bluuebunny/crossref_metadata_2025 huggingface dataset:
Autologous macrophages stimulated by epoxides of polyunsaturated fatty acids and protected by inhibitors of soluble epoxide hydrolase or cGAS/STING pathway repair amyloid‐β pathology in the Alzheimer’s disease (AD) brain
Authors: Fiala Milan , Whitelegge Julian , Hammock Bruce D. , Kesari Santosh
Published: January 2025

Background

Brain accumulation of amyloid‐ß1‐42 (Aß) in plaques and neurons is the cause of AD neuropathology that is opposed by autologous monocyte/macrophages (MMs) in health but this defense fails in AD.

Method

RNAseq, immunochemistry of the brain, immunofluorescence, and confocal microscopy of macrophages.

Result

In the AD brain, MMs shuttle Aß from parenchyma to vessels, which develop vasculitis, causing amyloid‐related imaging abnormalities (ARIAs). AD patients’ MMs are inflammatory and lack enzymes in energy, and chaperones for unfolded protein response (UPR) and Aß degradation. Epoxides of polyunsaturated fatty acids (EpFAs), in combination with the inhibitors of soluble epoxide hydrolase (sEH) TPPU or EC5026 or the cGAS/STING pathway, regulate in macrophages in a homeostatic fashion Aβ‐degrading enzymes, inflammatory cytokines, and unfolded protein response (UPR) transcripts, and recover a pro‐resolution macrophage phenotype. The repaired macrophages display increased phagocytosis of FITC‐ Aß at 2 hours and increased degradation of Aβ at 24 hours. Others showed in a mouse model that restoration of cellular bioenergetics through inhibition of the prostaglandin E2 (PGE2) receptor 4 (EP4R) signaling restored cognition.

Conclusion

Inhibiting macrophage inflammation by the sEH receptor inhibitors TPPU and EC5026 or the STING inhibitor H‐151 in AD macrophages could restore cognition in AD patients.
Single‐nucleus multi‐ome profiling of epigenomic modifications and transcriptome characterization of heterogeneity in early and late‐stage Alzheimer’s disease
Authors: Shi Zechuan , Das Sudeshna , Morabito Samuel , Emerson Nora , Rahimzadeh Negin , Kwang Nellie , Head Elizabeth , Swarup Vivek
Published: January 2025

Background

Alzheimer’s disease (AD), characterized by tau lesions and amyloid plaques, has traditionally been investigated within the cortical domain. Recent neuroimaging studies have implicated micro‐ and macrostructural abnormalities in cortical layers during the progression of AD. While examinations from diverse brain regions have contributed to comprehending the regional severity, these approaches have constrained the ability to delineate cortical alterations in AD. Our study employed a single‐cell resolution approach to characterize transcriptomic and epigenomic alternations in the human brain affected by the disease.

Method

We conducted a comprehensive analysis utilizing snRNA‐Seq and single‐nucleus epigenomic profiling on samples obtained from more than 2 million cells over 100 individuals with early and late‐stage AD cases, along with controls. Four samples were procured from each participant, derived from the human pre‐frontal cortex (PFC) and temporal cortex (TCX). Our analysis utilized multi‐ome profiling, which simultaneously profiles gene expression and epigenomic changes. Data processing utilized Scanpy and Signac for gene expression and histone processing. Cicero identified cis‐regulatory elements (cCREs), overlaid with GWAS variants, creating a genome‐wide map. Transcription factor (TF) footprinting was done for cell types and disease‐associated subclusters.

Result

UMAP and Leiden clustering on batch‐corrected data identified discrete cell‐type clusters from snRNA‐Seq and additional multi‐ome profiling. Enhancer‐promoter links were identified, constructing disease‐enriched, region‐specific, and shared TF regulatory networks in AD. Pseudotime trajectory analysis revealed changes from early to late‐stage AD.

Conclusion

The single nucleus multi‐ome data produced in this study represents a valuable asset for the AD research community. Compared to bulk ATAC‐seq, our single‐nucleus epigenomic data provides precise insights into active and repressive activities. The study illuminates crucial TFs and their roles in AD, offering insights into cell‐specific and region‐specific mechanisms in AD pathology. Experimental validation underscores the functional relevance of the targeted TF in AD, highlighting its potential medical significance.
Prevalence of people living with dementia with cyclic temporal pattern of behavioral and psychological symptoms of dementia in a tertiary memory clinic: A descriptive diary‐based study
Authors: Rak‐Areekul Tara , Likijaroen Yuttachai , Hiransuthikul Akarin , Booncharoen Kittithatch , Sarutikriangkri Yuthachai
Published: January 2025

Background

Behavioral and psychological symptoms of dementia (BPSD) profoundly impact individuals with dementia and their caregivers. Despite existing pharmacological interventions, symptom control remains challenging, often prompting polypharmacy with potential risks. Notably, in clinical practice, caregivers frequently report recurring patterns in patients' BPSD but lack empirical studies supporting these observations. The primary objective of our research is to explore the prevalence of predictable, cyclic BPSD patterns to enhance symptom control and minimize risks associated with excessive medication use.

