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Results for “Alzheimer disease”

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At least 19 recordsLinked to original sources

PubMed2025

Assessing the causal association between celiac disease and Alzheimer disease and frontotemporal dementia: A bidirectional Mendelian randomization approach.

This study aimed to investigate the bidirectional causal relationship between celiac disease (CD) and the risk of Alzheimer disease (AD) or frontotemporal dementia (FTD) using Mendelian randomization (MR), in order to clarify prior inconsistent findings. We analyzed summary-level genome-wide association study (GWAS) data for CD, AD, and FTD. Single-nucleotide polymorphisms (SNPs) strongly associated with each condition were selected as genetic instruments. MR analysis was conducted in 2 directions: from CD to AD/FTD and from AD/FTD to CD. Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) was used to detect and correct for pleiotropy, and Cochran Q assessed heterogeneity. Leave-one-out and Mendelian Randomization-Egger (MR-Egger) regression sensitivity analyses were performed to evaluate robustness. No evidence of a causal effect was found between CD and either AD or FTD in either direction (P > .05). Similarly, genetic liability to AD or FTD did not increase the risk of CD. Sensitivity analyses supported the robustness of the results, showing no pleiotropy or heterogeneity. Our findings suggest that CD is not causally linked to the development of AD or FTD. While shared genetic factors or comorbidities may exist, the association is likely noncausal, and other mechanisms of cognitive decline in CD patients warrant further study.

Humans↗

PubMed1978

Huntington disease associated with Alzheimer disease.

The clinicopathological study of a case of Huntington disease with early severe dementia is presented. The pathological findings were those of Huntington disease (atrophy with neuronal loss and astrocytosis in the neostriatum) and Alzheimer disease (neuronal loss with numerous senile plaques and neurofibrillary tangles in the neocortex). Ultrastructural study of neurofibrillary tangles showed that they were composed of twisted tubules similar to those found in Alzheimer disease.

Alzheimer Disease↗

PubMed2026

Prion disease mimicking rapidly progressive Alzheimer disease: case series and systematic review.

BACKGROUND: Prion disease and Alzheimer disease (AD) are common causes of rapidly progressive dementia (RPD). Although most patients with prion disease are distinguished by MRI and CSF findings, selected cases mimic rapidly progressive AD. We characterized AD-prion disease mimics within a prospective cohort and the extant literature to identify the clinical features and tests that support accurate diagnoses in these patients. METHODS: Patients with prion disease initially diagnosed as rapidly progressive AD were identified from a prospective cohort study at Mayo Clinic (February 2020-June 2026) and through systematic review of MEDLINE and Embase. RESULTS: Of 204 patients with RPD, five (2.5%) were initially diagnosed with clinically probable AD but ultimately determined to have prion disease. Systematic review identified 10 additional cases (n=15, median age-at-onset, 59 years; 67% male). Presentations reproduced amnestic (53%), dysexecutive (27%), primary progressive aphasia (13%), and posterior cortical atrophy (7%) AD phenotypes; median time from AD diagnosis to consideration of prion disease was 2 months. Diffusion-weighted MRI abnormalities were absent in Mayo Clinic cases and absent/equivocal (n=2) or overlooked (n=8) in published cases. CSF biomarkers were consistent with AD in 6/9 tested patients, with elevated total tau levels in 11/13 patients and total-tau/p hosphorylated-tau181 ratios in 5/9 patients. Real-time quaking-induced conversion assays for prions were positive in the CSF of 9/12 patients. Prion disease was confirmed by neuropathology (n=7), genetics (n=2), or real-time quaking-induced conversion (n=6) assays. CONCLUSIONS: Prion disease may rarely mimic rapidly progressive AD. Disproportionate elevations in CSF total-tau levels or total-tau/p hosphorylated-tau181 ratios should prompt consideration of prion disease.

Humans↗

PubMed1979

Studies in aging of the brain: IV. Familial Alzheimer disease: Relation to transmissible dementia, aneuploidy, and microtubular defects.

