Journal of Alzheimer’s Disease

BackgroundMild cognitive impairment (MCI) is a condition between healthy cognition and dementia with a high probability of progression to Alzheimers disease (AD). Elevated levels of orexin (OX) have been reported in the cerebrospinal fluid of patients with MCI and AD. ObjectiveTo investigate the efficacy of dual OX receptor antagonists (suvorexant and lemborexant) in an early-stage AD mouse model (App-KI). MethodsThe expression of the OX receptor gene, the levels of suvorexant and lemborexant in the brain after a single oral dose, and their effects on locomotor activity were investigated in wild-type mice. In addition, the cognitive function of wild-type and App-KI mice was assessed using the Y-maze test after oral administration of suvorexant or lemborexant once a day for 60 d. After the behavioral test, amyloid-beta levels were quantified in the hippocampal CA1 region of App-KI mice. ResultsThe expression of the OX receptor gene was highest in the lateral hypothalamus and was also observed in other brain regions. Drug levels peaked at 20-40 min for suvorexant and 15 min for lemborexant and declined, still detectable 24 h later. Locomotor activity was reduced after suvorexant or lemborexant administration; however, 24 h after administration, locomotor activity did not differ from the control group. In particular, the Y-maze test showed that suvorexant and lemborexant prevented cognitive impairment in App-KI mice. Furthermore, suvorexant and lemborexant suppressed amyloid-beta accumulation in the hippocampal CA1 region of App-KI mice. ConclusionThe results suggest that suvorexant and lemborexant effectively suppress the early stages of AD.

Olfactory dysfunction is a prevalent and early feature of neurodegenerative diseases including Alzheimers disease while the features and underlying mechanisms remain inadequately understood. This investigation aimed to elucidate the olfactory function characteristics of presenilin-1/2 double knockout (DKO) mice, an established mouse model of dementia. Through a series of behavioral tests on DKO and wildtype (WT) mice at 2 and 6 months of age, we assessed their abilities in odor detection, discrimination, and olfactory memory. The findings revealed a substantial deficit in odor detection in 2-month-old DKO mice compared to WT mice, with a noteworthy age-related deterioration observed from 2 to 6 months. Although DKO mice exhibited normal odor discrimination and olfactory memory capabilities at 2 months, these functions declined with age, falling significantly lower levels than observed in WT mice by the age of 6 months. Subsequently, 2-month-old DKO and WT mice underwent a 4-month chronic nicotine treatment through drinking water. This intervention failed to ameliorate olfactory dysfunctions in DKO mice and exhibited no significant impact on WT mice, despite a discernible trend of a potential negative effect. In summary, this behavioral study elucidates that Presenilin-1/2 double knockout impairs odor detection in young adult mice and accelerates declines of olfactory discrimination and memory. The chronic administration of nicotine did not effectively mitigate olfactory function deficiencies in young adult DKO mice, and the results also highlight age as an important contributing factor.

BackgroundAltered mitochondrial function contributes to the pathogenesis of mild cognitive impairment (MCI) and late-onset dementia due to Alzheimers disease (AD). ObjectiveTo test for differential methylation in nuclear genes that encode proteins that participate in mitochondrial function between cognitively unimpaired participants (CU) and those with MCI and AD. MethodsRecently published whole genome methylation sequencing (WGMS) in blood from CU participants (N=174), and those with MCI (N=99) and AD (N=109) was used to test for differential methylation in 1,121 nuclear genes that encode proteins that participate in mitochondrial function in the Human Protein Atlas. ResultsSeventy-four nuclear genes that encode proteins that participate in mitochondrial function were differentially methylated between persons with MCI and CU. Seventy-one genes were differentially methylated between persons with AD and CU, and 132 genes were differentially methylated between persons with MCI and AD. Thirteen differentially methylated genes shared between the 3 comparisons support contributions from disrupted metabolism and oxidative stress pathways in AD pathogenesis. ConclusionsNuclear genes that encode proteins that participate in mitochondrial glucose metabolism, fatty acid metabolism and oxidative stress pathways are differentially methylated between persons who are CU and those with MCI and AD.

