bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Late‐Life Depression and Amyloid Beta Burden in Older Adults Without Cognitive Impairment: A. Systematic Review and Meta‐Analysis
Authors: Castro Natalia Pozo , Paradela Regina Silva , Allen Isabel Elaine , Ruiz‐Castillo Karla Paulina , Vrillon Agathe , Delgado Carolina , Windon Charles
Published: January 2025

Background

Late‐life depression (LLD) is a risk factor for cognitive impairment. Some studies have shown an association between higher amyloid‐beta (Aβ) burden, a known marker of Alzheimer’s Disease (AD), and LLD, but research findings are mixed. We performed a systematic review and meta‐analysis to compare the Aβ burden between cognitively unimpaired subjects with and without LLD.

Method

We searched MEDLINE, Embase, and ScienceDirect for studies comparing Aβ burden between LLD patients and controls (molecular imaging and/or fluid‐biomarker confirmation) and included subjects aged ≥60 years with LLD, and absence of cognitive impairment (MMSE ≥24 and/or description of normal cognition). The review process was performed by 2 independent reviewers (Covidence‐software). A random effects meta‐analysis was executed to evaluate the pooled difference of Aβ burden between LLD and control groups (JASP‐software).

Result

372 studies were identified and eight met the inclusion‐exclusion criteria (combined sample: 725 LLD subjects and 885 controls). The weighted‐mean age was 69.3 and 68.9 years for subjects and controls. Six studies evaluated Aβ in blood (4 on serum and 2 on plasma, one of them also evaluated PET‐Aβ), and two evaluated cerebrospinal fluid (CSF) (table 1). One of the serum studies (Namekawa) included two subgroups, one with subjects that besides depression after 60 years old also had a history of depression before age 60, and one with participants with a first episode of major depressive disorder after 60 years old. Both subgroups were analyzed separately in the meta‐analysis. The meta‐analysis of plasma and serum studies showed that individuals with LLD had lower levels of Aβ42 (estimate ‐0.344, p<0.001) (Fig. 1) and higher levels of Aβ40/42 ratio (estimate 0.428, p<0.001) compared to controls (Fig. 2). The results remained significant when plasma and serum were analyzed independently.

Conclusion

In this systematic review and meta‐analysis, we found significantly lower levels of Aβ42 and higher levels of Aβ40/42 ratio in cognitively unimpaired older adults with LLD compared to controls. These findings support the idea that LLD is associated with AD pathology. This is a relevant area of research for increasing the understanding of AD’s clinical presentation that could potentially impact access to early diagnosis and treatment.
Design of YΦ motif peptides to promote 20S proteasome mediated degradation of tau
Authors: Ryder Bryan D. , Yan Nicholas L. , Gestwicki Jason E. ,   ALBORADA Drug Discovery Team
Published: January 2025

Background

An optimized 6 amino acid peptide (NLSYYT; herein YΦ) derived from the C‐terminus of h19S proteasome activator Rpt5 has been shown to activate the 20S proteasome and promote tau degradation. Further analysis of this peptide has identified the highly conserved leucine in position 5 (P5) as a key part of the 20S activation mechanism to drive degradation of tau monomers in the absence of proteasome activator complexes.

Method

Recombinant peptides were used to identify key amino acids required for binding and activating the h20S proteasome. Degradation activity from YΦ‐mediated activation was measured with small peptide markers. Using archaeal activator complex aPA26 with YΦ and P5 mutants cloned onto its tails, P5 was shown to use hydrophobic interactions to stabilize YΦ interactions with the h20S α‐subunit ring. Finally, YΦ activation of the h20S proteasome increased tau degradation in vitro, in cell lysates, and in cells.

Result

In vitro tau degradation experiments show that simultaneous binding of linked YΦ peptides is sufficient to promote degradation of tau monomer in an ATP‐independent and ubiquitin‐independent system. Mutations to the P5 leucine result in a 3‐fold reduction in h20S proteasome activity for aromatic substitutions, and complete loss of activity for all other natural amino acid substitutions. However, P5 substitutions do not have as dramatic of an effect on binding, demonstrating that the role of P5 leucine uncouples activity and binding, unlike the other amino acids. In the context of aPA26, YΦ mediated activation clears 80% of native tau monomer over the course of 30 minutes, with similar results observed in degrading tau derived from cell culture.

Conclusion

Structure‐activity relationship data of YΦ activation of the 20S proteasome provides insight into future designs of proteasome activators. With an improved understanding of the role of P5 leucine, a more refined interaction network can be considered when designing h20S proteasome activators for clearing disease‐associated tau in cells.
Relationship between electrophysiological performance during an incidental memory task and cholinergic integrity in a pilot study in adults with Down syndrome
Authors: Conley Alexander C , Russell Jason K , Begnoche John Patrick , Boyd Brian , Key Alexandra P , Rosenberg Adam J , Stranick Allison , Schlossberg Rachel , Martin Dann , Acosta Lealani Mae Y. , Wilson Jo Ellen , Rafii Michael , Newhouse Paul A
Published: January 2025

Background

Adults with Down syndrome (DS) are at a high risk of developing Alzheimer’s disease (AD) due to the triplication of the amyloid precursor protein on chromosome 21. Despite the high incidence of AD within the DS population, there is less understanding of how AD progresses, although it may be reflected in an accelerated aging phenotype. Compared to typically developing populations, there is less understanding of the decline of cholinergic integrity with aging in adults with DS. In this pilot study we are investigating the impact of cholinergic system integrity using [18F]‐FEOBV PET on cortical structure and cognitive function in adults with DS. One measure of cognitive function that we used was attention and memory processes recorded by high‐density electroencephalography (EEG).

