bluuebunny/crossref_metadata_2025 huggingface dataset:
Pooled Modeling of Disease Progression in Two BACE1 Inhibitor Verubecestat Trials in Prodromal to Moderate Alzheimer’s Disease
Authors: Kleijn Huub Jan , Stone Julie A , Hu Henry , Crockett Theresa Y , Xu Ming , Robey Seth , Egan Michael F.
Published: December 2023

Background

The BACE inhibitor verubecestat (MK‐8931) at doses of 12 and 40 mg demonstrated cognitive and functional decline relative to placebo in a Phase 3 trial of prodromal AD (APECS, NCT01953601) and no effect on progression in a Phase 3 trial of mild‐to‐moderate AD (EPOCH, NCT01739348). Disease progression modeling was used to investigate the temporal pattern of the cognitive and functional drug effects and to explore covariate, dose‐ or exposure‐dependency in the pooled data from both trials. The key objective was to determine whether the rate of progression was slowed by BACEi but obscured by an early detrimental drug effect.

Method

Disease progression models for the clinical efficacy outcomes (ADAS‐cog11, CDR‐SB) were developed using similar methodology to an established ADAS‐cog disease progression model (Ref). Parameters describing placebo response were first estimated. Akaike Information Criteria (AIC) were then used to select among potential drug effects (effects on progression rate and/or early detrimental offset) and to test for dependencies on dose, drug exposure, and patient characteristics. A simulation exercise confirmed that a true 25% or 50% reduction in the progression rate with treatment could be reliably identified in the setting of the early detrimental effect.

Result

Results were generally concordant across ADAS‐cog11 and CDR‐SB. An early symptomatic (detrimental offset) response was identified with verubecestat; no effect on rate of disease progression was supported. The magnitude of the drug effect offset was estimated 1.8 for ADAS‐cog11 and 0.33 for CDR‐SB. Covariates were generally concordant across measures with disease severity at baseline identified for both progression rate and detrimental offsetting. Additionally, age, weight, geographic region, and education effects were identified on progression. Threshold analysis of the detrimental offsetting effect suggested that the effect was present in less severe disease but absent in the most advanced AD patients (ADAS‐cog11 baseline>24 and CDR‐SB baseline > = 12).

Conclusion

No dose or AUC dependency on the detrimental offsetting effect of verubecestat was found, indicating that the maximum effect is achieved at 12 and 40 mg doses. There was no evidence supporting a slowed rate of disease progression by BACEi after accounting for the early detrimental drug effect.
Blood brain barrier damage in a mouse model of frontotemporal dementia
Authors: Orsini Franca , Micotti Edoardo , Martucci Annacarla , Pascente Rosaria , Bosica Marco , Forloni Gianluigi , Fioriti Luana
Published: December 2023

Background

Clinical evidence supports a major contribution of vascular insufficiency to the development of tauopathies. Interestingly, observations in patients with Fronto‐Temporal Demetia (FTD) highlighted microvascular changes predominantly within the areas affected by neuronal pathology. Further, data in animal model demonstrated that Tau‐P301L induces neurovascular dysfunctions independent of neurodegeneration, suggesting that cells of the Blood Brain Barrier (BBB) may represent a novel therapeutic target. However, the molecular mechanisms of vascular insufficiency in FTD remain elusive.

Method

To establish the pathological relationship between BBB alteration and FTD progression, we used JNPL3 mice, which express human Tau‐P301L mutation, and wild‐type (WT) controls. We assessed their memory at 5, 10 and 15 months using the Radial‐Arm‐WaterMaze (RAWM) and Y‐maze and their white matter integrity by MRI. We assessed Tau pathological changes (hyperphosphorylation and aggregation) and vascular alterations by WB and RT‐PCR. In addition, to determine the causal link between Tau and BBB damage we assessed viability of brain microvascular endothelial cells (BMECs) exposed toTau oligomers (oP301L) in vitro.

Result

Compared to WT, white matter integrity is significantly compromised as early at 5 months in JNPL3 mice, when modest alterations in cognition also appear, while more pronounced memory deficits occur at 10 months. pTau‐(199/202) and IgG extravasation increase over time starting at 5 months and Claudin5 (CLND5), the most enriched tight‐junction protein in BMECs, is reduced in JNPL3 at 15 months. In addition, the mRNA for ICAM‐1(Intercellular Adhesion Molecule‐1) is upregulated already at 5 months in JNPL3 mice, indicating that BMECs acquired a proinflammatory phenotype. Further, oP301L reduced significantly BMECs viability in vitro after 24h.

Conclusion

Our data demonstrate that endothelial alteration occur at early stages of disease in JNPL3 mice. Based on these we hypothesize that: 1) Tau deposition in blood vessel might be an early event that precedes neuronal loss; 2) cognitive deficits arise from the toxic effects of oTau both on neurons and endothelial cells, thus suggesting that targeting both cells might be more effective to slow down disease’s progression.
Performance testing of a novel GFAP ELISA for CSF and blood based matrices
Authors: Demeyer Leentje , Vanhooren Melanie , Sluijs Jacqueline , Hol Elly , Stoops Erik
Published: December 2023

Background

Glial Fibrillary Acidic Protein (GFAP) and its isoforms are intermediate filament cytoskeletal proteins expressed in astrocytes. Reactive astrogliosis, hallmarked by an increase in GFAP expression, is part of the pathogenesis of Alzheimer’s disease (AD). A reliable and globally available method for measurement of GFAP in CSF and plasma is required as a pharmacodynamic biomarker of astrocyte reactivity in AD drug development programs. Here we describe the specificity and performance of a monoclonal antibody (mAb) based colorimetric ELISA for measurement of GFAP in human CSF and plasma while comparing with existing benchmarked measuring methods.