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may prevent/ or delay the progression of various neurodegenerative diseases including Alzheimers disease (AD). To investigate this protective effect, APPNL-G-F/NL-G-F mice at 3 months of age were exposed to repeated, single- or multi-domain cognitive training. Cognitive training was given at the age of 3, 6, 9 & 12 months of age. Single-domain cognitive training was limited to a spatial navigation task. Multi-domain cognitive training consisted of a spatial navigation task, object recognition, and fear conditioning. At the age of 12 months, behavioral tests were completed for cognitive training groups and control group. After completion of behavioral testing, mice were sacrificed, and their brains were assessed for pathology. AppNL-G-F mice given multi-domain cognitive training compared to APPNL-G-F control group showed an improvement in cognitive functions, reductions in amyloid load and microgliosis, and a preservation of cholinergic function. There were mild reductions in microglosis in the brain of APPNL-G-F mice with singledomain cognitive training. These findings provide causal evidence for the potential of certain forms of cognitive training to mitigate the cognitive deficits in Alzheimer disease.

IntroductionAlzheimers disease (AD) affects speech, language, and executive functions. Combining blood biomarkers with non-invasive speech analysis may aid early detection. MethodsA speech battery was administered to three groups aged 65-70: cognitively normal low-risk (LRC), high-risk (HRC), and mild cognitive impairment (MCI). ResultsVariance in Mel-Frequency Cepstral Coefficients (MFCCs) predicted p-tau217 (F = 3.71, p = 0.005), with group-specific effects in LRC and HRC. In MCI, articulation rate, speech percentage, and pause percentage predicted p-tau217 (all p < 0.01). Language features including idea density, content density, and open-class word rate also predicted p-tau217 (all p < 0.05). MFCCs and syllable timing correlated with NfL (all p < 0.01). Lexical diversity differed between groups, notably in HRC and MCI. DiscussionSpeech timing, fluency, and voice quality, along with lexical richness and idea density, predicted p-tau217 and NfL, supporting acoustic and linguistic features as non-invasive digital biomarkers for early AD-related neurodegeneration.

INTRODUCTIONClinical and genetic studies have implicated lipid dysfunction in Alzheimer Disease (AD) pathogenesis. However, lipid consumption at the individual-level does not vary greatly within most cohorts, and multiple lipids are rarely measured in any one study. METHODSMean country-level lipid intakes were compared to Age-Standardized Alzheimer-Disease-Incidence-Rates(ASAIR) in 183 countries across all inhabited continents. Penalized spline regression and multivariable-adjusted linear regression, including a lag between intake and incidence, were used to assess the relationships between five lipid intakes and ASAIR. Validation was conducted using longitudinal within-country changes between 1990 and 2019. RESULTSOmega6 Polyunsaturated-Fatty-Acid(PUFA) intake exhibited a positive linear relationship with ASAIR(multivariable-adjusted model: {beta}=2.44; 95%CI: 1.70, 3.19; p=1.38x10-9). ASAIR also increased with saturated-fat, trans-fat, and dietary-cholesterol up to a threshold. The association between Omega6-PUFA and ASAIR was confirmed using longitudinal intake changes. DISCUSSIONDecreasing Omega6-PUFA consumption on the country-level may have substantial benefits in reducing the country-level burden of AD.

BackgroundVerbal speech-in-noise (SIN) measures are impaired in early Alzheimers disease (AD) but may be confounded by linguistic and cultural factors. We investigated whether non-verbal auditory memory could predict cognitive impairment in AD. MethodsWe evaluated 158 cognitively healthy individuals, 26 with mild cognitive impairment (MCI), and 28 with AD dementia using the Addenbrookes Cognitive Examination (ACE-III), pure-tone audiometry, verbal SIN tests, and non-verbal auditory memory tests for basic sound features. Group differences were assessed adjusting for age, sex, and education. Logistic regression and receiver operating characteristic (ROC) analyses compared model fit of verbal and non-verbal auditory variables. ResultsAll auditory cognition measures were significantly associated with cognition. Non-verbal measures provided a better fit to diagnosis than verbal measures (AIC difference >10), although ROC analyses showed no significant differences between models. ConclusionsNon-verbal auditory measures are effective measures in distinguishing between cognitively healthy, MCI, and AD dementia individuals.