Method

Implementing a diary‐based approach, we recruited 24 dementia patients attending a memory clinic. Participants documented patients’ BPSD occurrences using hourly recordings across a 28‐day period. We categorized and quantified BPSD subcategories based on the Neuropsychiatric Inventory Questionnaire (NPI‐Q) framework. Cyclic patterns were defined by the recurrence of BPSD in at least 3 episodes, showing consistent intervals within a permissible range exceeding 50% of all episodes. This range allowed a deviation of up to 50% from the median interval.

Result

Strikingly, 83% (n = 20) of participants exhibited cyclic BPSD patterns. Among the various BPSD subcategories, anxiety, apathy, nighttime behavioral disturbances, and appetite/eating abnormalities emerged as the most prominent features within these predictable fluctuations. Median intervals varied among subcategories, with irritability exhibiting the longest duration (3.5 days) and anxiety, delusion, and nighttime disturbances displaying the shortest (1.0 day), supporting the biopsychosocial model of BPSD pathogenesis.

Conclusion

Cyclic BPSD patterns are surprisingly common, suggesting potential for personalized medication schedules based on predicted symptom peaks. Further research with larger populations is needed to validate these findings and develop tailored interventions for improved dementia care.
Remote and unsupervised digital memory assessments can reliably detect cognitive impairment in Alzheimer’s disease
Authors: Berron David , Olsson Emil , Andersson Felix , Janelidze Shorena , Tideman Pontus , Düzel Emrah , Palmqvist Sebastian , Stomrud Erik , Hansson Oskar
Published: January 2025

Background

Remote unsupervised cognitive assessments have the potential to complement and facilitate cognitive assessment in clinical and research settings.

Method

Here we evaluate the usability, validity and reliability of unsupervised remote memory assessments via mobile devices (see Figure 1) in individuals without dementia from the Swedish BioFINDER‐2 study and explore their prognostic utility regarding future cognitive decline in combination with a plasma marker for p‐tau217.

Result

Usability was rated positively. The app was easy to use with clear instructions, a majority of participants enjoyed completing the tests and preferred digital assessments over pen‐and‐paper tests, and more than 80% of participants found the frequency and length of remote assessments were appropriate. Remote memory assessments showed good construct validity with traditional neuropsychological assessments (see Figure 2) and were significantly associated with medial temporal lobe subregional tau‐PET and downstream MRI measures (see Figure 3). Memory performance at baseline was associated with future cognitive decline and prediction of future cognitive decline was further improved by combining remote digital memory assessments with plasma p‐tau217. Finally, retest reliability was moderate for a single assessment and good for an aggregate of two sessions.

Conclusion

Our results demonstrate that unsupervised digital memory assessments might be used for diagnosis and prognosis in Alzheimer’s disease, potentially in combination with plasma biomarkers.
Early presentations of dementia across cultures: Analysis of primary care data from a diverse population
Authors: Zabihi Sedigheh , Bestwick Jonathan P , Bothongo Phazha LK , Zhang Qiqi , Carter Christine , Roche Moïse , Morgan‐Trimmer Sarah , Birks Yvonne , Wilberforce Mark , Dobson Ruth , Noyce Alastair J , Robson John , Walter Fiona M , Cooper Claudia , Marshall Charles R
Published: January 2025

Background

Dementia is associated with a range of non‐cognitive features that can occur during the prodromal phase. Improved recognition of non‐cognitive presentations of dementia could reduce inequalities in dementia diagnosis, particularly if sociocultural factors influence rates of help‐seeking for cognitive symptoms. We aimed to investigate presentations to primary care in the years before dementia diagnosis in a deprived and ethnically diverse population with universal access to health care.

Method

We conducted a nested case‐control study using electronic health care records on 1,016,277 individuals from primary care practices in East London, UK between 1990 and 2018. Individuals with a diagnosis of dementia were compared to controls without dementia. We ran a matched analysis (four controls matched to each person with dementia according to age and sex) using multivariable logistic regression to assess the associations between pre‐diagnostic presentations to primary care with subsequent diagnosis of dementia. We analysed three time periods (<2, 2‐5, 5‐10) before diagnosis.

Result

We included 4,137 individuals and 15,754 controls in the matched analysis (51.8% White; 42.7% Black, South Asian and other ethnicities). Neuropsychiatric presentations including depression (odds ratio [OR] = 2.71; 95% CI: 2.33 to 3.16), anxiety (OR = 1.67; 95% CI: 1.46 to 1.92), initiation of antipsychotic medication (as a proxy for psychotic symptoms) (OR = 5.84; 95% CI: 4.80 to 7.11) and insomnia (OR = 1.69; 95% CI: 1.31 to 2.17) were more frequent in the years before dementia diagnosis. Associations were found for autonomic features including constipation (OR = 1.54; 95% CI: 1.39 to 1.71) and incontinence (OR = 2.63; 95% CI: 2.32 to 2.97) up to a decade, and hypotension (OR = 1.89; 95% CI: 1.35 to 2.63) up to five years before dementia diagnosis. Sensory features including hearing loss (OR = 1.36; 95% CI: 1.14 to 1.63), imbalance and dizziness were also associated with subsequent dementia diagnosis. Memory difficulty was more strongly associated with subsequent dementia diagnosis than any non‐cognitive presentation (OR = 51.00; 95% CI: 43.87 to 59.29).

