bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive integrity in Non‐Demented Individuals with Alzheimer’s Disease Neuropathology is associated with preservation and remodeling of dendritic spines
Authors: Guptarak Jutatip , Scaduto Pietro , Tumurbaatar Batbayar , Jupiter Daniel , Taglialatela Giulio , Fracassi Anna
Published: January 2025

Background

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder leading to dementia. The existence of individuals who remain cognitively intact despite presenting histopathological signs of AD, here referred to as “Non‐demented with AD neuropathology” (NDAN), suggests that some mechanisms are triggered to resist cognitive impairment. These individuals are distinguished by the presence of highly phagocytic microglia capable of clearing damaged synapses near plaques, mitigating further damage to axons and dendrites.

Method

We conducted a comparative analysis of dendritic spines morphology in the post‐mortem frontal cortex of NDAN individuals, AD patients, and age‐matched healthy controls. Our investigation included an in‐depth examination of synaptic structures both near and far from Aβ plaques, quantifying aspects such as dendrite length, diameter, spine density, and types. We expanded our research to investigate levels and distribution of Pin1, identified as a potential key player in the protective mechanisms against AD, influencing the regulation of dendritic spine formation and maintenance.

Result

Within 100 µm of Aβ plaques, significant synaptic toxicity was observed in all groups. However, in areas distal to plaques, NDAN exhibited significantly higher spine density than AD, suggesting the existence of a compensatory mechanism. We also measured the relative abundance of four spine types: mushroom, stubby, filopodia, and long thin, finding stubby spines to be the most common across all groups. Mushroom spines, the least dynamic, were significantly more abundant in AD compared to NDAN and control subjects. Conversely, NDAN individuals showed a higher density of more dynamic and plastic spines, such as filopodia and long thin spines, than AD. These findings suggest that the rearrangement of dynamic dendritic spines in NDAN may underlie the ability of these individuals to replace damaged synapses and preserve cognitive integrity. Furthermore, our results revealed lower expression of Pin1 in AD patients than control and NDAN groups, across regions, proximal and distal to plaques. This finding suggests that reduced Pin1 expression in AD may contribute to the compromised synaptic integrity and plasticity observed in these individuals.

Conclusion

This study sheds light on the potential mechanisms allowing NDAN individuals to retain cognitive function despite AD pathology, offering insights for future therapeutic strategies.
Delivery of mRNA encoding an anti‐tau monoclonal antibody and engineered scFv intrabody results in functional antibody expression in neurons
Authors: Wongsodirdjo Patricia , Caruso Alayna C , Yong Alicia , Lester Madeleine , Vella Laura J , Hung Ya Hui , Nisbet Rebecca M
Published: January 2025

Background

Monoclonal antibodies have emerged as a leading therapeutic agent for the treatment of disease, including Alzheimer’s disease. Such antibodies, however, are expensive and timely to produce and require frequent dosing regimens to ensure disease‐modifying effects. Synthetic in vitro‐transcribed mRNA encoding antibodies presents a promising alternative to conventional passive immunotherapy and overcomes the need to generate recombinant antibodies.

Method

In vitro‐transcribed (IVT) mRNA encoding a tau specific antibody as a full‐sized IgG and as a single chain variable fragment (scFv) was synthesised. Human neuroblastoma SH‐SY5Y cells and mouse primary hippocampal neurons were transfected with the IVT mRNA and antibody translation and ability to bind tau was assessed.

Result

Transfection of mammalian cells with IVT synthesised mRNA results in the translation of a secreted tau‐specific IgG and an intracellular scFv intrabody. Importantly, both antibody formats engage tau, with the intrabody engaging tau directly within the cell cytoplasm.

Conclusion

IVT synthesised mRNA can be used to generate both functional full‐length IgG antibodies and scFv intrabodies targeting tau. Our study highlights the utility of mRNA as an inexpensive and versatile delivery platform for antibody therapeutics.
Amyloid β and cardiovascular risk factors promote endothelial cell apoptotic and mitochondrial stress, blood‐brain barrier dysfunction and angiogenesis impairment
Authors: Fossati Silvia
Published: January 2025

Background

Brain endothelial cell (EC) stress, including that induced by vascular amyloid β (Aβ) deposits in cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD), contributes to cerebral blood flow impairment, blood brain barrier (BBB) damage, neurovascular unit dysfunction, microhemorrhages and hypoperfusion, precipitating neurodegeneration and neuroinflammation processes. Epidemiological and experimental evidence suggests that hyperhomocysteinemia (Hhcy) contributes to increasing AD risk as well as CAA pathology. However, the cellular and molecular mechanisms through which Aβ and Hhcy drive EC and BBB dysfunction, whether the molecular effects of these challenges are additive or independent, and possible therapeutic strategies, remain to be determined.

Methods

Our work analyzed specific mitochondria‐ and death receptor‐mediated pathways in human cerebral microvascular ECs challenged with Aβ, high Hcy, or their combination. We also assessed the effects of these challenges, alone or combined, on the loss of BBB Resistance, junction proteins expression and structure and angiogenic activity, as well as the potential protective effects of carbonic anhydrase inhibitors.

Results

Our data demonstrates that Aβ activates death receptors 4/5 (DR4/5)‐ and mitochondria‐mediated apoptotic pathways in human cerebral microvascular ECs and promotes loss of mitochondrial respiratory function (OXPHOS). Hhcy potentiates the Aβ‐mediated activation of both the extrinsic and intrinsic mitochondria‐mediated apoptotic pathways, the loss EC barrier permeability, a deregulation of multiple junction proteins and the impairment in VEGF‐A/VEGF‐receptor signaling and angiogenic capabilities. However, Hhcy does not affect endothelial Aβ‐mediated OXPHOS impairment and metabolic defects. Carbonic anhydrase inhibitors successfully improve EC apoptotic outcomes and microvascular fitness both in vitro and in vivo.