Alzheimer disease was transmitted in a pattern consistent with an autosomal dominant trait in three families. This brings to 50 the number of such families reported. In one of our families, one patient had histologically confirmed Alzheimer disease, whereas her sister had proved spongiform encephalopathy. Other data suggest a link between familial Alzheimer disease and transmissible dementia. Alzheimer disease is associated with abnormal neurofibrillary structures, Down syndrome, and abnormal numbers of chromosomes in lymphocytes (aneuploidy). These observations are consistent with a disorder in the physiology of tubular-filamentous structures involving different cell types.

Adult↗

PubMed2026

Multilevel genomic, transcriptomic, and epidemiologic evidence linking diabetic retinopathy to Alzheimer disease.

BACKGROUND: Diabetic retinopathy (DR) and Alzheimer disease (AD) share metabolic and vascular dysfunctions, but the extent to which they reflect overlapping genetic susceptibility and neurovascular-metabolic regulatory pathways remains unclear. We combined multi-omics analyses with population-based data to examine the genetic convergence, cellular pathways, and longitudinal association between DR and AD. METHODS: We performed a two-sample Mendelian randomisation (MR) to estimate the association between genetically predicted DR liability and AD risk. We used Bayesian colocalisation analysis to identify shared genomic loci, and summary-data-based MR (SMR) to detect expression-mediated genes jointly associated with DR and AD. We analysed single-cell RNA sequencing data to characterise shared cellular features and related biological pathways. We also conducted an MR-based mediation analysis to explore whether lipid-related, metabolic, or inflammatory traits mediated the observed DR-AD association, and a longitudinal analysis of the UK Biobank cohort to assess the association between DR and incident AD. RESULTS: With the MR analysis, we found that genetically predicted liability to DR was associated with a modest increase in AD risk. Colocalisation analysis supported a shared genetic signal. We identified three genes with shared expression-mediated associations across DR and AD through SMR. Functional enrichment analyses revealed partially overlapping neurovascular and metabolic pathways. Using MR-based mediation analysis, we found no significant intermediary traits linking DR and AD. Findings from the UK Biobank cohort were directionally consistent with the genetic analyses. CONCLUSIONS: Genetic liability to DR is associated with an increased risk of AD and is accompanied by shared expression-mediated effects and convergent neurovascular-metabolic pathways. These findings support the possibility that DR may serve as a clinically accessible indicator of increased neurodegenerative vulnerability.

Humans↗

PubMed1979

Skin fibroblast microtubular network in Alzheimer disease.

A preliminary observation from another laboratory recently suggested that a systemic microtubular defect may exist in Alzheimer disease. To investigate this hypothesis, we obtained skin biopsies from 4 patients with Alzheimer disease and 2 age-matched controls. Fibroblast cultures were established and the tubulin networks examined using immunoadsorbent purified antitubulin antibody and the indirect immunoperoxidase technique as well as electron microscopy. The cells were also examined after treatment with vinblastine and at senescence. The microtubular network appeared as delicate fibers radiating from the perinuclear region toward the cytoplasmic margins. No differences were recognized between the controls and the fibroblast cultures from patients with Alzheimer disease. Microtubules were not visualized following incubation with vinblastine, but positively staining intracytoplasmic paracrystalline inclusions were noted. No abnormalities of microtubules were recognized in the electron microscopic examinations. These findings suggest that the neurofibrillary neuronal degeneration of Alzheimer disease is not a manifestation of a systemic disorder of the microtubular network.

Alzheimer Disease↗

PubMed1979

Increased aneuploidy in Alzheimer disease.

The purpose of this study was to determine if cytogenetic changes are present in Alzheimer disease, one of the presenile dementias. The chromosomes of three groups of people were studied: 1) sporadic cases of Alzheimer disease (eight cases), 2) familial cases of Alzheimer disease with affected individuals in at least two generations of their families (five cases), and 3) currently unaffected siblings of the affected individuals in these families (nine cases). One hundred cells per individual were examined using GTG banding to allow chromosome identification. A statistically significant increase in aneuploidy was found in five of eight patients in group 1 (P less than 0.05) and in each of five patients in group 2 (P less than 0.001) when compared with the rate of aneuploidy in age- and sex-matched controls. In addition, two individuals in group 3 exhibited a significant increase in aneuploidy over the control group, raising the possibility that finding increased aneuploidy may allow one to anticipate the clinical expression of the disease state.

