bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1b trial on the safety, tolerability and immunogenicity of anti‐amyloid vaccine ALZ‐101 in subjects with MCI or mild AD
Authors: Zetterberg Henrik , Rinne Juha O. , Sandberg Anders , Lovró Zsófia , Scheinin Mika , Pierrou Stefan , Harting Kirsten
Published: January 2025

Background

ALZ‐101 is a vaccine comprised of stabilised oligomeric Aβ42 that stimulates a humoral immune response primarily targeting a toxic, low‐abundant oligomeric form of Aβ. Part A of a clinical Phase 1b trial (ALZ‐C‐001; NCT05328115) was recently concluded with the objectives to assess the safety, tolerability and immunogenicity of ALZ‐101 in subjects with mild AD or MCI due to AD.

Methods

Participants were randomised to receive placebo (n = 6), 125 µg (n = 10) or 250 µg (n = 10) doses of ALZ‐101 at weeks 0, 4, 8, and 16. Primary endpoint safety parameters, including brain MRI scans, were assessed at baseline and before each injection with a follow‐up assessment at week 30. Secondary endpoints included immunogenicity assessments for which blood samples were collected throughout the study. Exploratory endpoints included measuring CSF levels of Aβ, tau, NFL, neurogranin, and inflammation biomarkers for which samples were collected at weeks 0 and 20. Part A of the study includes all data up to week 30; brain MRI was not carried out on all participants at this time point.

Results

26 eligible participants were dosed in the randomised, double‐blind, placebo‐controlled Part A of study ALZ‐C‐001. The average MMSE and CDR‐SB scores at baseline were 23.9±0.6 and 2.9±1.1, respectively.

The study met its primary and secondary endpoints. The vaccine was well tolerated. There were no cases of suspected meningoencephalitis or ARIA‐E. One participant had an MRI finding suggestive of an increase in size of a pre‐existing microhaemorrhage.

The vaccine proved immunogenic with oligomer‐specific antibody titres evolving after three administrations. Th2 activity was confirmed by antigen‐recall assays on PBMCs using ELISpot. Higher antibody titres at week 20 correlated with decreases in several CSF biomarkers of AD (p‐tau181, total tau, and neurogranin), but no such associations were observed for neuroinflammation markers (YKL‐40 and sTREM‐2).

Conclusion

The results suggest that ALZ‐101 vaccination is safe and generates an Aβ oligomer‐specific humoral immune response that has an impact on several biomarkers associated with disease progression. Taken together, these findings support further development of ALZ‐101 as a potential novel disease‐modifying treatment for patients with AD.
Treatment landscape and caregiver status for Alzheimer’s disease patients in Canada by disease severity: results from a real‐world survey
Authors: Glass Jennifer , Walker Chloe , Boulay Luc , Estrada Brenda Botello , Cotton Sarah , Laforce Robert , Gauthier Serge , Tarride Jean‐Eric
Published: January 2025

Background

Caregiver burden associated with Alzheimer’s disease (AD) increases with AD severity, and current treatment options are limited. We aimed to describe the caregiver and treatment landscapes for patients with AD in Canada, split by disease severity.

Method

Data were drawn from the Adelphi Real World AD Disease Specific Programme (DSP)™, a cross‐sectional survey of physicians in Canada, from March to October 2023. Physicians reported data on caregiver involvement in the care of patients with mild cognitive impairment (MCI)/AD and on patients’ current treatment profiles in patient record forms. Non‐professional caregivers of these patients were invited to complete a voluntary caregiver survey, which included caregivers’ characteristics. Patients were defined as having MCI or mild, moderate, or severe AD, according to current diagnostic label and physician‐reported disease severity. Analyses were descriptive.

Result

Fifty physicians reported data on 384 patients with MCI/AD (mean age 77.6±9.1 years, 54.2% female). Data from 41 non‐professional caregivers was captured in the caregiver survey. The average number of caregivers per patient overall was 1.7 (1.0) and 2.1 (1.1) for patients with severe AD (Table 1). Professional caregivers were primarily home help (49.2%). Most patients (77.8%) received non‐professional care. Partners cared for 60.5% of patients overall and 58.6% of patients with severe AD. Non‐professional caregivers spent 87.7±65.0 hours per week on average caring for patients with severe AD and 63.7±63.8 hours per week caring for patients overall. The symptom caregivers cited as causing them the most trouble was the patient forgetting recent events (52.6%) (Table 2). Patients needed most help with preparing meals or cooking (75.6%). Physicians indicated that 49.5% of patients were receiving treatment for AD symptoms, primarily acetylcholinesterase inhibitors (91.1%; Table 3). Treatment was being received by 48.6% of patients with severe AD versus 61.8% of patients with moderate AD and 58.5% of patients with mild AD.

Conclusion

The burden of care on the family of patients with AD in Canada is substantial. More caregivers and caregiver time were required on average for patients with severe AD than patients overall, and fewer patients with severe AD received treatment for AD.
Plasma biomarkers of Alzheimer’s Disease and neurodegeneration in relatively healthy older community‐dwelling individuals
Authors: Ryan Joanne , Murray Anne , Wu Zimu , Mielke Michelle M.
Published: January 2025

Background

Blood‐based biomarkers of Alzheimer’s Disease (AD) are ideally suited for use at the population level for screening, diagnosis, and for serial assessments to track disease progression. However, a number of critical knowledge gaps remain. Importantly, 1) these biomarkers have not been sufficiently examined in longitudinal studies of older community‐based populations without diagnosed dementia; and 2) it is unclear how participant characteristics such as sociodemographic characteristics and chronic conditions affect the clinical interpretation of these biomarkers.

