bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissecting the shared genetic basis of Alzheimer’s disease and hippocampal volumes
Authors: Jiang Chenyang , van der Lee Sven J , van der Flier Wiesje M. , Tijms Betty M. , Reus Lianne M.
Published: December 2023

Background

Hippocampal atrophy is an important pathophysiological event in Alzheimer’s disease (AD) etiopathology. Still the mechanistic link between these volumetric abnormalities and AD remains poorly understood. In this study, we estimated polygenic overlap with mixed effect directions between AD and bilateral hippocampal volumes, and identified commonly shared genetic variants between two traits, involved in several synaptic and immunomodulatory genes.

Method

For this study we used GWAS summary statistics on AD (1,11,326 cases and 6,77,663 controls) (Bellenguezet et al., 2022) and hippocampal volumes (33,224 populations controls) (Smith et al., 2021). First, we applied Bivariate causal mixture model (MiXeR version1.3, Frei et al., 2021) to quantify the polygenic overlap between AD and bilateral hippocampal volumes. For each AD‐volume pair, MiXeR estimated the shared polygenic architecture between two traits, irrespective of the direction of individual variants effects.

To explore the MiXeR estimated shared genetic basis at individual variant level, we used the conjunctional false discovery rate (conjFDR) analysis (Andreassen et al., 2013) on the association of AD with bilateral hippocampal volumes, and vice versa. The conjFDR analysis is built on an empirical Bayesian statistical framework. Four regions (MHC, 8p23.1, MAPT, APOE) with complex LD patterns were excluded from the analyses because complex correlations in regions with intricate LD might bias the estimation.

Result

MiXeR univariate analysis estimated the number of AD risk variants to be around 343 genetic variants, and the number of variants for bilateral hippocampal volumes between 901 and 942 variants. MiXeR bivariate analysis estimated that the number of shared variants between AD and bilateral hippocampal volumes was around 75 and 96 variants (see Figure 1). At conjFDR < 0.05, we identified 10 common loci shared by AD and left hippocampal volume,6 lead SNPs had consistent effect directions, while 4 loci have opposite effect directions according to their Z value. 8 common loci shared by AD and right hippocampal volume, 5 lead SNPs have consistent effect directions, 3 have opposite effect directions. (see Figure 2 and Table 1)

Conclusion

This study provides evidence of a shared genetic architecture between AD and bilateral hippocampal volumes. The identification of common loci helps to understand the role of hippocampus in AD pathology.
Novel Bace 1 selective inhibitor does not affect dendritic spine plasticity
Authors: Herms Jochen , Pratsch Katrin , Unemura Chie , Ito Mana , Horiguchi Naotaka
Published: December 2023

Background

All clinical BACE‐inhibitor trials for the treatment of Alzheimer´s Disease have failed due to insufficient efficacy or side effects like worsening of cognitive symptoms. The latter could have been the result of the inhibition of BACE at the synapse where it is expressed in high amounts. We have previously shown that prolonged inhibition of BACE interferes with structural and functional synaptic plasticity (Filser et al. Biol. Psych 2015, Blume et al. Front. Aging Neurosci. 2018), most likely due to the diminished processing of the physiological BACE substrate Seizure protein 6 (Sez6, Zhu et al. Biol. Psych. 2018), which is exclusively processed by BACE1 and it is required for dendritic spine plasticity. The aim of the current study was to elucidate the effects of selective BACE1 inhibitors on dendritic spine plasticity at a dose that affects Sez6 cleavage to various degrees but not completely.

Method

By using longitudinal in vivo two‐photon microscopy, we investigated the effect on dendritic spine dynamics of pyramidal layer V neurons in the somatosensory cortex in mice treated with 2 novel highly selective BACE1 inhibitors developed at Shionogi in comparison to Elenbecestat which reduce soluble Sez6 to 27% (Elenbecastat), 17% (Shionogi Compound 1) and 39% (Shionogi Compound2) of baseline levels in untreated animals. For the detection of the soluble Sez6 ectodomain, the BACE cleavage product from full‐length Sez6, Western blot analysis was performed using a highly specific Sez6 antibody generated in the lab of Stefan Lichtenthaler (Pigoni et al. Mol. Neurodeg. 2016).

Result

We observed that BACE1 selective inhibitors do not alter dendritic spine density and plasticity in cortical neurons if at least 27% of soluble Sez6 remains. In detail, the density of gained and lost spines does not change under the treatment with Shionogi Compound 2 or Elenbecastat. Also, no differences in the stability of dendritic spines were found during treatment with these two compounds. With Compound 1 however, a significant spine loss occurs after 21 days of treatment.

Conclusion

Selective BACE1 inhibitors do not alter dendritic spine plasticity in mice if dosing reduces synaptic BACE1 cleavage of Sez6 not below 27% of baseline soluble Sez6 levels. BACE1 selective inhibitors may be potential novel candidates for clinical trials treating AD if dosing is carefully adjusted to the amount of Sez6 cleavage, which can be easily monitored during the first weeks of treatment.
Replication of HLA‐DRB1*04:04 allele subtype protective effect against Alzheimer’s Disease in cognitively healthy centenarians using long‐read sequencing
Authors: Sirvent Daniel Alvarez , Salazar Alex N , Tesi Niccoló , Hulsman Marc , van der Lee Sven J , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Holstege Henne
Published: December 2023

Background

Genomic‐Wide Association Studies (GWAS) of Alzheimer’s Disease (AD) have identified several single‐nucleotide‐polymorphisms (SNPs) in the Human Leukocyte Antigens (HLA) gene cluster. Fine mapping of the genetic signals, by means of model‐based HLA allele imputation from SNP‐array‐based genotyping data, was linked to a protective effect of three HLA‐DRB1*04 allele subtypes. These alleles would favor the binding of an aggregation‐prone Tau peptide by T‐cells, promoting early clearance of toxic Tau aggregate seeds, and reducing neurodegeneration. Here, we aim to replicate this association by means of HLA genotyping with long‐read sequencing.