Method

Nine non‐demented adults with DS (4 female, aged 37.8±7.7 years), recruited from the Trial Ready Cohort – Down syndrome, completed an MRI, [18F]‐FEOBV PET scan and an EEG recording. Participants completed an incidental memory task, a passive memory task with a series of complex images half of which are novel, and half repeated. Oscillatory power across the frontal, central and parietal regions was defined as a repeated–novel power. [18F]‐FEOBV PET images were coregistered to structural MR images and referenced to the supraventricular white matter. Initial analyses focused on memory‐related evoked power from the delta, theta, alpha and beta frequency bands, and their association with [18F]‐FEOBV PET uptake.

Result

Unexpectedly, recognition memory for repeat vs novel stimuli was associated with reduced power for delta, theta and beta bands and increased alpha power. This pattern of results reflect memory processes identified with older adults in the typically developing population rather than an age‐matched sample. Increased cholinergic uptake was associated with this pattern of older age‐like power across all frequency bands.

Conclusion

Evoked oscillatory activity on a recognition memory task in a small sample of adults with DS displayed similar characteristics as older adults in the typically developing population. Cholinergic integrity was associated with evoked power during recognition memory. These results demonstrate functional markers of accelerated aging in adults with DS as well as their relationship with cholinergic integrity.
Phase 2 Clinical Trials of NA‐831 for the Treatment of Alzheimer’s Disease and Major Depressive Disorder, support the Neurogenesis Hypothesis
Authors: Tran Lloyd , Tran Zung Vu , Vu Fern
Published: January 2025

Background

Adult Hippocampal Neurogenesis has been shown to be involved in Major Depressive Disorder (MDD) and Alzheimer’s disease (AD) pathology. NA‐831 is a small drug molecule, exhibiting neuroprotection, neurogenesis and memory enhancing properties.

Method

For AD: A randomized clinical trial of NA‐831 was performed in 112 participants with mild and moderate Alzheimer’s disease (AD), half received the drugs and half received placebo. The patients with MCI received 10 mg of NA‐831 and patients with mild and moderate AD received 30 mg of NA‐831 or placebo orally per day.

Subjects with MCI met the NIA‐AA core criteria. CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline. MMSE score ≥22. Subjects with mild & moderate AD to meet the NIA‐AA core criteria. MMSE: 17‐21.

For MDD: A randomized, clinical study was conducted to investigate the efficacy and safety of two fixed doses (20 and 40 mg/d) of NA‐831 vs. that of placebo after 6‐week treatment in 32 adult patients with major depressive disorder (MDD).

Result

For AD: NA‐831 showed a significant improvement for patients with mild and moderate AD with the ADAS‐Cog‐13 score change of an average of 4.1 as compared to the placebo after 24 weeks of treatment (p = 0.001; ITT). CIBIC‐Plus showed 78% patients improved (p = 0.01; ITT). mNA‐831 was well‐tolerated at 30 mg/day. There were no serious adverse events observed.

For MDD: The difference between active treatment and placebo of ∼7 points on the MADRS translates into a clinically relevant difference in response rates of 32.5% units, compared to an average of 16% units for antidepressants approved by the USA FDA. Treatment with NA‐831 for 6‐week was well tolerated and efficacious in reducing depressive and anxious symptoms in patients with MDD.

Conclusion

The Neurogenesis Hypothesis has been shown to be a viable approach for further research for Alzheimer’s disease and Major Depressive Disorder. Phase 3 trials of NA‐831 for the treatment of AD and MDD are being conducted. Results of the clinical trials will be provided as soon as they are available.
Daily Perceptions of Dementia Symptoms Within Care Dyads: Links to Diurnal Cortisol Rhythms in Couples Living With Early‐Stage Dementia
Authors: Polenick Courtney A. , Turkelson Angela , Garner Charity , Daniel Nikita R , Salwi Shreya M , Kaba Diarratou , Birditt Kira S.
Published: January 2025

Background

Symptoms of Alzheimer’s disease and related dementias (ADRD), including memory problems, are often stressful for people living with dementia (PLWD) and family caregivers. However, we know little about daily perceptions of ADRD symptoms and links to physiological stress reactivity within care dyads. We evaluated how daily ADRD symptom stress (i.e., perceived stress related to ADRD symptoms) reported by PLWD and their spouse caregivers predict diurnal cortisol rhythms among heterosexual couples living with early‐stage ADRD.

Method

Participants included 39 PLWD (M = 72.1 years, SD = 7.6, range = 52‐86 years) and their spouse caregivers (M = 70.7 years, SD = 9.0, range = 49‐88 years) who both completed 7 consecutive days of brief morning and evening phone interviews and collected saliva samples (four times per day) during four of those days. Outcomes included the cortisol awakening response (AR; awakening to 30 min post‐awakening), decline (DEC; 30‐min post‐awakening to bedtime cortisol), and total area under the curve (AUC). Multilevel models controlled for study day, age, gender, and education.

Result

Higher caregiver‐reported daily ADRD symptom stress was associated with their own higher AR on the next day when PLWD‐reported daily ADRD symptom stress was high (b = 1.04, SE = 0.38, p = .006). Higher caregiver‐reported daily ADRD symptom stress was associated with a higher AUC among caregivers (b = 2.51, SE = 0.87, p = .006) but a lower AUC among PLWD (b = ‐1.65, SE = 0.69, p = .021) on the same day. Higher caregiver‐reported daily ADRD symptom stress was associated with a lower PLWD AUC on the next day when PLWD‐reported daily ADRD symptom stress was low (b = ‐5.75, SE = 1.90, p = .002) but a higher PLWD AUC when PLWD‐reported daily ADRD symptom stress was high (b = 5.27, SE = 1.51, p < .001). Caregiver‐reported and PLWD‐reported daily ADRD symptom stress were not associated with DEC.