Aged↗

PubMed1976

Myoclonus in Alzheimer disease. A confusing sign.

Myoclonus in association with dementia of later adult life has been considered almost pathognomonic of Creutzfeldt-Jakob disease. However, myoclonus may also be seen with Alzheimer disease, and when the myoclonus occurs as an early manifestation of Alzheimer disease, distinction from Creutzfeldt-Jakob disease may prove difficult.

Aged↗

PubMed1978

Possible biochemical basis of memory disorder in Alzheimer disease.

Damage to the hippocampal formation, whether focal or diffuse, leads to severe impairment of short-term memory. The most common presenting symptom of Alzheimer disease is loss of short-term memory, and histologically the hippocampus is characteristically affected. Choline acetyltransferase, which is involved in the synthesis of acetylcholine, is depleted in the hippocampus in the disorder. Anticholinergic drugs administered to normal subjects can simulate some aspects of the memory defect seen in Alzheimer disease. It is postulated that damage to a cholinergic neuronal pathway running to or from the hippocampus underlies the memory disorder. This suggestion implies that it may be possible to improve memory in patients with Alzheimer disease by pharmacological means.

Acetylcholine↗

PubMed2025

A multi-ancestry polygenic risk score for Alzheimer disease is associated with cognitive decline, hippocampal atrophy and neuropathological hallmarks in diverse populations.

Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF Aβ42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.

Journal Article↗

PubMed2026

Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.

The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset ≤65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOAD patients-unaffected parents trios. After assessing known monogenic genes, we performed trio-based exome sequencing and jointly analyzed novel trios with 12 previously reported ones. Of these, we selected 16 trios for genome sequencing. We identified three patients with a pathogenic DNM in APP or PSEN1. Then, from the 46 remaining trios, we identified 38 non-synonymous coding DNM and 4 de novo copy number variants (CNVs) in exome data. Four DNM (2 novel, in SPHK2 and DDR1) and bi-allelic inherited variants in two genes affected Alzheimer disease-related genes. No significant burden of rare coding variants in exome/genome data from 5643 EOAD cases and 16097 controls was identified using nested windows centered on each DNM position, at the transcript level. From genome data, one non-coding DNM was predicted to affect splicing in an AD-associated gene, PINX1. Overall, 48% probands carried ≥1 inherited risk factor with odds ratio (OR) > 1.5 and GWAS-defined Genetic Risk Scores (GRS) distribution was more consistent with random distribution than enrichment in higher scores in probands. We confirm that DNMs in known monogenic genes explain sEOAD in a minority of cases, while candidate DNMs in other genes might account for a small proportion of additional cases. The majority of sEOAD patients may have a complex etiology including multiple inherited variants, however, GRS might not explain most of its genetic component.

Humans↗

PubMed2026

Causality between noise pollution and Alzheimer disease: A Mendelian randomization analysis.

The role of noise pollution as a risk factor for Alzheimer disease (AD) is unclear, with observational studies yielding conflicting results susceptible to confounding and reverse causality. To clarify this relationship, we performed a 2-sample Mendelian randomization (MR) study using summary statistics from large-scale genome-wide association studies of European populations. Genetically predicted daytime and evening noise exposure was used as an instrumental variable to assess a causal effect on AD risk. The primary analysis was conducted using the inverse-variance weighted method, with weighted median and MR-Egger methods as key sensitivity analyses. We assessed instrument validity and pleiotropy using the Cochran Q test, the MR-Egger intercept, and leave-one-out analysis. Our MR analysis found no evidence of a causal association between genetically predicted daytime noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.006], P = .819) or evening noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.005], P = .643) and the risk of AD. Sensitivity analyses were consistent, with no evidence of heterogeneity or directional pleiotropy. In conclusion, this study does not support a direct causal link between noise and AD. While our findings mitigate common observational biases, they do not preclude indirect mechanisms whereby noise may influence AD pathogenesis via established risk pathways, such as chronic sleep disruption and cardiovascular stress. Studies are needed to focus on disentangling these potential indirect effects.