Method

A prototype colorimetric ELISA was designed using a 96‐well microplate with capture mAb ADx RD‐089 paired with the biotinylated detection mAb ADx RD‐090. High specificity for GFAP was verified by testing recombinantly expressed intermediate filaments like vimentin, nestin, and synemin up to a concentration of 10,000 pg/mL. A method comparison study was performed using a set of 15 CSF and 13 plasma samples (commercially sourced, no clinical typing). Finally the prototype ELISA was compared to a commercially available QTX Simoa GFAP assay (Cat# 102336).

Result

The assay design is a 3‐step sequential incubation (2‐1‐0.5 hrs) procedure while shaking with a respective 20‐ and 4‐fold dilution of CSF and EDTA plasma. The assay calibration ranges between 25 and 5,000 pg/mL and GFAP levels of the CSF and plasma samples tested were above LLOQ and within the measuring range. Furthermore, reproducibility was between 2.0 – 13.6% for CSF, and between 5.4 – 11.4% for EDTA plasma. An appropriate parallelism was obtained with back‐calculated concentrations between 80‐120% across the measuring range. Finally, the assays’ GFAP levels correlated well with QTX Simoa for both CSF Pearson r = 0.98 (0.94 – 0.99) and plasma Pearson r = 0.97 (0.90 ‐ 0.99).

Conclusion

This colorimetric ELISA prototype assay enables the quantification of GFAP in both CSF and plasma. Alternatively it is a new accessible immunoassay method to support clinical trials where reactive astrogliosis needs to be assessed.
Differential expression of 5mC epigenomic regulators in Alzheimer’s disease
Authors: PerezGrovas‐Saltijeral Adriana , Rajamani Anto Praveen Rajkumar , Knight Helen Miranda
Published: December 2023

Background

Epigenetic processes are molecular mechanisms that contribute to the pathogenesis of neurodegenerative diseases. 5‐methylcytosine (5mC) and the oxidised state, 5‐formilcytosine (5fC), are known transcriptional regulators moderated by sets of writer, reader, and eraser effector proteins. We propose that gene expression variation in DNA effector proteins may contribute to Alzheimer’s Disease (AD) neuropathology. We also aimed to characterize the distribution of 5fC modifications across brain regions and within cellular compartments to better understand the role of 5mC/5fC modifications in AD.

Methods

RNA sequencing data for 17 effector proteins obtained from the Aging, Dementia and Traumatic Brain Injury Study was analysed to assess variation in abundance of 5mC writers, readers, and erasers. Gene expression data were compared across four brain regions in 51 AD and 56 healthy control samples, and between Braak and CERAD neuropathological scales. In addition, we examined the presence and distribution of 5fC by immunofluorescence (IF) across four brain regions in sections from healthy individuals.

Results

Transcripts of DNA methylation writers DNMT1, DNMT3A and DNMT3B were found increased in the AD cohort across 3 brain regions, whilst the reader UHRF1 mRNA was decreased in the same assessment. GADD45B and AICDA, DNA methylation erasers, showed changes in mRNA abundance across Braak and CERAD neuropathological load groupings. IF analysis indicated 5fC modification to be highly abundant in dentate gyrus and within the cytoplasm of hippocampal mossy cells and of neurons in cortical layer III. Within neuronal cells, we observed 5fC partially colocalizing with mitochondria especially within hippocampal neurons.

Conclusion

Our findings indicate that changes in 5mC/5hmC/5fC effector protein expression are associated with AD and its neuropathology. The characterisation of 5fC localisation in human brain indicates high abundance within the cytoplasm of hippocampal cells suggesting that 5fC may be involved in pre‐ and post‐transcriptional control of memory processing pathways and, when disrupted, may lead to neurodegenerative disease.

References: Sanchez‐Mut JV, et al. Transl Psychiatry. 2016; Miller JA, et al. Elife. 2017; Bachman, M., et al. Nat Chem Biol. 2015; Zhang Y, Zhou C. DNA Repair (Amst). 2019; Aging, Dementia and TBI Study (2017) Available from Allen Brain Atlas
The theory of the multiple reserves: The cognitive, physical, psychological and social factors that determine the quality of aging
Authors: Friedland Robert Paul
Published: December 2023

Background

In the 1980s the finding that education was linked to lower risk of Alzheimer’s disease (AD) led to the concept of cognitive reserve (CR). Extensive evidence of the protective role of cognitive activities in school, as well as at home and at work has supported the concept of CR. However, AD is clearly a multifactorial condition and there are other important lifestyle factors linked to AD risk.

Method

The literature was searched to find factors other than CR that are protective against the development of AD.

Result

The theory of the multiple reserves presents the physical, psychological and social factors that must be considered. Physical reserve includes the health of all the bodies' systems, including the microbiome. Psychological reserve considers emotional stability and ability to maintain healthy mental functions in response to stress. Social reserve considers interpersonal networks and support systems and the ability to be connected to others and society.

Conclusion

The multiple reserve concept helps to demonstrate the opportunities for reducing AD risk through development of the four reserves. Cognitive activities throughout life should be enhanced, and ways to elevate the other reserve factors should be developed, Persons should be encouraged to enhance all of the four reserve factors to reduce their risk of the disease, as well as reduce the rate of progression. Furthermore, public policy should be designed to augment all four of the reserves all each stage of life.
Physical Activity in Community‐Dwelling Older Persons With Mild Traumatic Brain Injury
Authors: Agrawal Sonal , Kim Namhee , Leurgans Sue E. , Dams‐O'Connor Kristen , Bennett David A. A , Buchman Aron S , Schneider Julie A
Published: December 2023

Background

To examine the association between traumatic brain injury (TBI) and physical activity in older adults.