Method

We used an HLA genotyping assay, [NGS‐go MX11‐3, GenDx], coupled with [PacBio] long‐read sequencing. This allows for genotyping of HLA genes at their full resolution of polymorphism. So far, we have genotyped HLA genes in 129 AD cases from the Amsterdam Dementia Cohort (ADC, mean age = 67.4 with SD = 7.56, N females = 85, N males = 44) and 138 cognitively healthy centenarians from the 100‐plus Study (mean age = 101.1 with SD = 3.33, N females = 92, N males = 46), thereby maximizing the analysis power. We then focused on the comparison of previously identified protective HLA‐DRB1*04 allele subtypes (DRB1*04:01, DRB1*04:04 and DRB1*04:07) between AD cases and centenarians.

Result

For all three HLA‐DRB1*04 allele subtypes, we observed no additional genetic variation concerning synonymous DNA substitutions in coding regions and changes in non‐coding regions. DRB1*04:04:01:02 had a frequency of 0.116 in centenarians, as compared to a 0.054 in AD cases (one‐sided Fisher’s exact test, p = 0.04). The frequency in centenarians was higher than the previously reported joint frequency of carriers in AD and controls, frequency = 0.073. DRB1*04:01:01:01 had similar frequencies in centenarians (0.174) and AD cases (0.178) (p>0.05). Similarly, DRB1*04:07:01:01 had a frequency of 0.014 in centenarians and 0.015 in AD (p>0.05).

Conclusion

We confirmed a protective HLA‐DRB1*04:04 allele subtype, previously described by HLA imputation, with the use of long read sequencing. Genotyped at full resolution as DRB1*04:04:01:02, we observed an enrichment in cognitively healthy centenarians compared to the original AD vs controls setting. The HLA system could play a role in the enhanced immunity of centenarians, and how they are able to escape neurodegenerative diseases.
Movement with Dementia: A feasibility study of a resource to support the personalisation of therapeutic exercise programmes for people living with dementia
Authors: Booth Vicky , Harwood Rowan H , Foster Nadine , Graff Maud , Schneider Stefan , Wong Geoff , Pugh Pearl , Howe Louise , Logan Pip A
Published: December 2023

Background

Therapeutic exercise is commonly used by healthcare professionals to support people recovering from injury or illness. There is little guidance on how to personalise these standardised programmes for people living with dementia (PLWD). The Movement with Dementia resource was co‐designed by PLWD, exercise instructors and healthcare professionals to address this knowledge gap. The aim of this study was to explore the feasibility and usability of implementing the Movement with Dementia shared decision‐making resource to assist prescribers and deliverers of therapeutic exercise interventions for PLWD.

Method

A single site, non‐blinded feasibility study was conducted with an NHS community therapy team and their patients living with dementia. Eligibility criteria were people with a diagnosis of dementia, prescribed and undertaking an exercise programme as part of their care by the therapy team, able to provide consent and participate in the shared decision‐making process.

Therapist participants undertook training (2‐hr session) on the Movement with Dementia resource and asked to use it during prescription and delivery of exercise with the patient participants, as part of their care episode. Questionnaires recorded demographic and usability information from all participants.

Result

Between January and March 2023 we recruited 9 therapist and 6 patient participants. Four physiotherapists (100% female; mean age = 39yrs) and six patient participants (50% female; mean age = 81yrs) completed the questionnaires. Patient participants had various dementia diagnoses (n = 1 AD, n = 3 VD, n = 1 LBD, n = 1 unsure), all were white‐British, and most lived with others (n = 4).

None of the patient participants could recall using the resource, but 83% (n = 5) were still undergoing active care. All therapist participants were ‘likely’ or ‘very likely’ to recommend it but found the current material too ‘wordy’, both for themselves and PWLD. Whilst it reinforced knowledge and provided supportive ‘prompts’ for their approach, it was recommended for those with less experience treating PLWD.

Conclusion

The co‐designed Movement with Dementia resource was successfully implemented into a clinical setting to support therapists prescribing and delivering exercise programmes for PLWD. Further refinement is required before wider evaluation and implementation. A focus on supporting therapists with less experience treating PLWD will direct future study.
Association of Polygenic Risk Score of Alzheimer’s disease with A/T/N Biomarkers and Cognitive Decline
Authors: Jung Joon Hyung , Byun Min Soo , Yi Dahyun , Jung Gijung , Ahn Hyejin , Liu Shiwei , Huang Yen‐Ning , Griswold Anthony J. , Pericak‐Vance Margaret A. A , Kim Yu Kyeong , Lee Yun‐Sang , Sohn Chul‐Ho , Kang Koung Mi , Lee Jun‐Young , Saykin Andrew J. , Nho Kwangsik , Lee Dong Young
Published: December 2023

Background

Polygenic risk scores (PRS) quantify the combined effects of genetic variants to enable the prediction of an individual’s risk of developing the disease. Alzheimer’s disease (AD) is a complex disorder in which the relationship among PRS, neuropathological substrates, and related cognitive decline remain especially understudied in Asian populations. We investigated the associations of PRS with AD neuroimaging biomarkers and cognitive phenotypes in a Korean Cohort.