Aging-related hearing loss (ARHL) is epidemiologically linked to the development of Alzheimers Disease (AD). The mechanisms underlying this relationship are not known and have important therapeutic implications. If ARHL is causally linked to the development of AD, then correction of hearing loss via hearing aids should mitigate cognitive impairments in AD and more aggressive campaigns to treat ARHL, which is widely undertreated, would be warranted. Here, we critically examine the literature involving the use of hearing aids to treat ARHL and examine the impact of hearing aids on cognition. Although many studies report beneficial effects of hearing aids on cognition, most of these studies have significant flaws in their experimental design, making it difficult to judge their outcomes. In our selection process, we prioritized randomized studies and those with blinded and placebo-controlled outcomes. We evaluated a total of 10 papers that met inclusion criteria. Within our literature review, we found two randomized placebo-controlled studies that examined the impact of hearing aids on cognition in cognitively-impaired or vulnerable older individuals with minimal risk of bias. Meta-analysis of these two studies did not yield a statistically significant benefit of hearing aid use after 6 or 12 months of use. We propose that the current literature on this topic currently lacks compelling evidence to demonstrate that hearing aid use directly benefits cognition or delays AD. We further recommend strategies for improving clinical trial design to bring greater clarity to this important issue.

Alzheimers Disease(AD) is a neurodegenerative disorder marked by the accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. It is known to be caused by a variety of risk factors, both modifiable and non-modifiable. This systematic review investigates obesity as a modifiable risk factor for AD, focusing on inflammatory pathways linking the two conditions. This review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. We searched five databases (PubMed, Cochrane Library, Scopus, ScienceDirect, and Directory of Open Access Journals (DOAJ)) for human studies published in English language in the last 10 years. Following full text analysis and quality assessment, 23 studies were included in the review. We found that obesity induces a state of neuroinflammation through blood-brain barrier and choroid plexus disruptions, adipokine dysregulation, and mitochondrial dysfunction, leading to the development or progression of AD. We also identified nine proteins namely, CHI3L1, PTP1B, GDF15, MMP9, PECAM1, C3AR1, IL1R1, PPARGC1, and COQ3 as potential biomarkers that may serve as therapeutic targets to delay AD onset or progression. These findings underscore the importance of targeting obesity-related inflammation in AD prevention strategies.

Aims/hypothesisBeta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is required for the production of toxic amyloid peptides and is highly expressed in the brain, but also to a lesser extent in major peripheral organs such as muscle and liver. In contrast, BACE2 is mainly expressed in peripheral tissues and is enriched in pancreatic beta cells, where it regulates beta- cell function and mass. Previous reports demonstrated that loss of BACE1 function decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice, whereas mice lacking Bace2 exhibit reduced blood glucose levels, improved intraperitoneal glucose tolerance and increased beta-cell mass. Impaired glucose homeostasis and insulin resistance are hallmarks of type 2 diabetes and have been implicated in Alzheimers disease. Therefore, we tested the contribution of the individual BACE isoforms to those metabolic phenotypes by placing Bace1 knockout (KO), Bace2 KO, Bace1/2 double knockout (dKO) and wild-type (WT) mice on a high-fat high-cholesterol diet (HFD) for 16 weeks. MethodsBace1 KO (n = 18), Bace2 KO (n = 18), Bace1/2 dKO (n = 18) and WT C57BL/6N mice (n = 54) were fed a HFD for 16 weeks (age 9-25 weeks). Body composition was measured before initiation of the HFD and after 11 weeks of HFD. Oral glucose tolerance and insulin sensitivity tests were performed after 12 and 13 weeks of HFD, respectively, and full blood chemistry was analyzed after 16 weeks of HFD. The effects of subchronic BACE1/2 inhibition were assessed by administration of 10 mg/kg/day of the dual BACE1/2 inhibitor MBi-3 in a HFD fed to C57BL/6N mice for 3 weeks. ResultsBace1 KO and Bace1/2 dKO mice showed decreased body weight and improved glucose tolerance and insulin resistance vs. WT mice. Conversely, Bace2 KO mice did not show any significant differences in body weight, glucose tolerance or insulin resistance under our experimental conditions. Finally, subchronic MBi-3-mediated BACE1/2 inhibition in mice in conjunction with a HFD resulted in a modest improvement of glucose tolerance. Conclusions/interpretationOur data indicate that lack of BACE1 - but not BACE2 - function contributes mainly to the metabolic phenotypic changes observed in Bace1/2 dKO mice, suggesting that inhibition of BACE1 has the greater role (vs. BACE2) in any potential improvements in metabolic homeostasis. HIGHLIGHTSO_LIInsulin resistance may develop in the brains of patients with Alzheimers disease (83/85 characters) C_LIO_LIBACE1 and BACE2 may play a role in glucose homeostasis and insulin sensitivity (80/85 characters) C_LIO_LIBody weight in mice decreased with Bace1 KO and Bace1/2 KO but not Bace2 KO alone (83/85 characters) C_LIO_LIBace1 and Bace1/2, but not Bace2, KO improved glucose tolerance/insulin resistance (84/85 characters) C_LIO_LIImproved metabolic homeostasis may follow loss of BACE1 rather than BACE 2 activity (85/85 characters) C_LI