Method

In the U.S and Australia, we recruited 19,114 community‐dwelling individuals aged ≥70 years (U.S African‐Americans and Hispanics ≥65 years), without major cognitive impairment, cardiovascular disease and physical disability. Over 13,000 participants provided blood samples, and plasma amyloid‐beta (Aβ40 and Aβ42), phosphorylated tau (p‐tau 181), neurofilament light (NfL), and Glial Fibrillary Acidic Protein (GFAP) were measured [Simoa N4PE and Ptau181 v2 assays].

Result

NfL levels were moderately correlated with the levels of GFAP (r = 0.51), and p‐tau181 had a low correlation with each of these biomarkers (r = 0.29 and 0.20 respectively). All other biomarkers were only weakly correlated with one another (Figure 1). Females (n = 7,218) had significantly lower levels of p‐tau181 (β: ‐0.117, p<0.001) but higher levels of NfL (β: 0.058, p<0.001), GFAP (β: 0.236, p<0.001), and Aβ42/40 ratio (β: 0.023, p<0.001) than males (n = 5,942). For both sexes, age was positively associated with levels of p‐tau181, NfL and GFAP, and negatively associated with Aβ42/40 ratio (Table 1). Ethnic and racial differences were also observed. After adjusting for age and sex, chronic kidney disease was associated with significantly higher levels of all plasma biomarkers, while alcohol consumption and obesity were associated with lower levels of p‐tau181, NfL and GFAP. Hypertension and polypharmacy were associated with significantly higher Aβ42/40 ratio and NfL, while frailty was only associated with higher NfL. Depression, dyslipidemia, gout, asthma and osteoarthritis, were not strongly associated with any biomarkers.

Conclusion

Plasma biomarkers of AD and neurodegeneration appear to vary across sociodemographic characteristics, and might be directly influenced by certain lifestyle factors and chronic conditions. These findings highlight the importance of considering these factors when interpreting biomarker levels in regards to AD risk.
Effects of regional neurotransmitter receptor densities on modelling amyloid and tau accumulation in Alzheimer’s disease with network spreading models
Authors: Soskic Sonja , Thompson Elinor , He Tiantian , Schroder Anna , Oxtoby Neil P , Alexander Daniel C
Published: January 2025

Background

Neurotransmitter receptors’ contribution to Alzheimer’s disease (AD) pathology development has been implicated by basic science studies but is yet to be fully established. Here, we incorporate receptor density maps into network spreading models to predict amyloid and tau patterns in AD, reflecting their potential roles in facilitating or impeding pathology production and connectivity‐mediated spread.

Method

Amyloid‐PET positive individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were divided into “early” (n = 119) and “late” (n = 69) pathology groups according to tau accumulation in the temporal cortex (Figure 1A). Cortical amyloid and tau SUVRs were group‐averaged and compared with model predictions using Pearson’s correlations.

Relevant regional cortical receptor densities (“receptors”) were obtained from PET data of healthy individuals (Hansen et al., Nat Neurosci 2022) (Figure 1B).

We used our centre’s Network Spreading Models Toolbox (https://github.com/ucl‐pond/network_spreading_models) to model connectivity‐mediated spread of amyloid and tau. We use the receptors to weight the spread and additional local production model terms, and assess the advantage of these receptor‐weighted models in predicting pathology patterns over models without receptors (Figure 1C).

Receptors showing significant negative regional correlation with pathology at baseline, indicating a possible protective role, were inverted and scaled to range 0‐1 to downweigh model terms; otherwise, they were scaled to range 1‐2 to upweight the terms. For tau prediction, we also weighted model terms with group‐matched regional amyloid, and with the regional product of amyloid and receptors to reflect their interaction. Best performing models were selected using Akaike weights.

Result

Amyloid deposition in both groups was modelled best by 5HT2A‐weighted models (r = 0.78) (Table 1, Figure 2A&B).

“Early” tau accumulation was best predicted by weighting with amyloid x inverted‐NMDA (r = 0.75), outperforming amyloid‐only weighting (r = 0.51) (Figure 2C).

For “late” tau accumulation, top three models performed similarly: weighting with amyloid x 5HT4 (r = 0.79), x inverted‐5HTT (r = 0.81) or x 5HT1A (r = 0.79). Amyloid‐only weighting also performed well (r = 0.75) (Figure 2D), and better than weighting with any receptor alone.

Conclusion

Neurotransmitter receptor densities can improve model predictions of amyloid and tau patterns in the AD continuum. Serotonergic and glutamatergic receptors appear most predictive, implying their possible role in AD pathology progression.
The role of the amyloid precursor protein (APP) on tau phosphorylation and aggregation in Alzheimer’s Disease
Authors: Yuwono Annetta , Guimaraes Thais Rafael , Thathiah Amantha
Published: January 2025

Background

Alzheimer’s Disease (AD) is characterized by the accumulation of amyloid‐β (Aβ) plaques and neurofibrillary tangles (NFTs). NFT formation is due to the progressive pathological accumulation and aggregation of the microtubule‐associated protein tau (MAPT) in degenerating neurons. Intriguingly, the amyloid precursor protein (APP), which is cleaved to generate Aβ, is specifically upregulated in NFT‐bearing neurons. Moreover, familial mutations in APP, but not MAPT, play a causal role in AD development. Although APP pathobiology is undoubtably involved in AD progression, the lack of appropriate models has hindered our understanding of whether APP directly impacts tau aggregation in AD.

Method

We investigated the involvement of APP in tau aggregation and phosphorylation using HEK293 cells that overexpress full‐length APP and a novel optogenetic system to induce tau aggregation, termed optoTAU. We utilized biochemical and immunocytochemical analysis of total tau, phosphorylated tau (pTau), APP, and Aβ species to establish a causal role and investigate the putative mechanism via which APP influences tau pathogenesis.