Method

We conducted a cross‐sectional analysis of 944 older persons (mean age = 85, SD = 7.48 years; 77% female) at their last available physical activity measure from the Rush Memory and Aging Project. Physical activity was measured 24 hours per day for 7‐10 days with wrist‐worn actigraphy (Actical; Philips Respironics, Bend, OR). We analyzed two separate outcomes from actigraphy: total daily activity and intensity of daily activity. To account for positive skewness, we applied a logarithmic transformation. TBI status was assessed by self‐report. We classified the participants as 1) TBI with loss of consciousness (LOC), 2) TBI without LOC, or 3) no TBI exposure (reference group). Multiple linear regression analyses, adjusted for age, education, and sex, were used to examine TBI with LOC and TBI with no LOC as separate predictors in a single model for each actigraphy outcome.

Result

A history of TBI was reported in 351 (37%) participants, of whom 89 (9%) had at least one TBI with LOC and 262 (28%) had TBIs that did not result in LOC. Individuals with TBI with LOC had less total daily physical activity, with their total daily physical activity being about 19% (95%CI = 3.4%, 32.5%) lower than the reference group. The intensity of daily physical activity in those with TBI with LOC was 10% (95%CI = 0.7%, 18.2%) lower than the reference group. These associations remained after controlling depression, BMI, vascular risk factors, vascular diseases, and motor ability. Those with TBI without LOC did not differ from the reference group in daily physical activity and intensity of daily physical activity. We analyzed a subset of the 944 consisting of 710 deceased individuals who had undergone pathologic examination from postmortem brain tissue. Even after accounting for brain pathologies of Alzheimer’s disease, Lewy bodies, and cerebral infarcts, TBI with LOC remained associated with daily physical activity (p = 0.002).

Conclusion

Our result suggests that people with a history TBI with LOC may be associated with lower daily physical activity levels independent of the accumulation of diverse brain pathologies.
Association of tau burden with sleep disordered breathing in adults with Down syndrome
Authors: Smith Anna C. , Hartley Sigan , Plante David T. , Johnson Aubrey S. , Guzmán Diana S. , Okafor Amarachukwu , Rossano Samantha , Tudorascu Dana , Brickman Adam M. , Christian Bradley T. , Okonkwo Ozioma , Ances Beau , Cohen Annie , Handen Benjamin L. , Lao Patrick J.
Published: December 2023

Background

Adults with Down syndrome (DS) overproduce the amyloid precursor protein and nearly all evidence clinical symptoms of Alzheimer’s Disease (AD) dementia in later life. Sleep disordered breathing, and specifically, obstructive sleep apnea (OSA), is common in adults with DS. OSA has been associated with risk of AD in adults without DS, and sleep disturbances may have a bidirectional relationship with AD pathology. We hypothesized that greater tau burden is associated with subsequent sleep disordered breathing in a time‐lagged design.

Methods

Eighty young adults with DS (37±8 yrs, 49% women, 94% cognitively‐stable/6% MCI‐DS) from the ABC‐DS study underwent tau PET ([18F]‐AV1451, Braak stage SUVRs) and were assessed 4±0.7 years after PET using WatchPAT home sleep testing. Sleep variables included oxygen desaturation index (ODI) and apnea‐hypopnea index (AHI). General linear models assessed tau burden on later sleep impairments. Models were run in the whole group and the cognitively‐stable group alone, with and without age adjustment. Analyses were run using overall sleep measures and those in REM and non‐REM (NREM) sleep separately.

Results

In unadjusted models, greater tau in early, middle, and late Braak stages were associated with a higher ODI, while greater tau in middle Braak stages was associated with a higher AHI. In the cognitively‐stable group alone, greater tau in early and middle, but not late, Braak stages were associated with a higher ODI, while greater tau in middle Braak stages was associated with a higher AHI. Adjusting for age, greater tau in late Braak stages was associated with ODI in the whole group and the cognitively‐stable group alone. Associations for overall sleep measures were driven by NREM measures (Table 1).

Conclusion

In adults with DS with a high prevalence of OSA, tau burden was associated with subsequent intermittent nocturnal hypoxemia as measured by the ODI during NREM sleep. These findings align with those in adults without DS, linking AD pathology, disturbed sleep, witnessed apneas, and nocturnal hypoxemia. Both longitudinal and randomized studies are required to clarify cause‐effect relationships, including the presence of mediating and/or moderating variables such as reduction in sleep depth or continuity.
Apolipoprotein E4 affects locus coeruleus functional connectivity in preclinical Alzheimer’s disease
Authors: Um Yoo Hyun , Wang Shengmin , Kang Dong Woo , Lim Hyun Kook
Published: December 2023

Background

Recent studies have demonstrated the pivotal implications of the locus coeruleus (LC) and in the early phase of Alzheimer’s disease (AD). However, the effects of apolipoprotein E4(APOE4) carrier status on the LC functional connectivity (FC) in preclinical AD remain elusive. We aimed to demonstrate disparities in LC FC in preclinical AD with regard to APOE4 carrier status.

Methods

A total of 112 patients with who were amyloid beta (Aβ) positive([18F] flutemetamol +) were recruited in the study, and they all had normal cognition. Seed to voxel analysis was conducted to measure LC FC differences between APOE4 non‐carrier and carrier. In addition, group by amyloid beta (Aβ) interactive effects on FC values were analyzed with a general linear model.

Result

The LC FC with intracalcarine cortex, lingual gyrus, occipital fusiform gyrus of the both hemispheres was reduced in APOE4 carrier. Moreover, there was a statistically significant group by regional standardized uptake value ratio interactions in LC FC with frontal, occipital cortices, the precuneus and the cerebellum.