Method

The study included 501 older adults (264 cognitively normal [CN], 146 mild cognitive impairment [MCI], and 91 AD dementia) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). Comprehensive clinical and neuropsychological evaluations, as well as multi‐modal neuroimaging including 3T MRI and 11C‐PiB‐PET were administered. A subset of participants underwent 18F‐AV‐1451 PET (n = 167). Imaging phenotypes including beta‐amyloid (Aβ) positivity, global tau deposition, and adjusted hippocampal volume (HVa) were used for amyloid (A), tau (T), and neurodegeneration (N) biomarkers, respectively., which was imputed using the TOPMed reference panel. PRS was calculated using the summary statistics of a recent large‐scale GWAS study for AD by PRS‐CS. The Apolipoprotein E (APOE) region was excluded in the calculation. The associations between standardized PRS and imaging/cognitive phenotypes were examined using either multiple linear or logistic regression analysis with covariates (age and sex for neuroimaging biomarker phenotypes; age, sex and education for cognitive phenotypes).

Result

PRS was significantly higher in the AD dementia group compared to the CN group. Higher PRS was associated with greater CDR‐sum‐of‐boxes (β[SE] = 0.233[0.083], t = 2.818, p = 0.005) and lower MMSE scores (β[SE] = ‐0.648[0.198], t = ‐3.271, p = 0.001). In terms of AD neuroimaging biomarkers (Figure 1), higher PRS was significantly associated with an increased likelihood of Aβ positivity (OR = 1.233, 95%CI = 1.024‐1.491), and lower HVa (β[SE] = ‐132.79[49.624], t = ‐2.676, p = 0.008), but not with global tau deposition (β[SE] = 0.075[0.048], t = 1.573, p = 0.118).

Conclusion

These findings suggest that higher PRS predicts increased pathological Aβ deposition and accelerated neurodegeneration, as well as greater cognitive decline. Further investigation in larger and multiethnic samples are needed to determine generalizability to other ethnoracial populations.
A Volume‐Based Alternative for classifying ATN: Data from the Tau Propagation over Time (T‐POT) cohort
Authors: Doering Elena , Hönig Merle C. , Dzialas Verena , Lothmann Julia , Giehl Kathrin , Theis Hendrik , Jäger Elena , Andrassy Gregory , Bauer Andreas , Elmenhorst David , Kroll Tina , Matusch Andreas , Krapf Philip , Neumaier Bernd , Lerche Christoph , Tellmann Lutz , Frensch Silke , Zeyen Philip , Sand Frederik , Richter Nils , Jessen Frank , Onur Oezguer A. , Ramirez Alfredo , van Eimeren Thilo , Drzezga Alexander , Bischof Gerard N
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by the cerebral accumulation of amyloid‐beta (A), tau (T), and progressive neurodegeneration (N). The widely used ATN system, with regard to positron emission tomography (PET) biomarkers, categorizes AD based on the mean signal in specific regions of interest (ROI). However, this procedure disregards the spatial extent of pathology and neurodegeneration. Here, we propose an alternative quantification of the volume, i.e., fill states, of A, T and N in (pre)‐clinical AD.

Method

We analyzed data from the Tau Propagation over Time (T‐POT) study, including cognitively unimpaired individuals (CU, n = 58), and patients with mild cognitive impairment (MCI, n = 20) or AD dementia (n = 4). C11‐PIB‐PET (A), 18F‐AV1451 (T) and perfusion‐phase 18F‐AV1451 scans (N) were spatially and intensity‐normalized (reference: cerebellum). To quantify the volume of A, T and N, we z‐standardized and subsequently binarized all scans within–modality using a z‐score threshold. Fill states were then computed as the sum of abnormal voxels relative to a whole‐brain mask. Finally, mean fill states were compared across groups of clinical status (CU, MCI, AD) and partial correlations of either fill states or mean PET signal in established, tracer‐specific ROIs with cognitive performance (MMSE) were computed, adjusting for age, sex and education.

Result

Mean fill states reflected clinical status, as they increased with disease progression (CU: A = 4%, T = 4%, N = 3%; MCI: A = 15%, T = 11%, N = 4%; AD dementia: A = 20%, T = 23%, N = 5%). Moreover, A and T fill states were negatively associated with MMSE (rhoA = ‐.299, p < .001; rhoT = ‐.318, p < .01; rhoN = ‐.147, p = .20), while associations of mean PET signal and MMSE tended to be weaker (rhoA(global) = ‐.255, p = .03; rhoT(temporalmetaROI) = ‐.275, p = .01; rhoN(metaROI) = .179, p = .12).

Conclusion

We present a competitive quantification scheme for ATN that is associated with both, clinical status and cognitive performance. These results, while currently validated in a larger sample, suggest that the spatiotemporal dynamics of pathology and neurodegeneration in the AD continuum are well captured by our multi‐parametric approach, which is possibly superior compared to classification from mean PET signal intensity.
GRADUATE I and II: Subgroup analysis and correlations of biomarkers
Authors: Bittner Tobias , Belousov Anton , Lane Christopher , Schwab Dietmar , Klein Gregory , Tonietto Matteo , Lott Dominik , Illiano Vittorio P , Blennow Kaj , Barkhof Frederik , Smith Janice , Doody Rachelle S. ,   for the GRADUATE I and GRADUATE II Investigators and the gantenerumab study group
Published: December 2023

Background

Gantenerumab is a subcutaneous fully human monoclonal antibody targeting aggregated forms of amyloid‐beta. Phase III GRADUATE I (NCT03444870) and II (NCT03443973) trials were designed based on previous key learnings to provide evidence on the benefit:risk profile of subcutaneous gantenerumab in early symptomatic AD. Although primary endpoints were not met, gantenerumab showed treatment effects on amyloid positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) and plasma biomarkers. Correlations of biomarkers with clinical outcomes in the GRADUATE studies were assessed to further evaluate their utility.

