bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial replenishment as a treatment for Alzheimer’s Disease
Authors: Baudo Gherardo
Published: January 2025

Background

Findings have demonstrated that mitochondrial dysfunction is vital to Alzheimer’s Disease (AD) pathogenesis and progression. This study explored an innovative treatment strategy involving transfer of polymer‐functionalized, healthy mitochondria to AD neurons. We hypothesized that this organelle transplantation approach would restore mitochondrial function and bioenergetics, preventing aberrant neuronal dynamics associated with AD.

Method

Neuronal cells (SH‐SY5Y) were stimulated with amyloid‐β (Aβ1‐42). Mitochondria were functionalized with dextran‐triphenylphosphonium (Dex‐TPP/Mt) and administered to neurons. Internalization of Dex‐TPP/Mt was assessed, as was the effect of mitochondrial transfer on Aβ‐treated SH‐SY5Y cell ROS levels, mitochondrial membrane potential, mitochondrial dynamics, ATP levels, and apoptosis.

Result

Dex‐TPP/Mt underwent efficient internalization into Aβ‐treated SH‐SY5Y cells. The treatment reduced intracellular ROS levels and restored mitochondrial membrane potential. Mitochondrial quality control was also re‐established, as mitochondrial fusion and fission processes were balanced and mitophagy reduced. Dex‐TPP/Mt treated neurons also increased ATP levels. Notably, mitochondrial transfer modulated the Bax/Bcl‐2 ratio, inhibited caspase‐3 activation, and suppressed the pJNK pathway, highlighting reduced neuronal apoptosis that was confirmed by Annexin V assay.

Conclusion

Mitochondrial transfer has potential as a therapeutic approach for AD. The treatment highlighted herein effectively mitigated the impact of Aβ on neuronal health by targeting mitochondrial dysfunction and oxidative stress. This opens several avenues for similar strategies aimed at addressing dysregulated bioenergetics and mitochondrial dynamics in AD.
Selective expression of HSP27 in cortex and hippocampus offers insights of TDP‐43 and APOE interaction
Authors: Abeer Muhammad I , Gitcho Michael A.
Published: January 2025

Background

Aggregation of transactive response DNA binding protein 43 (TDP‐43) is the major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, in up to 50% of Alzheimer’s disease (AD) cases TDP‐43 pathology was discovered and this pathology has been referred to as limbic‐predominant age‐related TDP43 encephalopathy (LATE). Several studies reported that TDP‐43 binds to heat shock protein family B (small) member 1 (HSPB1 or HSP27) but no functional evaluation of this interaction has been explored. Inducing expression of HSP27 has been shown to be protective of many other disease conditions and has been shown to reduce aggregation of amyloid in AD. In general, the goal is to utilize both primary neuronal cultures and mice that are selectively expressing pathogenic TDP‐43, HSP27, and apolipoprotein E (APOE) in the brain to characterize the effect of HSP27 overexpression on TDP‐43 and APOE. This will give us a better model to understand TDP‐43 proteinopathies. In the present study, we hypothesize that increased expression of HSP27 may reduce TDP‐43 aggregation and alter mitochondrial morphology.

Method

A new transgenic mouse model was developed to selectively drive human HSP27 and pathological TDP‐43 with a defective nuclear localization signal (DNLS) in the hippocampus and neocortex using the Ca2+/calmodulin protein kinase (Camk2a) tetracycline inducible system. The following genotypes have been evaluated for immunohistochemistry, biochemistry (solubility fractionation), and Western blot: wild‐type, Camk2a/DNLS, Camk2a/HSP27 and Camk2a/HSP27/TDP43DNLS at 4 months of age.

Result

Preliminary in vitro results show that cells overexpressing HSP27 reduce aggregation and protein levels of TDP43. However, mice overexpressing HSP27 in a TDP43DNLS background in the hippocampus and cortex does not show any reduction in the soluble fraction. Interestingly, increased expression of HSP27 in the hippocampus of Camk2a/HSP27 mice showed a significant reduction of endogenous APOE expression. Immunohistochemical and bioenergetic experiments are currently being carried out to evaluate the brain and mitochondrial morphology upon HSP27 overexpression.

Conclusion

Overall, our initial data suggests that modifying HSP27 expression modulates endogenous APOE level.
Cognitive Complaint, Mild Cognitive Impairment, and Mild Behavioral Impairment as Predictors of Dementia or Alzheimer’s Disease in a Population‐Based Sample: The Cache County Study
Authors: Herd Ryan C. , Mills Maddy , Hammond Alexandra G. , Gonzalez Hector L. , Drewel Mikaela , Rattinger Gail B. , Tschanz JoAnn T.
Published: January 2025

Background

Mild Cognitive Impairment (MCI) and Mild Behavioral Impairment (MBI) represent transitional states between normal aging and incipient dementia. We examined whether presence of cognitive complaint (CC), MCI, and MBI differentially predicted risk for all‐cause dementia or Alzheimer’s disease (AD) in a population‐based sample.