Conclusion

A range of non‐cognitive presentations are seen during the prodromal period of dementia in a diverse population. Improved recognition of these associations could increase access to dementia diagnosis, through improved recognition of potential presenting symptoms in people from different backgrounds.
Exploring the Immediate Impact of APOE ε4ε4 Genotype Disclosure among Latinos
Authors: Caro Daniela Diaz , Rodriguez Sophia , Wetmore John Brandon , Godinez Jonathan D , Camarillo Itzel A , Goldman Jill , Uhlmann Wendy R. , McCain Sarah , Caban Maria , Leu Cheng‐Shiun , Abraido‐Lanza Ana F , Lantigua Rafael A. , Chung Wendy K , Roberts J. Scott , Siegel Karolynn , Ottman Ruth
Published: January 2025

Background

Alzheimer’s disease (AD) risk is markedly increased among APOE ε4/ε4 homozygotes. Previous studies of APOE genotype disclosure impact have included few ethnic minorities. This study addresses this gap by investigating the immediate impact of disclosing an APOE ε4/ε4 genotype in the Información de la Enfermedad de Alzheimer para Latinos (IDEAL) study, a Latino community‐based study.

Methods

IDEAL participants attended semi‐structured genetic counseling sessions conducted via Zoom in Spanish or English by certified genetic counselors. Sessions included a PowerPoint presentation covering genetics, genotype results, risk estimates, and AD prevention methods. Risk estimates were based on data from the Washington Heights‐Inwood Columbia Aging Project, a longitudinal study conducted in the same communities. The estimate of risk to age 85 among ε4 homozygotes was 55%. We transcribed session recordings and conducted content analysis.

Results

Eleven ε4/ε4 participants aged 41‐64 attended risk evaluation sessions (English 8, Spanish 3). Six had a family history of AD (first‐degree 1, distant 5). Nine were women and two men. Overall, participants did not show strong emotional reactions. Many expressed surprise, accompanied by thoughtful reflections on the connection between their AD risk and perceived memory problems or emotional well‐being. Participants generally appreciated the information provided during the genetic counseling sessions because it offered insights into the importance of AD risk awareness and prevention strategies.

Conclusion

Latinos at high AD genetic risk showed limited immediate emotional response to risk disclosure and appreciated the information that was shared. Longitudinal analyses may provide further insight into the impacts of this disclosure.

This study is supported by the National Institute on Aging (R01 AG062528) and registered in ClinicalTrials.gov (NCT04471779).

Keywords: Alzheimer's disease, APOE ε4ε4, genetic counseling, Latinos, qualitative research, risk disclosure
Harmonised neuropsychological assessment for Vascular Cognitive Disorders: a Delphi consensus study
Authors: Bentvelzen Adam C. , Kochan Nicole A. , Sachdev Perminder S. ,   VasCog‐2 Neuropsychological Consortium
Published: January 2025

Background

Harmonization of neuropsychological assessment for vascular cognitive disorders (VCD) is important for ensuring the highest standards for diagnostic and post‐diagnostic care. A battery jointly proposed by the NINDS‐CSN has received much support. Considering significant developments in the field, and an urgent need for consensus on remote and computerised assessment methods, an international expert group was commissioned to develop an updated harmonized battery and associated assessment guidelines for VCD using the Delphi process.

Methods

A modified Delphi consensus method was used, involving an iterative, multi‐staged series of structured surveys with feedback of anonymized responses from experts in the neuropsychological assessment of vascular cognitive disorders. Three rounds were planned, with the possibility of a fourth round, if required to reach consensus. Literature reviews on harmonized neuropsychological assessment were conducted by a team of researchers, which informed the first structured questionnaire. Consensus was sought on the cognitive domains and subdomains that should be assessed, on specific tests per domain, and for additional guidelines including on non‐traditional assessment methods and cultural‐linguistic considerations. Consensus was defined as agreement or disagreement on any statement of ≥ 75%, near consensus as 66 – 75%, and <66% as non‐consensus. Statements that reached consensus were removed from subsequent rounds, as were most that had non‐consensus, with some being reworded. A virtual meeting was held for experts to discuss contentious issues and advise on the process.

Result

Forty‐four experts in neuropsychological assessment from a range of international regions consented to participate, and 31 completed the Round 1 survey. The final survey is being completed, then the assessment battery and additional guidelines will be finalized to be approved formally by all participants.

Conclusion

The harmonized neuropsychological assessment standards could be adopted internationally and complement the NINDS‐CSN battery, thereby further facilitating consistent neuropsychological assessment of VCD between clinicians and researchers.
Spermidine Treatment Attenuates Systemic and Gut Oxidative Stress, Neuropathology and Cognitive Deficits in D‐galactose Induced Aging Rats
Authors: Saiyasit Napatsorn , Pratchayasakul Wasana , Kangwan Napapan , Kaorop Wichida , Maneechote Chayadom , Kunasol Chanon , Ngowthammatas Nattapat , Arunsak Busarin , Donchada Suriphan , Kongkaew Aphisek , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: January 2025

Background

Our previous studies reported that D‐galactose (D‐gal) administration for four to eight weeks caused metabolic disturbance, brain mitochondrial dysfunction, and brain aging, leading to cognitive dysfunction in similar with natural aging condition. Spermidine is a polyamine that can be found naturally. Spermidine has been showed the beneficial effects on various models, such as attenuating metabolic/gut impairments in obesity, and ameliorating memory loss in aged model. However, those beneficial effects of spermidine in D‐galactose‐induced aging condition is still unclear.