Conclusion

The aforementioned findings suggest that there are differential patterns of LC FC in APOE4 non‐carrier and carrier with preclinical AD, which interact with regional Aβ deposition.
Neuronal pentraxin‐2 by Simoa ‐ a potential synaptic biomarker in Alzheimer’s disease
Authors: Nilsson Johanna , Sauer Mathias , Grötschel Lana , Stomrud Erik , Janelidze Shorena , Blennow Kaj , Zetterberg Henrik , Brinkmalm Ann , Hansson Oskar , Ashton Nicholas J.
Published: December 2023

Background

Synaptic dysfunction and degeneration are believed to be among the earliest and most reliable indicators of cognitive impairment in neurodegenerative disorders, including Alzheimer’s disease (AD). Discovering and verifying novel biomarkers that can quantify synaptic degeneration and serve as prognostic indicators would be valuable to track cognitive decline in clinical and drug trial settings. By using mass spectrometry, we have studied a panel of 17 synaptic proteins as potential biomarkers for AD and a broad range of neurodegenerative disorders. Of these proteins, neuronal pentraxin‐2 (NPTX2) has shown great promise as a synaptic biomarker, showing a decrease in symptomatic disease. Therefore, we aimed to develop a Single molecule array (Simoa) for NXPT2, a method more suited for routine clinical assessment than mass spectrometry‐based workflows.

Method

We developed an in‐house NPTX2 Simoa assay on the HD‐X platform (Quanterix) with paramagnetic beads coupled with a rabbit monoclonal capture antibody (EPR24020‐38, Abcam) and biotinylated rabbit monoclonal detector antibody (EPR15618, Abcam), both specifically targeting NPTX2. Full‐length recombinant NPTX2 (7816‐NP‐050, Biotechne) was used as the calibrator. Using the assay, we analyzed 55 healthy controls (78.0 (6.5 SD) years) and 54 AD patients (73.5 (7.0 SD) years) using 2 uL cerebrospinal fluid (CSF) in the BioFINDER pilot study. Group comparisons were performed using the Wilcoxon rank sum test and linear models adjusted for age and sex were used to assess associations of NPTX2 protein levels with cognitive function (mini mental status exam (MMSE)) and with neuroimaging, e.g., Aβ‐PET, tau‐PET (temporal ROI, Braak I‐IV) as well as cortical thickness in an AD signature composed of temporal regions in the AD group.

Result

CSF NPTX2 concentration was found to be lower in AD compared with controls (p = 0.017, Figure). Lower NPTX2 concentration was associated with greater tau PET SUVR (β(SD) = ‐0.25(0.079), p‐value = 0.0027) and cortical thickness atrophy (β(SD) = 0.075(0.024), p‐value = 0.0034)) but not with amyloid‐β PET SUVR. Lower NPTX2 concentration was also associated with lower MMSE score (β(SD) = 2.62 (0.75), p‐value = 0.0010).

Conclusion

We have successfully developed a Simoa assay of a novel CSF biomarker, NPTX2. This semi‐automated method allows for large‐scale evaluation of NPTX2, a leading candidate for synaptic degeneration in neurodegenerative disorders.
Proteomic characterization of small vessel pathology in PSEN1 E280A familial Alzheimer’s disease
Authors: Littau Jessica Lisa , Amri Yassir El , Villalba‐Moreno Nelson David , Shafiq Mohsin , Lopera Francisco , ‐Lanau Andres Villegas , Sepulveda‐Falla Diego
Published: December 2023

Background

Vascular pathology is a main contributor to Alzheimer’s disease (AD) progression and severity. We have previously characterized vascular pathology in the PSEN1E280A Colombian kindred. In postmortem analyses we identified that the occipital cortex (OC) is the most affected region by small vessel disease (SVD), including other cortical areas and basal ganglia. Interestingly, frontal cortex (FC) is spared from tau pathology in protected PSEN1E280A cases, while the OC is not. Here we study the proteome of isolated vessels from frontal and occipital cortices to identify differences in molecular pathways.

Method

Approximately 400 mg of FC and OC of postmortem brain tissue from PSEN1E280A familial AD (FAD, n = 10), sporadic AD (SAD, n = 10) and controls (HC, n = 5) were homogenized, centrifuged at 2000 g / 5 minutes before using gradient centrifugation at 10000 g / 15 minutes with dextran to receive the microvessel containing pellet which was retrieved and resuspended in lysis buffer for tandem mass tag (TMT) proteomics. Proteomics spectral data were matched to peptide sequences in the human UniProt protein database using the MaxQuant software package. The MaxQuant output files were analysed by MSstatsTMT using R software for statistical analysis. clusterProfiler package was used to perform Gene Ontology enrichment analyses.

Result

Microvessels isolated from AD OC showed 1597 significantly dysregulated proteins when compared to controls, while FC showed 523. FAD showed the majority of upregulated proteins in FC (181 > 88 in SAD), and OC (428 > 84). This pattern was similar in downregulated proteins in the OC (391>171), but not in the FC (106<156) (Fig. 1A). The comparison between FAD cases and controls was the only one that identified a variety of biological processes (BP) during Protein set enrichment analysis. Notably, FAD FC showed upregulation of BP associated to vessel proliferation (Fig. 1B), while the OC showed downregulation of BP associated to immune system and mRNA regulation (Fig. 1C).