Conclusion

This data highlights new and specific molecular mechanisms that drive endothelial and BBB pathology in AD/CAA in the presence or absence of a comorbid cerebrovascular condition such as Hhcy. Moreover, we discovered a new potential therapeutic target, carbonic anhydrase, whose inhibition can revert the cerebrovascular effects of Aβ in vitro and in vivo.
Blood‐Brain Barrier Dynamics in Vascular Dementia: Unravelling the Tripartite Crosstalk between the Endothelium, Pericytes, and Microglia
Authors: Montagne Axel
Published: January 2025

Background

Small vessel disease (SVD) is a disorder of the brain’s microvessels and a common cause of dementia and stroke. Evidence links normal ageing features to SVD progression, involving endothelial activation, pericyte dysfunction, BBB failure, and microglia response. Here, we aim to examine this relationship through a series of translational investigations.

Method

Using microscopy, we quantified pericyte coverage and endothelial VCAM‐1 expression in young/aged mice and control/SVD cases. Pericyte and endothelial fluid biomarkers were analysed in a mild stroke cohort, correlating with SVD MRI markers. We employed a novel AAV targeting brain endothelial cells to overexpress (OE) Vcam1, Icam1, Selp and Sele in mice, shedding light on endothelial activation’s role in pericyte and BBB dysfunctions, but also the reciprocal influences with the microglial response. Finally, we genetically manipulated brain pericytes using our novel Atp13a5‐CreER mouse model, offering insights into their biological impact on endothelial and BBB functions.

Result

Aged mice and SVD cases showed reduced pericyte coverage and increased VCAM‐1 expression in microvessels (<10 µm). Biomarker analyses revealed associations between PDGFRB, PDGF‐BB, ICAM‐1, VCAM‐1, and E‐selectin concentrations with specific SVD manifestations. AAV experiments highlighted correlations between endothelial activation, pericyte dysfunction, reduced brain perfusion, and BBB breakdown, with distinct immune responses observed in AAV‐Vcam1OE and AAV‐Icam1OE groups. The Atp13a5‐CreER model unveiled diverse pericyte subtypes and their pro‐inflammatory impact on capillary endothelial cells.

Conclusion

Our approach underscores endothelial‐pericyte crosstalk’s crucial role in dementia. Integrating post‐mortem tissues, fluid biomarkers, viral manipulations, and mouse models enriches understanding, guiding potential therapeutic interventions in vascular dementia.
Evidence for impaired clearance leading to amyloid beta (Aβ) accumulation in the Alzheimer’s eye
Authors: Wijesinghe Printha , Hosseini Amir , Campbell Matthew , Xi Jeanne , Haynes Justin R , MacKenzie Ian R , Hirsch‐Reinshagen Veronica , Hsiung Ging‐Yuek Robin , Spiller Benjamin , Wadzinski Brian E , Pham Wellington , Matsubara Joanne A
Published: January 2025

Background

An imbalance between the production and clearance of amyloid beta (Aß) has emerged as a major cause of sporadic Alzheimer’s disease (AD). Retinal wholemount studies can identify cell‐specific involvement in Aß clearance mechanisms which cannot be accomplished in the brain ex vivo.

Methods

Eye cross‐sections of double transgenic (Tg, APP‐PS1) and non‐carrier sibling female mice (n = 16, 4 per group) at 3‐ and 9‐ month ages were probed with antibodies 6E10 (Aβ1‐16 amino‐acid residues, soluble and insoluble species), ionized calcium‐binding adapter molecule 1 (IBA1, microglia/macrophage), glial fibrillary acidic protein (GFAP, astrocytes), glutamine synthetase (GS, Müller cells) and aquaporin‐4 (AQP4, membrane water channel) using immunofluorescence. Wholemount neuroretinas of human AD (n = 10, mean age = 76.8, 6 females) and control (n = 10, 72.5, 5 females) donor eyes were probed with antibodies 12F4 (Aß1‐42 amino‐acid residues, misfolded oligomers), IBA1, GFAP, GS, AQP4 and Ulex europaeus agglutinin (UEA‐l, vascular endothelium). Finally, a nanobody (soluble Aß oligomer against human Aβ1‐42 peptide) conjugated with near‐infrared dye (NIR‐E3) was probed with 12F4 using a nanobody staining protocol in wholemount retinas.

Results

In eye cross‐sections, a significant increase in 6E10, IBA1, GFAP and AQP4 was found in the older vs. younger Tg mice, suggesting Aβ accumulation resulted in gliosis and AQP4 mislocalization. In contrast, a significant reduction for 6E10 in the older vs. younger non‐carrier siblings, suggests the existence of an effective Aβ clearance mechanism (e.g., macrophages and glymphatic drainage) as IBA1 and AQP4 levels were increased. In wholemount neuroretinas, macroglia degenerations (GFAP, GS and AQP4) which form the inner limiting membrane were prominent in human AD eyes, suggesting defective ocular glymphatic systems. The microglia phenotype was different from its resting stage in AD eyes, however, due to complexity of IBA1 positive resident microglia, and macrophages including monocytes, perivascular macrophages, pericytes and hyalocytes, it is difficult to define microglia phenotype, particularly activated and ameboid types between AD and control eyes. Interestingly, NIR‐E3 positive perivascular macrophages (but negative to 12F4), indicating soluble Aβ clearance were predominantly found within the blood vessels of control donor eyes.