Method

Participants aged 50‐90 years with mild cognitive impairment due to AD or mild AD dementia were randomised 1:1 to subcutaneous gantenerumab or placebo. Gantenerumab was up‐titrated over 36 weeks to target dose of 510 mg every 2 weeks. Changes in amyloid centiloid levels were obtained from [18F]Florbetaben or [18F]Flutemetamol PET. Regional changes in tau standardised uptake value ratio were obtained with [18F]GTP1 PET. Whole brain and regional atrophy were assessed via volumetric MRI. Fluid pharmacodynamics biomarkers were measured using Elecsys® immunoassays from Roche Diagnostics.

Result

Significant (but not corrected for multiple testing) treatment effects of gantenerumab on change from baseline to Week 116 were observed for CSF biomarkers (pooled GRADUATE I and II population) including Aβ40 (–10.42%, p = 0.0188), Aβ42 (26.06%, p<0.0001), tTau (–16.49%, p<0.0001), pTau181 (–23.35%; p < 0.0001), NfL (10.76%; p = 0.0159), GFAP (–5.49%; p = 0.0003), and plasma biomarkers including Aβ42 (GRADUATE I: 65.1%, p<0.0001; GRADUATE II: 54.9%, p<0.0001) and pTau181 (GRADUATE I: –17.2%, p<0.0001; GRADUATE II: –15.3%, p<0.0001). Preliminary biomarker analyses showed changes in amyloid PET in gantenerumab‐treated participants had a numerically higher correlation with changes in plasma Aβ42 (R = –0.43), versus pTau181 (R = 0.34) and GFAP (R = 0.16). Biomarker changes in subgroups will also be presented.

Conclusion

Phase III GRADUATE I and II study results provide evidence of the effect of subcutaneous gantenerumab on biomarkers of AD pathology and neurodegeneration in subgroups.
Measuring “What Matters Most™” to individuals living with Alzheimer’s disease and care partners: A conceptual model of Alzheimer’s Disease
Authors: Romano Carla (DeMuro) , Slota Christina , Bratlee‐Whitaker Emily , Edwards Teresa , Herring William L , McLeod Lori , Callahan Leigh F , Bullok Kristin E , Raimundo Karina , Taylor James , Taylor Geri , Kremer Ian N. , Lappin Debra , Frangiosa Theresa , Goss Diana , Gnanasakthy Kajan , Comer Meryl , Monks Doreen , Paulsen Russ , Hartry Ann , DiBenedetti Dana B
Published: December 2023

Background

The Alzheimer’s Disease Patient and Caregiver Engagement™ Initiative‘s What Matters Most™ (WMM) Research Program includes seminal studies to identify and measure treatment‐related needs, preferences, and priorities of people living with Alzheimer’s disease (PLWAD) and their informal care partners (CPs). WMM research identified 42 concepts deemed to be of highest relevance and importance in treatment related needs across the AD spectrum (preclinical – severe AD). Now, the WMM Next Generation Studies (WMM NG) are generating data to contextualize findings through a conceptual model of disease, verify previously identified concepts, and learn of new emerging concepts from a more diverse and inclusive study sample. Results will be used to broaden the context of an online survey to inform additional studies, including health economic evaluations, across the Alzheimer’s research field.

Method

A draft conceptual model of disease was developed building on an existing model (Hartry, 2018) after careful examination of previously collected WMM data (DiBenedetti, 2020; Hauber, 2023). A cross‐sectional, observational qualitative research study was conducted, comprised of a series of individual, in‐depth interviews of those with clinically confirmed PLWAD and their CPs. Analyses of these data include qualitative content analysis and thematic analysis methods (Hsiu‐Fang, 2005).

Result

The 42 WMM concepts were categorized across thought processing (14), communication (3), mood/emotions (6), daily activities (12), social life/activities, (3) and independence (4) domains to form a draft conceptual model of disease. A total of 64 PLWAD and CPs of diverse ethnic and cultural backgrounds participated in in‐depth, web‐based interviews. Results reaffirmed the 42 WMM concepts, informed the model structure, and added missing concepts. Further, cognitive debriefing approaches elucidated participant perception of the terms “bother” and “interference” describing emotional connotation of these words, compared to the assessment of “impact”, to inform development of AD burden survey items.

Conclusion

WMM concepts contextualized by domains offer a roadmap to support future clinical trials seeking to measure clinically meaningful outcomes and patient‐centric endpoints. WMM NG data collection will enhance robustness of the findings to evaluate the impact of disease symptoms and inform health economic evaluation. The conceptual model will be refined continuously over the WMM research.
Sovateltide prevents loss of spatial memory retention and reduces neuroinflammation in a transgenic mouse model of Alzheimer’s disease
Authors: Briyal Seema , Sadigale Vaishnavi , Gulati Anil
Published: December 2023

Background

Amyloid‐β (Aβ) accumulation, fibrillary tangles, neuroinflammation, and memory loss are hallmarks of Alzheimer’s disease (AD). We still lack an effective treatment for AD. Our group has demonstrated that endothelin B receptors (ETBR) in the brain could be a potential drug target to treat AD. However, a direct link between ETBR stimulation and regulation of AD‐related pro‐inflammatory cytokines is still lacking. In this study, we aimed to investigate the effect of sovateltide, an ETBR agonist, on inflammation and cognitive function improvement in transgenic AD (APP/PS1) mice.