Conclusion

We have identified the OC as a critical region of FAD pathology. Proteomic analysis of isolated microvessels from this region point towards a more deleterious profile while the FC microvessel proteome indicates an earlier stage of SVD pathology.
Racial and Ethnic Differences in Plasma Biomarker Eligibility in a Preclinical Alzheimer’s Disease Trial
Authors: Molina‐Henry Doris P. , Raman Rema , Liu Andy , Langford Oliver , Johnson Keith A. , Shum Leona K , Glover Crystal M , Aisen Paul S. S , Dhadda Shobha , Irizarry Michael C. , Sperling Reisa A. , Grill Joshua D.
Published: December 2023

Background

In Alzheimer’s disease (AD) trials, differential screen failure due to cognitive and biomarker requirements may contribute to underrepresentation of racially and ethnically minoritized groups. The AHEAD 3‐45 Study (NCT04468659) is an ongoing program testing lecanemab at the stage of preclinical AD that utilizes plasma biomarker prescreening, acquired before cognitive, clinical, and medical history eligibility assessments, to enrich for participants likely to qualify based on amyloid PET eligibility criteria.

Methods

We examined the frequency of plasma amyloid biomarker eligibility among racial and ethnic groups in the AHEAD Study. We assigned participants ages 55‐80 to mutually exclusive groups: Hispanic Black (HB), Hispanic White (HW), Non‐Hispanic Asian (NHA), Non‐Hispanic Black (NHB), and Non‐Hispanic White (NHW). We used univariate logistic regression models to explore group differences in screen failure rates as determined by an algorithm that includes the plasma Aβ 42/40 ratio, age, and APOE status. The algorithm indicates an adequately high probability of elevated brain amyloid (>20 centiloids). We further explored whether APOE ε4 status (carrier vs non‐carrier) contributed to group differences.

Results

Among 4274 participants undergoing plasma screening, 59 (1.4%) were HB, 622 (14.6%) were HW, 74 (1.73%) were NHA, 329 (7.7%) were NHB, and 3190 (74.6%) were NHW. Screen failure rates were 86% for HB, 76% for HW; 80% for NHA; 77% for NHB, and 62% for NHW. Using NHW participants as a reference group, we observed increased odds of screen failure among all other groups (HB OR = 4.0 95% CI 2.0, 9.1; HW OR = 2.0 95% CI 1.6, 2.4; NHA OR = 2.5 95% CI 1.4, 4.5; NHB OR = 2.1, 95% CI 1.6, 2.7). Observed differences were consistent across APOE ε4 carriers and non‐carriers.

Conclusion

Differential rates of amyloid eligibility were observed despite the lack of systematic sample bias due to clinical or cognitive requirements observed in previous studies. Potential explanations for these observations include differences in clinical trial access, incidences of elevated amyloid, needed cutoffs for biomarker assays, and confounding due to comorbidities or other unmeasured covariates.

This work is supported by a public‐private partnership between Alzheimer’s Clinical Trial Consortium (U24 AG057437) and Eisai.
Glucose intake is influencing the concentration of AD‐related plasma biomarkers in healthy adults
Authors: Grötschel Lana , Huber Hanna , Ashton Nicholas J. , Schieren Alina , Weinhold Leonie , Schmid Matthias , Coenen Martin , Blennow Kaj , Stehle Peter , Zetterberg Henrik , Simon Marie‐Christine
Published: December 2023

Background

Blood biomarker analyses are seen as a great aid to early diagnose and confirm underlying Alzheimer’s disease (AD) pathology. Developing evidence suggests that certain confounders need to be considered which may affect the reliability of biomarker results, e.g., chronic kidney disease. However, little is known with respect to potential confounding effects of energy/nutrient intake on these biomarkers. Thus, we aim to study the short‐term effects of oral glucose intake in healthy, obese adults.

Method

111 participants (60±7y, BMI 31±4kg/m2, 47 males) ingested 300ml of a glucose syrup (75g glucose, Accu‐Chek, Roche). Neurofilament light, glial fibrillary acidic protein [GFAP], amyloid‐β 42/40 ratio, phosphorylated tau ([p‐tau] 181 and p‐tau 231) were measured in fasting (0 minutes) and postprandial blood samples collected 15, 30, 45, 60, 120 and 180 minutes after ingestion of the glucose syrup using ultra‐sensitive Single molecule array assays. Additionally, a fasting (control) group (n = 26) was followed over the same time period. Statistical analysis was done using polynomial spline of degree 3 to test for differences in parameter progression over time within and between groups.

Result

In both groups, all biomarkers changed significantly over time (glucose group: all p<0.0001, fasting group all p<0.05) compared to baseline (0 minutes). The changes to baseline in GFAP were significantly different after glucose ingestion compared to the fasting state (p<0.0001). The GFAP level decreased in the early postprandial phase (until 60 minutes) and subsequently increased in the late postprandial phase.

Conclusion

Our results suggest that plasma biomarkers for AD‐related pathologies are influenced by the individual nutritional status (prolonged fasting, postprandial situation). This should be considered when using AD‐related biomarkers for screening and diagnostic purposes.
Cognitive sequealae of COVID‐19 is not predicted by SARS‐CoV‐2 variants
Authors: de Erausquin Gabriel A. , Zwir Jorge Igor , Snyder Heather M , Gonzalez‐Aleman Gabriela , Zamponi Hernan P. , Figueredo‐Aguiar Mariana , Fumagalli Emiliano , Blangero John , Yécora Agustín , Vaca Fabiana , Kukoc Gabriela , Dominguez Maria Eugenia , Calvó Maria , Padilla Eduardo G , Guerrero Gonzalo , Habes Mohamad , Fox Peter T , Seshadri Sudha ,   Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2
Published: December 2023

Background

The long term sequelae of COVID‐19 in older adults are only beginning to be clarified, and its predictors and underlying molecular mechanisms may shed light on the relationship between viral infections and Alzheimer’s disease and related dementia.