Conclusion

This study confirms the existence of different impaired clearance mechanisms in human AD eyes.
Revised diagnostic criteria for Vascular Cognitive Disorders: the VASCOG‐2 criteria
Authors: Sachdev Perminder S. , Bentvelzen Adam C. ,   VasCog‐2 Criteria Consortium
Published: January 2025

Background

Several sets of diagnostic criteria have been published for vascular cognitive disorders (VCD) since the 1960s. The International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) working group published a comprehensive and operationalized criteria set in 2014. Considering the significant developments in the field in the last decade, an international expert group was commissioned to revise these criteria using the Delphi process.

Methods

A modified Delphi consensus method was used, involving an iterative, multi‐staged series of structured surveys with feedback of anonymized responses from experts in the fields of cerebrovascular disease and dementia. Three rounds were planned, with the possibility of a fourth round, if required to reach consensus. Literature reviews on topics related to the criteria were conducted by a team of researchers, which informed the first structured questionnaire. Each salient point in the criteria was put to consensus, and relevant recent reviews and publications provided for background information. Consensus was defined as agreement or disagreement on any statement of ≥ 75%, near consensus as 66 – 75%, and <66% as non‐consensus. Statements that reached consensus were removed from subsequent rounds, as were most that had non‐consensus, with some being reworded. One in‐person meeting in Gothenburg, Sweden and one virtual meeting were held for experts to discuss contentious issues and advise on the process.

Results

Seventy experts from a broad range of international regions and disciplines consented to participate, and 54 completed the Round 1 survey. The final round is being completed, after which the revised criteria will be finalized for formal approval by all participants. In addition to the criteria for clinical use, which include neuroimaging criteria, a set for research use will be agreed upon.

Conclusions

The updated VASCOG‐2 criteria could serve as the international standard for VCD diagnosis, thereby facilitating diagnostic consistency between clinicians and researchers.
Prebiotic‐based snack from banana improves cognitive decline via decreased brain inflammation and brain oxidative stress in obese rats
Authors: Sa‐nguanmoo Piangkwan , Apaijai Nattayaporn , Pintana Hiranya , Chunchai Titikorn , Arunsak Busarin , Kerdphoo Sasiwan , Pratchayasakul Wasana , Devahastin Sakamon , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: January 2025

Background

Consuming prebiotics demonstrated therapeutic potential against obesity, as illustrated by our previous study on xylooligosaccharide (XOS), revealing that XOS reduced adiposity, diminished systemic inflammation, and restored cognitive function in obese insulin‐resistant rats through the gut‐brain axis. Fresh bananas at various ripening stages are being transformed into snacks, indicating potential as prebiotic‐based treats enriched with fructooligosaccharide and inulin. Despite those findings, there remains a notable gap in the literature concerning the impact of these prebiotic‐based snacks on brain inflammation, reactive oxygen species (ROS) production, and cognitive function in high‐fat diet (HFD)‐induced obese rats.

Method

Seventy‐two male rats were divided into two groups, receiving either a normal diet (ND) or an HFD for total 16 weeks. At 13th week, ND‐fed rats were randomly assigned to 6 subgroups (n = 6/group) to receive either vehicle (NDV, 21 ml/kg/day), prebiotic‐based snacks prepared from bananas at ripening stages 2‐5 (NDS2‐5) (7.47 g dissolved in reversed osmosis water, 21 ml/kg/day in each subgroup), and inulin (NDI, 2 g/kg/day). Similarly, HFD‐fed rats were divided into 6 subgroups (n = 6/group): HFD‐fed rats receiving vehicle (HFV), prebiotic‐based snacks prepared from bananas at ripening stages 2‐5 (HFS2‐5) and inulin, with the same dose as ND‐fed rats, for 4 weeks. Cognitive function was assessed by novel object recognition (NOR). Serum malondialdehyde (MDA) levels, gut microbiota, brain inflammation, and brain ROS production were determined at the end of treatment.

Result

The HFV group exhibited elevated serum MDA levels, increased brain mitochondrial ROS production, heightened TNF‐α levels, indicating brain inflammation, and an augmented Firmicutes to Bacteroidetes (F/B) ratio, indicating gut dysbiosis, when compared to the NDV group (p<0.05, Figure 1). Additionally, the HFV group showed cognitive decline, evidenced by a reduced percentage preference index in the NOR test (p<0.05, Figure 1). Remarkably, HFV rats receiving a prebiotic‐based snack showed reduced serum MDA levels, brain mitochondrial ROS production, brain inflammation, and improved gut dysbiosis, resulting in enhanced cognitive function. (p<0.05, Figure 1).

Conclusion

A prebiotic‐based snack at all ripening stages holds promise as a neuroprotection against HFD‐induced obesity, offering multifaceted benefits by mitigating oxidative stress, gut dysbiosis, brain inflammation, and attenuated cognitive dysfunction in HFD‐fed rats.
Interrogating the cognitive‐behavioural impairment in a motor‐dominant neurodegeneration (ALS), based on brain state dynamics of resting‐state EEG
Authors: Metzger Marjorie
Published: January 2025

Background

Amyotrophic lateral sclerosis (ALS) shares pathological and genetic underpinnings with frontotemporal dementia (FTD). ALS manifests with diverse symptoms, including progressive neuro‐motor degeneration, muscle weakness, but also cognitive‐behavioural changes in up to half of the cases. Resting‐state EEG measures, particularly spectral power and functional connectivity, have been instrumental for discerning abnormal motor and cognitive network function in ALS [1]–[3]. Based on our recent findings using EEG microstates [4], we hypothesized that dynamic analysis of time‐varying spectral EEG measures at source‐level can further interrogate the altered functional network that underpin the cognition and behaviour in ALS as a motor‐dominant neurodegeneration.