Result

First, we show that overexpression of APP in optoTAU expressing cells increases tau aggregation, favoring increases in pTau levels. Despite a known relationship between Aβ generation and pTau formation, we show that treatment with α‐, β‐, and γ‐secretase inhibitors does not reverse APP‐mediated tau aggregation. As such, we investigated Aβ‐independent mechanisms through which APP may influence tau aggregation. We show that tau and APP directly interact, and this interaction is enhanced in cells undergoing tau aggregation. Furthermore, APP‐bound tau is not bound to tubulin and aggregated tau displays reduced co‐localization with tubulin, suggesting a putative effect of tau aggregation in disrupting tau physiological interactions. Lastly, we show that APP overexpression enhances cell toxicity in the presence of tau aggregation, which could further potentiate neuronal death in AD brains.

Conclusion

Our results elucidate a direct impact of APP on tau aggregation and confirm the synergistic effect of APP and tau in AD pathogenesis. Future studies aimed at harnessing this relationship in patient‐derived neurons will continue to dissect APP‐dependent mechanisms upstream of tau pathogenesis.
Genetic Association Analyses of Longitudinal Cognitive Changes Related to Alzheimer’s Disease in Diverse Populations
Authors: Wu Xian , Aung Khine Zin , Abner Erin L. , Nelson Peter T , Fardo David W. , Katsumata Yuriko
Published: January 2025

Background

Late‐onset Alzheimer’s disease (LOAD) is highly heritable. 1 Recent research suggested that population‐specific LOAD genetic risks may exist. 2 The Mini‐Mental State Examination (MMSE; a measure of global cognitive function) has been commonly used to monitor AD‐related cognitive changes. MMSE raw scores have a strong ceiling effect (upper limit = 30 points). In a previous study, we demonstrated that the Tobit model utilizing ceiling information for estimation, is a superior approach compared to the linear model. 3 In this study, we aim to employ Tobit modeling to investigate associations of single nucleotide variants (SNVs) with MMSE scores to identify population‐specific genetic risks.

Method

The phenotype data were drawn from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) September 2022 data freeze. The genotype data were obtained from the Alzheimer’s Disease Genetics Consortium (ADGC). Alongside self‐reported race/ethnicity, we applied the principal component analysis (PCA) and uniform manifold approximation and projection (UMAP) to identify genetic‐ancestry (GA) groups (Fig. 1). Within each GA group, we performed association analyses of 82 AD‐related SNVs identified by a genome‐wide association study (Bellenguez et al., 2022), on MMSE using mixed‐effect Tobit modeling, adjusting for age at baseline, sex, education, and 2‐4 PC scores. We utilized Bonferroni correction to set P = 6.10 × 10−4 for multiple testing.

Result

Three GA groups were included in analyses: non‐Hispanic White (NHW, n = 15,112), African American (AA, n = 2,392), and Hispanic (n = 1,159). Genetic variants were associated with MMSE shown in Table 1. At baseline, in NHW, genes CR1, SORT1, PRKD3, BIN1, INPPSD, MME, UNC5CL, CD2AP, TMEM106B, SPDYE, USP6NL, MS4A4A, EED, SLC24A4, SPPL2A, MAF, PLCG2, and ABCA7 were associated with initial cognitive performance (ICP). In contrast, only BIN1 showed an association with ICP in AA, while LILRB2 was associated with ICP in Hispanics. Moreover, CR1 in NHW, NCK2 in AA, and EED in Hispanics were associated with change in MMSE scores over time.

Conclusion

Our findings underscore the importance of considering population‐specific genetic variants when studying AD‐related longitudinal cognitive changes. Novel genetic risks may vary across GA groups and be further revealed in future studies.
Resting state EEG theta/beta power ratio and cognitive reserve in cognitively unimpaired older adults
Authors: Korthauer Laura E. , Sinople Julia , Gemelli Zachary T , Heindel William C , Festa Elena K
Published: January 2025

Background

Patients with mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease show a pattern of “slowing” on resting state electroencephalography (EEG), often indexed by ratio of theta to beta power. The objective of this study was to investigate associations between theta/beta power ratio, subjective cognitive decline, and cognitive reserve in cognitively unimpaired older adults at high versus low risk for AD.

Method

Cognitively unimpaired older adults at high risk (APOE e4 carrier and positive family history; N = 25) or low risk (APOE non‐e4 carrier and negative family history; N = 25) for AD completed questionnaires about subjective cognitive decline (SCD; Everyday Cognition Scale) and cognitive reserve (Cognitive Reserve Index Questionnaire). Five minutes of eyes‐open 64‐channel resting state EEG was acquired. Data were separated into 2s epochs for analysis, and ratio of theta to beta power at left (F3, F5, F7), mid (Fz, FCz, Cz), and right (F4, F6, F8) frontal electrodes was calculated.

Result

After controlling for age, there was a significant positive association between cognitive reserve index and theta/beta power across left, right, and midfrontal regions (all r’s > .30, p’s < .03). The magnitude of these associations did not differ between people at high versus low risk for AD. However, only the high‐risk group showed a significant positive association between higher right and left frontal theta/beta ratio and greater SCD symptoms (r’s > .4, p’s < .05).

Conclusion

A pattern of EEG slowing (higher theta/beta ratio) was associated with greater SCD selectively in those at high risk for AD. Interestingly, increased EEG slowing was also associated with greater cognitive reserve in cognitively unimpaired older adults. One potential explanation for these findings is that people with higher cognitive reserve are able to maintain a cognitively unimpaired state despite the presence of AD‐related EEG slowing while those with lower cognitive reserve cannot; however, biomarker studies are needed to clarify.
Characterizing A‐T+ PET participants across the Alzheimer’s disease spectrum in the ADNI cohort
Authors: Bowie Daniel C , Yakoub Yara , Villeneuve Sylvia ,   Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

For individuals on the Alzheimer’s disease trajectory, amyloid positivity generally precedes tau positivity, as defined by PET biomarkers. However, multiple studies report amyloid‐negative tau‐positive PET (A‐T+) participants, whose clinical implications remain unclear. Here, utilizing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we examined how A‐T+ participants differ from other A/T profiles based on cognition, fluid biomarkers, and neuropathology—we also investigated the longitudinal trajectories of A‐T+ participants.

