bluuebunny/crossref_metadata_2025 huggingface dataset:
P‐tau217 significance as marker of brain Abeta and tau pathologies
Authors: Barthélemy Nicolas R. , He Yingxin , Salvadó Gemma , Janelidze Shorena , Li Yan , Ghoshal Nupur , Mukherjee Soumya , Horie Kanta , Spina Salvatore , VandeVrede Lawren , Paterson Ross W. , Perrin Richard J. , Benzinger Tammie L.S. , Boxer Adam L. , Gabelle Audrey , Sato Chihiro , Schindler Suzanne E. , McDade Eric , Gordon Brian A. , Hansson Oskar , Bateman Randall J.
Published: January 2025

Background

P‐tau217 has emerged as a compelling alternative to long‐established p‐tau181 to accurately measure tau modifications in biofluids in response to brain Abeta and tau deposition in Alzheimer’s disease (AD). Understanding the specificity and significance of p‐tau217 changes over AD stages is critical to interpret its potential response to treatments against Abeta and tau aggregation.

Methods

We measured p‐tau217 phosphorylation by mass spectrometry. We analyzed brain, cerebrospinal fluid (CSF) and plasma samples from participants with late‐onset AD (LOAD), dominantly‐inherited AD (DIAD) and primary tauopathies.

Results

Soluble and insoluble tau species extracted from LOAD and DIAD brains are p‐tau217 hyperphosphorylated [1‐2]. P‐tau217 abundance in insoluble tau extracts from AD and most primary tauopathies associates with brain tau aggregates level. In LOAD CSF and plasma, slight p‐tau217 phosphorylation changes are detected in response to early Abeta deposition in participants without cognitive symptoms [3‐4]. Early Abeta‐associated changes are observed in DIAD around 20 years before symptoms onset [5]. Subsequently, p‐tau217 increases with brain Abeta build‐up until cognitive symptoms onset. At asymptomatic stages, CSF and plasma p‐tau217/tau ratio better associates with Abeta PET than p‐tau concentration [3,6]. While brain Abeta deposition plateaus at symptoms onset, we observe p‐tau217 increases and significantly associates with Tau PET. This association weakens then disappears at dementia stage when p‐tau217 decreases. Finally, abnormal soluble p‐tau217 is observed sporadically in participants with primary tauopathies in absence of Abeta positivity [7].

Conclusions

P‐tau217 is a highly accurate marker of Abeta deposition. The strong association between p‐tau217 and Abeta PET, when tau PET remains negative, supports tau hyperphosphorylation is a neuronal response to Abeta pathology independent from tau aggregation. On the other hand, p‐tau217 associates with tau‐PET at prodromal AD stage and occasionally changes in participants with primary tauopathies free of amyloid deposition. This corroborates soluble p‐tau217 also increases because of the presence of brain tau aggregates. The duality of p‐tau217 response to amyloid and tau pathology in AD complicates its utility as marker of tau aggregation. Lastly, plasma p‐tau217 use as a single marker of Abeta positivity may expose to risk of false positive AD diagnosis for patients with primary tauopathies.
Younger Age of First Exposure to American Football is Associated with Worse Informant‐Reported Clinical Outcomes in Older Age
Authors: Nosek Sophia , Gil Stephanie Gonzalez , Nowinski Christopher J. , Tripodis Yorghos , Martin Brett , Palmisano Joseph N. , Cantu Robert C. , Stern Robert A. , Huber Bertrand Russell , Stein Thor D. , McKee Ann C. , Mez Jesse , Alosco Michael L. , Daneshvar Daniel H.
Published: January 2025

Background

Exposure to repetitive head impacts (RHI) is associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). There is substantial heterogeneity in the clinical presentation of CTE. Younger age of first exposure (AFE) to American football has not been associated with odds or severity of CTE. Yet, it has been associated with earlier onset and severity of symptoms, potentially by decreasing resilience to RHI‐related neuropathologies. We examined the association between AFE to football and clinical and neurobehavioral outcomes in deceased football players across the age continuum.

Methods

The sample included 677 male football players who donated their brains to the UNITE Brain Bank. Informants of brain donors completed modified scales assessing donor cognitive function (Cognitive Difficulties Scale [CDS], BRIEF‐A Metacognition Index [MI]), daily function (Functional Activities Questionnaire [FAQ]), mood (Geriatric Depression Scale‐15 [GDS‐15], Beck Anxiety Inventory [BAI] Apathy Evaluation Scale [AES]), and neurobehavioral dysregulation (Barratt Impulsiveness Scale [BIS‐11], BRIEF‐A Behavioral Regulation Index [BRI], Brown‐Goodwin Aggression Scale Adult Sum). Dementia was adjudicated through consensus conferences. Neuropathologists were blinded to clinical history. Global p‐tau burden was calculated by summing semi‐quantitative ratings of p‐tau severity across nine brain regions. Regressions tested the association between AFE and each scale, dementia status, and CTE status. Analyses were performed stratified by age 60 to isolate the effect of neurodegenerative disease resilience adjusting for age, global p‐tau burden, and duration of football play.

Results

Sample characteristics are in Tables 1‐2. Most donors played football in college and/or professionally (n = 509, 76%). CTE was the most common neuropathological diagnosis (n = 471, 70%). AFE was not associated with CTE neuropathology. Global tau and age were consistent predictors of the clinical scales (Table 3). There were significant associations between AFE and the clinical scales among those older but not younger than age 60. Among those over age 60, younger AFE to football was associated with higher CDS (p = 0.02), BRIEF‐A MI (p = 0.02), and BIS‐11 (p = 0.03) scores.