Method

For this purpose, we aimed to identify transient brain states associated with specific functional networks and to characterise the spatio‐temporal and spectral alterations in these brain states using high‐density resting‐state EEG, recorded from 99 individuals with ALS and 78 healthy controls (HC). Using a time‐delay embedded Hidden‐Markov‐Model on source‐reconstructed EEG data [5], we identified transient and recurrent brain states characterised by spectral power and coherence. The model was trained to convert source‐reconstructed time courses into sequences of functional networks (brain states).

Result

Twelve brain states were identified with distinct patterns of spectral power and coherence for individuals with ALS and HC. The Brain States 1, 3, 7 and 9 showed significant association between brain states fractional occupancy and behavioural decline (Beaumont Behavioural Inventory [7]; >0.25, q<0.03, >0.65), while state 5 showed association with fluency decline (Edinburgh Cognitive and Behavioural ALS scale [8]; = ‐0.3, q = 0.004, = 0.83). States 1, 7 and 10 were characterised by frontal lobe activation (spectral power higher than the average within the state), while state 3 exhibited activation in the sensorimotor network. Highest spectral power during state 5 was in the supplementary motor area, a region primarily associated with motor planning but also possibly associated with language [9].

Conclusion

This study demonstrated the utility of resting‐state EEG and its temporal decomposition based on spatio‐spectral dynamics for investigating and interrogating the less‐dominant cognitive‐behavioural decline in ALS. It shows clear potentials for applications in cognate conditions such as FTD and Alzheimer’s disease with a dominant cognitive‐behavioural decline.
Complement receptor 1 length polymorphism impacts glial functions relevant to Alzheimer’s disease
Authors: Daskoulidou Nikoleta , Morgan Paul
Published: January 2025

Background

Genome‐wide association studies (GWAS) in Alzheimer’s disease (AD) implicate complement in pathogenesis. Complement receptor 1 (CR1; CD35) is a top AD‐associated GWAS hit; the long variant, CR1*2, associates with risk. The roles of CR1 in brain and how variants influence AD risk are poorly understood. We investigated the impact of the AD‐associated CR1 length polymorphism on phagocytosis in induced pluripotent stem cell (iPSC)‐derived microglia and astrocytes.

Methods

Donors were screened for erythrocyte expression of CR1 variants to identify homozygote donors (CR1*1/CR1*1, CR1*2/CR1*2); peripheral blood mononuclear cells (PBMCs) were isolated and reprogrammed to iPSCs. Clones were differentiated into microglia and astrocytes, confirmed by specific marker expression, then tested for phagocytosis of diverse targets (pHrodo‐E.coli bioparticles, pHrodo‐human synaptoneurosomes, Alexa‐488‐amyloid β fibrils), either unopsonised or opsonised with human serum or Factor I (FI)‐depleted human serum. Uptake of fluorescent targets was measured in real‐time.

Results

CR1*1 and CR1*2 homozygote iPSC lines were established, differentiated into microglia and astrocytes, confirmed by cell‐specific marker expression. CR1 was expressed in all iPSC‐microglia and astrocytes for both variants. iPSC‐microglia and astrocytes were phagocytic and phagocytosis was enhanced by target opsonisation with human serum; FI depletion of serum reduced the enhancing effect. Comparison of CR1*1 and CR1*2 expressing microglia and astrocytes showed that expression of CR1*2, the AD risk variant, enhanced phagocytosis of opsonised targets.

Conclusions

CR1 is an important component of microglial and astrocytic phagocytic activity; CR1*2‐expressing cells showed increased phagocytosis of opsonised targets, providing clues to mechanism of association with AD risk.
Abrupt‐Onset Dementia: Differential Diagnosis and Clinical Characteristics of a Rare Condition
Authors: Piura Yoav D , Brigham Tara , Dabrh Moain Abu , Day Gregory S
Published: January 2025

Background

The term rapidly progressive dementia (RPD) may be applied to patients with precipitous declines in cognitive function resulting in dementia within one year or complete incapacitation within two‐years of symptom onset. Although most patients present with subacute, progressive declines, selected patients develop complete incapacitation within seven days of symptom onset. The differential diagnosis and clinical characteristics of patients with abrupt‐onset dementia are not known.

Method

187 patients with RPD were prospectively enrolled from February 2016 to September 2023 in a study of RPD at Mayo Clinic (Jacksonville, Florida) and Washington University (Saint Louis, Missouri). Patients with ≤7 days from first symptom to onset of RPD were labelled as abrupt onset. Patient characteristics, results of investigations, and causes of abrupt‐onset dementia were further characterized. We further explored the causes of abrupt‐onset dementia in the extant literature to refine the differential diagnosis and approach to evaluation and management of these patients.

Result

Two patients in our study of RPD had abrupt‐onset RPD (2/187, 1.1%), attributed to autoimmune and vascular. An additional 63 cases were identified through comprehensive meta‐narrative review of the literature (40 publications). Causes of abrupt‐onset dementia include vascular, infectious, inflammatory, and toxic. Compromise of structures within the Papez circuit was a common unifying feature common across patients with varying etiologies, informing the localization of abrupt‐onset dementia. 20% cases had potentially treatment‐responsive causes of abrupt‐onset dementia.