Method

We assessed Aβ load, neuroinflammation, and cognitive changes in 3, 6, and 12 months old APP/PS1 transgenic mice. Animals were treated with vehicle or sovateltide (5 µg/kg) intravenously, and memory deficit was assessed using the Morris water maze test. In addition, the levels of beta‐amyloid plaques and inflammatory cytokines in the mouse brain were evaluated by immunoblotting.

Result

Our results showed a significant (p<0.001) increased expression of pro‐inflammatory cytokines IL‐2 and IL‐6 and decreased expression of anti‐inflammatory cytokines IL‐4 and IL‐10 in APP/PS1 transgenic mice at 6 and 12 months of age. The expression of IL‐2 and IL‐6 was significantly (p<0.001) decreased, and IL‐4 and IL‐10 increased following sovateltide treatment in these mice, indicating an association of ETBR in regulating inflammatory factors. Moreover, APP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory with elevated amounts of Aβ plaque. While treatment with sovateltide rescued learning and memory deficits and significantly (p<0.001) decreased Aβ plaque load compared to vehicle in 6 and 12 months aged transgenic mice. There were no changes in the expression of any of these markers at three months.

Conclusion

Altogether, our work suggests a novel strategy by improving memory deficits and reducing Aβ plaque load and neuroinflammation by targeting ETBR and suggests that sovateltide could be an effective therapeutic option to treat AD.
The detection of phosphorylated tau in tear fluid
Authors: Molfetta Guglielmo Di , Demleitner Antonia Franziska , Gomes Lucas Arujo Caldi , Jeromin Andreas , Vanmechelen Eugeen , Blennow Kaj , Zetterberg Henrik , Lingor Paul , Ashton Nicholas J.
Published: December 2023

Background

The recent development of ultrasensitive immunological methods has allowed for the detection of biomarkers related to neurodegenerative disorders in blood, e.g., phosphorylated tau (p‐tau). This allows for a cost‐effective and scalable assessment of the causes behind cognitive decline. Nevertheless, other biofluids, e.g., tear fluid, have the potential to surpass these metrics. Previously, tear fluid from patients with neurodegenerative conditions has been explored both with mass‐spectrometry and immunoassays. Hereby, we established a method for the detection of p‐tau181, p‐tau217 and p‐tau231 in tear fluid from patients.

Method

A total of 40 participants with neurodegenerative diseases (amyotrophic lateral sclerosis [n = 11], dementia [n = 9], Parkinson’s disease [n = 20]) and control subjects without clinical signs of neurodegeneration [n = 20], were recruited at the Department of Neurology at the Klinikum rechts der Isar, München, Germany. Tear fluid from both eyes was collected with Schirmer strips. The strips from both eyes were combined and eluted by centrifugation (16,000g) in sample buffer. The eluate was then analysed for p‐tau181, p‐tau217 and p‐tau231 by Single molecule array (Simoa). Results were normalised to tear fluid running length.

Result

All tear fluid samples were above the lower limit of detection (LLOD) for all p‐tau assays ([mean] p‐tau181, 92.1pg/ml; p‐tau217, 0.398pg/ml; p‐tau231, 52.9pg/ml) improving on previous attempts found in literature. There was a highly significant correlation between all p‐tau biomarkers in tear fluid (r = 0.90–0.98; P<0.001). The normalised concentration of tear fluid p‐tau had a significant positive correlation with age (R
p‐tau181 = 0.28, R
p‐tau217 = 0.27, R
p‐tau231 = 0.39; P<0.05) but there was no association with the corresponding p‐tau in serum. No significant group differences in tear fluid p‐tau were observed but a trend towards increased serum p‐tau181 was found in the neurodegenerative group (6.37pg/ml) compared to controls (4.37pg/ml).

Conclusion

In this pilot study, we describe quantifiable levels of p‐tau181, p‐tau217 and p‐tau231 in tear fluid samples. However, the detectable levels of p‐tau in tear fluid do not seem to correlate to p‐tau levels in serum. Further studies will show p‐tau in tear fluid of patients with suspected AD, stratified by CSF biomarkers, and thus establish the relevance of tear fluid as a diagnostic biofluid in AD.
Neuromodulation for Mild Cognitive Impairment: Improvements in Spatial Navigation and Associative Memory with Acute Transcutaneous Vagus Nerve Stimulation: VINCI‐AD
Authors: Dolphin Helena , Dyer Adam H , Dukelow Tim , Commins Sean , Finucane Ciaran , Kennelly Sean
Published: December 2023

Background

New therapeutic strategies to treat Mild Cognitive Impairment (MCI) are urgently needed. Transcutaneous Vagus Nerve Stimulation (tVNS) is a neuromodulation technique which uses a handheld device to peripherally stimulate the afferent vagus nerve. tVNS has shown promise in augmenting memory in cognitively healthy populations but data in cognitively impaired populations is sparse.

Method

VINCI‐AD is an investigator‐led, single‐blind, sham‐controlled crossover pilot study assessing the effects of tVNS in amnestic MCI. All participants have MCI (CDR global 0.5) with amnestic neuropsychological profile (RBANS delayed memory index <85). Participants are randomised over 3 study visits to baseline (no stimulation) active stimulation (at the CC of left ear) or sham stimulation (earlobe). Cognitive tests include Face‐Name Association Task (FNAT), Sustained Attention Response Test (SART) and Sea Hero Quest Navigation Test (SHQ) among others.