Method

Eighteen female Wistar rats were divided into two groups which received either NSS as a control group (n = 6) or D‐gal (150 mg/kg/day, n = 12), subcutaneously for total twenty weeks. At week 12, D‐gal‐treated rats were divided into two subgroups; NSS as a vehicle and spermidine (20 mg/kg/day), orally for 8 weeks (n = 6 per subgroup). At the end of protocol, the cognitive tests; novel object location (NOL) and novel object recognition (NOR) were performed. After animals were euthanized, brain/gut tissues and blood samplings were collected to determine the biochemical parameters.

Result

Systemic/gut oxidative stress by increasing the serum malondialdehyde (MDA) level and attenuating colon SOD2 protein expression respectively were shown in D‐gal‐treated rats (Figure 1A‐B). Levels of colon ZO‐1 mRNA was decreased in D‐gal‐treated rats, in comparison to control group (Figure 1C). Upregulation of hippocampal senescence‐associated b‐galactosidase (SA‐b‐gal), elevation of brain mitochondrial ROS level, and cognitive impairment by reducing the percentage of preference index of NOL and NOR were also observed in D‐gal‐treated rats (Figure 1D‐E, G‐H). Interestingly, spermidine treatment in D‐gal‐treated rats alleviated serum MDA and upregulated colon SOD2 protein levels, compared to D‐gal‐treated rats with vehicle (Figure 1A‐B). Spermidine also reduced hippocampal SA‐b‐gal protein expression, decreased brain mitochondrial ROS level and swelling (Figure 1D‐F), and attenuated the learning and memory impairment by restoring the percentage of preference index of NOL and NOR in D‐gal‐treated rats (Figure 1G‐H).

Conclusion

Our findings suggest that spermidine exerts the beneficial effects on cognition through reducing systemic/brain oxidative stress in D‐galactose‐induced aging rats. Therefore, it is possible that spermidine should be considered as a novel therapeutic option for ameliorating neuropathology in aging condition.
Mitochondria Localized MicroRNAs and Alzheimer’s disease
Authors: kumar Subodh
Published: January 2025

Background

Mitochondria plays a crucial role at synapses in providing synaptic energy, healthy synaptic function, and cognitive functions. Amyloid‐beta and phosphorylated tau protein oligomers cause severe mitochondrial defects in Alzheimer’s disease (AD), which leads to the lack of synaptic energy and impaired synapse functions in AD. MicroRNAs (miRNAs) present within the mitochondria are involved in multiple mitochondrial activities and mitochondrial function. Mitochondrial dysfunction is well established in AD; but status of mitochondria localized miRNAs are unknown in AD. This current study is focused on the identification of mitochondria localized miRNAs in AD and to unveil their possible roles in disease pathogenesis.

Method

Mitochondria and cytosolic fraction were extracted from postmortem AD brains (n = 5) and cognitively normal postmortem brains (n = 5). Mitochondria purity was characterized by transmission electron microscopy (TEM) and immunoblot analysis of mitochondrial marker proteins. Mitochondria activity was determined by mitochondrial function assay. Further, total RNA was extracted from mitochondria and cytosolic fraction and subjected to miRNAs HiSeq analysis. The significantly deregulated mitochondrial miRNAs were further validated on large number of AD postmortem brain and subjected to in‐silico bioinformatic analysis.

Result

TEM analysis, immunoblotting and mitochondrial function assay confirmed the extraction of intact and active mitochondria from AD and control postmortem brains. MiRNAs HiSeq analysis showed the mitochondria localized distribution of some novel miRNAs in AD and control samples. We found some miRNAs localization and differential expression in mitochondrial fraction relative to cytosolic fraction. Our validation analysis unveiled previously unknown, most potential mitochondria localized miRNAs in AD. Further, in silico bioinformatic analysis revealed the critical roles of mitochondrial localized miRNAs in several mitochondrial function and synaptic pathways in AD.

Conclusion

Our study discovered some novel mitochondria localized miRNAs, which could be a potential therapeutic target to retrieve mitochondrial and synaptic dysfunction in AD.
Evaluating the Impact of Combined Clinical and Genetic Risk Factors on Dementia Onset
Authors: Andrews Shea J , Solsberg Caroline Warly , Renton Alan E. , Fulton‐Howard Brian , Yokoyama Jennifer S. , Yaffe Kristine
Published: January 2025

Background

Integrating clinical and genetic risk factors for dementia in a precision medicine framework can play a crucial role in primary prevention. Here, we ascertained the proportion of individuals who are at heightened risk of developing dementia based on their family history, genetic, and clinical risk factors and evaluated how the additive burden of these risk indicators is associated with incident dementia.

Method

We analyzed longitudinal data from 3,395 diverse older adults, dementia‐free at baseline with follow‐up and whole genome sequencing, enrolled in the National Alzheimer’s Co‐coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative (Table 1). Our risk indicators comprised: 1) self‐reported first‐degree relative with cognitive impairment; 2) carriage of the APOE*e4 allele; 3) an AD polygenic risk score, incorporating 24 variants and normalized for genetic ancestry, ranking in the top 2% (AD‐PRS); 4) presence of dominantly inherited AD mutations in PSEN1, PSEN2, or APP; and 5) a score of ≥6 on a modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Score (mCAIDE), comprised of age, sex, education, obesity, hypertension, and hypercholesterolemia. We calculated the total risk burden as the sum of these indicators. Cox proportional hazard models were employed to estimate the risk of dementia progression associated with increasing risk burden.