Conclusion

Cases of abrupt‐onset dementia are rare overall and associated with a limited differential diagnosis. Evaluation of patients with abrupt‐onset dementia should prioritize testing for vascular, autoimmune, infectious, and toxic causes. Early‐recognition of patients with potentially treatment‐responsive causes of dementia may promote earlier intervention leading to better outcomes in selected patients.
Original Adverse Outcome Pathway linking neuronal exposure to nanoparticles to the onset of Alzheimer’s disease
Authors: Schneider Benoit
Published: January 2025

Alzheimer’s disease (AD) is the most common dementia in humans that today concerns 50 million individuals worldwide and will affect more than 100 million people in 2050. Except for familial AD cases (<5% of AD patients) for which AD pathology connects to mutations in critical genes involved in the processing of the amyloid precursor protein into neurotoxic Aß peptides, it remains unknown what provokes the overproduction and deposition of Aß peptides in the brain of sporadic AD cases (>95% of AD patients). Some nanosized materials, e.g., nanoparticles (NPs), are suspected of playing a role in the growing incidence of AD, due to their reactivity with biological systems, easiness of crossing physiological barriers, capacity to reach the central nervous system and accumulate in the brain. Incriminated NPs are the ultrafine air‐borne particulate matter and manufactured NPs, such as titanium dioxide (TiO2) NPs widely used in food and cosmetic industries or carbon black (CB) NPs used in rubber and as black pigment. Both TiO2‐ and CB‐NPs display neurotoxicity, but the mechanisms by which those NPs affect neuronal homeostasis and place neurons on the path to degeneration are unknown.

Combining in vitro and in vivo approaches, we provide prime evidence that TiO2‐ and CB‐NPs bind a plasma membrane neuronal receptor, the cellular prion protein PrPC, well‐known for its implication in prion diseases, and corrupt PrPC signaling activity. Dysregulation of PrP signaling by TiO2 ‐ or CB‐NPs pomotes the NADPH oxidase‐mediated overproduction of reactive oxygen species that alter neuronal redox equilibrium and the activation of 3‐phosphoinositide‐dependent kinase 1, at the root of an increased vulnerability of NP‐exposed neurons to inflammation and the overproduction of neurotoxic Aß peptides. By showing that neuronal exposure to some TiO2‐ and CB‐NPs induce molecular signs of AD, these mechanistic data provide new insight into how human exposure to some engineered and environmental NPs may predispose to neurodegenerative diseases.

Identifying the mechanisms by which nanoparticles and other pollutants alter neuronal homeostasis would enable the generation of a database of pollutant‐associated Adverse Outcome Pathways and provide clues for counteracting the adverse effects of those pollutants on the central nervous system.
The association of cardiovascular risk factors and depressive symptoms on cognitive function in the U.S. POINTER study
Authors: Thro Amber A , Garcia Katelyn R , Krueger Kristin R , Howard Marjorie , Snyder Heather M , Baker Laura D , Papp Kathryn V
Published: January 2025

Background

Cardiovascular risk factors and depressive symptoms have both been independently shown to be negatively associated with cognitive function. However, the nature of the influence of comorbid depressive symptoms and cardiovascular risk on cognitive function is unclear, and there have been inconsistent findings as to which cognitive domains may be most associated with this relationship.

Method

U.S. POINTER is a randomized controlled trial of two multidomain lifestyle interventions. We examined the baseline relationship between cardiovascular risk, depressive symptoms, and cognitive function in 2103 U.S. POINTER participants (mean age = 68.19±5.16y). The Framingham Risk Score (FRS) using lipids was used to calculate the 10‐year risk of developing cardiovascular disease, and depressive symptoms were assessed using the 15‐item Geriatric Depression Scale (GDS). Cognitive function was measured using composite scores (global, episodic memory, executive function, and processing speed) derived from the U.S. POINTER modified Neuropsychological Test Battery. After computing correlations, generalized linear regression models were used to determine the presence of an interaction between GDS (using a median split of 0‐1 and 2+) and FRS for each cognitive composite while controlling for demographic variables.

Result

Higher GDS was significantly associated with lower global cognition (r = ‐0.04, p = 0.04) and slower processing speed (r = ‐0.06, p = 0.01) but not episodic memory (r = ‐0.03, p = 0.17) or executive function (r = ‐0.02, p = 0.37). FRS was negatively associated with global cognition (r = ‐0.25, p<0.01), episodic memory (r = ‐0.27, p<0.01), executive function (r = ‐0.13, p<0.01), and processing speed (r = ‐0.20, p<0.01). Regression models identified the presence of an interaction between FRS and GDS with global cognition (p<0.01). Specifically, participants with lower GDS scores (0‐1) had higher global cognition at lower levels of FRS than those with higher GDS scores (2+), but as FRS approached 16%, participants with lower GDS scores had lower global cognition than those with higher GDS scores. The presence of an interaction between FRS and GDS was also found with the executive function (p<0.01) and processing speed (p = 0.04) composites, but not with the episodic memory (p = 0.12) composite.

Conclusion

In U.S. POINTER participants at baseline, the effect of cardiovascular risk on global cognition, executive function, and processing speed may vary depending on the presence and severity of depressive symptoms.
Calcium‐ and Tyrosine Kinase‐Dependent Suppression of Macroscopic Homomeric Kv1.2 and Heteromeric Kv1.1/1.2 current by Amyloid Beta (1‐42) Peptide: Implications for Alzheimer’s Disease
Authors: Jamshidi Dina , Yaklin Logen , Burch Sebastian , DeBoeuf Kristi , Farley Joseph
Published: January 2025

Background

The roles of Aβ in the pathogenesis of Alzheimer ’s disease (AD) include disruption of synaptic communication/function and synaptic plasticity mechanisms thought to underlie learning and memory. Exactly how these abnormal processes arise is incompletely understood, but evidence suggests that dysregulation of intracellular Ca2+ levels is involved in alterations of neuronal excitability, synaptic remodeling, and neurodegeneration in AD. Our lab has focused on the potential involvement of voltage‐gated potassium channels (VGKCs) in these processes, particularly Kv1.x family members. VGKCs contribute to resting membrane potential, regulate Ca2+ influx, and their inhibition may lead to and synapto‐ and neuro‐toxicity through hyperexcitability and excess glutamate release. Kv1.x family members are expressed as homotetramers, or as select heterotetramers (e.x Kv1.1/1.2) contributing to the diversity of electrical signaling. Previously, we have observed rapid and robust suppression (50% in 30 minutes) of macroscopic current by Aβ(1‐42) in homomeric Kv1.1 expressing Xenopus laevis oocytes. We sought to understand 1) if suppression by Aβ(1‐42) is exclusive to Kv1.1, or is able to affect other Kv1.x members such as homomeric Kv1.2 and heteromeric Kv1.1/1.2 channels 2) The extent to which the suppression is Ca2+ dependent, and 3) whether the suppression is additionally dependent on endogenous tyrosine kinase activity.