Result

Interim data analysis of 28 participants is presented (mean age 71.5 (range 55‐85), 17 male, RBANS DMI 73.3 ±11.1). CSF AD biomarkers were positive for 75% (21/28) (AB‐42 460.4pg/ml (± 83.3pg/ml) and p‐tau181 82.5pg/ml [± 53.2pg/ml]) and 78% (22/28) of participants had a Charleston Comorbidity Index of ≥3. Mean tVNS stimulation time pre‐cognitive assessments was 21.2 minutes, with mean amplitude setting during active stimulation of 2.5mA (1.8‐4.5) and sham of 2.0mA (0.9‐3.1). During FNAT, active tVNS had no effect on facial recognition or reaction times, however recall accuracy was significantly improved (69.2% ±3.13) compared to baseline (44.7% ±3.51 p = 0.016) and sham (50.1% ±3.28 p = 0.021) and during active tVNS spatial navigation (38.94sec [±1.68]) was quicker than baseline (51.49sec (±3.2) p = 0.0164) and sham (51.9sec (±3.15) p = 0 .0038). We noted no significant improvements in SART or other cognitive tests performance during tVNS.

Conclusion

tVNS may be a useful complementary tool to augment spatial and associative memory in MCI. Further larger studies are needed to delineate precise settings in this population.
The impact of air pollution and pollutants on the progression of dementia
Authors: Li Chien‐Hsun , Tsao Yu‐Hsiang , Ho Pei‐Shan
Published: December 2023

Background

Air pollution is known to increase the incidence of dementia, but whether dementia in areas with high air pollution likely to get worse is still unclear. We investigate the impact of high air pollution areas on the progression in dementia, and which air pollutants have more obvious influences.

Method

A retrospective case‐control study was performed using the data from the Kaohsiung Medical University Hospital Research Database and Environmental Protection and Administration, Taiwan. Clinical data and air pollution data were concatenated with addresses to assess the exposure to each case. Further, divide Kaohsiung into areas with severe air pollution and compare them with general areas. Exacerbation of dementia was defined as detection with use of advanced medications. We constructed conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Result

There were 529 cases in the group of worsening dementia and 2351 cases in the control group. The OR of dementia exacerbation in the general area is significantly lower than that of the high SO2 exposure area (OR: 0.745, 95% CI: 0.616‐0.901). Exposure to SO2 and PM2.5 at all five time points studied were significantly associated with an increased risk of worsening dementia of all types and non‐degenerative types. The maximum total peak ORs (95% CI) were 1.285 (1.154–1.431) in the first year with exposure to high SO2 and 1.111 (1.043–1.183) in the four years with exposure to high PM2.5, respectively. In the dementia of degenerative types, exposure to SO2 were significantly associated with an increased risk of worsening dementia. The maximum total peak ORs (95% CI) were 1.386 (1.174–1.638) in the first year.

Conclusion

This study confirms that cumulative exposure in the previous one to five years in high‐exposure areas has a significantly higher risk of all dementia worsening. SO2 pollutant has the obvious effect on the progression of dementia of all types, degenerative and non‐degenerative types. PM2.5 pollutant has the obvious effect on the progression of dementia of all types and non‐degenerative types. The protection from air pollution, especially SO2 and PM2.5 pollutants is very important in the treatment of dementia.
Modeling and Simulation to Inform Potential New Strategies for BACEi in Treatment of Alzheimers Disease
Authors: Stone Julie A
Published: December 2023

Background

The β‐secretase‐1 inhibitors (BACEi), including verubecestat, were extensively studied in prodromal to moderate AD and demonstrated early cognitive decline at doses achieving >50% inhibition of amyloid production. Questions remain as to whether BACEi may still have utility, if used earlier in disease, in combination with other therapies, and/or at lower doses. Modeling and simulation approaches were used to maximize learnings from the prior trials and to make predictions around potential alternative therapeutic approaches.

Method

Two models were developed: 1) A joint plaque turnover model, linking drug exposure with amyloid plaque load (PET data in centiloids), to describe natural progression and treatment response to BACEi and amyloid mAb therapies. All plaque data from natural progression (control arms), BACEi and amyloid mAb treatment arms were well described by a joint model, after accounting for differences in baseline plaque load, dosing and titration regimens, and mechanism of action. 2) Disease progression models for the clinical efficacy outcomes (ADAS‐cog11, CDR‐SB) were developed using a methodology similar to Ref. Evidence for BACEi drug effects (on progression rate and/or early detrimental offset) was tested and dependencies on dose, drug exposure and patient characteristics were explored.

Result

The joint plaque turnover model well described natural progression and treatment response to BACEi and amyloid mAb and allows for prediction of alternative regimens and therapeutic approaches. Simulations indicate that 20‐30% inhibition of BACE would be sufficient to stabilize plaque loads in prodromal patients. Disease progression results for ADAS‐cog11 and CDR‐SB identified a verubecestat drug effect of early detrimental offset with no effect on rate of disease progression supported. The magnitude of the early detrimental offset was small relative to the overall progression seen over 18‐24 months and results suggested that this effect may be reduced in advanced AD patients. A simulation engine utilizing the progression model allows for estimation of sample size needed to check for the detrimental effect in future trials.

Conclusion

Model‐based simulations can help inform future BACEi therapeutic strategies and trial designs.