Method

Participants included 598 older adults [55% female, with mean (SD) age = 78.84 (7.51) years] without dementia at baseline of the Cache County Study on Memory in Aging. All completed a clinical assessment and were followed in subsequent waves until dementia diagnosis or non‐participation, for a maximum follow‐up time of 12 years. MCI classification was based on neuropsychological assessment with test scores falling 1.5 SD < mean on a single measure or 1.0 SD < mean on multiple measures per cognitive domain, according to aged‐based norms. CC was based on informant report of difficulties in memory, orientation, judgment, social functioning, home‐based activities, language, and recognition of others. MBI was based on the Neuropsychiatric Inventory (NPI), supplemented with informant interview. Participants were categorized as positive/negative for CC, MCI, or MBI only, or in combination; those negative on all three attributes served as the reference category. Separate Cox regression models examined CC‐MCI‐MBI status and time to all‐cause dementia/AD or right censoring, covarying age, sex, education, and APOE ε4 status.

Result

One hundred fifty‐six individuals developed dementia (118 AD). Compared to the reference category, MCI only [Hazard Ratio HR (95% CI) = 3.51 (1.49 – 8.22)], CC+MCI [HR (95%CI) = 5.24 (2.33 – 11.79), CC+MBI [HR (95%CI) = 5.29 (1.96 – 14.32)], MCI+MBI [HR (95%CI) = 4.31 (1.24 – 14.94), and CC+MCI+MBI [HR (95%CI) = 17.11 (7.58 – 38.65)] were associated with increased risk of dementia whereas MBI only or CC only was not. For AD, results were similar, except that MCI+MBI was not associated with increased risk (p = .165).

Conclusion

The presence of MCI with or without cognitive complaint or in combination with MBI predicted future AD or all‐cause dementia. However, MBI was predictive only in combination with cognitive complaint/MCI. These results emphasize the importance of conducting both cognitive and behavioral assessments to buttress reports of cognitive concerns.
Variability in Reaction Time Predicts Transition to Mild Alzheimer Disease and is Sensitive to CSF Biomarkers in Cognitively Normal Older Adults
Authors: Welhaf Matthew S. , Balota David A. , Schindler Suzanne E. , Morris John C. , Hassenstab Jason J. , Aschenbrenner Andrew J.
Published: January 2025

Background

The ability to detect cognitive impairment from Alzheimer Disease (AD) in its earliest possible symptomatic stage is a highly desirable characteristic for neuropsychological measures. Because early cognitive changes are often subtle, measures with high sensitivity are of great importance. Variability in attention, often assessed using reaction time (RT) tasks, have been shown to discriminate between cognitively normal older individuals with and without positive AD biomarkers and is correlated with biological markers of neurodegeneration. However, what is less clear is how well measures of RT variability predict later development of cognitive symptoms of AD and whether common AD biomarkers predict declines in attention.

Method

Cognitively normal older adults (N = 478, baseline age = 66.8 ± 8.9 years) completed a go/no‐go task, the Sustained Attention to Response Task (SART). Participants were instructed to respond to all numbers except for the digit “3”. Variability in RT was measured using the Coefficient of Variation (CoV) to correct “go” trials. Cognitive status was assessed using the Clinical Dementia Rating® (CDR®). Logistic regression was used to test for the sensitivity of RT CoV in predicting eventual conversion to CDR > 0, adjusted for baseline age, education, and gender. A subset (N = 197) of participants had CSF Aβ42/Aβ40 within 3 years of the first SART assessment and 2+ visits allowing for testing longitudinal changes. Mixed effect models were used to track longitudinal change in RT CoV based on amyloid status.

Result

Greater RT CoV (and thus poorer attention) predicted later conversion to CDR > 0 (p = 0.008), after accounting for baseline levels of education, age, and gender. There was a significant interaction between amyloid status and time (p = 0.048). Increases in RT CoV over time occurred for individuals designated as being amyloid positive (Aβ42/Aβ40<0.0673), but not for those initially identified as amyloid negative (see Figure 1).

Conclusion

Variability in RT is a significant predictor of later development of cognitive symptoms associated with AD. Longitudinal changes in RT CoV are also sensitive to baseline amyloid status. These findings highlight the sensitivity of within‐person fluctuations of attention as a cognitive biomarker for AD.
Bin1 regulates synaptic endocytic trafficking compromised by Alzheimer’s genetic risk variants
Authors: Almeida Claudia G. , Barata Mariana Afonso , Perdigão Catarina , Ramalho Jose
Published: January 2025

Background

Alzheimer’s disease (AD), an untreatable synaptic disorder, is the most frequent cause of dementia. It is still unclear which mechanisms drive the early synapse dysfunction in the most common late‐onset AD (LOAD). The second most important LOAD risk gene identified, BIN1, is an endocytic regulator. We implicated Bin1 in BACE1 recycling with Bin1 loss of function, increasing axonal beta‐amyloid42. Since endocytic trafficking is essential for synapse function, we hypothesize that Bin1 may regulate synaptic endocytic trafficking, which may be disrupted by Bin1’s loss of function or beta‐amyloid42. We aim to dissect Bin1 causal mechanisms of synaptic dysfunction to assess how the risk for LOAD increases.

Method

Synaptically mature mouse primary cortical neurons and brain hippocampus were used to investigate Bin1 synaptic endocytic localization with immunofluorescence and synaptosomes. Using knockdown, overexpression, and rescue approaches the impact on synaptic endosome size and synaptic density was determined using super‐resolution fluorescence microscopy and quantitative subcellular image analysis.