Results

Among participants, 55% had a family history of dementia, 36% were APOE*e4 carriers, 33% had high mCAIDE scores, 2.2% had extreme AD‐PRS, and none had ADAD mutations. Distribution of risk indicators was as follows: 20% had none, 41% one, 32% two, 7.5% three, and 0.2% four (Figure 1). Our analysis revealed a graded increase in dementia risk with more indicators: compared to those with none, individuals with one, two, three, or four indicators had 1.67, 3.14, 4.41, and 15.22 times increased dementia risk, respectively (Figure 2).

Conclusion

The majority of our cohort exhibited at least one dementia risk indicator, with a higher risk burden markedly increasing dementia risk. These findings underscore the value of integrating genetic and clinical risk factors in predicting dementia, highlighting the potential of precision medicine in guiding preventive strategies for at‐risk individuals.
Elucidating the role of mitochondrial Alzheimer’s Disease risk gene LACTB in myeloid cells
Authors: Molina Carmen Romero , See Wen Yi , Patel Tulsi , Liu Yiyuan , Marcora Edoardo , Goate Alison M.
Published: January 2025

Background

While compelling evidence highlights the importance of myeloid cells in the etiology of Alzheimer’s Disease (AD), the relevance of immunometabolism still requires further exploration. Our analysis integrating AD genetics and myeloid cell genomics shows that lower levels of LACTB expression in myeloid cells is protective against AD, a finding supported by proteomics studies. As a mitochondrial active‐site serine protein, LACTB has implications for mitochondrial morphology and bioenergetics. LACTB levels are also linked to succinyl‐carnitine levels, a metabolite predicted to be protective for AD risk. Furthermore, LACTB has been associated with tumorigenesis and obesity, suggesting a potential role in cell dynamics and lipid metabolism, although its function remains elusive.

Method

Human immortalized THP‐1 cells monocytes were differentiated into macrophages and treated with small‐interfering RNA to knock‐down LACTB (KD) expression. CRISPR‐edited human induced pluripotent stem cells (hiPSC) were generated to knock‐out (KO) LACTB and differentiated into microglia cells (iMGL). Metabolomic and lipidomic analyses were outsourced with collected samples, and functional assays evaluating how LACTB alters myeloid cell functions were performed.

Result

Our studies revealed an upregulation of LACTB expression upon differentiation (in iMGLs compared to iPSCs, and in THP‐1 macrophages compared to monocytes) and LPS stimulation. Downregulation of LACTB in THP‐1s and iMGLs resulted in elevated succinyl‐carnitine levels, and THP‐1 LACTB KD cells showed an increase in histone succinylation levels, which might indicate epigenetic modulation. We also detected a reduction in nascent protein synthesis levels in our LACTB KD and KO models. Additionally, lipidomics showed a decrease in acylglycerides, and an increase in cholesterol efflux was observed in THP‐1 LACTB KD cells.

Conclusion

LACTB potentially modulates myeloid cell function by modifying protein synthesis and lipid metabolism. Future directions include a novel xenotransplantation model involving the direct introduction of human microglia precursor cells into the mouse brain to study the effects of LACTB on microglia in‐vivo and in the context of disease using 5xFAD mice. The distinct identity of LACTB as an enzyme, coupled with its protective phenotype upon reduced expression and the potential of succinyl carnitine as a biomarker, makes it a promising therapeutic target in AD.
Midlife Sensory and Motor Measures Among Best Predictors in Parsimonious Models of Long‐Term Cognitive Decline and Onset of Cognitive Impairment in Middle‐Aged Adults
Authors: Merten Natascha , Pinto A Alex , Paulsen Adam J , Chappell Richard J , Chen Yanjun , Engelman Corinne D. , Hancock Laura M , Johnson Sterling C. , Schubert Carla R
Published: January 2025

Background

Over the past decades, many risk factors for dementia have been identified including sensory and motor functions. Established risk scores to predict onset of cognitive impairment and/or dementia (e.g., the CAIDE and Framingham Risk Score) often focused on cardiovascular risk factors and have not been updated in more recent generations. Risk scores for asymptomatic middle‐aged people, which are based on practical test batteries will be useful for targeted population screenings. The aim of this study was to construct a parsimonious risk prediction model of 10‐year cognitive decline and impairment using factors measured in midlife in a current cohort.

Method

This longitudinal study is based on N = 1529 (54% women, mean age 49 years) Beaver Dam Offspring Study participants with data from baseline, 5‐year and 10‐year follow‐up. We assessed objectively measured and self‐reported hearing, vision, olfactory, and motor function, lifestyle, cardiovascular and general health factors, and blood‐based markers of inflammation, neurodegeneration, and amyloid. We determined 10‐year cognitive decline (trail‐making test B time;10% most decline) and cognitive impairment (neurocognitive case review). We constructed least absolute shrinkage and selection operator (LASSO) logistic regression models with 10‐fold cross‐validation and evaluated predictive ability via receiver operating characteristic curves (AUCs). The effect selection percentage indicated the percentage of times specific predictors were selected in the n = 100 bootstrapped samples of models and was used to establish final models.