Reference: Clin Pharmacol Ther. 2015 Mar;97(3):210‐4
Exploring the value of hope in dementia
Authors: Furlano Joyla A , Bandler Zach , Dasgupta Jayashree , Fittipaldi Sol , Canty Alison Jane , McGettrick Grainne , Yasoda‐Mohan Anusha , El‐Jaafary Shaimaa Ibrahim , Ucheagwu Valentine A , la Cruz‐Góngora Vanessa De , Nguyen Kim Huong , Lawlor Brian , Haas Aline Nogueira
Published: December 2023

Background

To hope is to be human, and it has been examined in diverse disciplinary perspectives across theology, philosophy and anthropology. However, hope is more than an idea. It has the potential to positively impact people across the life course, particularly those living with conditions like dementia. Hope can be meaningfully experienced at the individual, group and community levels through its potent power to build resilience. Despite this significance, there are sizeable gaps in our knowledge of the brain mechanisms underlying hope.

Method

We explore how understanding hope as a neurobiological entity is an exciting prospect. As a possible key to tackling challenges of dementia, it could buoy the ability for patients and their families to cope with the devastation of diagnosis, as well as the sense of doom, anxiety, loss and despair that follows.

Results

The literature suggests that hope may be situated in the frontal cortex, although more research in this area is needed. With an understanding of the neurobiological basis of hope, interventions focused on instilling hope to improve quality of life are needed urgently.

Conclusion

If hope can be harnessed for brain health, both therapeutically and preventatively, it has the potential to be used as a ‘tool’ to improve patient and family experiences with dementia, as well as that of our greater society.
Association of Gut Microbiome with Diabetes Mellitus and Alzheimer’s Disease in a Puerto Rican Adult Population: A Preliminary Report
Authors: Soler‐Llompart Cecilia Michelle , Godoy‐Vitorino Filipa , Sala‐Morales Ana Cecilia , Santiago‐Berríos Michel , Ruiz‐Adames Javier A. , Olivieri‐Henry Gerianne , Herrero‐Rivera Carlos , Pérez‐Luzunaris Fabián J. , Sepulveda Vanessa
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common cause of dementia, consisting in a highly debilitating disorder, progressing from slight memory impairments to a complete loss of mental function, resulting in significant disability and death. In Puerto Rico, AD is the fourth leading cause of death. Caribbean Hispanics, including Puerto Ricans living on the island have shown a more severe AD symptomatology and disease mortality than any other ethnic group. This disparity may be due to health, diet, lifestyle, socioeconomic risk factors and more prevalent chronic health conditions such as diabetes in Hispanic people. Diabetes Mellitus is nowadays considered a risk factor for AD. Evidence suggests that the gut microbiome plays a role in the pathophysiology of AD through neuroinflammation and amyloid deposition leading to cognitive impairment. Main objective: Study the microbiome composition and diversity of Puerto Ricans with AD compared to cognitive‐intact controls in association with Diabetes Mellitus.

Method

Fifty‐three participants (n = 53), 28 with AD and 25 controls were evaluated clinically and cognitively with the Montreal Cognitive Assessment (MoCA) to associate the gut microbiome with cognitive impairment. Stool was collected for genomic DNA extractions and microbiome characterization. NextGen Illumina MiSeq was used to sequence 16S rRNA genes (V4 region) and analyzed with standard pipelines.

Result

No statistically significant differences in bacterial diversity and richness between AD vs. controls. We found slight differences in composition, including an abundance of Euryachaeota in AD, while controls had higher levels of Bacteroidetes. Compared to cognitively intact, a decrease in gut microbiome diversity was seen among participants with cognitive decline (p = 0.02). Roseburia (butyrate producing bacteria) seems to decrease with cognitive impairment severity. Diabetics have significantly reduced Anaerostipes and Ruminococcus also butyrate producing bacteria. AD participants with/without Diabetes have predominance of Euryarchaeota. Controls with Diabetes have more Proteobacteria and Bacteroidetes compared to cognitively impaired.

Conclusion

Both Diabetes and neurocognitive decline appear to reduce butyrate‐producing bacterias, which may be related to a decrease in the homeostasis of the gut‐brain axis and lead to microbiome dysbiosis in the setting of disease. A better understanding of the gut microbiome will be an invaluable approach for development of modulation‐based therapeutic interventions.
Rate of clinical progression in mixed Limbic‐Predominant Age‐Related TDP‐43 Encephalopathy (LATE) and Alzheimer disease
Authors: Ospina‐Romero Monica , Salamat Shahriar , Betthauser Tobey J , Bendlin Barbara B
Published: December 2023

Background

Limbic predominant age‐related encephalopathy neuropathologic change (LATE‐NC) is associated with amnestic type dementia. LATE‐NC frequently coexists with Alzheimer disease neuropathologic change (ADNC). It is unclear whether LATE and Alzheimer disease neuropathologic change interact or independently affect clinical disease progression.

Methods

Data was from 80 autopsied participants with TDP‐43 immunohistochemical studies from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention. We used linear mixed effects models to estimate associations of ADNC and LATE‐NC with rate of progression of Clinical Dementia Rating Sum of Boxes (CDR‐SB) and investigated whether co‐occurrence of these two pathologies would modify these trends.

Results

Participants in our sample were 42% female with mean age at death of 77.8 years (SD 9.6). Neuropathologic diagnoses were low/intermediate ADNC in 20 (25%), high ADNC in 29 (36%), LATE‐NC in 8 (10%), and LATE‐NC + high ADNC in 23 (29%) participants. Clinical progression of cognitive impairment was faster in participants with high ADNC than in those LATE‐NC (Slopes:1.82 units/year [95% CI: 0.93‐2.71] vs 1.33 units/year [95% CI: 0.29‐2.38]) (Figure). Co‐occurrence of LATE‐NC + high ADNC predicted similar progression than high ADNC alone (Slope: 1.83 units/year [95% CI: ‐0.45 – 4.12]) demonstrating interaction (p = 0.013) between LATE‐NC and high ADNC.