Conclusions

Younger AFE was associated with worse informant‐reported clinical outcomes in older but not younger deceased football players, independent of tau. Youth exposure to RHI from football might decrease resilience to cope with neuropathologies later in life.
Decision‐Making Capacity and Awareness in People with Young‐Onset Alzheimer´s Disease
Authors: Dourado Marcia C. N. , Souza Nataie , Belfort Tatiana , Nogueira Marcela Moreira Lima , Baptista Maria Alice , Baptista Maria Alice
Published: January 2025

Background

There is a lack of research on differences between decision‐making capacity and awareness according to age at onset of dementia. We investigated the relationship between decision‐making capacity and awareness domains in people with young‐ (YOAD) and late‐onset Alzheimer´s Disease (LOAD).

Method

A cross‐sectional study included 169 consecutively selected people with AD and their caregivers (124 people with LOAD and 45 people with YOAD).

Result

People with YOAD were more cognitively impaired, but more aware of their cognitive deficits and health condition, with moderate effect sizes. All people with AD presented deficits in the domains of decision‐making capacity, with more impairment in understanding. There was a relationship between understanding and awareness domains, such that awareness was particularly important for decision‐making capacity in the YOAD group.

Conclusion

Better awareness involved better understanding in the YOAD group. Clinically, our findings shed light on the need to consider the differences in the domains of awareness and their relationship with other clinical aspects such as decision‐making capacity according to age at onset of AD.
Multi‐omics assessment of genotype and sex‐specific effects of organochlorine pesticide DDT in humanized APOE mice
Authors: Mhatre‐Winters Isha , Eid Aseel , Zhan Jiada J , Hart Ronald P , Barahona Arturo J , Tran ViLinh , Han Yoonhee , Go Young‐Mi , Jones Dean P , Richardson Jason R
Published: January 2025

Background

The Apolipoprotein‐E (APOE) ε4 gene variant is the strongest genetic risk factor for late‐onset Alzheimer’s Disease, but is not entirely predictive. Emerging evidence suggests environmental factors contribute to disease etiology, with epidemiological studies associating pesticide exposure with lower cognitive scores. Dichlorodiphenyltrichloroethane (DDT), a pesticide used extensively in the US until 1972, persists in trace amounts due to its long half‐life, bioaccumulation, and existing dumpsites. We have previously reported that DDT induces AD pathology in multiple models and also shown increased serum levels of DDE, the primary metabolite of DDT, in AD patients, where APOE genotype modified MMSE scores and contributed a ∼4‐fold increase in AD risk. Here, we sought to identify the mechanism(s) by which APOE4 genotype alters pathological response to DDT by a multi‐omics approach.

Method

To assess the effects of DDT exposure, three‐month‐old male and female APOE3 (E3) and APOE4 (E4) mice were exposed to 3 mg/kg DDT by oral gavage every 3 days for 5 months. Hippocampus was dissected out and frozen for RNA‐sequencing and metabolomic analysis, while serum was collected for metabolomic analysis and biomarker measurement.

Result

RNA‐sequencing analysis between genotypes of female DDT‐exposed mice indicated significantly downregulated pathways and functions (p<0.05) in the hippocampus of E4‐females, including phosphatidylserine decarboxylase activity and neuron projection. Similarly, DDT‐exposed E4‐males indicated downregulation of ion channel regulator activity, nucleotide binding, cell‐cell and synaptic signaling, and neuron projection. Further, untargeted metabolomic analysis of DDT‐exposed mice was compared. Top pathways (p<0.05) altered in E4 vs. E3 female‐DDT hippocampus were carnitine shuttle and glycolysis‐gluconeogenesis, while serum changes included TCA cycle and tryptophan metabolism. In E4 vs. E3 male‐DDT, hippocampal alterations included purine metabolism, fatty acid mitochondrial beta‐oxidation, TCA cycle, glycolysis, and carnitine shuttle, while serum changes involved cholesterol biosynthesis, TCA cycle, and glycolysis‐gluconeogenesis. Finally, DDT increased serum neurofilament light chain (NfL) levels, a biomarker for neurodegeneration, by 1.9 and 2.1‐fold in E4‐male and E4‐female mice compared to respective controls. NfL was 1.4‐fold higher in DDT‐exposed E4‐females compared to E4‐males.

Conclusion

These data demonstrate gene‐by‐environment interactions modified by sex, providing a platform to investigate mechanisms in AD‐related neurodegeneration and corroborating previous epidemiological findings.
Whole‐Genome Sequencing Study in Koreans Identifies Novel Loci for Alzheimer Disease
Authors: Kang Moonil , Farrell John J. , Zhu Congcong , Park Hyeonseul , Kang Sarang , Seo Eun Hyun , Choi Kyu Yeong , Jun Gyungah R , Won Sungho , Gim Jungsoo , Lee Kun Ho , Farrer Lindsay A.
Published: January 2025

Background

With a rapidly aging population, South Korea anticipates a surge in Alzheimer disease (AD). However, the genetic basis of AD in Koreans is not well understood.

Method

We sequenced the genomes of 3,540 Koreans (1,583 AD cases and 1,957 controls) older than age 60 and performed a genome‐wide association study (GWAS) of AD using logistic regression models that included covariates for age, sex, five ancestry principal components, and an empirical genetic relationship matrix. We also conducted association tests in subgroups stratified by APOE ε4 status or sex. Findings from the Korean sample were combined with results from two Japanese GWAS datasets using the inverse‐variance meta‐analysis method. We also performed gene‐based tests of aggregated rare variants in the Korean dataset. Novel findings were evaluated by pathway enrichment analysis and by differential gene expression analysis in brain tissue from controls and AD cases who were either cognitively impaired or healthy prior to death.