Method

We studied 806 participants from the ADNI cohort who underwent an initial amyloid (18F‐Florbetaben, FBB, or 18F‐Florbetapir, FBP) and tau (18F‐Flortaucipir, FTP) PET‐scan. The amyloid‐positivity thresholds for FBB and FBP were SUVR = 1.08 and SUVR = 1.11, respectively. Tau‐positivity was set as 2SD above the mean of Aβ‐PET negative CU participants in a neocortical ROI (SUVR = 1.24). The A‐T+ participants were then compared to other A/T biomarker groups in terms of clinical diagnoses, CSF/plasma Aβ and ptau, and hippocampal volume. Using a similar approach, we assessed the concordance of A‐T+ participants using CSF Aβ42 (981 pg/mL) and phosphorylated tau 181 (24.3 pg/mL) instead. Finally, we assessed the cognitive and biomarker trajectories of PET A‐T+ participants.

Result

Twelve participants were classified as PET A‐T+. Of eleven PET A‐T+ participants with CSF biomarker data, only two (18%) were also CSF A‐T+ (A‐T‐ = 4, A+T‐ = 2, A+T+ = 3). Across all outcomes, A‐T+ (PET or CSF) participants fared similarly to A‐T‐ participants (Figures 1 and 2). Overall, PET A‐T+ exhibited benign longitudinal trajectories (Figure 3). However, one participant, classified as PET A‐T+ but CSF A+T+, displayed concomitant precipitous declines across all cognitive domains, which coincided with an acceleration in neocortical tau burden.

Conclusion

While displaying pathological levels of cerebral tau, PET A‐T+ participants are highly similarly to PET A‐T‐ participants. Additionally, there is minimal overlap between PET A‐T+ and CSF A‐T+ participants, emphasizing the fact that PET and CSF biomarkers are not interchangeable. While A‐T+ may reflect participants with primary age‐related tauopathy (PART), in which amyloidosis is not the primary driver of tau accumulation, some A‐T+ participants might also have amyloidosis levels that are not yet detectable with PET.
Associations between Neighborhood‐Level Disadvantage and Neuroimaging Markers of Microstructural Neurodegeneration Across the Alzheimer’s Disease Continuum: A Mixed‐Longitudinal Study
Authors: Moody Jason F , Buckingham William R. , Powell W. Ryan , Dean Douglas C , Alexander Andrew L , Kind Amy J.H. , Bendlin Barbara B.
Published: January 2025

Background

Residence in highly socioeconomically disadvantaged neighborhoods has recently been associated with Alzheimer’s disease (AD) neuropathology at autopsy, cognitive decline, and magnetic resonance imaging (MRI) markers of volumetric brain atrophy in cognitively unimpaired adults. Furthermore, there is mounting evidence that markers of brain microstructure derived from diffusion‐weighted MRI (DWI), including neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISO), are sensitive to AD‐related neurodegeneration.

In this study, we used linear mixed‐effects (LME) modeling to investigate the hypothesis that neighborhood‐level disadvantage is associated with mixed‐longitudinal trajectories of microstructural neurodegeneration in 539 late‐middle‐aged participants across the AD continuum.

Methods

539 participants (Table 1) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center were imaged between 1 and 5 times with multi‐shell DWI (constituting 865 total scans). For each scan, average NDI, ODI, and ISO values were extracted from the hippocampus, anterior parahippocampal gyrus, and whole brain cortical gray matter. Geocoded participant addresses were linked to neighborhood disadvantage as measured by the Area Deprivation Index, a marker derived from 17 census indicators of education, employment, poverty, and housing quality. Statewide ADI was binarized for each participant (the highest quintile/most disadvantaged or lowest 4 quintiles/least disadvantaged) and used as a predictor of DWI metrics in LME models with age, sex, diagnosis, education level, and interactions between ADI and age and ADI and diagnosis as covariates.

Results

NDI—a measure sensitive to axonal and dendritic loss—was significantly lower (denoting more neurodegeneration) in the most disadvantaged group in all three assessed brain regions (PCorrected < 0.05), and there was a significant interaction between ADI and age (PCorrected < 0.05) for hippocampal NDI (Figures 1‐2). No other ADI‐DWI associations or ADI interactions survived Benjamini‐Hochberg correction for multiple comparisons.

Conclusion

Our findings suggest that living in a disadvantaged neighborhood is associated with neuronal degeneration, evidenced by the apparent loss of neurites, and that this process accelerates with age across the AD continuum. As a result, addressing disparities in the social determinants of health may have the potential to reduce the likelihood of neuronal injury in aging adults.
Independently validating a novel modification to the Single Molecule Array technology in a pilot Alzheimer’s disease cohort
Authors: Alawode Deborah O T , Fernandes Syrena , Heslegrave Amanda J , Kan Cheuk W , Rissin David , Duffy David C , Zetterberg Henrik
Published: January 2025

Background

A novel improvement to Quanterix Corporation Single molecule array (Simoa) SR‐X instrument has been shown to offer up to 100‐fold increased sensitivity compared with standard Simoa HD‐X and SR‐X instruments. We independently validated this increased sensitivity using the Simoa interleukin 17A (IL17A) assay.