Method

A prospective cohort of 874 older adult Amerindians from Argentina with COVID‐19 illness confirmed by PCR of nasal swabs as well as controls, was established during the first year of the COVID‐19 pandemic. We obtained data on the severity of the acute illness, as well as extensive neuropsychiatric and cognitive assessments, neurological exams (including quantitative hyposmia/anosmia), plasma for biomarkers and preliminary brain MRI images using the ADNI‐3 protoco (n = 300)l,and whole genome sequencing (n = 300). Isolates from SARS‐CoV‐2 were obtained by the provincial Direction of Epidemiology and sequenced by the national Ministry of Health. Variants of interest/concern were allocated to each case on the basis of the prevalent community isolate at the time of confirmed positive PCR. A deep learning strategy was used to identify predictive factors of cognitive and clinical outcomes.

Result

Four distinctive cognitive profiles were identified. Greater cognitive impairment was associated with older age (p = E−9), worse acute COVID‐19 illness (p = 0.008), unvaccinated status (p = E−7), and severity of anosmia (p = E−5). SARS‐CoV‐2 variant was associated with severity of acute illness ((p = E−6) but notably not with cognitive impairment. Preliminary analysis of genomic and brain imaging data will be presented.

Conclusion

Our data strongly suggest that all SARS‐CoV‐2 variants of interest up to the omicron wave seem equally likely to result in cognitive impairment in older adults, modulated by the severity of the acute illness.
Development and Validation of the Modified Neuropsychological Test Battery (PmNTB) in the Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER)
Authors: Papp Kathryn V. , Farias Sarah Tomaszewski , Ngandu Tiia , Sachs Bonnie C. , Chan Michelle L , Krueger Kristin R , York Michelle , Lee Athene KW , Hartman Elizabeth , Thro Amber Adkins , Caudle Brad A , Howard Marjorie , Leng Xiaoyan , Snyder Heather M , Carrillo Maria C. , Whitmer Rachel A. , Espeland Mark A. , Baker Laura D
Published: December 2023

Background

The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) will determine whether interventions that simultaneously include multiple risk reduction strategies can protect cognitive health in older adults. The primary outcome, a global cognitive composite score derived from the POINTER‐Modified Neuropsychological Test Battery (PmNTB), was developed to allow for outcome harmonization with its forerunner, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and other large trials (e.g., A4, EXERT). Here we describe the PmNTB and its initial validation in the baseline U.S. POINTER sample.

Method

U.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two interventions varying in intensity and format, in older adults at increased risk for cognitive decline and dementia. The PmNTB includes performance from 7 cognitive tests and is computed as the mean of three domain‐specific composites: Episodic Memory, Processing Speed, and Executive Function. The Episodic Memory Composite includes Free and Cued Selective Reminding Test, Story Recall, and Visual Paired Associates. The Processing Speed Composite includes Trail Making Test (TMTA) and Digit Symbol Substitution Test. The Executive Function Composite includes Number Span, Word Fluency, and TMTB. PmNTB was assessed in relation to age, clinical status (Clinical Dementia Rating‐CDR), and other cognitive composites able to be computed in the current sample using overlapping measures (i.e., FINGER NTB, Preclinical Alzheimer’s Cognitive Composite‐PACC‐5).

Result

2094 participants completed the baseline assessment (mean age = 68.2±5.2 years; 68.8% female, 69.1% non‐hispanic white, mean MMSE = 28.9± 1.3). Global CDR was 0 for 79.5% of participants, and 0.5 for 20.5% of participants. After adjusting for education, race, ethnicity, and sex, each additional year in age was associated with a drop in PmNTB z‐score by ‐0.064 (95%CI = ‐0.071,‐0.056, p<0.001). Likewise, global CDR = 0.5 (questionable dementia) was associated with a lower PmNTB score (z = ‐0.549) compared with global CDR = 0 (‐0.134 z‐scores). PmNTB correlated with the FINGER NTB (r = 0.858, p<0.001) and the PACC‐5 (r = 0.876, p<0.001).

Conclusion

The PmNTB is a valid measure of cognitive functioning, capturing age‐related cognitive decrements and is associated with clinically relevant, functional outcomes. It also exhibits convergent validity with established cognitive outcomes.
Six‐month risk of non‐traumatic intracranial hemorrhage in cognitively impaired patients following Covid‐19 infection
Authors: Gillis Cai , Wang Nasha , Montenigro Philip H. , Maserejian Nancy Nairi
Published: December 2023

Background

Studies suggest dementia patients have higher rates of non‐traumatic intracranial hemorrhage (nt‐ICH) compared to cognitively‐unimpaired peers. Recent studies also suggest increased risk of nt‐ICH, following infection with Covid‐19 in the general population. However, the risk of nt‐ICH following Covid‐19 infection in cognitively‐impaired individuals is currently unknown.

Method

Using US electronic health records ICD codes, we matched Alzheimer’s disease (AD), dementia, and mild cognitive impairment (MCI) cases with a history of Covid‐19 to similarly cognitively impaired controls without Covid‐19 history and examined incidence of nt‐ICH over six‐months following infection. Cases and controls were propensity score matched on age, sex, race, ethnicity, time since cognitive‐diagnosis, anticoagulant use, antiplatelet use, and 37 comorbidities. Analyses focused on the first year of the pandemic in 2020, prior to availability of at‐home tests and vaccines, to reduce misclassification bias. Individuals with prior history of nt‐ICH, traumatic ICH, or stroke were excluded to focus on incident nt‐ICH. Cox proportional hazard models compared risk between those with and without Covid‐19.