Result

We identified genome‐wide significant (GWS) associations (P < 5.0 × 10‐8) with two well‐established AD loci (APOE and SORL1) in the total sample and with one novel locus, ROCK2 (rs76484417, P = 2.71 × 10‐8) among APOE ε4 non‐carriers. Another novel study‐wide significant association (P < 2.47 × 10‐6) was found with aggregated rare variants in MICALL1 (P = 9.04 × 10‐7). We also observed suggestive associations (P < 1.0 × 10‐6) with 14 novel loci (MSX1, BCL11A, ARMH3, CTNNA3, YTHDF1P1, GRM3, LINC02479, LRCH1, COL9A1, TTC8, MCTP2, DLGAP2, TBC1D32, and EXD2). Expression of several novel genes, including ROCK2 and MICALL1, was significantly different in multiple cortical regions in AD cases compared to controls (P < 3.33 × 10‐3). ROCK2 was also differentially expressed between AD cases with and without cognitive impairment (P = 1.34 × 10‐4).

Conclusion

We identified GWS and suggestive association for AD with several loci in Koreans and Japanese not previously observed in other populations. Our results provide additional insight into genetic mechanisms leading to AD and cognitive resilience, as well as emphasize the need for further genetic studies of East Asian populations.
Pathway‐specific polygenic risk score analysis to explore the inverse association between cancer and Alzheimer’s disease neuropathologic changes
Authors: AUNG KHINE ZIN , Wu Xian , Abner Erin L. , Nelson Peter T. , Karanth Shama D , Fardo David W. , Katsumata Yuriko
Published: January 2025

Background

Recent research reported that cancer patients had lower risk of Alzheimer’s disease (AD). Common signaling pathways, hormonal systems, and genetic predispositions have been hypothesized as important factors contributing to this inverse association. However, the exact mechanisms are still unknown. Polygenic risk scores (PRS) represent genetic susceptibility and are useful for disease genetic risk prediction. To date, there have been no published findings connecting cancer with AD through PRS. In this study, we investigated the genetic association between various types of cancer and AD/ADRD using biological pathway specific PRS.

Method

We obtained phenotype data from the National Alzheimer’s Coordinating Center (NACC), genotype data from the Alzheimer’s Disease Genetics Consortium (ADGC), and summary statistics for five cancers (liver, lung, prostate, breast, colon cancers) from the United Kingdom (UK) Biobank. We mapped genes to each of the 18,826 Gene Ontology (GO) categories for Homo sapiens and discovered 7,300 biological processes comprised of groups of three or more genes. We removed the APOE region and analyzed the associations between AD and each cancer by using pathway specific PRS. AD neuropathologic changes were evaluated by NACC neuropathology (NP) data including Thal phase, Braak NFT Stage (B0 = no NFTs, B1 = Stage I or ll, B2 = Stage IIl or IV and B3 = V or Vl) and CERAD score (density of neocortical neuritic plaques: C0 = No neuritic plaques, C1 = Sparse neuritic plaques, C2 = Moderate neuritic plaques, C3 = Frequent neuritic plaques).

Result

The most significant biological processes were cell cycle related pathways, apoptotic pathways, angiogenesis, and neurodevelopmental pathways between C scores and B scores (Table 1). Angiogenesis and atherosclerosis pathways were positively significant in TDP‐43 and cerebrovascular pathologies respectively.

Conclusion

While selection and survival bias cannot be completely ruled out, disruptions of specific biological pathways may contribute to the observed inverse relationship of cancer and AD. Further research may clarify the underlying mechanisms between AD and cancer inverse relationship by incorporating with cancer PRS.
AlphaFold 2 predicts a markedly different MTBR conformation for 3‐repeat and 4‐repeat tau isoforms
Authors: Chain Daniel G , Margolin Richard A , Pollack Scott , Goncalves Maria Beatriz de Castro V.
Published: January 2025

Background

Tau abnormalities are a central feature of Alzheimer’s disease (AD) and the defining feature of non‐AD tauopathies, which include frontotemporal lobar degeneration (FTLD) due to Pick’s disease (PiD) or Mapt mutations (FTLD‐tau), as well as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and others. Mapt transcripts undergo alternative splicing to produce 6 distinct isoforms. Exon 2 splicing produces 0, 1 or 2 inserts; exclusion or inclusion of exon 10 results in 3‐repeat (3R) or 4‐repeat (4R) forms, respectively. These forms are differentially present in tauopathies, e.g., 3R in PiD; 4R in almost all FTLD‐tau, PSP, and CBD; and equal 3R/4R in AD. 3R tau is reported to have lower microtubule binding affinity and a higher propensity to form soluble oligomers. Combining structural modeling of tau by AlphaFold 2 (AF2) with biochemical analyses may illuminate the impact of repeat and insert differences. While tau is considered generally disordered, AF2 modeling of 4R tau that we performed predicted a mainly ordered structure for the MTBR from Leu243 to Asp368. Biochemically, we found that the MTBR conformation is altered by some FTD associated mutations and caspase‐3 cleavage. In the present study, we studied the MTBR conformations for the 6 isoforms.

Method

We first analyzed FASTA sequences of the tau isoforms by AF2 and aligned them based on the predicted MTBR conformations. We then compared intramolecular distances between selected MTBR residues.