BackgroundThiamine diphosphate (TDP) reduction plays an important role in cerebral glucose hypometabolism, the neurodegenerative indicator, in Alzheimers disease (AD). The mechanism underlying TDP reduction remains elusive. Thus, it is critical to define the mechanism and its effect on neurodegeneration, the pathological basis of the disease occurrence and progression. MethodsThe mRNA levels of all known genes associated with thiamine metabolism, including thiamine pyrophosphokinase (TPK), Solute Carrier Family 19 Member 2 (SLC19A2), SLC19A3, and SLC25A19, in brain samples of patients with AD and other neurodegenerative disorders in multiple independent datasets were analyzed. TPK protein levels were further examined in the brain tissues of AD patients and control subjects. A mouse model with conditional knockout (cKO) of TPK gene in the excitatory neurons of adult brain was established. ResultsThe brain TPK mRNA level was markedly lower in AD patients, but not in other neurodegenerative disorders. The brain TPK protein level was also significantly decreased in AD patients. TPK gene knockout in the mice caused cerebral glucose hypometabolism, {beta}-amyloid deposition, Tau hyperphosphorylation, neuroinflammation, and neuronal loss and brain atrophy. Cross-species correlation analysis revealed the similar changes of gene profiling between the cKO mice and AD patients. ConclusionsThe deficiency of brain TPK, a key enzyme for TDP synthesis, is specific to AD. The cKO mice show AD-associated phenotypes and could serve as a new mouse model for AD studies. Our study provides a novel insight into the critical role of TPK in AD pathogenesis and its potential for the disease treatment.

BackgroundAPOE-{varepsilon}4, the strongest genetic risk factor for Alzheimers disease (AD), is linked to early motor vulnerability, including subtle speech control changes. Because speech integrates fine neuromotor processes, acoustic analysis could offer a sensitive, noninvasive marker of preclinical effects. ObjectivesTo determine if speech acoustics distinguish cognitively healthy APOE-{varepsilon}4 carriers from non-carriers, and to assess which speech tasks provide optimal classification performance. DesignA cross-sectional observational study employing supervised machine learning to analyze acoustic features extracted from multiple speech tasks. Genetic algorithms (GAs) were used for feature selection, and model performance was compared across task contexts. SettingAll assessments and recordings were conducted in a sound-attenuated laboratory at MGH Institute of Health Professions. ParticipantsForty-four cognitively healthy adults (19 APOE-{varepsilon}4 carriers, 25 non-carriers), aged 57-79 with no history of neurological and psychiatric conditions. MeasurementsDigitized speech was analyzed for 88 eGeMAPS acoustic features. Random Forest classifiers were trained to distinguish genotypes; model optimization employed GAs and stratified cross-validation. Performance was evaluated using F1 scores and subgroup analyses for sex effects. ResultsRandom Forest classification of spontaneous speech achieved F1 scores above 0.90 for distinguishing APOE-{varepsilon}4 carrier status, outperforming performance on structured tasks. GA-based feature selection consistently improved classification. Accuracy was highest among female participants. The combined speech dataset confirmed the robustness and generalizability of results. ConclusionsAutomated analysis of speech acoustics especially from spontaneous speech, detects APOE-{varepsilon}4 carrier status in asymptomatic adults, supporting speech as a scalable digital biomarker for early Alzheimers risk.