Result

Our sample included 2,287 AD cases with Covid‐19 matched to 6,861 AD controls; 5,726 dementia cases matched to 17,178 dementia controls; and 807 MCI cases matched to 2,419 MCI controls. The incidence of nt‐ICH following Covid‐19, among AD cases, was 12.53/1,000 person‐years (95% CI: 7.66‐19.36) vs. 4.16/1,000 person‐years (95% CI: 2.51‐6.50) in AD patients without Covid‐19; HR = 3.1 (95% CI: 1.7, 5.8), p = 0.0004. Similarly in dementia patients, Covid‐19 increased the risk by 3.0 times (95% CI: 1.8, 4.7), p<0.0001. The incidence in dementia Covid‐19 cases was 8.48/1,000 person‐years (95% CI: 5.91, 11.80) vs. 2.97/1,000 person‐years (95% CI: 2.07, 4.13) in dementia patients without a history of Covid‐19 over the study period. The incidence in MCI patients with a history of Covid‐19 was 5.03/1,000 person‐years (95% CI: 1.37, 12.87), vs. 1.56/1,000 person‐years (95% CI: 0.32, 4.57) in MCI controls, but risk was not significantly different; HR = 3.4 (95% CI: 0.8, 15.0), p = 0.11.

Conclusion

Although nt‐ICH was rare among cognitively impaired patients following Covid‐19 infection in 2020, the risk over 6‐months in AD and dementia cases was approximately 3 times higher than controls without a history of Covid‐19.
Post‐mortem MRI white matter hyperintensities are associated with cortical astrocytopathy and water channel expression in the oldest‐old
Authors: Roese Natalie E , Hurworth Justin , Krajbich Victoria , Schwartz Daniel , Lahna David , Wall Rachel C , Woltjer Randy L , Silbert Lisa C
Published: December 2023

Background

Cerebrovascular small vessel disease, a common cause of cognitive impairment in older individuals, is characterized by the presence of MRI white matter hyperintensities (WMH). Our previous MRI‐targeted histopathological studies have found WMHs and the surrounding NAWM penumbra to be associated with glial markers. This study aims to assess the relationship between cortical markers of glial dysfunction and post‐mortem (PM) MRI WMH.

Method

Left brain hemispheres were obtained from 45 Oregon Alzheimer’s Disease Research Center subjects >/ = 80 years of age without significant AD pathology. Intact and sliced hemispheres were scanned at 7T MRI. MRI scans were used to target histological sampling. Slides were stained for glial fibrillary acid protein (GFAP), ionized calcium binding adapter molecule‐1 (IBA1), aquaporin‐1 (AQP1), aquaporin‐4 (AQP4), vimentin and amyloid‐beta (ABETA). Slides were co‐registered to MRI. Tissue masks were hand‐drawn to delineate white matter and cortex. Cortical ROIs were quantified for mean pixel value (AQP1, AQP4, GFAP, and Vimentin) or area coverage (IBA1, ABETA). Cassettes with no local WMH were compared with those in the top third of slide WMH coverage (187 cassettes). Global WMH burden was dichotomized at the mean. Linear mixed‐effects models regressed stain quantification on local WMH (in slide) and global WMH burden, with a random effect for staining batch (levels = 4). The final model controlled for age at death and ABETA expression within a slide. Interactions between local and global WMH were included where appropriate.

Result

High local WMH burden was associated with greater cortical vimentin (p = 0.036), GFAP (p = 0.066), and AQP4 (p = 0.004), while high global WMH burden was associated with greater IBA1 (p = 0.034) and AQP1 (p = 0.071). An interaction was identified between local and global WMH burden for AQP1 (p<0.10), such that in subjects with high global WMH burden, high local WMH burden was associated with higher AQP1. Greater local cortical ABETA was associated with cortical AQP1 (p = 0.004) expression.

Conclusion

In oldest‐old individuals without significant AD pathology, high local and global PM‐MRI WMH burden is associated with cortical astrocytopathy, including increased water channel expression and inflammation. Findings implicate WMH as a state marker of widespread cortical pathology that may confer increased vulnerability to cognitive decline with advanced age.
Amygdala tau deposition best discriminates between stages of memory impairment
Authors: Huyghe Lara , Gérard Thomas , Colmant Lise , Salman Yasmine , Malotaux Vincent , Lhommel Renaud , Dricot Laurence , Ivanoiu Adrian , Quenon Lisa , Hanseeuw Bernard J
Published: December 2023

Background

The recent development of positron emission tomography (PET) radiotracers for tau aggregates allows quantifying the regional tau burden in‐vivo. We aimed to investigate the associations between regional tauopathy and episodic memory outcomes in the AD spectrum from clinically normal to the dementia stage.

Method

We recruited 111 participants between 2019 and 2023 at the Memory Clinic of Saint‐Luc University Hospital. Each participant underwent [F18]‐MK6240 tau‐PET, 3DT1 MRI, cognitive assessment, and either lumbar puncture or [F18]‐Flutemetamol PET for amyloid status. Tau burden was quantified using Freesurfer by referring to the Desikan‐Kiliany lobe cortical parcellation, as well as in several medio‐temporal regions (MTL; i.e., entorhinal cortex, amygdala, hippocampus). Memory was assessed using three Z‐scores from the FCSRT: Sum of Free Recall (SFR), Sum of Total Recall (STR), and Sum of Delayed Free Recall (DFR). The average of these scores forms the Memory Composite Score (MCS). Participants were classified in three groups (Table 1): amyloid‐negative clinically normal participants (n = 44); non‐demented participants with AD pathology (early AD, n = 45); and AD dementia participants (n = 22). Based on their SFR and STR scores, subjects were also classified as having retrieval and/or encoding memory deficits according to a Stage of Objective Memory Impairment (SOMI) classification, inspired from Grober and colleagues (2018). Analyses were corrected for multiple comparisons.