Method

IL17A was measured in 32 paired Alzheimer’s disease (AD; n = 13) and control (CTRL; n = 19) serum and cerebrospinal fluid (CSF) samples. Mean IL17A concentrations were compared in both biofluids measured using four Simoa instruments ‐ one HD‐X instrument and three SR‐X instruments modified to improve the efficiency of reading beads.

Result

HD‐X quantified IL17A in 0% of CSF samples and 37.5% of serum samples, with mean serum IL17A concentrations of 0.126pg/mL in AD and 0.228pg/mL in CTRLs. In contrast, the modified SR‐X instruments A, B and C quantified CSF IL17A in 84.4%, 96.9% and 96.9% of CSF samples, respectively, with mean AD concentrations of 2.92fg/mL, 5.95fg/mL and 7.25fg/mL, respectively, and mean CTRL concentrations of 3.60fg/mL, 4.75fg/mL and 9.02fg/mL, respectively. Furthermore, the modified SR‐X instruments A, B and C all quantified IL17A in 100% of serum samples, with mean serum AD concentrations of 0.145pg/mL, 0.285pg/mL, and 0.249pg/mL, respectively, and mean CTRL concentrations of 0.300pg/mL, 0.406pg/mL and 0.362pg/mL, respectively. There were no statistically significant intra‐instrument differences between AD compared with CTRLs. All three modified SR‐X serum concentrations showed a strong positive statistically significant correlation with HD‐X serum concentrations. All three modified SR‐X serum concentrations also showed a strong positive statistically significant correlation with one another. Finally, all three modified SR‐X instruments showed no correlation between serum and CSF concentrations, in line with previous literature.

Conclusion

Increasing the bead reading efficiency of the SR‐X exhibits increased sensitivity compared with the standard Simoa HD‐X instrument, allowing the quantification of IL17A in CSF and a greater yield of serum samples.
Effect of CYP2C9 Polymorphism on Neuropsychiatric Symptoms in Alzheimer’s Dementia
Authors: Gutiérrez Evelyn , Tangarife Maria Alejandra , Rao Jagadeesh S , Venegas Margarita , Arbeláez María Juanita , Sánchez Laura Tatiana , De Jesus William Julio , Pujals Karen Y , Grimaldi Claudia , Hong Elliot , Mukunda Ram
Published: January 2025

Background

Alzheimer’s Disease (“AD”) presents a significant global health burden, often requiring medication management of comorbidities, some of which are metabolized by the polymorphic enzyme CYP2C9. We investigated the impact of CYP2C9 polymorphism on the reduction of Neuropsychiatric Inventory (NPI‐12) scores following administration of IGC‐AD1, comprising THC and melatonin, in AD patients.

Method

Thirteen Puerto Rican AD patients (mean age: 80.18±6.22 years, 70% women) participated in a Phase‐1 trial. Ten active participants received IGC‐AD1 once a day (“Cohort 1”, “QD”), twice a day (“Cohort 2”, “BID”), or thrice daily (“Cohort 3”, “TID”) for 14 days (“EOT”) with a washout period. NPI‐12 was assessed at baseline and endpoint, and participants were grouped by CYP2C9 phenotype. CYP2C9 polymorphisms include normal (“NM”, allele *1/*1), intermediate (“IM”, alleles *1/*2, *1/*3), and poor (“PM”, alleles *2/*2, *3/*3, and *2/*3) metabolizers, among others. Wilcoxon signed‐rank and t‐tests compared baseline to endpoint NPI‐12 scores.

Result

No significant associations were found between CYP2C9 NM and IM phenotypes in reducing NPI‐12 scores from baseline to EOT across all cohorts. However, NM showed higher NPI reductions than IM in Cohorts 1 (NM: 53.95%, IM: 45.65%) and 2 (NM: 67.65%, IM: 32.64%). In Cohort 3, IM had a comparable reduction (NM: 33.33%, IM: 35.04%).

Conclusion

IGC‐AD1 demonstrated tolerability and potential efficacy in reducing Neuropsychiatric Symptoms in AD, with NM showing greater reductions after 1‐ and 2‐mL administrations, though similar reductions were observed with 3 mL. Further investigation with a larger sample is continuing.
The effect of exercise and ApolipoproteinE ε4 on hippocampal volume in middle‐aged sedentary adults with heightened risk for Alzheimer’s disease
Authors: Slutsky‐Ganesh Alexis B , Etnier Jennifer L , DuBois Samantha L , Vance Jarod C , Park Kyoung Shin , Bechke Emily , Som‐Pimpong Hadassah , O'Brokta Megan M , Thibodeau Delaney , Ueno Aiko , Karper William B , Armstrong Brittany D , Labban Jeffrey D , Hugenschmidt Christina E , Wideman Laurie
Published: January 2025

Background

ApolipoproteinE ε4 carriers (ε4+) have a heightened risk for Alzheimer’s disease (AD) and experience accelerated hippocampal volume (HV) loss during older adulthood, which tends to precede cognitive decline. Exercise interventions can increase HV in sedentary older adults, however it’s currently unknown how exercise affects HV in sedentary middle‐aged adults and if ε4 carrier status moderates this relationship.

Methods

A subset of 44 adults from an ongoing randomized controlled clinical trial (NIH/NIA: R01AG058919) completed baseline (pre), 6‐month (mid), and 12‐month (post) testing during a one‐year exercise intervention (n = 29, 52% ε4+, 5 males, Agemean = 55.05±6.20) or usual care control (control; n = 15, 53% ε4+; 3 males, Agemean = 60.27±3.65). Participants were cognitively normal, sedentary, and had a family history of AD (FH+). Genetic sampling was completed at pre‐test via passive drool. Structural neuroimaging was completed at pre‐, mid‐, and post‐test. Brain segmentation was completed with Freesurfer’s automated hippocampal longitudinal pipeline (v7). Left and right HVs were extracted and normalized based on intracranial volume. Group (exercise, control) x time (pre, mid, post) x carrier status (ε4+, ε4‐) interactions were examined with mixed model analysis of covariance for the left and right HV, controlling for age. Posthoc examinations included group x time interactions within ε4+ and ε4‐ and follow‐up pairwise comparisons.