Result

Bin1 was enriched in synaptic vesicle brain fractions, supporting its presynaptic function. Unexpectedly, Bin1 is enriched proximal synapses, identified as inhibitory GABAergic presynaptic terminals in primary neurons and the brain. Notably, Bin1 down‐regulation specifically reduced inhibitory synapse density and increased neuronal excitability. Bin1 loss increased inhibitory synaptic vesicle release and endocytosis, exhausting presynaptic endosomes. Interestingly, the impact on inhibitory synapses is independent of beta‐amyloid production. Moreover, Bin1 LOAD mutations interfere with Bin1 function and are likely to cause loss of function.

Conclusion

Bin1 is an inhibitory presynaptic protein. The LOAD mutations may cause Bin1 loss of function, affecting inhibitory synapses. Losing inhibitory transmission may turn excitatory neurons hyperactive, accelerating the loss of excitatory synapses. In the future, we aim to dissect the underlying mechanisms by which Bin1 mutations interfere with Bin1’s role in synaptic vesicle mechanisms at inhibitory presynaptic terminals.
Known and novel genes significant to AD across tissues may help to uncover comprehensive changes of disease
Authors: Moore Anni , Bradford Yuki , Kumar Rachit , Venkatesh Rasika , Shivakumar Manu , Bao Jingxuan , Shen Li , Kim Dokyoon , Ritchie Marylyn D.
Published: January 2025

Background

Alzheimer’s disease (AD) is neurodegenerative disease brought on by a combination of changes in multiple pathways that conglomerate to promote disease progression. AD often occurs alongside comorbid diseases, most often immune or vascular in nature, which have been shown to further increase AD risk. We previously showed that known AD variants also associate with secondary diseases in these categories, including rheumatoid arthritis, ischemic myocardial infarction, and both Type 1 and Type 2 diabetes. To better understand which pathways play a significant role in AD etiology and how comorbid diseases may contribute to risk through shared pathways, we aimed to identify gene expression changes associated with AD status in tissues throughout the body.

Method

We conducted a transcriptome‐wide association study (TWAS) using genotypes from the Alzheimer’s Disease Sequencing Project (ADSP) including 11,074 cases and 14,310 controls from multiple ancestry groups and reference expression‐trait quantitative loci (eQTLs) from 49 tissues in Genotype‐Tissue Expression (GTEx) Project (v8). Using an ensemble approach we first predicted genetically regulated gene expression (GREx) and gene‐associations per tissue within each of the 49 tissues available in GTEx using PrediXcan. Secondly, to better predict cross‐tissue signals we used MulTiXcan with GREx to test for gene‐associations across tissues.

Result

Both known and novel genes appeared in the single tissue and cross tissue gene associations. Previously AD‐associated genes PET117, RAB35, NECTIN2, APOC1, and TOMM40 were significantly associated (p<1.51e‐7) with AD across tissues, with many of these known to lie within the APOE region. Additionally, genes previously unreported with AD, but involved in relevant disease processes including macro‐autophagy (SUPT20H), nucleosome binding (HMGN2), histone acetylation (KAT14), DNA damage repair (HFM1), and immune response (TSPAN2) showed significance. Many of these novel genes have previously been associated with immune, vascular and other neurological diseases, many of which are better known to appear as AD comorbidities.

Conclusion

In addition to known APOE region genes, novel genes with implications relevant to AD etiology and ties to other immune, vascular, and neurological diseases also appeared significant across tissues. Next we will investigate how these gene expression changes apply to pathways within relevant tissues.
Intracranial atherosclerosis is linked to lower volume in the posterior portion of the hippocampus
Authors: Chowdhury Gulam Mahfuz , Tazwar Mahir , Evia Arnold M , Kapasi Alifiya , Agrawal Sonal , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: January 2025

Background

Intracranial atherosclerosis is a common age‐related neuropathology that has been linked to cognitive decline and dementia and often mixed with Alzheimer’s and other neuropathologies. But the association of atherosclerosis with brain morphometric abnormalities has not been explored. This work combined Deformation‐based morphometry on ex‐vivo MRI with detailed neuropathological examination in a large number of community‐based older adults to investigate the association.

Method

Hemispheres from 891 community‐based older adults from four cohort studies of aging: the Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and African American Clinical Core of the Rush Alzheimer’s Disease Research Center were imaged ex‐vivo on 3T clinical MRI scanners using a multi‐echo spin‐echo sequence with a voxel size = 0.6 × 0.6 × 1.5 mm3. All images were non‐linearly registered to an ex vivo brain hemisphere template using ANTs. The logarithm of the Jacobian determinant of the deformation fields was calculated in each voxel and the resulting maps were smoothed using a Gaussian filter with a FWHM = 4mm. All hemispheres underwent detailed neuropathologic examination. The assessed pathologies included atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts, Alzheimer’s pathology, Lewy bodies, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change, and hippocampal sclerosis.

Voxel wise linear regression was used to test the association of atherosclerosis with deformations shown in the smoothed LogJ maps, controlling for other age‐related neuropathologies, demographics (age at death, sex, years of education), postmortem interval to fixation, postmortem interval to imaging, and scanner (Fig. 1,2). The FSL PALM tool with 1000 permutations, threshold‐free cluster enhancement, and tail acceleration was used for the statistical analysis. Associations were considered significant at p<0.05 after family‐wise error rate correction for multiple comparisons.

Result

Voxel‐wise linear regression showed that intracranial atherosclerosis was significantly associated with lower volume in the posterior body and tail of the hippocampus (p<0.05), independently of the effects of other age‐related neurodegenerative and vascular pathologies (Fig. 3). No part of the brain showed significantly higher volume with atherosclerosis.