Result

Absence of the second repeat in 3R tau causes a dramatic difference in the MTBR conformation compared to 4R tau. Specifically, the inward fold N‐terminus to Pro301 is lost, thereby producing an “open” conformation (Figure, b vs a). The number of inserts does not affect the conformation of 4R tau (Figure, d vs. a) but significantly alters that of 3R tau (Figure, c vs. b).

Conclusion

3R tau’s open MTBR conformation may explain its increased propensity to oligomerize and suggests the possibility of additional binding sites that may increase the interactome compared to 4R tau. The absence of the inward fold in 3R tau suggests that this region may be important for microtubule binding.
Search for the fourth elusive haplotype of the APO E2/E3/E4 polymorphism and its potential effect on AD risk
Authors: Cheema Asma Naseer , Lawrence Elizabeth C , Zafari Narges , Fan Kang‐Hsien , Aslam Muhammad Muaaz , Acharya Vibha , Bedison Margaret A , Feingold Eleanor , Kamboh M. Ilyas
Published: January 2025

Background

The common APOE2/E3/E4 polymorphism, the strongest risk factor for Alzheimer’s disease (AD), is determined by two‐site haplotypes at codons 112 (Cys>Arg) and 158 (Arg>Cys), resulting into six genotypes. Due to strong linkage disequilibrium between the two sites, 3 of the 4 expected haplotypes (E2, E3, E4) have been observed and extensively studied in relation to AD risk. Compared to the most common haplotype of E3 (Cys112 – Arg158), E4 (Arg112 – Arg 158) and E2 (Cys112 – Cys158) haplotypes are determined by a single‐point mutation at codons 112 and 158, respectively. The fourth haplotype having mutations at both sites (Arg112 – Cys158) has been reported only as an incidental finding in five kindreds. To our knowledge, no systematic search has been done to determine its distribution in many AD and non‐AD subjects. The study aimed to search for the elusive fourth haplotype, elucidate its frequency and contextual association with AD.

Method

A DNA fragment of 177bp from subjects with the APOE 2/4 genotype was subcloned with single deoxyadenosine (A) overhang on 3’ end that was amplified and ligated into 4kb PCRTM II‐TOPO vector with single 3’ deoxythymidine(T) residue then transformed into chemically competent cells (E.coli DH5aTM ‐T1R) to construct the phased haplotype clones. Plasmid DNA was extracted from successful clones and sequenced. We also confirmed the haplotype phasing by whole‐ genome sequencing.

Result

We extracted APOE genotype data on more than 14,000 AD and non‐AD subjects previously genotyped in our laboratory and identified 344 subjects with the APOE 2/4 genotype who are compound heterozygotes by carrying mutations at both sites. Thus far, subcloning followed by single‐stranded sequencing in 313 of the 344 samples have yielded phased haplotypes and the results indicate that the E4 and E2 mutations are present on opposite chromosomes. Thus, no example was observed where both the E4 and E2 mutations are on the same chromosome (Arg112 – Cys158). We are in the process of determining the haplotype phases in the remaining samples.

Conclusion

No example of the elusive fourth haplotype was found in our large AD case‐control dataset, suggesting it might have a minimum effect, if any, on AD risk.
Association of Blast‐induced Hearing Loss with Progression of Alzheimer’s Disease Pathology
Authors: Kerr Nadine A , Sangaletti Rachele , Walters Winston , Rajguru Suhrud M
Published: January 2025

Background

Exposures to hazardous noise causes irreversible injury to the structures of the inner ear, leading to changes in hearing and balance function with strong links to age‐related cognitive impairment. While the role of noise‐induced hearing loss in long‐term health consequences, such as progression or development of Alzheimer’s Disease (AD) has been suggested, the underlying mechanisms and behavioral and cognitive outcomes or therapeutic solutions to mitigate these changes remain understudied. This study aimed to characterize the association between blast exposure, hearing loss, and the progression of AD pathology, and determine the underlying mechanisms.

Method

We employed a well‐accepted preclinical mouse model (3xTg) with a predisposition to AD pathology. Wild type (WT) and 3xTg (AD) mice were exposed to blasts in an ecologically valid oxyacetylene gas tube at 4 months of age. We compared functional outcomes (auditory brainstem responses and vestibular evoked myogenic potentials), cognitive deficits (novel object recognition, water maze), affective deficits (open field) and anxiety between WT and AD sham and blast‐exposed mice over 3 months. We also carried out immunohistochemical and Western Blot analysis for amyloid beta (Ab) amyloid fibrils, Tau, and Gasdermin‐D of the peripheral auditory system and multiple brain regions including auditory cortex and brainstem.

Result

Auditory and vestibular analyses revealed a combination of temporary and permanent functional loss post‐blast combined with hair cell loss and synaptopathy. We assessed changes in cognitive function and anxiety after the induction of hearing loss in WT and AD mice. The AD, WT‐blast and AD‐blast animals had challenges with the novel object recognition. AD mice post‐blast exhibited significant increases in fecal boli present when compared to WT mice. In open field, there was a decrease in overall mean speed and total distance traveled in AD mice. Finally, there was significant elevation of Ab, Tau and Gasdermin in the cochlea as well as brainstem and cortex suggesting that pyroptosis related mechanisms play a significant role in the pathology of AD.