INTRODUCTIONThis retrospective study investigates whether exposition to levodopa/carbidopa (LA/CA) medication is associated with modified Alzheimers disease (AD) trajectories. METHODSMultivariate analysis used cerebrospinal fluid (CSF) biomarker information included in the National Alzheimers Coordinating Center Uniform Data Set for subjects with normal cognition (NC), mild cognitive impairment (MCI) and dementia (DE). Survival analyses examined the progression to MCI/DE and death events. RESULTSLA/CA use is associated with lower levels of CSF amyloid beta, phosphorylated tau (P-tau) and total Tau. After adjusting for age, sex and APOE {varepsilon}4 allele presence, that effect was quantified by negative coefficients of the fitted linear mixed models - P values <0.01 in all cases except for P-tau in the MCI subgroup (P=0.02). No similar effects were identified for other antiparkinsonian drugs. Exposition to LA/CA decreased the progression from MCI to DE (P=0.03). DISCUSSIONThe identified effects of LA/CA exposition on AD biomarkers and progression deserve further investigation in controlled clinical trials.

BackgroundEmerging evidence suggests that microbiota play a role in Alzheimers disease (AD) pathology and cognitive performance. Interventions targeting the oral-brain axis may offer neuroprotective benefits, particularly during the early stages of cognitive impairment. This randomized controlled trial (RCT) investigated whether a multistrain probiotic supplement could modulate AD-related plasma biomarkers and cognitive function in older adults with early cognitive impairment. MethodsParticipants from the Gwangju Alzheimers Disease and Related Dementia (GARD) Cohort in Korea were enrolled in a double-blind, randomized, placebo-controlled trial. Older adults with early cognitive impairment were randomized to receive either a multistrain probiotic supplement (KL-P301) or a placebo for 24 weeks. Plasma pTau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were quantified at baseline and follow-up. Cognitive and clinical assessments included the Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), CERAD neuropsychological battery, Stroop test, and Rey-Osterrieth Complex Figure (ROCF). Treatment effects were analyzed using paired t-tests, linear mixed models, and ANCOVA adjusted for baseline and demographic covariates. ResultsOf the 87 participants analyzed (probiotic, n=40; placebo, n=47), the probiotic group exhibited a significant reduction in plasma pTau181 levels compared with the placebo group (p < 0.001). While GFAP and NfL levels remained stable in the probiotic group, the placebo group showed significant longitudinal increases (p = 0.014 and p = 0.041, respectively). Clinically, the probiotic group demonstrated improved CDR (p = 0.010), primarily driven by the memory domain. Domain-specific cognitive analyses revealed that the probiotic group significantly improved in visuospatial construction (Constructional Praxis, p = 0.036; ROCF copy, p = 0.027) and maintained stable constructional recall, whereas the placebo group showed a significant decline (p = 0.025). No significant between-group differences were observed in MMSE, verbal memory, or executive/attentional functions. ConclusionThe multistrain probiotic supplement reduced tau-related pathology and neuroinflammation-associated biomarkers and selectively preserved visuospatial construction and visual memory in older adults with early cognitive impairment. These findings suggest that modulating the oral-immune-brain axis with multistrain probiotics represents a viable, non-pharmacological strategy to slow AD-related pathological progression and cognitive decline in early-stage patients.

BackgroundAlzheimers disease (AD) is an intractable and multi-factorial neurodegenerative disorder. Given the globally rapid increase in obesity and its role in AD pathogenesis, understanding the impact of body weight, its changes, and the role of physical activity on AD development can provide important guidance for preventative strategies. MethodsThis population-based retrospective cohort study analyzed data from Korean national health and disability databases, including 3,741,424 individuals aged 30 to 80 years at baseline, who underwent health assessments between 2003 and 2006, followed by biennial check-ups over a decade. Exposures included BMI categories (underweight, normal, overweight, obese) and body weight changes (stable, acute increase, steady increase, weight cycling, acute decrease, steady decrease). Regular physical activity was defined as consistent weekly exercise over ten years. The primary outcome was AD incidence, identified by ICD-10 codes F00 or G30. Hazard ratios (HRs) were calculated using Cox proportional hazard models adjusted for multiple risk factors. ResultsBaseline BMI was not significantly associated with AD incidence after adjusting for confounders, except for underweight (adjusted HR [aHR], 1.10, 95% CI, 1.05-1.15). Weight changes were significantly linked to increased AD risk, particularly weight cycling (aHR, 1.37, 95% CI, 1.35-1.40), acute decrease (aHR, 1.78, 95% CI, 1.55-2.03), and steady decrease (aHR, 1.33, 95% CI, 1.30-1.35). Regular physical activity mitigated these risks, nullifying statistical significance. ConclusionWeight changes are significant risk factors for AD, and regular physical activity mitigates these risks. Public health strategies should focus on maintaining stable weight and promoting consistent physical activity. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSPrevious studies assessing the risk of Alzheimers disease (AD) in relation to body weight or body mass index (BMI) have shown inconsistent results, probably due to short periods of follow-up, limited assessment of AD risk factors, and lack of washout periods to exclude the potential reverse causation between weight changes and AD development. What this study addsIn an 18-year cohort study with 3741424 adults in Korea, weight changes significantly impacted the risk of AD, while baseline BMI did not. Both increases and decreases in weight, as well as weight cycling, increased the risk of AD after controlling for AD risk factors. Regular physical activity, defined as at least one exercise per week over the 10-year period, mitigated these risks. How this study might affect research, practice or policyThese findings suggest that maintaining stable body weight and engaging in regular physical activity may be crucial in reducing the risk of AD, emphasizing the need for public health strategies focusing on weight stability and consistent exercise rather than simple correction of body weight.