Results

There were N = 121 cognitive decline and N = 217 cognitive impairment cases. The six top predictors for cognitive decline (age, income, fine‐motor skill performance, olfactory function, peripheral artery disease, serum neurofilament light chain protein (NfL)) and for cognitive impairment (sex, fine‐motor skill performance, olfactory function, self‐rated vision, alcohol consumption, NfL) yielded models with an AUC of 0.80(95% confidence interval:[0.76‐0.83]) and 0.73[0.69‐0.77], respectively.

Conclusion

In middle‐aged adults, measures of sensory and motor function and NfL were among the best predictors of 10‐year onset of cognitive decline and impairment and only 6 factors were needed to achieve acceptable to excellent AUCs. Cross‐validation in another cohort is needed to verify these factors as reliable and valid predictors to identify those at high risk for neurodegeneration and cognitive decline who could benefit from early prevention and intervention strategies.
Discussion and Documentation of Hearing Difficulty by Providers in the Presence of Cognitive Concerns‐ study of the Medicare Annual Wellness Visit and Medial Record
Authors: Powell Danielle , Nothelle Stephanie , Smith Jamie , Oh Esther S , Reed Nicholas S , Wolff Jennifer
Published: January 2025

Background

How clinicians discuss, document, and diagnose health concerns within a visit shapes patient perceptions of their health conditions. Undiagnosed hearing loss among older adults with dementia or cognitive concerns may exacerbate neuropsychiatric symptoms and care challenges. This study investigates clinician documentation of hearing concerns and whether documentation, diagnosis, and referral vary for older adults with dementia/cognitive concerns.

Method

We use patient‐level health and demographic information from the electronic medical record and associated clinician visit notes for Medicare beneficiaries who indicated hearing concerns for the first time at an Annual Wellness Visit (AWV) between 2017‐2022 at a large academic health system. We analyzed the text of a random sample of AWV clinical notes to evaluate clinical documentation of hearing concerns/loss and placement of hearing‐related referrals. Logistic regression models investigate odds of clinician documentation of hearing concerns or diagnosis by diagnosed dementia (from ICD codes) or cognitive concerns (from AWV health risk assessment).

Result

Among 2,593 beneficiaries who reported hearing concerns at an AWV (mean age 78.8 years, 56.6% female), 6.5% had a concurrent dementia diagnosis, nearly 40% indicated congruent cognitive concerns, and 20% had a prior diagnosis of hearing loss in the medical record. Text analysis (Table 1) of clinician visit notes from a random sample of patients (n = 474) found hearing concerns were less frequently documented for those with (versus without) diagnosed dementia (44.2% vs 30.2%). Clinicians were half as likely to comment on hearing (OR:0.51; 95%CI:0.34,0.76) or indicate known hearing loss in the AWV note (OR:0.56; 95% CI:0.38,0.84) for those with vs. without dementia (Table 2). Regardless of dementia status, about 8‐10% were recommended/received a referral to hearing care; only 50% with index hearing concerns received a diagnosis of hearing loss in the medical record following the AWV.

Conclusion

Clinicians are less likely to document hearing concerns and incorporate hearing concerns as a health problem at the AWV for patients with dementia. The complex care needs of dementia may inhibit clinician ability to attend to other patient health concerns‐ like hearing. Opportunity to embed hearing and communication educational interventions which support clinicians in addressing patient‐collected health risks can improve overall dementia care.
Path integration deficits are related to Alzheimer’s disease pathology
Authors: Colmant Lise , Boyer Emilien , Gérard Thomas , Huyghe Lara , Quenon Lisa , Kunz Lukas , Axmacher Nikolai , Lefèvre Philippe , Hanseeuw Bernard J
Published: January 2025

Background

The medial temporal lobe (MTL) is the first cortical region affected by tauopathy in Alzheimer’s disease (AD) and is implicated in spatial orientation. In early AD stages, navigation deficits, including path integration deficits, could be present, even before memory deficits. We investigated whether these deficits were related to AD pathology (amyloidosis and/or tauopathy) using a path integration task, the “Apple Game”.

Method

During the task, participants navigated through a virtual arena and were asked to return to a starting location after visiting one intermediate location. Two subtasks were tested: with a proximal cue (landmark‐supported path integration, LPI), and without (pure path integration, PPI). We recruited 90 participants (mean age: 69): 66 clinically normal (CN) and 24 patients with mild cognitive impairment (MCI). We classified them according to amyloid status: Aβ+ (n = 34) or Aβ‐ (n = 56) based on amyloid‐PET or CSF measurements. All participants underwent [18F]MK‐6240 Tau‐PET to disclose tau pathology in the MTL (entorhinal cortex and hippocampus). Task performances were analyzed in relation to amyloid status and MTL tauopathy using linear‐mixed‐effect models. First, we evaluated the error according to amyloid status, neuropsychological status, subtask, and their interactions. Then, we evaluated the error and its components (rotation and distance errors) according to MTL tauopathy, and amyloid status for each subtask. Education, gender, and video game experiences were adjusted for.

Result

Preclinical AD individuals (CN, Aβ+) had a deficit in pure path integration (p = 0.02) compared to CN Aβ‐ individuals, but not in landmark‐supported path integration (Fig. 1). The amyloid status did not influence performances among MCI patients. Rotation errors depended on MTL tauopathy in PPI (p = 0.02) and LPI (p = 0.0004) (Fig. 2), whereas distance errors depended on age in PPI (p = 0.004), and on the age (p = 0.015) and MTL tauopathy (p = 0.02) in LPI.