Conclusion

These results suggest that strong association between early hearing loss and progression of AD pathology. Our novel results may inform potential biomarkers and therapeutic strategies.
Cognitive characteristics in a Uruguayan cohort of healthy subjects with high educational level in risk of development dementia and its relation with ApoE genotype
Authors: Mariani Francesca , Damian Andres , Leites Alice , Cortabarría Lucia , Bocos Laura , Santero Sofia , Contreras Valeria , Ferrando Rodolfo , García‐Fontes Margarita , Reyes Laura , Arredondo Florencia , Abin‐Carriquiry Juan Andrés , Menendez Mercedes , Amestoy Alejandra , Torheim Maren , Superchi Roberto , Suarez Ramon , Preciozzi Fabian , Uriarte Laura , Dansilio Leandro , Dansilio Sergio , Charamelo Ana , Allegri Ricardo , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Sevlever Gustavo , Sosa Ana Luisa , Calandri Ismael Luis , Crivelli Lucia , Salinas‐Contreras Rosa Maria , Suemoto Claudia Kimie , Vellila Lina Marcela , Yassuda Monica Sanches
Published: January 2025

Background

ApoE has been linked to individual differences in risk and resilience to neurodegeneration in normal aging. The ApoE4 genotype has been associated with an increased risk of developing late‐onset Alzheimer’s disease (age 65 and older). Within the cognitively healthy population, important differences have been reported in the distribution of ApoE4 alleles and their association with cognitive performance, especially in underrepresented groups. We describe the distribution of ApoE alleles in healthy subjects at risk of developing dementia in Uruguay, and its association with cognitive assessment and risk factors for dementia.

Method

we studied 73 subjects from the LatAm FINGERS project – Uruguayan cohort. Individuals had biobank analysis for the ApoE4 genotype, cognitive evaluation and risk factors for dementia. We compare the performance of participants in cognitive testing in relation with their ApoE allele characterization, and its relation with risk factors.

Result

demographic characteristics of study subjects are shown in Table 1. We report only one participant with E4/E4 allele combination and was exclude of analysis groups. Kruskal‐Wallis test (Table 2) revealed a significant difference in CERAD and CERAD Delayed measures between the different APOE allele combinations. We didn´t observed differences in other cognitive parameters. Also, Spearman´s Correlation showed an association between educational level, CERAD and CERAD delayed, GDS and CDR. Framingham Risk score was significantly correlated with CAIDE score.

Conclusion

our results suggest that the CERAD and CERAD Delayed may vary in different APOE allele combinations in normal subjects with a high educational level at risk of dementia in Uruguay. Understanding how genetic variability contributes to individual differences in cognition is important for the design of multidomain assessments and interventions, not only in subjects with cognitive impairment, but also in normal ageing in underrepresented populations.
Mosaic Loss of Chromosome Y in Peripheral Blood Cells from Whole‐Genome Sequencing and Alzheimer’s Disease in the Amish
Authors: Song Yeunjoo E. , Laux Renee A. , Fuzzell Sarada L. , Hochstetler Sherri D. , Miskimen Kristy L. , Lynn Audrey , Wang Weihuan , Main Leighanne R. , Wang Ping , Liu Yining , Moore Noel C. , Prough Michael B. , Dorfsman Daniel A. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Gulyayev Alex V. , Slifer Susan H. , Adams Larry D. , Vance Jeffery M. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Pericak‐Vance Margaret A , Scott William K. , Bush William S. , Haines Jonathan L.
Published: January 2025

Background

Mosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, this has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer’s disease (AD). We investigated mLOY estimated from whole genome sequencing (WGS) as a risk factor for AD in the Midwestern Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors.

Method

The calling of mLOY was performed using the Mosaic Chromosomal Alterations (MoChA) pipeline, utilizing long‐range phase information to search for imbalances between maternal and paternal allelic fraction in a cell population. A loss was called when the slope of coverage over allelic deviation was ‐0.94. The cognitive status of each individual was assigned via consensus review of medical history and neuropsychological testing. The cognitively‐impaired (CI) group combined AD, MCI and Unclear individuals and compared to the cognitively‐unimpaired (CU) group. Individuals in 3 age groups (65‐74, 75‐84, ≥85) were included. To evaluate the association between mLOY and risk of developing CI in follow‐up, we fit a Cox proportional hazards model associating mLOY to years of disease‐free follow‐up within individuals for whom blood was sampled prior to CI diagnosis.

Result

After extensive QC, 457 males (mean age = 80.48±5.12) were included. mLOY frequency increased with age (p = 0.029): 18.75% (65‐74; n = 48), 31.86% (75‐84; n = 317) and 39.13% (85+; n = 92). A subset of 372 males were assigned to the CU (n = 202) or CI (n = 170) group and mLOY was slightly higher in the CI group (26.2% in CU vs. 34.1% in CI; p = 0.099). Within 217 males for whom blood was sampled a priori, there were 48 subsequent CI events. mLOY was associated with an increased risk of CI diagnosis with hazard ratio (HR) = 1.90 (1.03‐3.56, p = 0.04). After adjusting for the age of sampling, HR increased to 2.31 (1.23‐4.36, p = 0.009).