Results

There were significant three‐way interactions for left (F(1,39) = 8.76, p = .005) and right (F(1,39) = 13.48, p<.001) HV. Follow‐up group x time interactions within ε4‐ were not significant, but were significant within ε4+ for the right HV (F(1,19) = 6.40, p = .02) but not the left HV (F(1,19) = 4.27, p = .05). ε4+ exercisers increased right HV from pre‐to‐post intervention (mean change = 0.41cm3, p = .02); no other tests were significant.

Conclusion

Exercise‐related benefits for HV for sedentary cognitively‐normal, middle‐aged adults with a FH+ are such that right HV increased following one‐year of exercise in ε4+ but not in ε4‐. Though exercise generally increases HV in older adults, during middle age the effects may be limited to a vulnerable population such as ε4+ who tend to have smaller HV relative to ε4‐ throughout adulthood. The content of this abstract is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Unveiling a role of the Gβγ/PLCβ3 signaling pathway on APP endolysosomal re‐distribution and Aβ‐induced amyloidogenesis
Authors: Almirón Romina soledad , Antonino Magdalena , Marmo Paula , Lorenzo Alfredo , Bignante Elena Anahi
Published: January 2025

Background

Aβ accumulation is a key event driving neurotoxicity in Alzheimer’s disease. Previously, we demonstrated that oligomers of amyloid beta (oAβ) induce an increase in the levels of APP and BACE1 in Rab11‐positive endosomes, leading to the intracellular accumulation of Aβ1‐42 in human neurons derived from iPSCs (HN‐iPSCs). This vicious cycle of Aβ generation induced by Aβ itself, is pivotal for the propagation of pathology. We now aim to deeper into the pro‐amyloidogenic mechanisms underlying the enrichment of APP in Rab11‐endosomes.

Method

We assessed APP distribution in N2a cells transfected with APP‐YFP/BACE1‐Ch and compartment markers fused to fluorescent tags. Cells were treated with vehicle or Gβγ inhibitor gallein (5μM), oAβ (1 µM) and 24 h later quantitative colocalization analyses were conducted. APP endocytosis rate was determined via pulse‐chase assays using 22C11 antibody. Levels of APP and AICD phosphorylated at thr668 (APP‐pho668 and AICD‐pho668) in rat cortical neurons and HN‐IPSCs were determinate by immunofluorescence. Western blotting was employed to determine the levels of APP‐pho668, βCTF‐pho668, Rab11, Rab5, and PLCβ3‐pho. Super‐resolution microscopy was utilized to quantify the number and size of Rab11‐endosomes.

Result

Aβ treatment induced an enrichment of APP in Rab11‐endosomes by increasing its rate of endocytosis while decreasing its localization to lysosomes. We observed a concomitant increase in the number of large Rab11‐endosomes (greater than 300 nm). These alterations in the distribution of APP within endolysosomal compartments were mediated by Gβγ signaling, as it were prevented by pretreatment with gallein (Fig. 1, 2). Aβ treatment also provokes an increase in the levels of APP‐pho668 in process and AICD‐pho668 in nuclear speckles of cortical neurons and HN‐iPSC. Both effects were prevented with gallein or inhibitor of p38MAPK (SB) incubation. WB analysis showed an increase in APP‐pho668, βCTF‐pho668, Rab11 and PLCβ3‐pho induced by Aβ, effects mitigated by gallein and SB treatments (Fig. 3).

Conclusion

These findings suggest that Aβ treatment triggers the activation of a signaling pathway involving Gβγ/PLCβ3/p38MAPK, leading to an increase in APP phosphorylation at Thr668. This event correlates with enhanced APP endocytosis and redirecting it from its normal pathway to lysosomes towards Rab11‐endosomes which facilitates its amyloidogenic processing.
Spatial transcriptomic of hippocampal subfield‐specific pathology in Alzheimer’s disease and Primary Age‐Related Tauopathy (PART)
Authors: Wu Di , Zhang Qilei , Liu Anqi , Gong Yun , Tianying Li , Xiao Zhengwu , Xiao Hongmei , Su Kuan‐Jui , Qiu Chuan , Shen Hui , Yan Xiaoxin , Deng Hong‐Wen
Published: January 2025

Background

Alzheimer’s disease (AD) and primary age‐related tauopathy (PART) both hyperphosphorylated‐tau (pTau)‐positive neurofibrillary tangles (NFTs) but differ in the spatial pTau development and Aβ‐positive in the hippocampus. Cognitive status has been shown to be related to the overall hippocampal pTau burden, as well as the presence of β‐amyloid deposit. Spatially dissecting the subregions and the cell‐type‐specific molecular dynamics within the hippocampus among control, PART, and AD individuals is crucial for understanding the mechanisms underlying AD progression.

This study aims to construct the transcriptome‐wide, high‐resolution atlas of human hippocampus across control, PART, and AD subjects to delineate the cellular and molecular dynamics linked to the progression of AD.

Methods

Human hippocampus samples were primary collected from six Asian subjects (two AD, three PART, and one control; aged 79‐92) for our 10X Visium spatial transcriptome and single‐nucleus RNA‐seq studies, as well as subsequent analysis. After identifying the subregions of hippocampus by clustering algorithms and manual annotation, differential gene expression (DGE) analysis was conducted to uncover the region‐specific molecular alternations across controls, PART, and ADs. Deconvolution using Bayesian methods provided a detailed assessment of cellular composition and transcriptional signatures. Cell‐Chat software was utilized to illustrate the regional specific inter‐cellular interactions.