Alzheimer Disease↗

PubMed2025

Exploring precision medicine by utilizing individual genetic information for the management of Alzheimer's disease.

Alzheimer's Disease (AD) represents a formidable challenge in neurology, characterized by progressive neurodegeneration and cognitive decline. Traditional therapeutic approaches have failed to deliver significant outcomes, underscoring the need for innovative paradigms such as precision medicine. The review explores integrating genomic, biomarker-driven, and individualized therapeutic strategies to tackle AD. It examines the role of key genetic factors, including APOE and MTHFR polymorphisms, in influencing disease susceptibility and treatment responses. Advances in biomarker technologies, such as blood-based and imaging biomarkers, are highlighted for their potential in early diagnosis and patient stratification. Additionally, the review underscores the importance of tailoring interventions across different stages of AD, incorporating lifestyle modifications and emerging tools like artificial intelligence & recent patented technologies. Precision medicine offers a transformative pathway, aiming to deliver personalized, effective care that addresses the complex and multifactorial nature of AD. The paradigm shift promises improved clinical outcomes and enhanced patient quality of life.

Humans↗

PubMed2026

Representation of Alzheimer Disease and Related Dementias in a Statewide Population Genomics Cohort: Early Findings from In Our DNA SC.

Alzheimer Disease and Related Dementias (ADRD) affect more than 125,000 individuals in South Carolina, yet equitable representation in population genomics initiatives remains a concern. We conducted a cross-sectional descriptive analysis of 247 In Our DNA SC participants aged 50 to 89 years with at least 1 ADRD-related diagnosis, identified using ICD-10 codes, to characterize demographic and clinical features and to compare the cohort with statewide ADRD estimates. Most participants were aged 65 years or older (82.2%), female (52.2%), and White (93.1%), while only 5.3% identified as Black. Nearly half had a Charlson Comorbidity Index score of 4 or greater (48.6%), and 49.5% had at least 10 years of longitudinal electronic health record data. Compared with statewide ADRD estimates, Black individuals were substantially underrepresented despite comprising ∼one-third of ADRD cases in South Carolina. These findings highlight the need for continued efforts to improve representation and support equitable, generalizable precision health research.

Humans↗

PubMed1978

Choline in Alzheimers disease.

Explore the source record for details and available documents.

Alzheimer Disease↗

PubMed2026

Bacterial polar metabolites modulate β-amyloid toxicity and cholinergic dysfunction in models of Alzheimer's disease.

Alzheimer's disease is characterized by progressive neurodegeneration driven by β-amyloid (Aβ) toxicity, oxidative stress, and cholinergic dysfunction. In this study, we investigated whether polar metabolites derived from a cultivable bacterial isolate could modulate Aβ-associated neurodegenerative phenotypes in complementary experimental models. A bioactivity-guided approach identified an aqueous fraction with high antioxidant capacity in DPPH, FRAP, and ORAC assays. In a transgenic Drosophila melanogaster model expressing human Aβ, treatment with this fraction significantly reduced amyloid accumulation and attenuated neurodegenerative histopathological alterations. In human SH-SY5Y neuronal cultures, the metabolites improved cell viability under therapeutic, but not preventive, conditions following exposure to aggregated Aβ. The aqueous fraction also exhibited significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Whole-genome sequencing assigned the bioactive isolate to the genus Providencia, with comparative genomic analyses suggesting its placement within a distinct taxonomic lineage. Metabolomic profiling by LC-ESI-MS/MS revealed a diverse set of polar metabolites, including metabolites putatively annotated based on spectral matching, previously associated with neuroprotective and cholinesterase-modulating activities. Collectively, these findings demonstrate that bacterial polar metabolites can modulate key pathological features of Alzheimer's disease, supporting their relevance for mechanistic studies of Aβ toxicity and cholinergic dysfunction.

Animals↗

PubMed2026

From prediction to mechanism: Explainable AI uncovers plasma and CSF proteomic signatures of Alzheimer's disease.