Conclusion

We assessed the impact of mLOY in males on the risks of CI. We observed the same trend as reported in other European descent populations: mLOY increased with age and the higher sensitivity with WGS data compared with array‐based data. We found that carriers of mLOY had an increased risk of impairment.
Systemic inflammation accelerates tau propagation in an experimental model of Alzheimer’s disease
Authors: Howard Sarah , Ahmed Zeshan , Deinhardt Katrin , Teeling Jessica
Published: January 2025

Background

Systemic inflammation in patients with Alzheimer’s disease (AD) has been associated with an exacerbation in cognitive decline, but the underlying mechanisms remain largely unknown. In AD, intraneuronal hyperphosphorylated tau spreads through the brain via trans‐synaptic prion‐like propagation. Evidence suggests that propagation of tau pathology is linked to neuroinflammation. Here we aim to investigate if a low‐grade systemic bacterial infection drives neuroinflammation and exacerbates the spread of tau using an experimental model of AD

Method

C57BL/6 mice underwent intracerebral injection of vehicle or AT8‐positive human tau lysate, isolated from post‐mortem AD tissue. Two months post‐injection, mice were given a systemic injection of saline or a life bacterial strain. Body and spleen weight was measured to confirm infection and brain tissue was collected 4 weeks post‐infection to assess tau pathology and markers of neuroinflammation.

Result

We observed tau pathology in mice exposed to human tau lysate. Pathology in the dorsal fornix and the supramammillary nuclei was observed only in mice exposed to a bacterial infection. We also examined the inflammatory markers MHCII and CD64 and detected increased expression in mice exposed to a bacterial infection. The inflammatory response was localised to regions where pathology was observed, such as the CA3‐dentate gyrus axis.

Conclusion

Following intracerebral injection of human tau lysate, propagation of tau was induced both dorsal and ventral to the injection site. The extend of pathological tau was exaggerated by the presence of low‐grade systemic inflammation. This suggests that systemic inflammatory episodes in AD patients may induce greater propagation of tau pathology.
Effect of Music Stimulation on Network Activity of Patients with Dementia with Lewy Bodies
Authors: Chenchu Vishnu Shandilya Mungamuru , Addo‐Osafo Kwaku , Stepter Joshua , Elrayes Karen , Mohammed Aisha , Kilgore Sydney , Figueroa Katy , Vossel Keith
Published: January 2025

Background

Dementia exhibits abnormal network activity, including altered gamma frequency (30‐100 Hz) in Alzheimer’s disease (AD). A non‐pharmacological, non‐invasive approach to AD treatment involves stimulating sensory inputs using gamma band, with 40 Hz as the most effective in eliciting a robust EEG response. Light and sound stimulation at 40 Hz reduces AD pathology in mouse models and improves cognition in humans with AD. However, the effects of this stimulation in patients with dementia with Lewy bodies (DLB) and mild cognitive impairment (MCI) is unknown, as well as whether musical sounds can be more efficient than sounds without music.

Method

Individuals with DLB, MCI, AD, and controls participated in a music‐based brain stimulation study. Participants listened to music enhanced at 40 Hz with an overlapped 40‐Hz tone using headphones while connected to an EEG with 200‐to‐2000‐Hz sampling rate and 10‐20 placement. 40‐Hz flickering light was stimulated transiently at time intervals alone or in combination with sound stimulation. Participants underwent a 10‐minute initial assessment consisting of combinations of light/sound inputs followed by 1 hour of music and intermittent light stimulation. Power spectral density (PSD) and correlations of PSDs with different stimuli were measured.

Result

In DLB (female, mid‐50 s), sampled at 200 Hz, PSD showed a broad increase in response during gamma frequency stimulations. Light at 40 Hz (L40) resulted in increased response at 40 Hz at O1 and O2 electrodes, with a visible spike on the PSD. Music with 40‐Hz enhancement and 40‐Hz overlaid tone (M40) resulted in a strong positive correlation (SPC; Pearson correlation coefficient ≥ 0.5) at C3, C4, P3, O1, F8, T3, T4, T5, T6 and strong negative correlation (SNC; coefficient ≤ ‐0.5) at Fp1. Previously, 4 patients (1‐AD,1‐MCI,2‐controls) were sampled at 2000 Hz, which generated very low signal‐to‐noise ratio (SNR) and responses to stimulations were variable in these groups.

Conclusion

In DLB, music with 40 Hz enhancement and tone increased gamma frequency response, especially in temporal regions, with strong positive correlations. Ongoing studies will determine the responses of brain oscillations to music‐based stimulations in additional participants with DLB, MCI, AD, and controls.
Peripheral metabolism informs on future cognitive decline and development of Alzheimer’s disease in population at risk
Authors: Liang Nuanyi , Nho Kwangsik , Newman John W. , Arnold Matthias , Huynh Kevin , Meikle Peter J , Borkowski Kamil , Kaddurah‐Daouk Rima ,   Alzheimer’s Gut Microbiome Project Consortium (AGMP),   the Alzheimer’s Disease Metabolomics Consortium, for the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2025

Background

Peripheral metabolic health status can reflect and/or contribute to the risk of Alzheimer’s disease (AD). Peripheral metabolic health status can be indicated by metabolic health markers, such as inflammatory biomarker glycoprotein acetyls (GlycA) and specific components of lipoproteins (e.g., triacylglycerol of high‐density lipoprotein). However, it is unclear if the relationship between peripheral metabolism and AD‐related markers is heterogenous among diverse populations and throughout the disease progression.

Methods

Utilizing Alzheimer’s Disease Neuroimaging Initiative data, we determined whether baseline plasma GlycA can inform on cognitive and brain structural changes among sub‐populations with different diagnosis status. Furthermore, correlation analyses were performed between blood metabolomics and cerebrospinal fluid (CSF) proteomics data in sub‐populations with different diagnosis status or different mild cognitive impairment (MCI)/AD outcomes in 3 years.