Results

Comparative analysis unveiled significant DEGs influencing specific hippocampal regions in control, PART, and AD samples, elucidating variations in cellular transcriptional expression levels across subject groups. Additionally, cell type‐specific gene communication pathways and directions are delineated, including the associated protein expressions and functional pathways.

Conclusions

Our study of the human hippocampus reveals unique, cell‐type‐specific molecular alterations to PART and AD, compared to the control samples, illuminating potential mechanisms that drive the progression of AD.
Higher locus coeruleus integrity and cognitive reserve attenuate tau‐related cognitive decline in older adults
Authors: Heinrich Lukas , Riphagen Joost M. , Koops Elouise A. , Papp Kathryn V , Rentz Dorene M , Sperling Reisa A , Johnson Keith A , Jacobs Heidi I.L.
Published: January 2025

Background

Previous research suggests that locus coeruleus (LC) integrity may partially underlie cognitive reserve (CR), as demonstrated by positive associations between composite measures of CR and MRI‐based integrity of the LC, one of the first regions in the brain to accumulate tau pathology. We investigated whether higher MRI‐based integrity of the LC confers resilience to cognitive decline related to Alzheimer’s disease pathology in individuals with higher cognitive reserve.

Method

Individuals (n = 154) with LC‐MRI, 18F‐Flortaucipir (FTP‐tau), and 11C‐Pittsburgh Compound‐B (PIB‐amyloid) PET were selected from the Harvard Aging Brain Study (Figure 1). Cognition over time was modeled using the PACC5 composite score. CR was quantified using a composite of verbal IQ, years of education, and occupational attainment (i.e., Hollingshead score). We used a data‐driven approach to cluster participants on the basis of both their CR and AD pathology. K‐means clustering was performed to group individuals based on CR and entorhinal FTP, FTP‐based Braak stage III or IV composites, or neocortical PiB. The relationship between LC MRI‐integrity and cognition over time across the cluster‐derived pathology‐cognitive reserve groups was assessed using linear mixed effects modeling (adjusted for age and sex).

Result

Cluster analysis consistently identified three groups (Figure 2, left side): High pathology/high CR; low pathology/high CR, and low pathology/low CR. Throughout all analyses, the high pathology/high CR cluster showed less steep cognitive decline over time in a dose‐response manner of LC integrity (Figure 3, right side). Attenuated cognitive decline was observed at higher levels of LC integrity in individuals with high cognitive reserve and elevated levels of FTP in entorhinal cortex compared to low FTP‐tau/low CR (ß = ‐6.19, p<0.001) and low FTP‐tau/high CR (ß = ‐6.72, p<0.001). Similar group comparisons were observed after grouping for tau in Braak stage 3 (ß = ‐10.78, p<0.001; ß = ‐10.37, p<0.001) and Braak stage 4 brain areas (ß = ‐9.61, p<0.001; ß = ‐8.80, p<0.001) and with PIB DVR (ß = ‐8.82, p<0.001; ß = ‐8.03, p<0.001).

Conclusion

These findings reveal that higher LC integrity may constitute a brain reserve measure bolstering CR in conferring resilience against cognitive decline in the face of elevated AD‐pathology. Future research aims to extend this research to LC function and networks.
A Therapeutic Small Molecule Enhances γ‐Oscillations and Improves Cognition/Memory in Alzheimer’s Disease Model Mice
Authors: Wei Xiaofei , Campagna Jesus J , Jagodzinska Barbara , Wi Dongwook , Cohn Whitaker , Lee Jessica , Zhu Chunni , Huang Christine S. , Molnár László , Houser Carolyn R. , John Varghese , Mody Istvan
Published: January 2025

Background

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ‐oscillations (30‐120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. High temporal resolution recording methods, such as magnetoencephalography, have made it clear that Alzheimer’s disease (AD) patients, starting as early as the mild cognitive impairment (MCI) stage, have diminished γ‐oscillations even before the Aβ load takes full effect. Moreover, it has been well established that almost all AD mouse models have diminished γ‐oscillations.

Method

We describe a unique pharmacological approach meant to enhance cognitive performance and working memory in a state‐dependent manner by engaging and amplifying the brain’s endogenous γ‐oscillations through enhancing the function of parvalbumin positive interneurons (PV+INs). We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule.

Result

We anatomically and pharmacologically identified GABAARs assembled of α1β2δ subunits responsible for the tonic inhibition of PV+INs. We further demonstrated that DDL‐920, a small molecule negative allosteric modulator (NAM) of these receptors, is a potent, efficacious, and selective blocker of the tonic inhibition of PV+INs and consequently enhances γ‐oscillations both in vitro and in vivo. When orally administered twice daily for two weeks, DDL‐920 restored the cognitive/memory impairments of 3‐4‐month‐old AD model mice as measured by their performance in the Barnes maze.

Conclusion

Our findings indicate that the unique subunit composition of extrasynaptic GABAARs of PV+INs should be a valid target for boosting γ‐oscillations and this should be beneficial in a variety of neurological and psychiatric disorders, including AD.
NLRP3 regulates immunometabolism, impacting microglial function in Alzheimer’s disease
Authors: McManus Roisin M. , Komes Max P , Griep Angelika , Santarelli Francesco , Schwartz Stephanie , Perea Juan , Khalil Michelle‐Amirah , Schlachetzki Johannes C.M. , Bouvier David S. , Lauterbach Mario , Schmidt Susanne V. , Gomez‐Cabrero David , Tegner Jesper , Glass Christopher K. , Hiller Karsten , Latz Eicke , Heneka Michael T.
Published: January 2025

Background

Our laboratory has demonstrated that the NLRP3 inflammasome has a critical role in the microglial innate immune response to Alzheimer’s disease (AD)‐related peptides, triggering the release of cleaved‐caspase‐1 and IL‐1β. NLRP3 activation was found in post‐mortem tissue from individuals with AD (Heneka et al., 2013) and in transgenic models of AD (APP/PS1 mice). However, APP/PS1 mice deficient for NLRP3 were protected from AD‐pathology and neuroinflammation. We wanted to examine the wider implications of NLRP3 deficiency and uncover other pathways and mechanisms employed by microglia to protect the brain from the buildup of Aβ.