Conclusion

Daily ADRD symptom stress reported by spouse caregivers was associated with physiological stress reactivity among caregivers and PLWD. These findings inform targets of clinical care and interventions to improve the well‐being of both care dyad members.
Blood transcriptomics of preclinical Alzheimer’s Disease patients
Authors: de Bittencourt Marcelo Madrid , De Bastiani Marco , Ferreira Pamela C.L. , Zimmer Eduardo R. , da Rocha João Batista Teixeira
Published: January 2025

Background

Blood transcriptomic differences have been described in patients with Alzheimer’s disease (AD). However, blood transcriptomic core molecular programs in cognitively unimpaired (CU) individuals positive to biomarkers of Amyloid and Tau pathology, defined as preclinical AD, remains to be explored. Therefore, we aimed to establish blood molecular core programs in preclinical AD.

Method

We selected 63 CU individuals negative or positive to amyloid‐B (A) and Tau (T) but negative for neurodegeneration from the ADNI database, with blood transcriptomics available (Fig. 1A). We performed microarray data analysis in R, utilizing the limma method, for identifying differentially expressed genes (DEGs) in CU A‐T‐; CU A+T‐ and CU A+T+. Amyloid‐B and Tau positivity was defined based on CSF levels of Aß(1‐42) and p‐tau (cutoffs of 977 pg/mL for Aß and 24 pg/mL for Tau). Gene Ontology (GO) enrichment analysis was conducted for all categories, separately for each comparison. P‐value < 0.05 was considered statistically significant.

Result

The comparison with the CU A‐T‐ group revealed 765 DEGs for CU A+T‐ and 1315 DEGs for CU A+T+. By comparing CU A+T+ with CU A+T‐, we identified 1171 DEGs. Only 29 DEGs were shared across all comparisons (Fig. 1B). Enrichment analysis identified 6 terms for CU A+T‐ versus CU A‐T‐, 17 terms for CU A+T+ versus CU A‐T‐, and 9 for CU A+T+ versus CU A+T‐. Only the second and the third comparisons shared the same terms, of which are “ATP‐dependent activity, acting on DNA“ and “single‐stranded DNA binding “. Among the non‐shared terms, CU A+T+ versus CU A‐T‐ included “ATP hydrolysis activity“, “ chromosomal region“, “tubulin binding“; for the CU A+T‐ versus CU A‐T‐, “cytoskeleton‐dependent intracellular transport“, “microtubule‐based transport“, “neuroprojection cytoplasm“; and for CU A+T+ versus CU A+T‐, “mononuclear cell differentiation”, “lymphocyte differentiation”, “regulation of macrophage chemotaxis”(Fig. 2).

Conclusion

Our results suggest changes in blood transcriptomics among preclinical individuals with Amyloid and/or Tau pathology. Amyloid was related to disruptions in immune‐mediated and cytoskeleton proteins, while individuals positive for amyloid and Tau presented disturbances in inflammatory responses. Altogether, both Amyloid and Tau contribute to deregulations in cell cycle and DNA repair systems compared with CU individuals with no pathology.
Integration of GWAS summary statistics with cell type‐specific eQTLs prioritizes potential causal genes for Alzheimer’s disease
Authors: Liu Shiwei , Huang Yen‐Ning , Park Tamina , Chaudhuri Soumilee , Cho Min Young , Rosewood Thea Jacobson , Bennett David A. , Saykin Andrew J. , Nho Kwangsik
Published: January 2025

Background

Analyzing disease‐linked genetic variants via expression quantitative trait loci (eQTLs) is crucial for identifying disease‐causing genes. Previous research prioritized genes by integrating Genome‐Wide Association Study (GWAS) results with tissue‐level eQTLs. Recent studies explored brain cell type‐specific eQTLs, but they lack a systematic analysis across various AD GWAS datasets, nor did they compare effects between tissue and cell type levels or across different cell type‐specific eQTL datasets. Here, we integrated brain cell type‐specific eQTL datasets with AD GWAS datasets to identify potential causal genes at the cell type level.

Method

To prioritize disease‐causing genes, we used summary data‐based Mendelian Randomization (SMR) and Bayesian colocalization (COLOC) methods to integrate the AD GWAS summary statistics with cell type‐specific eQTLs in human brain. We utilized five latest AD GWAS datasets and a cell type‐specific eQTL dataset comprising 424 participants of the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP) cohort. We replicated our analysis using a cell type‐specific eQTL dataset of 192 participants from Bryois et al., 2021. For comparison, we utilized a previous tissue‐level metabrain eQTL dataset from a meta‐analysis of 14 datasets. Furthermore, we visualized the colocalization of novel candidate causal genes using eQTpLot.

Result

We identified 17 cell type‐specific candidate causal genes using the ROSMAP eQTL dataset. Our results showed that the largest number of candidate causal genes are identified in microglia, followed by astrocytes, oligodendrocytes, excitatory neurons, inhibitory neurons, and oligodendrocyte progenitor cells (OPCs). Four candidate causal genes were common across different cell types. Interestingly, JAZF1, detected as a candidate causal gene affected by the same leading variant in both microglia and OPCs, showed a congruous (same direction) colocalized SNP effect on the gene expression level and AD in OPCs, but an incongruous (opposite direction) colocalized SNP effect in microglia. After comparing our results with previously known prioritized causal genes, we identified PABPC1 in astrocyte as a novel potential causal gene.