Conclusion

This work demonstrated that intracranial atherosclerosis is associated with lower volume of the posterior body and tail of the hippocampus. This finding is of great interest due to the important role of the hippocampus in cognition.
Altered neutrophil glycolysis contributes to microvascular inflammation in an AD mouse model
Authors: Bracko Oliver
Published: January 2025

Background

Cerebral blood flow is decreased in mouse models and patients of Alzheimer’s disease (AD). We identified that about 2% of cortical capillaries in the APP/PS1 mouse model of AD had stalled blood flow due to neutrophils obstructing capillaries and contributing to vascular inflammation. Neutrophils are more reactive in AD. Here we are investigating if changes in metabolism contribute to reactive neutrophils driving low‐level chronic vascular inflammation and cerebral blood flow (CBF) reductions in mouse models of AD.

Methods

AD and control neutrophils were isolated and transferred into donor mice. The number of stalled capillaries and blood flow speeds were measured using high‐resolution from in vivo two‐photon imaging. Mitochondrial stress and glycolysis were determined using the Seahorse platform.

Results

We found that neutrophils from AD mice caused capillary stalling and contributed to CBF reductions in control mice. Furthermore, we identified that glycolysis is reduced, and mitochondrial stress is increased in AD neutrophils compared to controls. Lastly, the maximal oxygen consumption rate is reduced in AD neutrophils indicating mitochondrial dysfunction.

Conclusion

This data demonstrates that reactive neutrophils in AD mice contribute to capillary stalling and CBF reductions. Glucose metabolism is reduced in neutrophils, indicating a metabolic shift from aerobic to anaerobic glycolysis. Overall, the data shows that neutrophils are more reactive at baseline in AD mice and likely contribute directly to chronic inflammation seen in mouse models and patients with AD.
Multi‐day at‐home assessments of speech acoustics in Dutch cognitively normal adults with‐and without AD pathology
Authors: van den Berg Rosanne L. , de Boer Casper , Zwan Marissa D. , Robin Jessica , Simpson William , Jutten Roos J , Dubbelman Mark A. , Barkhof Frederik , Collij Lyduine E. , van Harten Argonde C. , Schlüter Lisa‐Marie , Teunissen Charlotte , van der Flier Wiesje M. , Sikkes Sietske A.M.
Published: January 2025

Background

Automated analysis of natural speech is emerging as a promising digital biomarker of Alzheimer’s disease (AD). As speech is a complex process, relying on multiple interacting cognitive functions, fine‐grained analysis of speech may have the potential to capture subtle cognitive deficits in the very early stages of AD. Here, we examined the association between amyloid‐beta (Aβ) pathology and acoustic speech characteristics in a group of cognitively normal Dutch adults.

Method

We included 50 cognitively normal (n = 23 Aβ‐positive, 46%) older adults from three clinical cohorts at the Alzheimer Center Amsterdam (Table 1). Aβ‐status was based on local cut‐offs for Aβ1‐42‐concentrations in cerebrospinal‐fluid or visual inspection of amyloid positron emission tomography (PET)‐imaging. In a five day remote burst assessment, seventeen tablet‐based tasks (picture description, journal‐prompt storytelling, verbal‐fluency) were administered, with a daily administration time of approximately 10 minutes. Various acoustic features, including silent pauses, pause‐to‐word‐ratio, and perceived loudness, were extracted from the voice recordings. Mean burst scores were calculated over the five‐day period. The association between Aβ‐pathology and acoustic features was investigated using linear regression models separately for each subtask.

Results

Pause‐to‐word ratio was higher in Aβ‐positive individuals in the repetitive picture description subtask (β = ‐0.05, p = 0.04) and the journaling subtask (β = ‐0.07, p = 0.03) compared to the Aβ‐negative individuals. Although statistical significance between groups was not reached for other acoustic features, a pattern was observed that the Aβ‐positive group consistently displayed more medium pauses, longer audio duration, more local jitter, higher intensity variance, a higher fundamental frequency, and fewer long pauses in all multi‐day subtasks (Figure 1).

Conclusion

Our results demonstrated that Aβ‐pathology was associated with more pauses during free speech in cognitively healthy adults. This supports the notion that remote multi‐day speech assessments have the potential to monitor cognitive changes, for example in observational studies and decentralized clinical trials in preclinical AD. Next steps include examining the association between Aβ‐pathology and linguistic features using the same sample.
The neurophysiological effects of frontotemporal lobar degeneration: linking synaptic loss, network connectivity and cognitive decline
Authors: Rowe James B
Published: January 2025

Background

Frontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP) have distinct molecular pathologies, with Tau and TDP43 aggregation, and distinct patterns of regional brain atrophy. However, they share the synaptotoxicity of protein aggregation, and neurotransmitter loss (including GABA), which contribute to clinical and neurophysiological similarities. Defining the relationships between synaptic loss, network physiology and cognition builds bridges between preclinical and clinical studies, and facilitates early phase trials.

Method

We quantified the effect of behavioural variant frontotemporal dementia (±parkinsonism) and progressive supranuclear palsy (Richardson’s syndrome, and PSP‐F), and controls with Magnetoencephalography (resting state, mismatch task, and motor control task); 11‐C‐UCBJ PET estimation of synaptic density; 3T T1w and fMRI.