BackgroundAsparagine (Asn) metabolism is essential for maintaining cellular homeostasis and supporting neuronal energy demands. Recent studies have suggested its dysregulation may contribute to Alzheimers disease (AD) pathogenesis; however, the specific genes and regulatory mechanisms involved remain incompletely understood. MethodsFour publicly available microarray datasets (GSE5281, GSE29378, GSE36980, and GSE138260) were utilized to investigate genes with differential expression between control and AD samples. Asparagine metabolism-related genes (AMGs) were retrieved from the GeneCards database, and their intersection with DEGs yielded candidate asparagine metabolism-related differentially expressed genes (AMG-DEGs). Functional enrichment analysis (Gene Set Enrichment Analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes), protein-protein interaction (PPI) network analysis, and centrality scoring identified hub genes. Regulatory mechanisms were investigated through construction of competing endogenous RNA and transcription factor networks. Potential therapeutic compounds were predicted via drug-gene enrichment and evaluated using molecular docking simulations. ResultsThirty-nine AMG-DEGs were identified and found to be enriched in neurodevelopmental, synaptic transmission, and inflammatory signaling pathways. PPI analysis and centrality screening revealed seven hub genes (HPRT1, GAD2, TUBB3, GFAP, CD44, CCL2, and NFKBIA). Regulatory network analysis highlighted specific miRNAs, long non-coding RNAs, and transcription factors involved in their modulation. Drug screening and docking identified Bathocuproine disulfonate, DL-Mevalonic acid, and Phenethyl isothiocyanate as promising compounds with strong binding affinities to hub proteins. ConclusionThis study comprehensively maps the dysregulation of asparagine metabolism in Alzheimers disease and reveals a set of hub genes and regulatory elements potentially involved in disease progression. The predicted therapeutic compounds provide a foundation for further experimental validation and may contribute to the development of novel metabolism-targeted strategies for AD treatment.

IntroductionSeveral Mendelian randomization studies have been conducted, which identified multiple risk factors for Alzheimers disease (AD). However, they typically focus on a few pre-selected risk factors. MethodsTwo-sample Mendelian randomization (MR) study was used to systematically examine the potential causal associations of 1,054 risk factors/medical conditions and 28 drugs with the risk of late- onset AD. To correct for multiple comparisons, the false discovery rate was set at <0.05. ResultsThere were strong evidence of a causal association between glioma risk, reduced trunk fat-free mass, lower education levels, lower intelligence and a higher risk of AD. For 28 investigated treatments (such as antihypertensive drugs), we found limited evidence for their associations. ConclusionMR found robust evidence of causal associations between glioma, trunk fat-free and AD. Our study also confirms that higher educational attainment and higher intelligence are associated with a reduced risk of AD.

This study evaluated hearing loss (HL) as a potential early indicator of dementia. We analyzed 16,270 participants from the All of Us database (1980 to 2022), including 1,224 (7.5%) with dementia, matched to controls by U.S. census demographics. Severe survey-reported HL showed the strongest association with dementia (odds ratio [OR] 6.76), followed by sensorineural HL (SNHL) (OR 3.90), smoking (OR 1.71), parental HL (OR 1.48), and hypertension (OR 1.48), all p < 0.001. Effect sizes were largest for severe survey-reported HL (1.91) and SNHL (1.36). These findings indicate that severe survey-reported HL and SNHL are strongly associated with dementia.