Conclusion

We detected a specific deficit in pure path integration in a virtual environment, in preclinical AD, suggesting a deficit to integrate self‐motion cues. Furthermore, we decomposed the path integration performances into rotation and distance errors, and found that rotation errors were associated with MTL tauopathy, possibly reflecting impairment of grid cells; whereas distance errors mainly increased with older ages.
A framework for automated speech and language analysis in Spanish‐speaking Latinos
Authors: Garcia Adolfo M.
Published: January 2025

Background

Automated speech and language analysis (ASLA) represents a powerful innovation for detecting and monitoring persons with or at risk for dementia. Given its cost‐efficiency and automaticity, its impact can be vital for under‐resourced communities, such Spanish‐speaking Latinos. However, ASLA markers are understudied in this group and may differ from those established in widely studied populations (e.g., English speakers). Here I will describe a novel framework to boost ASLA research among Spanish‐speaking Latinos.

Method

We have created hypothesis‐driven metrics to capture semantic and episodic memory alterations via (semi‐) spontaneous speech in Latinos. Our initial work includes measures of word selection patterns during verbal fluency, speech timing proxies of word retrieval effort, and algorithms quantifying egocentric/exocentric references in discourse. These metrics have been incorporated into the TELL app, our web‐based speech testing platform. Initial analyses have been performed on 60 Latinos with Alzheimer’s disease (AD), 65 with mild cognitive impairment (MCI), and 50 with behavioral variant frontotemporal dementia (bvFTD), including tests of cross‐linguistic generalizability with English speakers.

Results

Compared with healthy controls, AD and MCI (but not bvFTD) patients exhibit atypical vocabulary patterns during verbal fluency tasks, favoring high frequency and conceptually unspecific words, separated by longer pauses. These alterations discriminate between persons with and without these disorders (AD: AUC = .89; MCI: AUC = 81), and they predict atrophy of and hypo‐connectivity among temporo‐parietal regions implicated in semantic memory. Cross‐linguistic generalizability between English and Spanish‐speaking AD patients was maximal (AUC = .79) when based on speech timing features (e.g., pause duration, articulation rate). Finally, bvFTD (but not AD) patients showed abnormally exocentric discourse, with increased reliance on third‐person references and reduced reliance on first‐person references when describing daily activities.

Conclusion

Our initial findings attest to the usefulness of hypothesis‐driven ASLA features to identify persons with AD, MCI, and bvFTD among the Latino population. The framework will now be leveraged in a large multicentric effort across the ReDLat consortium to establish the most robust markers in large, heterogeneous samples. This work will help us streamline ASLA research as an avenue for more equitable clinical testing of dementia in Latin America and beyond.
Genetic variation of tandem repeats as a cause of Alzheimer’s Disease
Authors: Trujillo Alejandro Martin , Jadhav Bharati , Garg Paras , Altman Gabrielle , Manigbas Celine , Shadrina Mariya , Sharp Andrew J
Published: January 2025

Background

Alzheimer’s Disease (AD) is a common neurodegenerative disorder affecting >35 million people worldwide. Despite extensive genetic studies, the identified factors only explain a small fraction of the heritable risk of AD. This suggests the contribution of yet‐unknown genetic factors to the development of AD, such as tandem repeats (TRs). TRs are stretches of DNA consisting of two or more contiguous copies of a sequence of nucleotides (motif) arranged in a head‐to‐tail pattern (e.g., CAG‐CAG‐CAG). Recent studies indicate that rare expansions of short tandem repeats (STRs, motif size 1‐10 bp) as well as common copy number variation of variable number tandem repeats (VNTRs, motif size >10 bp) can act as risk modifiers for AD. However, despite this evidence, there has been no comprehensive evaluation of TR variation in large cohorts of AD patients. Therefore, we hypothesize that variation in TR sequences can contribute to the development of AD in a fraction of cases.

Method

To uncover the link between TR variation and AD, we are performing a comprehensive profiling of TR variation using whole genome sequencing (WGS) data generated by the UK Biobank (https://www.ukbiobank.ac.uk/). This involves estimating copy numbers in ∼220,000 polymorphic loci, including 77,000 STRs and 150,000 VNTRs, across ∼349,000 genomes (∼9,000 cases and ∼340,000 unrelated controls) using novel bioinformatic approaches, followed by extensive quality control to ensure the reliability of our estimates. Subsequently, we will use the resulting high‐confident estimates to identify TR alleles that exhibit significantly different copy numbers in AD patients compared to controls.

Result

To date, we have successfully designed efficient pipelines for profiling both STRs and VNTRs using WGS on a large scale to be executed on the UK Biobank cloud‐based environment (https://ukbiobank.dnanexus.com). Using these pipelines, we have generated copy number estimates in approximately 200,000 UK Biobank samples, including ∼1,200 AD cases.