Results

GlycA was elevated in AD patients compared to cognitively normal participants. Baseline GlycA level was associated with executive function decline at 3‐9 year follow‐up in participants diagnosed with late mild cognitive impairment (LMCI) at baseline, with similar but not identical trends observed in the future decline of memory and entorhinal cortex volume. In addition, peripheral metabolomics signatures of CSF proteomics were well‐distinguished between cognitive normal participants and AD patients. Moreover, different peripheral‐central metabolic connection was also observed in MCI‐AD converters vs. MCI‐MCI non‐converters across 3 years follow up.

Conclusion

Peripheral inflammation was linked to future cognitive decline and brain structural atrophy for population at risk. In addition, peripheral metabolomics‐CSF proteomics correlation reveals distinguishing peripheral‐central connection patterns in AD patients as well as MCI participant soon to develop AD in 3 years. Findings here point to peripheral systemic inflammation and metabolic health in general as risk factors in AD development, pointing to therapeutic intervention related to periphery metabolic health for patients at risk.
Analyzing the expression of candidate genes in whole blood of autosomal dominant Alzheimer’s Disease
Authors: Comas‐Albertí Aina , Ramos‐Campoy Oscar , Pérez‐Millan Agnès , Bosch Bea , Gómez‐Núñez Alba , Puey Roger , Fernandez‐Villullas Guadalupe , Balasa Mircea , Lladó Albert , Antonell Anna , Sánchez‐Valle Raquel
Published: January 2025

Background

Autosomal dominant Alzheimer’s Disease (ADAD) represents around 0.5% of all AD cases, and is caused by mutations in PSEN1, PSEN2 and APP genes. Gene expression studies can be useful for unravelling the physiopathology of AD and identifying potential biomarkers. However, most studies are focused on late‐onset AD (LOAD), and mainly on brain tissue or immune cells. Preliminary data from our group showed 9 common differentially expressed genes (DEGs) both in brain tissue and lymphoblastoid cell lines in ADAD versus healthy controls (AMMERCR1L, FMR1, FXYD5, PRR3, RNU2.1, SCARNA2, SLC35A1, TCEAL8, TMEM184B). We aim to investigate these DEGs along with 3 AD relevant genes (APP, PSEN1 and MAPT) in whole blood of ADAD with the goal to explore new potential biomarkers.

Method

Our cohort (N = 69) consisted of ADAD symptomatic mutation carriers (SMC; N = 19), asymptomatic mutation carriers (AMC; N = 18) and healthy non carriers (CTRL; N = 32). RNA was extracted from whole blood and relative gene expression was determined by RT‐qPCR and ΔΔCt method. Permutation tests were used to determine the differential gene expression between groups. Additionally, a correlation analysis was performed between estimated years of onset (for AMC) or years since onset (for SMC) and relative expression.

Result

DEGs were mainly down‐regulated in ADAD with respect to CTRL, except for FXYD5 and MAPT, which were up‐regulated. When comparing ADAD mutation carriers versus CTRL the significant genes were APP (p = 0.045), FXYD5 (p = 0.018), MAPT (p = 0.041), PSEN1 (p = 5e‐4), SCARNA2 (p = 0.042) and TMEM184B (p = 0.0042) (Fig. 1). Then, we compared AMC versus CTRL and SMC versus CTRL and found two DEGs in both comparisons: FXYD5 (p = 0.015; p = 0.033) and MAPT (p = 0.015; p = 0.034). In AMC group we also found these DEGs: FMR1 (p = 0.011), PRR3 (0.029), PSEN1 (p = 2e‐4), SCARNA2 (p = 0.027) and TMEM184B (p = 5e‐4) (Fig. 2). Results showed a significant negative correlation for RNU2.1 (p = 0.016) and PRR3 (p = 0.029) between relative expression and years since onset in SMC (Fig. 3).

Conclusion

Mutation carriers show some DEGs in whole blood, even in the asymptomatic stage. FXYD5 and MAPT genes show a consistent up‐regulation in both SMC and AMC, suggesting it could be further validated as a possible genetic biomarker in whole blood of ADAD.
Neurodegenerative Changes to Subiculum Cell Type Morphology in 5xFAD Mice
Authors: Smith Zion MK , Becerra Marlene , Zepeda Nancy C , Pham Luc , Lee Darrin J , Bienkowski Michael S
Published: January 2025

Background

Alzheimer’s disease (AD) is a neurological disorder marked by progressive cognitive decline, memory deficits, and neuronal cell loss (Knopman, 2021). A brain region significantly impacted by the progression of AD is the subiculum, a structure responsible for spatial navigation, cognitive processes, and the modulation of emotional and affective behaviors within the hippocampus (Fanselow and Dong, 2010). Although subiculum cell loss has been well‐established as an early indicator of AD (Carlesimo et al., 2015), neurodegenerative changes to cell morphology can only be observed post‐mortem and are limited by tissue histology and staining approaches that cannot completely label neuronal morphology. Using AD mouse models, G‐deleted rabies viral tracers can fluorescently label full projection neuron cell type morphology for 3D reconstruction analysis and identify neurodegenerative changes to soma and dendrites across varying disease timepoints. Understanding morphological changes during disease progression can help identify neuronal cell type susceptibility, which precedes cell death.

Methods

Using 5xFAD mice at 2 and 8 mo. timepoints, we injected G‐deleted rabies viral tracers into the medial mammillary (MM) and lateral hypothalamus (LHA) to retrogradely label MM‐ and LHA‐projecting subiculum neurons. After a 1‐week survival time, brains were extracted, sectioned into 500µm thick coronal sections, processed for SHIELD tissue clearing histology, and 3D imaged using a confocal microscope with 250nm isotropic resolution.