Alzheimer's disease (AD) plasma and cerebrospinal fluid (CSF) proteomics can distinguish AD from cognitively normal controls, but the generalizability of machine learning performance and the recurrence of biological signals across datasets require cautious interpretation. We developed an explainable artificial intelligence framework spanning two fluids and four ADNI proteomic datasets, covering 2082 modality specific samples, all analysed internally within ADNI. Phase 1 analysed plasma using a 119 analyte NULISA and targeted UPENN panel (n = 727; 216 CE, 511 controls). Phase 2 extended the analysis to CSF using SOMAscan7k, TMT-MS and targeted SET2, with Elecsys Aβ42, Aβ40, total tau and p-tau181 as anchor biomarkers. Only SOMAscan was subject-independent relative to Phase 1 plasma; TMT-MS and SET2 overlapped with Phase 1 for 96.0% and 97.7% of subjects and therefore are not independent replication cohorts. Under subject-level splits with fold internal preprocessing, we compared Elastic Net, Explainable Boosting Machines and gradient boosted trees with SHAP-based explanations. Among the candidate pipelines, we selected the pipeline with the highest held-out test ROC AUC for each platform; the selected values were 0.927 in plasma and 0.954-0.973 across the three CSF datasets. Because the same held out test performance was used for pipeline selection and headline reporting, these are optimistically selected single-holdout estimates, not unbiased estimates of generalizable or clinical performance. Explanations identified five recurring biological axes within ADNI: cholinergic (ACHE), tau/14-3-3 (YWHAG, YWHAZ, YWHAB, YWHAE), neuro-axonal (NEFL, NEFH), microglial/complement (CHIT1, SMOC1, CHI3L1, C7, CFH) and synaptic (NPTXR, NPTX2, DLG4, SYT5, VSNL1, ELAVL2). CSF analyses showed synaptic vesicle-cycle enrichment (q = 2 × 10-6), and CSF YWHAG correlated strongly with total tau (ρ = 0.87). Cross-fluid directional concordance was modest overall (54-57%) but increased to 73-80% among mapped analyte/protein rows reaching q < 0.05 in CSF. These findings provide hypothesis-generating, internally supported evidence within ADNI. Independent external cohorts with locked pipelines are required to evaluate generalizable performance and biological reproducibility; the overlapping TMT-MS and SET2 analyses should not be interpreted as independent replication.

Alzheimer Disease↗

PubMed2025

Integrating explainable artificial intelligence with multiomics systems biology and electronic health record data mining for personalized drug repurposing in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by region- and patient-specific molecular heterogeneity, which hinders therapeutic design. In this study, we introduce PRISM-ML (PRecision-medicine using Interpretable Systems and Multiomics with Machine Learning), an open-source integrated analysis pipeline that combines interpretable machine learning with systems biology and electronic health records data mining to elucidate the molecular diversity of AD and predict promising drug repurposing opportunities. First, we integrated and harmonized transcriptomic (bulk RNA-seq) and genomic (genome-wide association study) data from 2105 brain samples, each with matched data from the same individual (1363 AD patients, 742 controls; 9 tissues), sourced from three independent studies. Random forest classifiers with SHapley Additive exPlanations identified patient-specific biomarkers; unsupervised clustering resolved 36 molecularly distinct subtissues (defined as clusters of samples within a brain tissue that share a specific expression pattern); and gene-gene coexpression networks prioritized 262 high-centrality bottleneck genes as putative regulators of dysregulated pathways. Next, knowledge graph-based drug repurposing predicted six Food and Drug Administration (FDA)-approved drugs that simultaneously target multiple bottleneck genes and multiple AD-relevant pathways. Notably, in a large US de-identified insurance-claims database (n = 364 733), exposure to promethazine, one of the candidate drugs, was associated with a 57%-62% lower incidence of AD versus an active antihistamine comparator (adjusted hazard ratio 0.38; inverse-probability weighted 0.43; both P < .001), providing real-world support for its repurposing potential. In summary, PRISM-ML, as an explainable multiomics analysis pipeline, is readily transferable to other complex diseases, advancing precision medicine.

Alzheimer Disease↗