Method

Single cell RNA sequencing (scRNAseq) and ATAC sequencing was performed on CD11b+ cells from the brains of wildtype, APP/PS1, NLRP3−/− and APP/PS1.NLRP3−/− mice. Microglia were prepared from wildtype and NLRP3−/− mice to assess metabolic function, phagocytosis and for flow cytometric analysis. Targets were investigated in the post‐mortem brain tissue of those with and without AD. In a separate experiment, APP/PS1 mice were treated with NLRP3‐targeted inhibitors.

Result

ScRNAseq found a unique cluster of microglia in APP/PS1.NLRP3−/− mice with pathways related to phagocytosis and glutamate metabolic signaling, with a specific increase in the glutamate transporter Slc1a3. Metabolically, NLRP3−/− microglia had increased mitochondrial and metabolic function with altered levels of the metabolite α‐ketoglutarate. NLRP3−/− microglia had greater Aβ phagocytosis than the wildtype cells, which was strictly associated with α‐ketoglutarate availability and epigenetic regulation. Importantly, we were able to replicate these findings in human cells and using NLRP3‐specific inhibitors in vitro and in vivo.

Conclusion

We have identified a new mechanism where loss of NLRP3 influences glutamine/glutamate metabolism, which modulates α‐ketoglutarate to affect epigenetic regulation and gene transcription, boosting downstream phagocytic activity (McManus et al., in revision). This pathway is conserved between murine and human cells. Critically, we can mimic this effect in vivo using NLRP3‐specific pharmacological inhibition. Together, our data strengthens NLRP3 as a master‐immune regulator and an important target in the treatment of AD and dementia.
GSK3α levels in Alzheimer´s disease mimicking models
Authors: Pinho Beatriz , Vaz Margarida , Martins Tânia Soares , da Cruz e Silva Odete , Henriques Ana Gabriela
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by the development of amyloid plaques and neurofibrillary tangles in the brain, which contribute to synaptic dysfunction and extensive neuronal loss. Protein phosphorylation is a key event in AD pathogenesis. Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase with two isoforms, GSK3α and GSK3β. While GSK3β link with AD is well stablished, the role of GSK3α in AD is not fully understood. Few studies suggest that GSK3α can be involved in tau phosphorylation, amyloid‐beta (Aβ) production, and neuronal cell death. Hence, the objective of this study was to test GSK3α levels and its potential contribution to AD.

Method

Two AD‐mimicking models were employed, SH‐SY5Y treated with the Aβ peptide and SH‐SY5Y carrying the Swedish mutation of APP695. Cell lysates were subjected to Western Blot analysis to monitor total protein levels and phosphorylation of both GSK3 and its isoforms α and β.

Result

Significant differences in the GSK3 total levels and in specific phosphorylation sites associated with protein activation were obtained for both isoforms in AD mimicking conditions.

Conclusion

This research supports that GSK3α is altered in disease conditions and offers new insights of GSK3 involvement in AD pathology. This research was supported by iBiMED UIDB/04501/2020 and UIDP/04501/2020, FCT, the COMPETE program, QREN, and the European Union. M.V. is supported by the FCT through the individual PhD grant UI/BD/151354/2021.
CCAB–Español: The California Cognitive Assessment Battery in Spanish
Authors: Jaramillo Isabella , Woods David L. , Hall Kathleen , Geraci Kristin , Blank Michael , Miranda Miranda , Ortiz‐Menchaca Alejandra , Garcia Elloise , Kahly Omar , Herron Timothy J , Williams Garrett , Johnson David K
Published: January 2025

Background

By 2060, the incidence of ADRD is predicted to increased 6‐fold in the US Hispanic population (Matthews, Xu et al. 2019). However, cognitive testing of US Hispanics is complicated by limited Spanish‐language test materials and a dearth of examiners fluent in Spanish. Here, we present preliminary results from an automated computerized battery, CCAB–Español, that administers and scores verbal and non‐verbal tests in Spanish.

Method

Spanish‐language equivalents of CCAB‐English test materials were created and presented with text‐to‐speech voices in a Mexican dialect. Participants (n = 61; age 43‐79; 64% women) completed 32 tests over three days, including verbal, visual, memory, and processing speed tests, as well as demographic and psychological questionnaires. Test were administered in participants’ homes and remotely monitored by Spanish‐speaking examiners. Verbal tasks were objectively scored using Consensus Automatic Speech Recognition (CASR). Selected tests were administered twice to assess test‐retest reliability.

Result

Reaction times, response accuracy, error types, and speech metrics were collected and analyzed. Participant satisfaction with the battery was high, with 100% of the participants completing all days of testing. Tests demonstrated excellent test‐retest reliabilities, for example the test‐retest value for delayed recall on a story recall task was .83.

Conclusion

The results from ongoing normative data collection show that CCAB‐Español is an efficient, scalable platform for the comprehensive cognitive assessment of US Spanish speakers.

Matthews, K. A., W. Xu, A. H. Gaglioti, J. B. Holt, J. B. Croft, D. Mack and L. C. McGuire (2019). “Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015‐2060) in adults aged ≥65 years.” Alzheimer’s & Dementia 15(1): 17‐24.