Conclusion

We systematically prioritized AD candidate causal genes based on cell type‐specific molecular evidence. The integrative approach enhances our understanding of molecular mechanisms of AD‐related genetic variants and facilitates the interpretation of AD GWAS results.
Assessment of Baseline Plasma p‐tau217 in TANGO, a Randomized, Placebo‐controlled Phase 2 Study of Gosuranemab in Patients with Early Alzheimer’s Disease
Authors: Czerkowicz Julie , Zhang Rong , Collins Jessica , Rubel Carrie E. , O'Gorman John , Shulman Melanie , Graham Danielle
Published: January 2025

Background

TANGO was a Phase 2 clinical study designed to assess the safety and efficacy of gosuranemab, an anti‐tau monoclonal antibody, in participants with mild cognitive impairment due to Alzheimer’s disease (AD) or with mild AD dementia. Despite robust target engagement of unbound N‐terminal tau, the clinical efficacy endpoint was not met. In this exploratory analysis of TANGO participants, we examine plasma p‐tau217 levels to assess the feasibility of using this biomarker to identify patients with AD pathology and predict disease progression.

Methods

Plasma was collected from 554 randomized TANGO participants at baseline and up to Week 78. Plasma p‐tau217 was measured using the ALZpath Quanterix Simoa assay. Plasma p‐tau181 was measured using the Quanterix Simoa p‐tau181 V2 Advantage assay. Tau PET was measured in a sub‐study of 357 participants at baseline and Weeks 52 and 78 using 18F‐MK‐6240. Amyloid PET was measured at screening using 18F‐florbetapir in n = 322 participants Clinical decline was measured using the CDR‐SB, MMSE, ADAS‐Cog13 and ADCS‐ADL cognitive assessment scales. Statistical analysis was performed using Spearman correlation coefficient.

Results

Plasma p‐tau217 and plasma p‐tau181 were correlated at baseline (Spearman = 0.7617, p‐value <0.0001). Baseline plasma p‐tau217 levels were correlated with both baseline amyloid PET using SUVR in a composite region of interest (Spearman = 0.4294, p‐value <0.0001) and baseline Tau PET using SUVR in composite regions of interest corresponding to Braak stages I‐II, III‐IV, and V‐VI (Spearman range = 0.4075‐0.6163, p = value <0.0001). Participants with higher concentrations of plasma ptau217 at baseline showed a greater rate of clinical decline at Week 78.

Conclusions

The correlations of plasma p‐tau217 with amyloid and tau PET at baseline suggest a relationship with both underlying pathological hallmarks of AD. Similar to results from observational cohorts, correlation of baseline plasma p‐tau217 and clinical decline observed during the TANGO trial supports the utility of plasma p‐tau217 as a potential prognostic biomarker of disease. Data from additional studies are needed to define appropriate use cases and relevant thresholds for plasma p‐tau217 as a biomarker of disease pathology that can be used to prescreen patients in clinical trials.
Sovateltide promotes regeneration and reduces β‐amyloid burden in a transgenic mouse model of Alzheimer’s disease
Authors: Briyal Seema , Roy Kathryn , Gulati Anil
Published: January 2025

Background

Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. We have demonstrated cerebral endothelin B receptors (ETBR) as a potential target to treat AD. However, the mechanism of action of sovateltide remains elusive. Therefore, we investigated its mechanism of action in neuronal regeneration in APP/PS1 transgenic mouse model.

Method

APP/PS1 transgenic mice and C57BL/6 control mice were divided into two groups (vehicle and sovateltide). Sovateltide (5 µg/kg) was intravenously injected, three times at 2‐hour intervals on days 1, 3 and 6 of every month until study end points (3‐, 6‐ and 12‐months age). Control mice received an equal volume of saline. Separate sets of mice were sacrificed at the end of 3, 6 and 12 months and beta amyloid plague formation, mitochondrial dysfunction, neuro‐ and synapto‐genesis were assessed in the brain.

Result

APP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory with elevated levels of Aβ plaque along with decreased levels of neuro and synaptogenic markers, which reflected the adverse effect of disease progression. Treatment with sovateltide rescued learning and memory deficits and significantly (p<0.001) decreased Aβ plaque load compared to vehicle in 6 months and 12 months aged transgenic mice. Moreover, sovateltide attenuated neuronal loss in the hippocampus and enhanced neurogenesis in APP/PS1 mice as evident by increased expression of NeuroD1 (p<0.0001), DoubleCortin (p<0.0001) and NeuN (p<0.0001) along with an upregulation of synaptic proteins (synapsin‐1, synaptophysin, and postsynaptic density‐95) compared to vehicle at 6 and 12 months. Sovateltide treatment also decreased mitochondrial fission (Drp1; p<0.001), increased mitochondrial fusion (Mfn2; p<0.001) and mitochondrial cross‐sectional area (p<0.01). Additionally, caspase‐3 level was significantly (p<0.001) higher in vehicle group than that in the sham group, and treatment with sovateltide significantly (p<0.01) reduced caspase‐3 level. There were no changes in the expression of any of these markers at three months.

Conclusion

These findings suggest that sovateltide treatment promotes regeneration while simultaneously decreasing the pathology associated with Alzheimer’s disease.
Non‐APOE Polygenic risk score derived from European ancestry data are more predictive of dementia among Hispanics who are APOE ε4 carriers
Authors: Xu Yuexuan , Reyes‐Dumeyer Dolly , Gunasekaran Tamil Iniyan , Qiao Min N , Piriz Angel , Lantigua Rafael A. , Medrano Martin , Mejia Diones Rivera , Vardarajan Badri N. , Mayeux Richard
Published: January 2025

Background

Despite concerns about the transferability of polygenic risk scores (PRS) derived from European ancestry data to Hispanics, recent research suggests that many genetic loci identified through European ancestry genome‐wide association studies (GWAS) for complex traits are also relevant in Hispanics. Furthermore, studies on dementia have shown improved PRS performance in this group, even with PRS developed from European GWAS. Recent research also indicates that APOE ε4‐independent PRS associations vary depending on APOE ε4 status. This study evaluates the relationship between multiple recent European GWAS‐derived APOE‐independent PRS in Hispanics and the interaction between APOE ε4 and PRS in relation to Alzheimer’s Disease (AD).

