knockdown MDMi also had reduced cholesterol uptake and lowered response to LPS stimulation, compared to other gene knockdowns.

Conclusion

TARDBP plays an important role in the regulation of cholesterol metabolism, specifically cholesterol uptake. The presence of TDP‐43 inclusions in AD may thus contribute to AD pathology through loss of function of TARDBP, causing defects in cholesterol homeostasis which lead to altered microglia function. This also has implications in better understanding Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), a recently characterized type of dementia associated with TDP‐43 proteinopathy.