Conclusion

By leveraging the power of large cohorts and innovative methods, our study aims to explore the contribution of one of the most abundant and polymorphic, and yet understudied, genetic elements in the genome to AD, expanding our understanding of the genetic risk factors and mechanisms underlying this condition.
The inhibition of necroptosis prevents neuronal death in a mouse model of Alzheimer’s disease pathology
Authors: Moonen Sebastiaan , Koper Marta J , Ronisz Alicja , Ospitalieri Simona , Vegh Zsuzsanna , T’Syen Dries , Rabe Sabine , Staufenbiel Matthias , De Strooper Bart , Balusu Sriram , Thal Dietmar Rudolf
Published: January 2025

Background

As neurodegenerative diseases advance, postmitotic neurons are affected by disturbed proteostasis and the accumulation of misfolded proteins. This renders neurons sensitive to cell death, ultimately leading to progressive neuron loss. Multiple studies show the involvement of distinct pathways of regulated cell death (RCD) in neurodegenerative diseases, such as necroptosis. In human AD, activation of necroptosis has been shown to contribute to the neurodegenerative process. However, despite considerable research efforts, it is still not clear which mechanism exactly underlies neuronal loss in AD.

Methods

We studied necroptosis activation in mouse models of AD pathology and primary mouse neurons after the addition of pTau seeds. Immunohistochemistry was used to study neuronal loss and the presence of the activated necroptosis‐related proteins pRIPK1, pRIPK3 and pMLKL. TAU22 and TAU58 mice were used to assess the influence of Tau pathology, APP23 for amyloid pathology, and APP23xTAU58 for both Tau and amyloid pathology, representing more closely human AD neuropathological changes. APP23xTAU58 mice were subjected to intraperitoneal injection of the necroptosis‐inhibiting drugs dabrafenib or ponatinib from two to six months old, followed by neuropathological assessment and behavior testing using the social preference and social novelty test, T‐maze, and fear conditioning.

Result

Necroptosis activation was detected in mice developing Tau pathology and in primary mouse neurons stimulated with AD pTau seeds. APP23xTAU58 mice showed the highest necroptosis activation, while no significant upregulation was observed in APP23 mice. The necroptosis‐related proteins (pRIPK1, pRIPK3, pMLKL) were present in neuronal granulovacuolar degeneration (GVD) bodies, predominantly in CA1 and subiculum of the hippocampus, entorhinal cortex, amygdala, parietal and frontal cortex. In the subiculum and amygdala, the number of neurons showing pMLKL‐positive GVD lesions was associated with neuronal loss, as seen in human AD. Both dabrafenib and ponatinib reduced the number of neurons showing pMLKL‐positive GVD bodies, prevented neuronal loss, and ameliorated social recognition memory.

Conclusion

Taken together, these results point to “GVD‐necroptosis”, as a presumably delayed form of necroptosis, and a mechanism underlying AD pathology‐related neuronal loss. Necroptosis inhibition as shown here in APP23xTAU58 mice is a novel approach to ultimately prevent “GVD‐necroptosis” induced neuronal death.

Funding: SAO/FRA and FWO.
The association between tau pathology and later stages of memory processing is mediated by medial temporal lobe atrophy in typical Alzheimer’s Disease
Authors: Wuestefeld Anika , Cui Salena , Das Sandhitsu R. , Xie Long , McGrew Emily , Yushkevich Paul A. , Wisse Laura , Wolk David A ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

Tau pathology is closely related to cognitive decline in Alzheimer’s disease (AD). Neurodegeneration is the putative mechanism by which tau leads to cognitive deficits. However, there is limited work on the associations between tau, neurodegeneration, and specific cognitive domains. We investigate potential mediating effects of medial temporal lobe (MTL) and neocortical neurodegeneration for different cognitive domains in amyloid‐β‐positive (Aβ+) adults.

Method

We included 325 positron emission tomography (PET) Aβ+ individuals across the AD spectrum from the Alzheimer’s Disease Neuroimaging Initiative (age: 72±8 [55–90]; 51.1% female, education: 16±2 years). Hippocampal volume and cortical thickness were measured from T1‐weighted structural magnetic resonance imaging in typical AD regions (Fig. 1). Using flortaucipir‐PET, tau was quantified for two composite regions (MTL, neocortical). Included cognitive measures are shown in Fig. 1. Mediation analyses between tau‐PET, thickness/volume, and cognition were performed. Cognitive measures were adjusted to isolate the function of interest (Fig. 1).

Result

Higher tau‐PET uptake and lower thickness were associated with lower performance on all cognitive measures.

In simple mediations, tau‐immediate recall associations were mediated by MTL, parietal, and temporal regions (Fig. 2A). Tau‐delayed recall associations were mediated by MTL regions. Tau‐late recall and tau‐recognition associations were mediated by MTL and parietal regions. Tau‐fluency and tau‐executive functioning associations were mediated by MTL and parietal regions, as well as temporal regions for fluency.

Complex mediations investigated significant mediators simultaneously (Fig. 2B+3). Depending if MTL/neocortical tau remained significant when covarying for the other tau measure in a regression, the complex mediation models focused on MTL and/or neocortical regions (Fig. 2B description). Hippocampus mediated the tau‐late recall and tau‐recognition associations. Brodmann area 35 mediated the tau‐delayed recall association. Tau‐fluency was, at a trend level, mediated by inferior temporal thickness. Tau‐executive functioning did not demonstrate a mediation effect, potentially due to limited frontal atrophy. All mediators were partial mediators explaining up to 23% of variance.

Conclusion

The results suggest that MTL tau pathology, partially mediated by macrostructural changes, lead to impairments in specific memory domains in early AD. Impairments in fluency and executive functioning, however, seem more likely to follow from tau‐induced effects in neocortical regions.