Methods

We constructed a range of PRS based on three recently published GWAS (Kunkle et al., 2019, Bellenguez et al., 2022, FinnGen) of European ancestry among 1,429 Hispanics from the Washington Heights‐Hamilton Heights‐Inwood Community Aging Project (WHICAP) using clumping and thresholding methods. For each GWAS, we first evaluated the associations of several P‐value thresholds with AD to determine the threshold for further analysis. Empirical P‐values were used to avoid overfitting for the optimized PRS. We then tested whether and how APOE ε4 can modify the association between PRS and AD. All associations were fitted by logistic regression with sex, age, education, and the first 5 principal components as covariates.

Results

Across all European GWAS, the optimal P‐threshold for the most predictive PRS is at a conservative P‐threshold (Kunkle: 2.87e‐6, Bellenguez: 1.11e‐6, FinnGen: 1.80e‐5). PRS constructed based on the Bellenguez GWAS are most strongly associated with AD (OR = 1.29, 95% CI: 1.17‐1.42), and the FinnGen‐derived PRS show the least association (OR = 1.06, 95% CI: 0.98‐1.14). The association of all three PRSs is stronger among APOΕ ε4 carriers (ORKunkle: 1.51, 95% CI: 1.26‐1.81; ORBellenguez: 1.60, 95% CI: 1.35‐1.91; ORFinnGen: 1.12, 95% CI: 0.97‐1.26) compared to non‐carriers (ORKunkle: 1.09, 95% CI: 0.96‐1.23; ORBellenguez: 1.16, 95% CI: 1.03‐1.31; ORFinnGen: 1.03, 95% CI: 0.93‐1.14). Similar findings were observed concerning cognition and progression to dementia.

Conclusion

PRS derived from a European GWAS identified individuals at high risk for AD dementia among Hispanics, and the association is strongest among APOE ε4 carriers.
Neuroticism and poor cardiovascular health may signal early cognitive dysfunction related to Alzheimer’s risk in older African Americans
Authors: Powell Ashley , Fausto Bernadette A. , Gluck Mark A.
Published: January 2025

Background

African Americans bear a disproportionate burden of both cardiovascular diseases and Alzheimer’s disease (AD). Assessment of the Five‐Factor personality dimensions–Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness, particularly, higher levels of neuroticism–is linked to greater adverse cardiovascular and cognitive outcomes, including AD. Generalization–the ability to apply prior learning to new circumstances–is presented as a putative cognitive marker for the earliest stages of preclinical AD. However, the relationship between personality, cardiovascular health, and cognition is understudied in older African Americans. This study explored the relationship between personality, cardiovascular health, and cognitive function in a cohort of older African Americans.

Method

83 cognitively healthy older African American participants from the Pathways to Healthy Aging in African Americans cohort study (Mage = 68.34 years, SD = 6.99; Meducation = 13.93 years, SD = 2.36; MMMSE = 27.65, SD = 1.95) provided a blood sample for blood sugar levels (HbA1c); participated in anthropometric/physiological measurements (e.g., body mass index and resting heart rate); completed an aerobic fitness assessment (six‐minute walk test for VO2max estimate); completed a cognitive battery including a generalization task (Concurrent Discrimination and Transfer Task) and neuropsychological tests; and responded to mood and demographic questionnaires. We binarized each personality dimension at the median creating a lower and higher group. Independent sample t‐tests and correlations were performed to assess the relationship between each of the personality dimensions, cardiovascular health, and cognitive variables.

Result

Individuals in the higher neuroticism group had higher resting heart rate (d = ‐0.45), HbA1c levels (d = ‐0.58), and depressive symptomology (d = ‐0.80) while also demonstrating poorer aerobic fitness (d = 0.58) than their lower neuroticism counterparts. Subsequently, higher HbA1c was associated with poorer performance on the generalization task: Concurrent Discrimination and Transfer Task training phase (r = ‐.343, p = .002) and probe phase performance, (r = ‐.292, p = .008).

Conclusion

We identified that cognitive function, specifically the ability to generalize prior learning is indirectly related to poor cardiovascular health in individuals that have a higher level of neuroticism. Our findings suggest that in older African American populations, the propensity to experience negative emotions (e.g., worry or any of the other neurotic traits) may negatively impact cardiovascular health, which may indirectly lead to poor cognitive outcomes such as dysfunction and AD.
Leukocyte Surface Biomarkers for Clinical Diagnosis of Sporadic Alzheimer’s Disease
Authors: Durrant Abe , Gu Ben J , Dickson Samuel P. , Nicodemus‐Johnson Jessie , Duncan Garrett B , Hendrix Suzanne B.
Published: January 2025

Background

Mounting evidence indicates that the accumulation of amyloid in AD starts 20 to 30 years before clinically detectable cognitive impairment is observed, suggesting the presence of a long period of asymptomatic AD. Although the specific onset of this preclinical period is difficult to target, it is potentially significant to identify subjects in this asymptomatic preclinical stage of the disease. This is because newly developed disease modifying treatments may have increased effectiveness if begun during this asymptomatic period. Currently, the preclinical phase of AD is identified in asymptomatic individuals as abnormal amyloid levels detected via neuroimaging or fluid biomarkers. However, this approach is not feasible as a routine screening tool in a clinical environment, therefore there is a critical need to develop blood‐based, cost‐effective screening tools to detect AD in asymptomatic patients. Because of this, the search for preclinical blood‐based biomarkers has become a major focus.