Method

Stage V/VI Xenopus laevis oocytes were injected with Kv1.2 cRNA or both Kv1.1 and 1.2 cRNA for homomeric and heteromeric expression respectively. The effects of bath application of 1 μM of Aβ(1‐42) were evaluated using two‐electrode voltage clamp electrophysiology (TEVC), and Ca2+ dependency was evaluated using BAPTA‐AM (a Ca2+ chelator) and Cyclosporin A (CsA; a PP2B inhibitor). Oocytes were additionally incubated in genistein, a non‐specific tyrosine kinase inhibitor.

Result

For both homo‐and heteromeric channel expressing oocytes, incubation in BAPTA‐AM significantly reduced suppression by ∼45%, while incubation with CsA blocked any suppressive effects of Aβ(1‐42). Oocytes incubated in genistein significantly blocked Aβ‐suppression at a level greater than CsA and BAPTA‐AM (>98%).

Conclusion

Reducing intracellular Ca2+ and inhibiting Ca2+ activated signaling molecules such as PP2B and tyrosine kinases reduces suppression of macroscopic Kv1.x current by Aβ(1‐42).
Plasma biomarkers of vascular injury and cerebrovascular reactivity in APOE4 carriers
Authors: Kapoor Arunima , Dutt Shubir , Nguyen Amy , Gaubert Aimée , Alitin John Paul M , Sible Isabel , Marshall Anisa J , Shenasa Fatemah , Engstrom Allison C , Shao Xingfeng , Bradford David , Rodgers Kathleen E. , Wang Danny JJ , Nation Daniel A.
Published: January 2025

Background

APOE4 carriers exhibit cerebrovascular dysfunction which may contribute to the development of cognitive decline and dementia; however, the mechanisms underlying this pathophysiology remain unknown. Impaired cerebrovascular reactivity (CVR) may be associated with vascular injury, inflammation, and endothelial dysfunction. To examine whether these processes may be involved in CVR deficits in APOE4 carriers, we explored whether plasma levels of vascular injury markers indicative of inflammation and endothelial dysfunction are associated with impaired CVR to hypercapnia and hypocapnia in older APOE4 carriers.

Method

Sixty‐five independently living older adults (mean age = 69.3 years; SD = 8.6; age range 55‐89 years; 30.8% male) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Plasma was assayed for vascular injury markers (Serum amyloid A (SAA), C‐reactive protein (CRP), intercellular adhesion molecule 1 (ICAM‐1), vascular cell adhesion molecule 1 (VCAM‐1)) and values were log‐transformed. APOE genotyping was conducted on blood samples. Pseudo‐continuous arterial spin labeling MRI quantified whole brain cerebral perfusion during CVR to hypocapnia (0.1Hz paced breathing; vasoconstriction).

Result

Adjusting for age and sex, multiple linear regression analysis revealed a significant association between whole brain CVR to hypocapnia and circulating levels of SAA, VCAM‐1 and ICAM‐1. Analyses stratified by APOE4 status revealed a significant association between whole brain CVR to hypocapnia and levels of SAA [B = ‐5.39, 95% CI (‐9.78, ‐1.01), p = .018], VCAM‐1 [B = ‐10.70, 95% CI (‐17.59, ‐3.82), p = .004] and ICAM‐1 [B = ‐10.95, 95% CI (‐17.44, ‐4.46), p = .002] in APOE4 carriers but not non‐carriers.

Conclusion

Findings suggest that elevated levels of vascular injury markers are associated with deficits in cerebral vasoconstriction, particularly in APOE4 carriers at genetic risk for Alzheimer’s disease. SAA, VCAM‐1 and ICAM‐1 are known to be involved in inflammation and endothelial dysfunction, and elevated levels are associated with cerebrovascular resistance and cognitive impairment. Our findings suggest that APOE4 carriers may be particularly vulnerable to these pathophysiological processes. Further longitudinal studies may elucidate whether inflammation and endothelial dysfunction precede or precipitate CVR deficits and contribute to cognitive decline in APOE4 carriers.
Application of restricted mean survival time method in Clinical Trials for Alzheimer disease
Authors: Shan Guogen
Published: January 2025

Background

The restricted mean disease progression (RMDP) is a measure of disease progression from baseline to a pre‐specified follow‐up visit. The RMST is a new statistical tool for survival analysis that is increasingly used in clinical trials. The RMST can be easily interpreted as the average survival time of patients from baseline to the pre‐specified follow‐up time.

Method

We developed a new restricted mean disease progression (RMDP) scale to estimate time savings based on the RMST approach.

Result

We found that the mean squared error (MSE) of the two new methods based on the RMDP is 30% less than that of the existing methods.