Result

In early AD, SFR and DFR correlated with tauopathy in the bilateral entorhinal cortex (EC) and amygdala (Fig.1). MCS correlated with tauopathy in the bilateral amygdala, and the right frontal lobe. Tau levels did not correlate with STR in any regions. Moreover, MTL tauopathy differed between SOMI stages: Specifically, amygdala tauopathy gradually increased with retrieval deficits (SOMI1‐2) and encoding deficits (SOMI3‐4). In contrast, tauopathy in the EC, the temporal lobe, and the parietal lobe was elevated in all participants with memory deficits, but did not distinguish between retrieval and encoding deficits (Table 2).

Conclusion

Tauopathy in the MTL ROIs is predictive of retrieval deficits in early stage of AD. SFR is a more sensitive measure of this early decline compared to STR. Amygdala tauopathy differs between patients with retrieval and encoding deficits.
Detection of Early Alzheimer’s disease at AdventHealth: A Davos Alzheimer’s Collaborative flagship site
Authors: Baldivieso Valeria , Erickson Kirk I. , Smith Steven R. , Pratley Richard E. , Baksh Magda R. , Shepherd Gayle , Lopez Janice , Jain Shivangi , Selzler Katherine J. , Murray James F , West Tim , Ortega Julia , Coppinger Justine , Venkatesh Venky , Monane Mark , Braunstein Joel B.
Published: December 2023

Background

Early identification of Alzheimer’s disease (AD) is critical for disease‐modifying therapies. The Davos Alzheimer’s Collaborative flagship program tested the feasibility of implementing a digital cognitive assessment (DCA) followed by a blood biomarker (BBM) for early detection of cognitive impairment (CI).

Method

Individuals ≥65 years without dementia were approached via their primary care provider (PCP) or through direct‐to‐consumer (DTC) social media. After consenting, participants completed the Cogstate Brief Battery (CBB) DCA. Participants with an abnormal or borderline CBB score were offered the Montreal Cognitive Assessment (MoCA) and the PrecivityAD® blood test, a CLIA‐certified laboratory developed test that uses mass spectrometry to analyze biomarkers to identify brain amyloid plaques (reported by the Amyloid Probability Score‐APS) in individuals with CI.

Result

Over 2300 participants expressed interest. Of 2001 eligible, 1076 (96% social media, 4% PCP) e‐consented. 742 completed the CBB of which 211 (28%) were borderline, 113 (15%) abnormal, and 418 (56%) were negative for CI. Of the 324 with borderline or abnormal CBB scores, 219 (67%) completed the MoCA (59% Normal range, 38% Mild CI range, 2% Moderate CI range, and 0.5% Severe CI range). Of the 324, 218 (67%) received BBM: 18.8% had High APS, 67.9% Low APS, and 13.3% Intermediate (e.g. non‐informative) APS. The APS result for participants with a normal MoCA showed 20% with High APS, 12% with an Intermediate APS, and 69% with Low APS. Of those with an impaired MoCA 18% had High APS, 15% Intermediate and 67% low APS. A Fisher’s Exact test determined there was no statistically significant relationship between MoCA impairment and APS category (p‐value 0.68).

Conclusion

This study highlights the success of a DTC approach. The MoCA, alone, is insufficient to identify risk of AD in individuals with CI. A more comprehensive clinical evaluation of AD can be enhanced with the addition of a BBM leading to better disease‐modifying strategies.
Cluster‐Derived Psychosocial Phenotypes, Cognitive Outcomes, and AD Plasma Biomarkers of Black and Hispanic/Latino Older Adults Enrolled in HABS‐HD
Authors: Clark Alexandra L. , Thomas Kelsey R. , Haley Andreana , Duarte Audrey
Published: December 2023

Background

Although Black and Hispanic/Latino older adults are at increased risk for Alzheimer’s disease (AD), there is considerable within‐group heterogeneity in psychosocial factors of risk and resiliency amongst these community members. The present study (1) used cluster analysis on measures of economic/social resources and psychiatric distress to identify distinct subgroups and (2) compared cognitive and AD biomarker outcomes of these groups in an effort to understand pathologic aging among racially/ethnically diverse older adults.

Method

Baseline data from 816 Black and Hispanic/Latino participants without dementia enrolled in HABS‐HD were included. Variables in the cluster analysis included: annual income, state area deprivation index, social support, occupational complexity, chronic stress, and symptoms of depression and anxiety. A discriminate function analysis (DFA) tested the extent to which the individual variables predicted cluster‐group membership. ANOVAs and chi‐squared tests compared the groups on demographics. ANCOVAs controlling for age, education, sex, and race/ethnicity examined group differences in subjective cognitive concerns, objective memory and executive functioning composite scores, and plasma AD biomarkers (AB42/40, t‐tau, NfL).

Result

The cluster analysis identified 3 distinct groups: Group 1 was low resource/high distress (n = 215); Group 2 was high resource/low distress (n = 248); and Group 3 was low resource/low distress (n = 353; Figure 1). The DFA correctly classified 95.3% of participants. Results revealed significant group differences in education and the proportion of women and Black adults across the groups (see Table 1). ANCOVAs revealed significant group differences in subjective memory concerns, executive functioning composite, and plasma AD biomarkers; Group 1 consistently displayed poorer cognitive outcomes and more severe AD biomarker patterns relative to Groups 2 and 3, but there no differences in outcomes between Groups 2 and 3. No group differences on the memory composite were observed.

Conclusion

Risk for AD among racially/ethnically diverse older adults may differ as a function of current levels of resources and psychiatric distress. Group 1 represents individuals with low resources and high levels of distress that may be at increased risk for poor outcomes in late life. Future work should further clarify precise mechanisms of resiliency, such as social support, in Group 3 and explore longitudinal trajectories of cognitive decline across the groups.