Result

Participants with bvFTD showed severe synaptic loss compared to controls which correlated strongly with baseline cognitive function (ACE‐r r∼0.8, p<0.001). Participants with PSP showed severe synaptic loss, which progressed over 12 months; the degree of synaptic loss over prefrontal cortex correlated with functional decline (PSPRS, r∼0.47, p<0.03. In both PSP and FTD, synaptic loss was more severe and widespread than cortical atrophy; prefrontal/ACC atrophy was significant in PSP, but less than in bvFTD. Synaptic loss correlated with the loss of weighted dress of fMRI‐based cortical network measures. On MEG, deviant‐versus‐repeat tones evoked the frontotemporal peak 160‐200ms and induced loss of beta‐power (∼20Hz) during this window. Both bvFTD and PSP reduced/abolished the effect of deviant stimuli on prefrontal beta power, and this reduction in beta‐power correlated with clinical severity, as FRS (in bvFTD) and PSPRS (in PSP). Inversion of the MEG response to biophysically informed dynamic causal models accurately explained the causes of the evoked response (r>0.9). Bayesian Model Comparison and second level parametric empirical Bayes analysis with UCBJ priors indicated the effect of bvFTD and PSP was attributable to loss of synapses from superficial cortical layers.

Conclusion

MEG, PET and MRI are each well tolerated by people with PSP/bvFTD. These methods indicate severe and progressive synaptic loss, more than atrophy, with resulting behaviourally‐relevant changes in prefrontal network beta‐power and connectivity. Biophysical modelling confirms in vivo the post mortem observation of superficial cortical vulnerability to PSP/bvFTD.
Trajectory of patients over five years in Multispecialty Interprofessional Team Memory Clinics
Authors: Jones Aaron , Lee Linda , Patel Tejal
Published: January 2025

Background

Multispecialty Interprofessional Team (MINT) Memory Clinics manage dementia care in primary care, allowing for more efficient use of limited specialist resources. This study examined the characteristics of patients on their initial assessment in the MINT clinic and investigated the five‐year trajectory of patients with mild cognitive impairment (MCI).

Method

We conducted a retrospective chart review of 751 patients assessed within a MINT Memory Clinic between June 2006 and May 2019 to collect data on age, gender, diagnosis, and MoCA scores. We plotted the five‐year trajectory of MoCA scores for patients with an initial diagnosis of MCI and calculated product‐limit estimates of the five‐year conversion rate to dementia. We also performed a Cox regression to investigate associations with receiving a dementia diagnosis.

Result

The median age of our cohort was 75 years; 54% were female. The majority of patients (70%) had a MoCA score of 25 or less; 35% had a score of 20 or less. Diagnoses at the initial assessment included MCI (37%), dementia (20%), subjective cognitive decline (SCD; 12%), and other miscellaneous diagnoses (3%); 27% did not a receive a definitive diagnosis, pending further investigations. Of the 214 patients with an initial diagnosis of MCI and at least one follow‐up visit, 28% (N = 60) received a dementia diagnosis at a later date, with 58% being diagnosed with mixed dementia, 22% with Alzheimer’s Disease, and 20% with other dementias. The product‐limit estimates of the five‐year conversion rate was 48.8% (39.5%, 59.2%). Lower MoCA scores at the initial visit were associated with a higher risk of a dementia diagnosis; each one‐point increase in MoCA was associated with a 10% decrease in the risk of a dementia diagnosis (aHR: 0.90, 95%CI: 0.85‐0.96). Similarly, age was significantly associated with a higher risk of a dementia diagnosis within five years; each five‐year increase in age was associated with a 37% increase in risk (aHR: 1.37, 95% CI: 1.12‐1.67).

Conclusion

As nearly half of the patients presenting to MINT Memory Clinics have MCI or SCD on initial assessment, MINT clinics provide a significant opportunity for detection and potential intervention at early disease stages.
A spatial transcriptomics platform for characterizing cellular vulnerability and molecular changes in AD‐affected human brain tissue
Authors: Close Jennie
Published: January 2025

Background

Alzheimer’s disease is defined by deposition of pathological proteins in spatially reproducible patterns within the tissue of affected individuals. Prominent pathological protein species found in Alzheimer’s disease are amyloid beta plaques and phospho‐tau tangles, which spread through a succession of brain areas. As this pathology spreads and worsens, it is accompanied by glial reactivity and activation and neuronal loss. Characterization of cell types changing or lost during disease progression and where those changes occur will be important for finding mechanisms of disease onset and progression.

Method

snRNAseq analysis from Alzheimer’s donors was used to determine which cell types are present and what changes in gene expression, if any, can be observed at the highest resolution of cell type identity: the supertype. We mapped these supertypes using highly multiplexed spatial transcriptomics on the same donor set to determine where these supertypes are in the tissue, where vulnerable types are lost at which stages, and whether gene expression changes can be observed in specific types near pathology.

Result

We have found that certain vulnerable cellular supertypes are more likely to be affected early, and a reproducible sequence of neuronal loss follows with increasing pathology. Surprisingly, one of the first neuronal subtypes to be affected are somatostatin inhibitory neurons, followed by L2/3IT excitatory neurons and parvalbumin inhibitory neurons. We have corroborated these results in human donor tissue using spatial transcriptomics to map and characterize loss of abundance of vulnerable cell types. We find that vulnerable neuronal types are predominately localized in supragranular layers.