Method

200 Participants were randomly selected from the Australian Imaging, Biomarkers, and Lifestyle study (AIBL). A total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Leukocyte markers were used in addition to age, ApoE4 status, years of education, and sex to predict the PET Aβ status. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses.

Result

We identified 12 specific leukocyte markers that were differentially expressed in cognitively normal (CN) patients designated as amyloid negative compared with CN individuals who are amyloid positive (Amyloid PET Centiloid >25). Combinations of these 12 markers produced AUC values as high as 0.94 in‐sample, and 0.90 out‐of‐sample. Specifically, markers CD11c, CD59, CD91, and CD163 had high performance when predicting amyloid positivity. These markers also showed strong predictive performance at other levels of Centiloid, maintaining AUCs greater than 0.85.

Conclusion

Results suggest that leukocyte surface biomarkers involved in Aβ transportation, innate phagocytosis and completement mediated clearance pathways are the first blood‐based biomarkers that can accurately predict amyloid load and detect amyloid at 25 centiloids. These biomarkers could have a major impact on clinical practice by allowing primary care physicians to identify individuals at high risk of having amyloid burden in their brains with a simple blood test.
Association of Social Determinants of Health with Acute TBI Care Among U.S. Older Adults
Authors: Sumida Catherine , Diaz‐Ramirez L. Grisell , Yaffe Kristine , Boscardin W John , Gardner Raquel C. , Kornblith Erica S
Published: January 2025

Background

Older adults have the highest incidence of traumatic brain injury (I‐TBI), which is associated with increased Alzheimer’s disease and related dementia (ADRD) risk. Timely medical assessment, including computed tomography (CT) or magnetic resonance imaging (MRI), is vital for optimal I‐TBI care and recovery. The current study builds on our recent work by examining social determinants of comprehensiveness of I‐TBI care amongst older adults.

Method

Enrollees 65+ years in the nationally representative Health and Retirement Study (HRS), whose HRS survey and Medicare claims data were linked and first TBI diagnosis code occurred between 2000‐2018, were studied. I‐TBI was defined by International Classification of Disease (ICD9&10) inpatient and outpatient codes in Medicare claims (2000‐2018). HRS participants’ acute TBI level of care (TBI‐LC) was ranked from least to most comprehensive: a)neither ER nor imaging codes, b)ER code only, or c)ER and imaging (MRI/CT) codes within ±1day of I‐TBI code. Cognitive status was defined at baseline using Langa‐Weir Dementia Probability, an HRS‐derived predictive model.

Result

Of those respondents with I‐TBI (N = 1148), 15.5% had neither ER nor imaging codes, 14.7% had ER code only, and 69.8% had an ER and imaging code within ±1 day of TBI code. TBI‐LC was associated with rural status (Rao‐Scottc2(2) = 11.97, p = .003): Rural elders received ER services (20.3% no ER code; 64.9% ER and imaging codes) less frequently compared to non‐rural elders (13.2% no ER code; 72.1% ER and imaging codes). Frequency of ER presentation without imaging were similar amongst rural (14.8%) and non‐rural elders (14.6%). TBI‐LC was not associated with marriage status, income, or cognitive status.

Conclusion

Consistent with prior findings amongst rural adults of all ages, rurality is associated with disparity in acute TBI care comprehensiveness amongst older adults specifically. Interestingly, monthly income, thought to account in part for differences between rural and non‐rural populations, was not associated with TBI care comprehensiveness. These findings suggest further research is needed to examine unique factors contributing to rurality as a barrier to care in elders with TBI (e.g. lack of transportation) and resulting downstream health outcomes (e.g., risk of cognitive decline, ADRD).
Assessment of the Empact of IGC‐AD1 on Hepatic Biomarkers in Alzheimer’s Disease: Insights from a Phase 1 Trial
Authors: Rodriguez‐Soacha Diego , Cañon Andres , Sánchez Laura Tatiana , Rao Jagadeesh S , Delgado‐Murillo Laura , Venegas Margarita , Tangarife Maria Alejandra , Arbelaez Maria Juanita , Gutiérrez Evelyn , Shahnawaz Saadia , Ghazaryan Varduhi , De Jesus William Julio , Grimaldi Claudia , Hong Elliot , Mukunda Ram
Published: January 2025

Background

IGC‐AD1 comprises of Tetrahydrocannabinol (“THC”) and melatonin. The two active pharmaceuticals are known for their neuroprotective properties. In this analysis we studied multiple dosing of IGC‐AD1 in Alzheimer’s (“AD”) populations vulnerable to hepatic complications. We present the impact of three different doses on hepatic functions, offering insights into dosage‐dependent safety and potential therapeutic implications.

Method

Thirteen Puerto Rican AD patients (mean age: 80.18±6.22 years, 70% women) participated in this three‐cohort trial to assess the effects of IGC‐AD1. Cohorts 1, 2 and 3 received 1 mL once, twice, or thrice daily, respectively, for 14 days (“EOT”) with ∼4‐day washout period between cohorts. Key hepatic and renal biomarkers measured at baseline and EOT included AST, ALT, ALP, total and direct bilirubin.