Conclusion

The saved time of the two new approaches is more accurate than that of the exiting methods in many applications.
A Common Epitope in p53 and Tau Protein Aggregates
Authors: Lynch David , Bhatt Nemil , Samples Madison , Demny Madeline , Tamamis Phanourios , Kayed Rakez
Published: January 2025

Background

The oligomers and fibrils of tau are well known as an indicator of Alzheimer’s disease (AD). Recently, other protein aggregates have been shown to be potentially involved in the development of the disease.

One of these proteins is p53, involved in DNA repair. Prior studies in our lab show that p53 will form oligomers and fibrils in AD cases but not healthy controls, and has even been observed as a co‐aggregate with tau protein. Owing to the importance of p53 in mitigating damage from diseased cells, it is possible that loss of function or even misfunction of p53 due to aggregation or mislocalisation could be an early contributing factor to AD, having been shown as a potential early biomarker for AD.

Because of the co‐aggregation of p53 and tau, it is possible that aggregate‐specific antibodies will bind to both p53 and tau. Besides giving mechanistic insights into the proteins’ aggregation, this would also suggest that these antibodies could inhibit aggregation in vivo. This study examines this common epitope.

Method

• Using recombinant wild‐type and mutant p53 and tau proteins, the interaction of p53 and tau specific antibodies with each other was determined based around their immunoreactivity, and compared to amyloid‐β.

• Co‐staining of AD mouse model and AD patient samples for both misfolded tau and p53 was used to determine if this conformation cross‐reactivity could also be observed in patient samples.

Result

Despite the lack of sequence homology, an in‐house conformation and aggregation specific p53 antibody was found to be able to react with tau protein, and vice versa. It was also observed that the p53 mutant proteins had different reactions to these aggregate‐specific antibodies. As these antibodies are conformation‐specific, this provides information on the similar conformation both proteins must adopt in order to react with MDM2.

Conclusion

The common epitope recognised by the p53 and tau antibodies suggests that this is a potential target for antibody therapy, as the ability to prevent the formation of the co‐aggregates may permit p53 to continue its role as the ‘guardian of the genome’, a role which, if inhibited, could be a contributing factor to AD.
Reduction of central arterial stiffness by senolytic quercetin improves age‐associated decline in cognitive function in a Dahl salt‐sensitive rat model of early vascular aging
Authors: Santos Carla Rocha Dos , Barnett Mackenzie J , McDevitt Ross A , Wei Wen , Zernetkina Valentina I , Juhasz Ondrej , Morrell Christopher H , Lakatta Edward G , Fedorova Olga V
Published: January 2025

Background

Early vascular aging (EVA), manifesting as increases in central arterial stiffness and BP, is associated with cognitive impairment in humans. EVA and cognitive impairment occurs in Dahl salt‐sensitive (DSS) rats consuming a normal salt (NS) diet with an advancing age. Quercetin (QRC), a flavonoid with anti‐oxidant, anti‐inflammatory and senolytic properties, previously shown to reduce salt‐sensitive hypertension in DSS. We hypothesized that QRC will not only reduce EVA but will also improve cognitive function in DSS consuming NS diet.

Method

Six month old male DSS rats were assigned to two groups: a control group (n = 12) on a normal salt diet (0.5% NaCl) and an experimental group (n = 24) receiving the same diet supplemented with QRC (100 mg/kg BW/daily) for a 3‐month period. Systolic and diastolic blood pressure (SBP, DBP), pulse wave velocity (PWV, an index of CAS), echocardiography, and visuospatial attention test were assessed before and after QRC treatment or placebo.

Result

Before treatment, no differences existed between groups. From 6 to 9 months of age in the control group, SBP, DBP, and PWV increased, while heart rate (HR) and ejection fraction (EF) showed a borderline decrease, and attention behavior showed a borderline increase for 1.0s of stimulus duration and no change for shorter visual stimulus, 0.2s (Figure and Table). QRC treatment reduced SBP, PWV, and increased EF and attention. The QRC effect was to increase the number of correct responses for 0.2s of stimulus and was negatively correlated with PWV (Pearson r = ‐0.420, P = 0.02) but not with BP, indicating that CAS is linked to cognitive function.

Conclusion

QRC supplementation demonstrated the ability to reduce EVA and enhance cognition in DSS rats, as indicated by attention behavior. Despite BP and CAS reflecting EVA, the association between attention decline and PWV, but not BP, implies that CAS is linked to cognitive function through mechanisms not directly related to BP. Further exploration is required to understand the mechanistic basis of QRC effects on EVA in DSS rats.

Supported by NIA/NIH/IRP
Immature and mature pathological tau forms in the retina of MCI and AD patients correlate with brain tauopathy
Authors: Fuchs Dieu‐Trang , Shi Haoshen , Mirzaei Nazanin , Koronyo Yosef , Davis Miyah R , Robinson Edward K , Rentsendorj Altan , Schneider Lon S. S. , Hawes Debra , Schneider Julie A. , Black Keith L , Kayed Rakez , Selenica Maj‐Linda B , Lee Daniel C , Koronyo‐Hamaoui Maya
Published: January 2025

Background

This study identifies and quantifies diverse pathological tau forms in the retina at both early and advanced stages of Alzheimer’s disease (AD) and assesses their correlation with disease status. In the pathogenesis of AD, the tau protein undergoes post‐translational modifications, including hyperphosphorylation (p‐tau). As the disease progresses, pathological tau can propagate as oligomers, aggregate into fibrils, and paired helical filaments (PHF), and ultimately form intraneuronal neurofibrillary tangles (NFTs). Previously, increased p‐tau and other abnormal forms were detected in postmortem retinas of AD patients; however, their presence and levels at earlier stages – in mild cognitively impaired (MCI due to AD) patients – and their association with brain pathology remain undefined.