Conclusion

Spatial methods are key to relating these neuronal vulnerabilities with pathological protein locations and specific locations within affected tissue. We have adapted spatial profiling and analysis methods to characterize the spatial relationships between specific neuronal types, amyloid plaques, tau tangles, and observed changes in gene expression. These data will offer novel insight into cell and molecular changes occurring at each phase of the disease and may inform the development of promising therapeutic interventions.
Propionate Decreases Microglial Activation and Alters Phagocytic Machinery in Response to Aggregated Amyloid Beta in vitro
Authors: Gold Andrew , Zhu Jiangjiang
Published: January 2025

Background

Microglia, the innate immune cells of the brain, are a principal player in Alzheimer’s Disease (AD) pathogenesis. Their surveillance of the brain leads to interaction with the protein aggregates that drive AD pathogenesis, most notably Amyloid Beta (Aβ). Aβ can elicit attempts from microglia to clear and degrade it using phagocytic machinery, spurring damaging neuroinflammation in the process. SCFAs, abundant microbial byproducts of dietary fiber fermentation, are blood‐brain‐barrier permeable molecules that have recently been shown to modulate microglial function. Further, as dietary manipulation can drastically alter SCFA abundances and thus modulate AD microglia, it is crucial to understand SCFAs effects. Propionate, one SCFA, is more poorly characterized than the rest, and thus we attempted to conduct a detailed characterization of propionate’s impact on microglial function in an AD‐relevant in vitro experiment.

Method

Using a multi‐omics approach, we characterized the transcriptomic, metabolomic, and lipidomic responses of immortalized murine microglia following 1 hour of Aβ stimulation, as well as characterizing secretion of reactive nitrogen species (RNS) in response to Aβ, using RNA sequencing, LCMS‐based metabolomics, and a fluorescently coupled RNS detector, respectively.

Result

Propionate significantly blunted the early inflammatory response driven by Aβ, driving down the expression of many Aβ‐stimulated immune genes, including those regulating inflammation, the immune complement system, and chemotaxis. Further, it reduced the expression of inflammation‐promoting Aβ‐binding scavenger receptors such as cd36 and msr1 in favor of more neutral lpl. Finally, propionate shifted microglial metabolism, altering phospholipid composition and shunting arginine synthesis away from nitric oxide synthesis, which resulted in decreased nitric oxide production.

Conclusion

Altogether, our data demonstrate a modulatory role of propionate on microglia that may dampen immune activation in response to Aβ and potentially improve AD pathogenesis.
Longitudinal association between CSF markers of Alzheimer Disease and inflammation in preclinical Alzheimer Disease
Authors: Sarty Isabel MacKenzie , Picard Cynthia , Labonte Anne , Breitner John C.S. , Poirier Judes
Published: January 2025

Background

Inflammation is central to Alzheimer Disease (AD), as astrocyte reactivity accompanies the appearance of Aβ and phosphorylated tau (Bellaver et al., 2023). As expected, therefore, AD patients have elevated levels of CSF inflammatory cytokines (Onyango et al., 2021). To understand the importance of these phenomena, exploration of individual inflammatory markers before and at the time of dementia onset is needed. To uncover key CK/Rs involved in the early pathogenesis of AD, we investigated selected cytokines and their receptors (CK/Rs) in the preclinical stages of the disease.

Method

We analyzed 433 longitudinal CSF samples from 104 participants in the PREVENT‐AD cohort. These persons, who were symptom‐free at baseline but at enhanced risk of developing AD because of their family history, have now been followed for over 10 years. We used ELISA to analyze Aβ42, p181, and total tau in the CSF [Fujirebio Innotest, Ghent, Belgium], while CK/Rs were assayed using the Olink proximity extension assay Target 96 Inflammation panel [Upsala, Sweden]. Linear mixed model analyses controlled for participant age and APOE4 status.

Result

We found that IL10RB, IL18, and CD40 levels in the CSF were significantly associated with both p(181)tau and Aβ42 levels in the CSF over time. IL10RB, IL18, and CD40 each showed significant positive association with p(181)tau levels across time (F(1,213.191) = 7.013, p = 0.009; F(1,237.624) = 9.972, p = 0.002; F(1,246.859) = 8.211, p = 0.005). The longitudinal effects of IL10RB and IL18 on Aβ42 were contingent on both sex and time (F(5,55.406) = 2.548, p = 0.038; F(5,54.792) = 4.280, p = 0.002), while the significantly positive association of CD40 levels on Aβ42 across time was stronger in females than in males (F(1, 59.669) = 4.099, p = 0.047).

Conclusion

These investigations of CSF proteins in preclinical AD persons identified inflammatory markers that exhibited specific relationships with p(181)tau and Aβ42 across time and sex. These results may guide further study of biomarkers for detection of AD in its preclinical stages, and/or therapeutic strategies. Of special importance, characterization of the pathogenesis of pre‐symptomatic AD may facilitate development of early interventions for the prevention of AD dementia.
Phospholipase D3 (PLD3) Regulates Lysosomal Biogenesis
Authors: Wang Yongchao , Fernandez Wilber Romero , Carvajal‐Tapia Cristian O , Shostak Alena , Rieschick Paige , Appelbaum Nathan , Schrag Matthew
Published: January 2025

Background

Genome‐wide association studies suggest mutations in endolysosomal genes are linked to Alzheimer’s disease (AD). Defective lysosomal function has been corroborated as a feature of AD by neuropathological and cell biology studies. PLD3 is a homolog of the phospholipase D family localized to lysosomes. Genetic variants in PLD3 are associated with increased risks for AD. Nevertheless, being a resident lysosomal protein, PLD3’s role in lysosome homeostasis has not been completely characterized. In this study, we conducted studies that combine transcriptomics, proteomics and cell biology to investigate the role of PLD3 in lysosome homeostasis.