Conclusion

LATE‐NC and ADNC are independently associated with clinical progression of cognitive impairment. Co‐occurrence of LATE‐NC and high ADNC is expected to have similar clinical progression than ADNC alone. Research is ongoing to examine differences among these groups using T1‐weighted volumetric imaging and CSF glial activation biomarkers.
Using Different Time Operationalizations To Investigate Relationships Among Amyloid PET, White Matter Hyperintensities, And Cognition In A Cognitively Unimpaired Sample
Authors: Langhough Rebecca E , Du Lianlian , Cody Karly Alex , Jonaitis Erin M. , Hermann Bruce P , Chin Nathaniel A. , Rivera‐Rivera Leonardo A. , Cadman Robert V. , Pompa Christian C. , Hudson Sarah , Christian Bradley T. , Eisenmenger Laura B. , Betthauser Tobey J , Johnson Sterling C
Published: December 2023

Background

Amyloid‐PET and white matter hyperintensities (WMH) associations in older adults have variously been interpreted as separate or dependent processes. In this study, we examine evidence for a temporal relationship between amyloid‐PET and WMH and investigate how both contribute to cognitive decline in a baseline cognitively unimpaired (CU) sample.

Method

We analyzed longitudinal WMH and PACC3 cognition in n = 240 Wisconsin Registry for Alzheimer’s Prevention participants who were CU at cognitive baseline with ≥1 amyloid‐PET and T2‐FLAIR scan. Amyloid burden was assessed using [C‐11]Pittsburgh Compound B (PiB) PET and a multi‐ROI DVR value; DVR>1.19 = PiB+. WMH lesion volume was segmented and summed by the Lesion Segmentation Tool (LST) version 1.2.3 in SPM12 from T1‐weighted and T2‐weighted FLAIR scans; TIV‐adjusted WMH >2.06 = WMH+. Sampled iterative local approximation (SILA) modeling aligned biomarker levels to positivity duration scale (years = 0 at biomarker+ threshold). To investigate how amyloid burden relates to WMH trajectories, time at each WMH scan was operationalized four ways: age, ∼WMH+ duration, years_since_baseline_scan, and ∼PiB+ duration. We compared model fits and interaction effects for the various PiB status*time interactions (mixed effects models; retaining significant quadratic time terms; random slopes and intercepts). We also examined whether PACC3 age‐related trajectories differed by PiB/WMH +/‐ groups (at last scan).

Result

More women were WMH+ and APOE4 was more common among PiB+ (see also Table1). Significant interactions using age or years_since_baseline_scan suggested slightly faster WMH accumulation in PiB+ vs PiB‐ at older ages. In parallel models, WMH+ duration*PiB status and PiB+ duration*PiB status did not show differences between PiB+ and PiB‐ WMH trajectories. Time operationalized as WMH+ duration yielded the best fitting model (see Table2 and Fig1A‐D). PACC3 decline was fastest in the PiB+/WMH+ group, followed by PiB+/WMH‐ (Fig1E). PiB+ was more common than WMH+ and tended to precede it when both were present (Table1; Fig1F).

Conclusion

In this baseline CU sample, WMH+ was less common and occurred later in life, on average, than PiB+. Associations between amyloid burden and WMH trajectories were driven by older ages, suggesting potential unidentified age‐related mediators in this relationship. Presence of both amyloid and WMH was associated with fastest preclinical cognitive decline.
AlphaFold 2 predicts opening of the tau hairpin conformation by Mapt mutations and the extent of opening reflects their location
Authors: Chain Daniel G , Margolin Richard A
Published: December 2023

Background

Dozens of Mapt mutations can cause FTD, but the molecular mechanisms involved are poorly understood. We recently reported that Pro301 mutations increase the susceptibility of full‐length tau (FLT) to caspase‐3 cleavage at Asp421, which produces the highly noxious C‐terminal fragment tauC3. We speculated that the increased susceptibility could be caused by exposing the cleavage site through impact on critical hairpin interactions between Ser432 and P301. In another study, we used the AI‐based AlphaFold 2 (AF2) algorithm to predict and compare structural models of FLT and tauC3. This revealed dramatic differences in their conformations: tauC3 has an open conformation while FLT is closed by a hairpin. We postulated that other Mapt mutations may also open the conformation of tau in the same way.

Method

We performed AF2 predictions on FASTA sequences of several 4‐repeat FLT variants: R5H, P301S, P301L, and R406W. We also obtained the predicted intramolecular distances between Ser432 and the MTBR to assess the effect of the mutations on the conformation of tau quantitatively.

Result

There were notable differences in the magnitude of opening across the variants. Rank order for openness (Figure) was tauC3 > P301L > P301S > R406W > R5H ∼ non‐mutated FLT. P301L had a strong effect that approximated the opening in tauC3. P301S and R06W had moderate effects, while R5H has a minimal effect.

Conclusion

The finding that P301L’s effect was greater than that of P301S may be explained by leucine’s greater hydrophobicity. The relatively strong effect of both Pro301 mutations reflect this residue being closest to Ser432. The R406W mutation’s intermediate but lesser effect is consistent with its relative proximity to Ser432, while the lack of effect for R5H suggests that the extreme N‐terminus is minimally involved. Collectively, our data shows the power of AF2 to predict effects of sequence alterations. The findings also have important implications for understanding tau biology and the development of therapeutics for tauopathies.