Method

In this study, we acquired 75 postmortem human eyes and 39 paired brains. Retinal cross‐sections in predefined geometric regions were prepared from 34 AD and 11 MCI patients, and 30 age‐ and sex‐matched cognitively normal controls. Histological analyses involved Bielschowsky silver staining and immunostaining of brains and retinas with antibodies for tau (pS396, AT8, AT100, CitR209, T22, PHF‐1, and MC‐1). Stereological examination and quantification were conducted, and correlations were determined with brain pathology and cognition. P‐tau forms were also determined by NanoString GeoMx digital spatial profiling.

Result

Our immunohistochemical examination revealed significant upregulation of immature hyper‐citrullinated (CitR209) and p‐tau forms, propagating tau oligomers, as well as mature PHF‐tau and NFT forms in the retinas of patients with early‐AD (MCI due to AD) and AD‐dementia stages. Interestingly, retinal PHF‐tau accumulated only in the AD‐dementia stage. GeoMx spatial profiling analyses revealed site‐specific increases in various p‐tau epitopes in AD, particularly at the early MCI stage. Tau oligomers had the largest accumulations in MCI and, moreover, AD retinas, showing a strong correlation to Braak staging, representing the spread of tauopathy across brain regions during disease progression. Strong correlations were also found between retinal tauopathy and brain NFTs, ABC, and MMSE severity scores.

Conclusion

Our data demonstrate that most forms of retinal tauopathy are increased in early AD and correlate with one or more AD neuropathology and cognitive parameters, encouraging the development of retinal tauopathy imaging for AD detection and monitoring disease progression.
Genomic Approaches to Study Alzheimer’s Disease Immunity
Authors: Gate David
Published: January 2025

Background

Much attention has been paid to the role of the perenchymal brain immune response in Alzheimer’s disease (AD). Yet, the peripheral immune system in AD has not been thoroughly studied with modern sequencing methods.

Method

Here, we used a combination of single‐cell sequencing strategies, including assay for transposase‐accessible chromatin and RNA sequencing, to investigate the epigenetic and transcriptional alterations to the AD peripheral immune system.

Result

We reveal a striking amount of open chromatin in peripheral immune cells in AD. In CD8 T cells, we uncover a cis‐regulatory DNA element co‐accessible with the CXC motif chemokine receptor 3 gene promoter. In monocytes, we identify a novel RELA transcription factor binding site adjacent to an open chromatin region in the nuclear factor kappa B subunit 2 gene. We also demonstrate apolipoprotein E genotype‐dependent epigenetic changes that correspond to altered cytokine gene expression in monocytes. Surprisingly, we also identify differentially accessible chromatin regions in genes associated with sporadic AD. Finally, we provide an online data portal resource to explore gene expression in the AD immune system.

Conclusion

Our findings provide novel insights into the complex relationship between epigenetics and genetic risk factors in the AD peripheral immune system.
IGFBP‐5 Potentially Mediates the Association of Brain Insulin Signaling with Late‐Life Cognitive Decline
Authors: Tong Han , Capuano Ana W. , Bennett David A. , Ahima Rexford S. , Arnold Steven E. , Arvanitakis Zoe
Published: January 2025

Background

Abnormal brain insulin signaling has been associated with Alzheimer’s disease pathology and a faster rate of late‐life cognitive decline. However, the underlying mechanisms remain unclear. In this study, we examined whether AD‐related cortical proteins identified using targeted‐proteomics play a role in the association of brain insulin signaling and cognitive decline.

Method

Among the Religious Orders Study participants who underwent annual clinical and comprehensive neuropsychological testing (summarized as global and domain‐specific cognitive measures), 118 deceased and autopsied older individuals (59 with diabetes matched to 59 without, by age at death, sex, and education) had both brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC‐alpha serine/threonine‐protein kinase or AKT1) and AD‐related cortical protein measurements. Levels of five cortical proteins including insulin‐like growth factor‐binding protein‐5 (IGFBP‐5), inositol‐tetrakisphosphate 1‐kinase (ITPK1), heat shock protein B2 (HSPB2), adenylate kinase 4 (AK4), and plexin B1(PLXNB1) were measured using selection reaction monitoring quantitative proteomics. We conducted linear mixed‐effect model analyses adjusted for age at death, sex, and education to examine associations of cortical proteins and insulin signaling measures with longitudinally assessed cognitive function.

Result

A higher level of IGFBP‐5 (estimate = 0.260, SE = 0.092, p = 0.005) and a lower level of ITPK1 (estimate = ‐0.278, SE = 0.092, p = 0.003) were each associated with a higher level of pT308AKT1 /total AKT1. In addition, a higher level of pT308AKT1 /total AKT1 was associated with a faster rate of decline in global cognition (estimate = ‐0.035, SE = 0.013, p = 0.007), and most cognitive domains including episodic memory (estimate = ‐0.039, SE = 0.014, p = 0.005), working memory (estimate = ‐0.031, SE = 0.009, p = 0.001), perceptual speed (estimate = ‐0.026, SE = 0.011, p = 0.015), and visuospatial abilities (estimate = ‐0.017, SE = 0.007, p = 0.019). Yet, when the level of IGFBP‐5 and its interaction with time were added to the models as covariates, the level of pT308AKT1 /total AKT1 was no longer associated with the decline rate of global cognition (estimate = ‐0.023, SE = 0.012, p = 0.067) and cognitive domains including perceptual speed (estimate = ‐0.018, SE = 0.010, p = 0.082) and visual spatial abilities (estimate = ‐0.014, SE = 0.007, p = 0.052).

Conclusion

AD‐related cortical proteins IGFBP‐5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in postmortem human brain. Further, IGFBP‐5 potentially mediates the association of AKT1 phosphorylation with late‐life cognitive decline.