Method

We generated PLD3 knockout (KO) SH‐SY5Y cells through the CRISPR/Cas9 approach. To identify the individual genes or gene sets impacted by PLD3 KO, RNA sequencing was performed with RNA isolated from wildtype (WT) and PLD3 KO neurons, followed by differential gene expression and gene set enrichment analyses. To narrow down to the targets that have direct lysosomal relevance, a proteomic study was conducted on the lysosome fraction of lysates from WT and PLD3 KO cells. To characterize lysosome morphology and function, lysosomes in these cells were labeled with Lysotracker or dextrans, followed by imaging, quantification and statistical analysis with CellInsight High Content Analysis platform. Lastly, we also examined the effects of PLD3 on lysosomal biogenesis by immunocytochemistry and Western blot.

Result

In RNA‐Seq analysis, the genes or gene sets relevant to endocytosis, autophagy and lysosomal biogenesis were significantly enriched in PLD3 KO cells. In line with these findings, our proteomic analysis also demonstrated an increase in lysosomal proteins in PLD3 KO cells. PLD3 loss caused an increase in lysosome size and endocytic activity and a decrease in the pH value of lysosomes, but it had no significant impact on lysosome number and positioning. Mechanistically, PLD3 deficiency promoted TFEB‐mediated lysosomal biogenesis.

Conclusion

PLD3 plays a role in lysosomal biogenesis. As endolysosomal abnormalities are increasingly appreciated as the causal agent for the pathogenesis of AD, this study may position the PLD3 pathway as a therapeutic target for the treatment of AD.
Photobiomodulation Therapy Increases Brain Cortex Neuroprotective Gene Expression and Improves Motor Function in an APP/PS1 Male Mouse Model of Alzheimer’s Disease
Authors: Barnett Mackenzie J , Haghkar Mahdi , Santos Carla Rocha Dos , McDevitt Ross A , Zernetkina Valentina I , Wei Wen , Syed Sunayana Begum , Juhasz Ondrej , Morrell Christopher H , Lakatta Edward G , Fedorova Olga V
Published: January 2025

Background

Photobiomodulation (PBM) therapy, using low intensity near‐infrared light is a noninvasive form of treatment with no side effects can be used to treat Alzheimer’s disease (AD). In a double‐transgenic mouse model of AD (APPswe/PS1dE9), chronic PBM therapy has been shown to reduce Aβ plaques accumulation in specific regions of the brain, including the neocortex and hippocampus. The aim of this study was to analyze the effects of PBM therapy on brain cortex neuroprotective gene expression and behavior in this APPswe/PS1dE9 mouse model.

Methods

Six‐month old male AD (AD‐PBM, n = 7) and wild type litter mate mice (WT‐PBM, n = 8) were exposed to near‐infrared light (wavelength 850 nm, 4.5 J/cm2, 3min/day, 5 days/week) for 6 months. Control mice (AD‐CNT, n = 7; WT‐CNT, n = 7) were placed under the PBM apparatus without turning the light on for 3min/day, 5 days/week. Motor function was assessed with treadmill‐based gait analysis, with metrics including hind propel, hind stance and hind step angle (DigiGait), and open field test (OFT; anxiety‐like behavior) following 6 months of treatment. Gene expression sampled from cortex was analyzed by qPCR. Data were analyzed by 2‐way ANOVA.

Results

In the AD group, PBM therapy significantly increased the expression of neuroprotective genes TGFb1, INFG, EGFR and MMP2, but did not affect the expression of these genes in WT (Fig. 1A‐D). In the gait analysis, PBM groups significantly reduced hind step angle in AD, but not WT (Fig. 1E). In the OFT, genotype had a significant effect on the amount of distance and time spent in the center of the arena (Table); non‐treated WT mice exhibited lower anxiety level vs. non‐treated AD mice (Fig. 1F). PBM did not have a significant effect, but the percent of distance spent in the center out of total distance had an increasing trend (Fig. 1F) indicating a trend in a reduction of anxiety in the AD group. Two‐way ANOVA analysis results are presented in Table 1.

Conclusion

PBM therapy significantly increased neuroprotective cortical gene expression and improved motor function in AD mice. It is possible that PBM treatment contributes to the upregulation of neuroprotective genes that reduced anxiety behavior and improved motor function.
Evidence for a role of adaptive immunity in Tau‐mediated neurodegeneration
Authors: Holtzman David M.
Published: January 2025

Background

Recent evidence suggests both the innate and adaptive immune system are involved in the pathogenesis of Alzheimer’s disease. We recently showed that the number of T cells, especially cytotoxic T cells, are increased in areas of tauopathy both in an animal model of tau‐mediated neurodegeneration as well as in the AD brain. We also found that depletion of T cells as well as microglia were both strongly neuroprotective in P301S tau transgenic mice (PMID: 36890231). We have been further characterizing T cells in this model as well assessing for other evidence for a role of the adaptive immune system in this model.