INTRODUCTIONWe developed a novel polygenic risk score (PRS) based on the A/T/N (amyloid plaques (A), phosphorylated tau tangles (T), and neurodegeneration (N)) framework and compared a PRS based on clinical AD diagnosis to assess which was a better predictor of cognitive decline. METHODSWe used summary statistics from genome wide association studies of cerebrospinal fluid amyloid-{beta} (A{beta}42) and phosphorylated-tau (ptau181), left hippocampal volume (LHIPV), and late-onset AD dementia to calculate PRS for 1181 participants in the Alzheimers Disease Neuroimaging Initiative (ADNI). Individual PRS were averaged to generate a composite A/T/N PRS. We assessed the association of PRS with baseline and longitudinal cognitive composites of executive function and memory. RESULTSThe A/T/N PRS showed superior predictive performance on AD biomarkers and executive function decline compared to the clinical AD PRS. DISCUSSIONResults suggest that integration of genetic risk across AD biomarkers may improve prediction of disease progression. Research in ContextO_ST_ABSSystematic ReviewC_ST_ABSAuthors reviewed relevant literature using PubMed and Google Scholar. Key studies that generated and validated polygenic risk scores (PRS) for clinical and pathologic AD were cited. PRS scores have been increasingly used in the literature but clinical utility continues to be questioned. InterpretationIn the current research landscape concerning PRS clinical utility in the AD space, there is room for model improvement and our hypothesis was that a PRS with integrated risk for AD biomarkers could yield a better model for cognitive decline. Future DirectionsThis study serves as proof-of-concept that encourages future study of integrated PRS across disease markers and utility in taking an A/T/N (amyloidosis, tauopathy and neurodegeneration) focused approach to genetic risk for cognitive decline and AD.

BackgroundAlzheimers disease (AD) is a complex neurodegenerative disorder which is multifactorial in nature. Some of its characteristics are slow cognitive decline, memory problems and behavioral changes. AD patient brains show a progressive synaptic toxicity, autophagy, neuroinflammation, excess generation of reactive oxygen species (ROS), neuronal death and oxidative stress, which occurs due to disrupted metal homeostasis along with tau and amyloid-{beta} protein deposition. Notably, lipid peroxidation, iron buildup and elevated oxidative stress in AD brains suggest a possible molecular connection between ferroptosis and AD neurodegeneration. MethodsThis study explores the genetic and bioinformatics perspective on the relationship between ferroptosis and AD aiming to identify potential therapeutic biomarkers using Neural network (NN) and Machine learning models. Six ferroptosis related genes were found to be differentially expressed in AD. Further machine learning analysis shortlisted four key biomarker genes. An NN-based diagnostic prediction model was developed and validated using AUC-ROC anaysis, which gave high diagnostic values (AUC-0.92) in the analysis. ResultsThe findings highlight a strong correlation between ferroptosis and altered metabolic functions in AD. miRNA-gene interaction analysis revealed that two biomarker genes, CYBB and ACSL4 can be regulated by several regulatory miRNAs i.e., hsa-miR-146-5p, hsa-miR-106b-5p, hsa-miR-223-3p, hsa-miR-155-5p, hsa-miR-34a-5p, hsa-miR-125b-5p and hsa-miR-27a-3p suggesting their potential as early diagnostic biomarkers. Immune microenvironment analysis revealed strong neuroinflammatory responses were in AD with increased infiltration of macrophages (M0, M1 and M2), monocytes and multiple T cell subsets. This heightened immune activity may be driven by ferroptosis-induced oxidative stress, contributing to neuronal death. Furthermore, druggability of these targets was evaluated and several drugs were identified that may be potentially repurposed for therapeutic intervention in AD pathogenesis. ConclusionThis study presents a diagnostic predictive model integrating gene expression, miRNA regulation and immune infiltration analysis, offering a novel perspective on early AD detection. The identified ferroptosis-related biomarkers and regulatory miRNAs could serve as valuable tools for clinical diagnosis and targeted therapeutic intervention, advancing personalized treatment strategies for Alzheimers disease.