Results

Our findings revealed that G‐deleted rabies vectors fluorescently labeled both ‘healthy’ and ‘sick’ pyramidal neurons within the subiculum, suggesting individual neurons at different stages of neurodegeneration. ‘Sick’ subiculum neurons displayed a variety of distinct alterations in their morphology, including shrunken cell bodies caused by decreased cytoplasm around the nucleus, the emergence of swellings and thinning of dendrites, and complete dendrite collapse. Our analysis of subiculum neurons suggests a progressive timeline of morphological degeneration that precedes cell death within the subiculum.

Conclusion

Our findings have the potential to not only deepen our understanding of the degenerative morphological process in AD but also determine the cellular processes that precede neuronal death, which may in turn lead to developing targeted interventions that could prevent this fate.
Systemic thymulin overexpression mitigates cognitive and molecular impairments in a rat model of sporadic Alzheimer’s Disease
Authors: Peralta Facundo , Escobedo Ana Abril Vidal , Hanotte Juliette López , Pardo Joaquín , Reggiani Paula Cecilia
Published: January 2025

Background

Sporadic Alzheimer’s Disease (sAD) is the most prevalent progressive neurodegenerative disease worldwide, without a cure. We propose to investigate therapies that contribute to the current state of this problem using a model of sAD in rats based on a single intracerebroventricular (icv) injection of streptozotocin (STZ). In this sense, thymulin (originally known as serum thymic factor, FTS), a thymic peptide, emerges as a potential therapeutic agent due to its proven anti‐inflammatory effects. Since the cerebral hippocampus (hc) is one of the key vulnerable areas in sAD, our study focuses on the analysis of this region.

Method

We used an adenoviral vector (RAd‐FTS) for systemic thymulin overexpression via intramuscular (IM) injections. Animals were divided into 3 groups (n = 8): SHAM, STZ and STZ+FTS. Rats received bilateral icv injections of artificial cerebrospinal fluid (SHAM) or STZ (STZ and STZ+FTS groups) (3 mg/kg). At weeks 1 and 6 post‐STZ, STZ+FTS animals received IM injections of RAd‐FTS. Prior to sacrifices (week 13), behavioural tests were performed to evaluate species‐typical, exploratory, anxious and depressive behaviours, and recognition memory. At the tissue level, immunohistochemical staining for immature neurons, microglia and astrocytes were performed.

Result

A significant deterioration in all assessed behaviours was observed in the STZ group. However, the STZ+FTS group did not show significant differences compared to the SHAM group in species‐typical, exploratory, anxious, and depressive behaviours. Moreover, it restored the recognition memory that was impaired in STZ animals. At the tissue level, systemic expression of FTS did not ameliorate the impact of STZ on immature neurons but showed an effect on microglia and astrocytes in the hc.

Conclusion

We explored a minimally invasive therapeutic strategy that allowed us to fully or partially reverse behavioural and molecular changes in our animals with sAD. Therefore, our results are encouraging and suggest that thymulin administration may be a promising therapeutic approach, warranting consideration in sAD studies.
Genetic overlap between Alzheimer’s disease and immune‐mediated diseases: An atlas of shared genetic determinants and biological convergence
Authors: Enduru Nitesh , Fernandes Brisa S. , Bahrami Shahram , Dai Yulin , Andreassen Ole , Zhao Zhongming
Published: January 2025

Background

An increasing body of evidence has suggested that the pathogenesis of Alzheimer’s disease (AD) is not confined to the neurons but instead that neuroinflammation plays a significant role in the disease, with an interplay between the brain and the immune system. So far, their shared genetic components have not been systematically studied.

Method

We investigated the shared genetic architecture between AD and a plethora of immune‐mediated diseases using the genome‐wide association studies (GWAS) summary statistics data: allergic rhinitis, asthma, atopic dermatitis, celiac disease, Crohn’s disease, hypothyroidism, primary sclerosing cholangitis, RA, systemic lupus erythematosus, ulcerative colitis, and vitiligo. We developed a pipeline for global and local genetic correlation analysis between diseases and quantifying the shared loci among diseases using MiXeR. We used the conditional/comjunctional FDR to identify the shared loci and, finally, performed bi‐directional MR to assess the causal relationship between AD and the 11 immune‐mediated diseases.

Result

Our results unveiled a significant genetic overlap between AD and 11 individual immune‐mediated diseases despite negligible genetic correlations, suggesting a complex shared genetic architecture distributed across the genome. With conjFDR <0.05, we identified 76 shared genomic loci. After excluding the 6 loci jointly associated with more than one pair of diseases, we had 70 unique shared genomic loci between AD and immune‐mediated diseases. Among them, 38 loci were novel for AD only, 25 were novel for immune‐mediated diseases only, and 17 were novel to both AD and immune‐mediated diseases. The shared loci between AD and immune‐mediated diseases implicated several genes, including GRAMD1B, FUT2, ADAMTS4, HBEGF, WNT3, TSPAN14, DHODH, ABCB9 and TNIP1, all of which are protein‐coding genes and thus potential drug targets. Enrichment analysis of these shared genes revealed pathways related to the immune system and cell adhesion. Finally, in silico single‐cell analyses showed enrichment of immune and brain cells, including neurons and microglia.

Conclusion

Our results suggest a genetic relationship between AD and the 11 immune‐mediated diseases, pinpointing the existence of a shared however non‐causal genetic basis. These identified protein‐coding genes have the potential to serve as a novel path to therapeutic interventions for both AD and immune‐mediated diseases and their comorbidities.