Method

We crossed P301S mice with Rag2KO mice that lack both T and B cells and then analyzed the mice at 9.5 months of age.

Result

P301S/Rag2KO mice have few to no T cells in the brain but also have strong suppression of the brain’s innate immune response and have significantly less brain atrophy and loss of synapses and compared to P301S mice.

Conclusion

This provides further evidence of a role for the adaptive immune response in tau‐mediated neurodegeneration.
Integrative multi‐omics epigenome‐wide association study identifies dysregulated DNA methylation near oligodendrocyte genes that associate with tau levels in the AD brain
Authors: Oatman Stephanie R , Reddy Joseph S. , Wang Xue , Quicksall Zachary , Atashgaran Amin , Vanelderen Floor , Bergman Jeremiah , Is Ozkan , Carrasquillo Minerva M. , Liu Chia‐Chen , Yamazaki Yu , Nguyen Thuy , Heckman Michael G. , Zhao Na , DeTure Michael , Murray Melissa E. , Bu Guojun , Kanekiyo Takahisa , Dickson Dennis W. , Allen Mariet , Ertekin‐Taner Nilüfer
Published: January 2025

Background

Alzheimer’s disease (AD) is neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often quantified by Thal phase and Braak stage, respectively. Aβ also frequently deposits in the cerebrovasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. These and related measures often show high variability within AD suggesting distinct underlying mechanisms. We hypothesize that, within the AD brain, neuropathology and levels of core AD‐related proteins are influenced by variations in DNA methylation (DNAm). To test this, we performed epigenome‐wide association studies (EWAS) using DNAm measures from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathologic measures (Braak, Thal, CAA) and brain biochemical levels of five proteins (apoE, Aβ40, Aβ42, tau, p‐tau).

Methods

DNAm from neuropathologically‐confirmed AD cases was measured by reduced representation bisulfite sequencing (RRBS) from 471 TCX samples, 200 of which also had CER RRBS. TCX levels of five AD‐related proteins from three tissue fractions (buffer‐, detergent‐, and in‐soluble) were measured previously by ELISA (Liu 2020). CpG methylation (CpGm) was binned by a 15‐state chromatin model (Kundaje 2015) and averaged into CpGm clusters (rCpGm). rCpGms were tested for association with each AD endophenotype and expression levels of nearby genes through multi‐variable linear regression. Replication of significant rCpGms was performed in two independent datasets with AD‐related endophenotypes (Shireby 2022, De Jager 2014).

Results

Our innovative binning method demonstrated biologically relevant CpGm patterns. We found epigenome‐wide significant associations primarily with tau‐related endophenotypes including 93 that had significant and concordant associations in the replication datasets. These rCpGms also significantly associated with expression of nearby genes showing enrichment in oligodendrocyte marker genes including those related to myelination. In vitro validation of tau effects on oligodendrocyte gene expression through DNAm is ongoing.

Conclusions

Although all endophenotypes tested are core to AD pathophysiology, our results suggest each has a distinct epigenetic architecture underlying their variability in the AD brain. In particular, we found evidence of DNAm variability associating with brain oligodendrocyte gene expression and TCX tau levels. By discovering AD brain endophenotype‐specific DNAm changes, we can identify core components of complex mechanisms revealing important biological insights into AD pathophysiology.
Bias in estimating brain‐cognition associations by clinical diagnosis: A simulation study
Authors: Gavett Brandon E , Fletcher Evan , Widaman Keith F. , Farias Sarah Tomaszewski , Mungas Dan M.
Published: January 2025

Background

Researchers often divide heterogeneous samples into homogeneous subgroups for analysis. For example, a sample of participants with normal cognition, mild cognitive impairment (MCI), and dementia might be divided into subgroups to answer questions about whether some exposure variable (e.g., brain atrophy) predicts some outcome variable (e.g., cognitive decline) differently across groups. It is unclear, however, whether subgroup analysis provides greater insight into the associations between neurodegeneration and cognitive decline, or whether it is counterproductive. The current study employed statistical simulation to address this issue.

Methods

Using data from the Alzheimer’s Disease Neuroimaging Initiative, we estimated the correlation between gray matter volume slopes and episodic memory slopes. This correlation (r = .813) and subgroup descriptives formed the population parameters upon which simulations were based. We generated plausible scenarios where the correlations in the three subgroups could differ while maintaining the same overall correlation in the combined sample. Diagnostic subgroups were derived by simulating a global CDR score (0 cognitively normal; 0.5 MCI; 1+ dementia) for each simulated case. We also manipulated the relative sample size differences between the three groups. The primary outcome variable was the amount of bias (difference between simulated sample correlation and known population correlation) in estimating the strength of association between gray matter change and cognitive change. Samples were (1) combined and (2) analyzed separately by diagnostic group.

Results

Estimates specific to a diagnostic subgroup were least biased when the analyses were limited to samples drawn from that population (e.g., an MCI sample to make inferences about the MCI population). In contrast, when making inferences about the entire spectrum of cognitive aging, more nuanced findings appeared. In general, the least bias was observed in the combined sample, but this was only true when cognitively impaired cases were adequately represented.

Conclusion

Decisions about whether to stratify analyses by diagnostic subgroup require consideration of the target of inference. If the goal of cognitive aging research is to understand the cognitive manifestations of neurodegeneration across the full spectrum of disease, then subgroup analysis is likely to be more biased than the combined sample. With representative samples, both approaches may provide complementary information.