Result

Findings showed a larger increase in the mean difference of ALTI in the placebo group compared to active in cohorts 2 and 3 (Cohort‐1, Active; = ‐2.11 ± 6.01, Placebo = ‐0.5 ± 0.71; Cohort‐2, Active = ‐2.25 ± 4,79, Placebo = ‐8.0; Cohort‐3, Active; = ‐3.5 ± 9.73, Placebo = ‐7.0 ± 8.49). ALP levels decreased for both treatments in cohort 1 but increased for cohorts 2 and 3 (ALP Cohort‐1, Active; = 2.89 ± 4.34, Placebo = 3.5 ± 7.78; Cohort‐2, Active = ‐0.6± 18.15, Placebo = ‐5.0; Cohort‐3, Active; = ‐2.8 ±5.57, Placebo = ‐3.0 ± 7.07). Indirect bilirubin levels increased in the active groups for cohort 3, no tendency was observed for placebos (Indirect bilirubin Cohort‐1, Active; = 0.02 ± 0.05, Placebo = 0.05 ± 0.03; Cohort‐2, Active = 0.07 ± 0.07, Placebo = ‐0.03; Cohort‐3, Active; = ‐0.04 ± 0.14, Placebo = 0.07). All other biomarkers were within expected ranges, supporting the treatment’s safety profile.

Conclusion

Based on this safety trial, the findings suggest that the treatment with THC and melatonin does not exert adverse effects on liver function in patients with AD. Overall, the treatment demonstrated good tolerability, with no significant differences in hepatic biomarkers compared to placebo, supporting its potential safety in elderly patients with AD. Future research should continue to monitor these biomarkers in larger, more diverse populations to confirm these findings and assess long‐term safety and efficacy.
Tracking the timeline: from initial documentation of cognitive decline to dementia diagnosis in the electronic health records
Authors: Wang Liqin , Yang Richard , Bates David W , Zhou Li , Marshall Gad A
Published: January 2025

Background

Recent breakthroughs in the treatment of Alzheimer’s Disease underscore the critical needs for early detection. In clinical settings, the diagnosis of Alzheimer’s disease and related dementias (ADRD) is often delayed or overlooked, potentially missing critical opportunities for timely care and treatment. Cognitive symptoms can appear many years before the stage of dementia, potentially serving as a trigger for thorough cognitive assessments, which could prompt an early diagnosis of cognitive decline. However, it remains unclear how this information is presented to clinicians and documented in patient charts, and how early these symptoms appear before an ADRD diagnosis.

Method

This retrospective cohort study utilized electronic health records (EHRs) from Mass General Brigham (MGB) to examine primary care patients aged 55 and older who received an initial ADRD diagnosis at MGB between 2018 and 2019. We analyzed EHR data to identify evidence of cognitive decline preceding the ADRD diagnosis. This analysis involved searching for cognition‐related keywords and diagnostic codes, and screening clinical notes using a validated deep learning model for cognitive symptoms. We assessed the duration from initial cognitive symptoms to ADRD diagnosis and examined demographic and socio‐economic factors for their correlation with documentation of cognitive decline.

Result

The study included 10,119 ADRD patients (median age of 80, 42.5% male). Of these, 2,890 (28.6%) had no prior documented cognitive decline. Patients without prior documentation were slightly older at diagnosis (median age: 81 years), more likely to have unspecified education background (39.2% vs. 20.3%), and came from more deprived areas. Among patients with prior cognitive decline documented, the average time to ADRD diagnosis was 3.7 years. Patients with initial cognitive evidence from clinical notes (78.7%, n = 5,692) experienced earlier documentation of cognitive symptoms compared to those identified through other sources. In contrast, those without documented marital status, with Medicaid insurance, and residing in highly deprived neighborhoods experienced delayed documentation of cognitive symptoms prior to ADRD diagnosis.

Conclusion

Our analysis reveals significant disparity in documenting cognitive decline among socio‐economically disadvantaged groups. This underscores the need for targeted outreach and intervention, and reinforces the role of comprehensive documentation in improving patient outcomes by facilitating earlier diagnosis and treatment.
Pathway Enrichment of Longitudinal AD Endophenotypes Identifies Potential Therapeutic Targets for Modifying Disease Trajectory
Authors: Rosewood Thea Jacobson , Nho Kwangsik , Risacher Shannon L. , Liu Shiwei , Gao Sujuan , Saykin Andrew J.
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by longitudinal changes of biomarker endophenotypes over the course of the disease prodrome, onset, and progression. The genetic pathways that influence these heterogenous changes in longitudinal endophenotype trajectories may provide insight into disease mechanisms and represent potential therapeutic targets.

Methods

Longitudinal endophenotypes from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were selected: amyloid‐β (Amyloid PET and CSF), total tau and phosphorylated tau (CSF), glucose metabolism (FDG PET), neurodegeneration (atrophy on MRI), and cognition (composite scores for memory and executive functioning). Genome‐wide association analysis for the selected longitudinal endophenotypes was performed using Linear Mixed Modelling (LMM; LME4 R package), with (Time x Subject) as a random effect and age as the time variable. Gene‐based association analysis was performed using MAGMA on SNP P values from the LMM. The SNP to gene assignment was performed in two steps to select SNPs with a functional relation to each target gene: SNPs within gene transcription start and end positions, and SNPs that have significant eQTLs in brain tissue from the MetaBrain eQTL project. Gene‐based analysis results were then processed for gene‐set enrichment with MAGMA and the C2 curated gene set collection from the Gene Set Enrichment Analysis (GSEA) Molecular Signatures Database (MSigDB).

Results

Pathway enrichment analysis identified 19 pathways (Figure 1) as significantly associated with longitudinal trajectories of AD endophenotypes. These pathways fall into six groups, with each pathway group having stronger association with different types of endophenotypes. Immune and cytoskeletal pathways largely associated with changes in amyloid trajectory. Metabolic pathways associated strongly with changes in amyloid and tau trajectories. Glycosylation pathways were associated with changes in brain atrophy. Pathways related to cell and neuronal signaling associated with changes in cognition, tau, and amyloid trajectories. Cell growth and survival was associated with changes in neurodegeneration trajectory (structural atrophy and hypometabolism).

Conclusions

Pathway enrichment analysis of genetic variation associated with longitudinal changes of AD endophenotypes identified pathways that uniquely associate with trajectories of key AD biomarkers and cognition. These pathways may provide insight into AD pathological mechanisms and constitute new potential therapeutic targets to modify disease trajectory.
Performance of plasma biomarkers for diagnosis and prediction of dementia in a Brazilian cohort
Authors: Santos Luis E , Mattos Paulo , Pinheiro Thaís , Silva Ananssa , Drummond Claudia , Sudo Felipe K. , Barros‐Aragão Fernanda , Vanderborght Bart , Brandão Carlos O , Ferreira Sergio T , Tovar‐Moll Fernanda , De Felice Fernanda G ,   IDOR Memory Clinic Initiative
Published: January 2025

Background

Dementia is a growing concern throughout the developing world and is severely underdiagnosed among the Brazilian population. Despite remarkable progress in the biomarker field in recent years, local testing and validation of plasma biomarkers of AD and dementia is still lacking in Brazil and Latin America.

Method

In this longitudinal cohort study of 145 participants, the diagnostic performance of plasma biomarkers was assessed based on clinical diagnosis and CSF biomarker positivity. Follow‐up data of up to 4.7 years were used to determine biomarker performance in predicting diagnostic conversions. The study was conducted at the Memory Clinic at the D’Or Institute for Research and Education (IDOR) in Rio de Janeiro. Participants were volunteers referred to the service. All were native Brazilians, had Portuguese as their first language and 60+ years of age. They were diagnosed (DSM‐5 criteria) and underwent extensive psychiatric and laboratory assessments. Diagnoses outside the scope of the study were excluded. CSF biomarker data was available for 34% of the sample. Participants were categorized as cognitively normal controls (n = 49), amnestic mild cognitive impairment (aMCI; n = 29), Alzheimer’s disease (AD; n = 37), Lewy body dementia (n = 23), or vascular dementia (n = 7). Plasma samples collected at initial and follow‐up visits were tested for relevant biomarkers.

Result

Plasma Tau, Aβ40, Aβ42, NfL, GFAP, pTau231 and pTau181 were measured on the SIMOA HD‐X platform. Results were evaluated against clinical diagnosis and CSF biomarker status. Plasma NfL and GFAP could discriminate between all‐cause dementia and controls with ROC AUCs of 0.79 (95% CI: [0.70–0.87]) and 0.74 [0.65–0.83], respectively. Plasma pTau181 had good diagnostic performance discriminating clinical AD (AUC = 0.89 [0.82–0.96]), CSF‐biomarker+ aMCI/AD (AUC = 0.90 [0.82–0.98]), or CSF‐biomarker‐confirmed AD (AUC = 0.95 [0.89–1.00]) from controls.

Conclusion

In this first description of the plasma biomarker profile of a Brazilian dementia cohort, plasma pTau181 confirmed its potential as a clinically useful diagnostic tool. This study comprises an initial step towards local validation and adoption of dementia biomarkers in Brazil and Latin America.
Anti‐epilepsy drug therapy in a dox‐regulatable TDP‐43 mouse model of ALS‐FTD with seizures
Authors: Ra Irene , Jia Elizabeth , Gujral Jaskreet , Rodemer William , Porta Sílvia , Lee Virginia M.‐Y.
Published: January 2025

Background

Cytoplasmic inclusions of TDP‐43 are the primary pathology in the majority of ALS and FTLD cases. Recent reports in cell and animal models suggest TDP‐43 pathology may enhance neuronal excitability, which could contribute to neurodegeneration via excitotoxicity. Dox‐regulatable rNLS8 mice express human TDP‐43 with mutations in the nuclear localization signal (hTDP‐43NLSm) to promote cytoplasmic accumulation. Preliminary electrophysiological data indicate these mice develop robust hyperexcitability in brain circuits along with generalized seizures. To test whether reducing hyperexcitability may be therapeutic, we administered the anti‐epilepsy drug, levetiracetam, to rNLS8 mice and assessed its effects on behavior and neurodegeneration.

Method

hTDP‐43NLSm expression was induced by replacing doxycycline‐chow with normal mouse feed (off‐DOX) in a cohort of 16 adult rNLS8 mice, approximately equal numbers male and female. Starting 1 week off‐DOX, 100mg/kg levetiracetam (LEV) or 0.5% w/w hydroxypropyl methylcellulose with 1% Tween‐80 vehicle (VEH) was administered by daily gavage. At 4 weeks off‐DOX, mice were subjected to a behavior battery including cognitive (Y maze, elevated zero maze, 3‐chamber social interaction test) and motor (accl. rotarod, open field) tests. Brains were collected for histology at 6 weeks off‐DOX.

Result

No improvement in behavioral deficits was observed in LEV treated mice. Preliminary analysis indicated a potential mild reduction in gross neurodegeneration. Mean hippocampus mass at 6 weeks off‐DOX was similar for both groups (21.7mg LEV, 22.mg VEH; Student’s t‐test, p = 0.84) but the LEV treated group showed a trend towards reduced cortical atrophy (mean motor cortex thickness on H&E stained sections: 943µm LEV, 870µm VEH; Student’s t‐test, p = 0.12).

Conclusion

Daily levetiracetam administration was not effective in significantly reducing disease severity. Future studies will examine the effect of orthogonal approaches, such as AAV encoded chemogenetics, and characterize downstream mediators of TDP‐43 ‐induced hyperexcitability, which may serve as more potent and specific therapeutic targets.
Rippl and the Alzheimer’s Association: Enhancing Community Support for Caregivers and People Living with Dementia
Authors: Evans Katie
Published: January 2025

N/A N/A N/A N/A N/A N/A N/A N/A