Monoclonal antibodies targeting amyloid-β, i.e., lecanemab and donanemab, have recently been approved for treating early Alzheimer’s disease (AD). Though these antibodies are by many considered milestones in AD therapy, clinical approvals have been inconsistent due to ongoing debates over their clinical benefit and safety. The reported cognitive decline slowing is modest and often below the thresholds for clinically significant differences on outcome scales. Moreover, these therapies are linked to adverse effects, including infusion reactions, headaches, and nausea, as well as more serious issues like amyloid-related imaging abnormalities (ARIAs), the long-term impact of which remains unclear.In this Viewpoint article, we highlight three safety concerns: ARIAs, accelerated brain volume loss, and therapy-related deaths. ARIAs occur much more frequently in treated AD patients than in placebo groups, yet their functional consequences remain poorly understood. Evidence also suggests that treatment with anti-amyloid antibodies may lead to more brain tissue loss than placebo treatments, though this has received limited attention in trials and regulatory evaluations. Finally, reliable data on therapy-related mortality is scarce due to insufficient access to detailed clinical and neuropathological information.These issues underscore significant uncertainties in assessing the risk-benefit profile of anti-amyloid therapies. A more systematic investigation—including routine brain volume monitoring, functional PET imaging, and independent death evaluations—is crucial for a comprehensive understanding of both benefits and risks in regulatory and clinical decisions.

Alzheimer’s disease (AD) is a leading form of dementia, marked by complex neuropathological features such as amyloid-β (Aβ) plaques and tau tangles. Recent research highlights the significant role of unmethylated cytosine–phosphate–guanine (CpG) motifs, short DNA sequences where a cytosine nucleotide is directly followed by a guanine nucleotide, linked by a phosphate group, in the disease’s development. CpG motifs, predominantly found in bacterial and mitochondrial DNA, can provoke immune responses when they appear in unexpected contexts. This review explores the intricate relationship between unmethylated CpG DNA and AD pathogenesis, investigating the mechanisms by which bacterial DNA enters the brain, activates immune pathways, and contributes to the progression of Alzheimer’s disease. Understanding these processes may offer new avenues for research and therapeutic intervention in AD.

BackgroundThe retrosplenial cortex (RSC) is a cortical area that functions as a key component of the core network of brain regions involved in cognitive functions such as episodic memory, navigation, and planning. The RSC is capable of theta rhythm generation and, like the hippocampus, could be compromised in neurological diseases such as Alzheimer's disease (AD). Importantly, detecting early changes in RSC of transgenic animals could be translated into non-invasive biomarkers that can detect preclinical stages of AD and related dementias.ObjectiveOur aim in the present study was to evaluate molecular and functional alterations in the RSC of very young 3xTg-AD mice (1-month-old).MethodsImmunohistochemistry, anterograde viral tracer using an adeno-associated virus, western blotting, and electrophysiology were all carried out.ResultsOur results show significant accumulation of intracellular amyloid-β (Aβ) and hyperphosphorylated tau (pTau) in principal neurons from 1-month-old 3xTg-AD mice, which correlates with GSK3β activation and tau phosphorylation at serine 396. Coincidentally, oscillatory activity from the RSC is altered in the young 3xTg-AD mice. Specifically, we found that theta frequency is significantly higher in the transgenic animals.ConclusionsIn summary, our results suggest that the early accumulation of intracellular Aβ may affect the excitability of the RSC network, possibly due to changes in pTau resulting from GSK3β activation.

OBJECTIVE:The LATTICE pilot randomized clinical trial found no statistically significant effect of low-dose lithium on 6 coprimary outcomes in mild cognitive impairment (MCI). We aimed to re-express these results in Bayesian terms and estimate the probability of benefit, negligible difference, or harm across cognitive, neuroimaging, biomarker, and safety outcomes. METHODS:We conducted a Bayesian reanalysis of published aggregate data from LATTICE, a single-site, randomized, double-blind, placebo-controlled 2-year trial of low-dose lithium carbonate versus placebo. The trial randomized 83 older adults with MCI, of whom 80 initiated treatment. Outcomes included verbal and visuospatial delayed recall, Preclinical Alzheimer Cognitive Composite, hippocampal and cortical volume measures, brain-derived neurotrophic factor, and serious adverse events. Posterior means, 95% credible intervals (CrI), and posterior probabilities were estimated using weakly informative priors. RESULTS:Lithium was associated with a posterior mean standardized effect of 0.38 SD for CVLT-II delayed recall (95% CrI, -0.03 to 0.80), corresponding to a 96.5% probability of benefit and an 80.6% probability of exceeding 0.20 SD. The raw between-group difference was 1.47 points (95% CrI, 0.18-2.75). Bayesian re-expression of the intention-to-treat model showed an annualized CVLT-II treatment-by-time effect of 0.69 points per year (95% CrI, 0.02-1.35). BVMT-R remained near null. Hippocampal outcomes were directionally favorable but imprecise. Other cognitive, biomarker, imaging, and safety outcomes showed no robust signal. CONCLUSIONS:This Bayesian reanalysis supports an inconclusive interpretation of LATTICE, while identifying a probabilistic signal for verbal delayed recall-not seen in the other outcomes-that warrants testing in adequately powered trials.

OBJECTIVE:Agitation and related neuropsychiatric symptoms are common in Alzheimer's disease (AD) and contribute to caregiver burden, functional decline, and institutionalization. Cannabinoid-based therapies have been investigated as potential symptomatic interventions, but evidence remains limited by small trials, heterogeneous formulations, and variable outcome reporting. We aimed to evaluate the efficacy, cognitive outcomes, and safety of cannabinoid-based therapies in AD. METHODS:This systematic review and meta-analysis were prospectively registered in PROSPERO and conducted following PRISMA 2020 guidelines. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched through April 2025 for randomized placebo-controlled trials evaluating cannabinoid-based therapies for agitation or neuropsychiatric symptoms in AD. One nonrandomized open-label study was retained as supplementary evidence for sensitivity analyses. Primary efficacy analyses were restricted to randomized between-group contrasts. Outcomes included Neuropsychiatric Inventory (NPI) total score, Cohen-Mansfield Agitation Inventory-Short Form (CMAI-SF), NPI agitation/aggression, Mini-Mental State Examination (MMSE), and safety outcomes. Random-effects meta-analyses were complemented by Bayesian models and Trial Sequential Analysis. RESULTS:Seven studies met the inclusion criteria, including six randomized trials and one open-label prospective cohort, with 221 participants enrolled. Cannabinoid-based therapies showed lower neuropsychiatric symptom and agitation scores than placebo in randomized between-group analyses: NPI total score (standardized mean difference [SMD], -0.31; 95% confidence intervals [CI], -0.47 to -0.15; k = 4), CMAI-SF (SMD, -0.40; 95% CI, -0.69 to -0.10; k = 3), and NPI agitation/aggression (SMD, -0.47; 95% CI, -0.69 to -0.25; k = 3). Bayesian posterior probabilities for lower symptom scores exceeded 95%. MMSE findings did not support a consistent cognitive benefit. Somnolence was the principal safety signal (risk ratios, 2.25; 95% CI, 1.43-3.54), with Trial Sequential Analysis suggesting sufficient accrued information for this outcome. Falls and fatigue were imprecisely estimated. CONCLUSIONS:Cannabinoid-based therapies showed lower agitation and neuropsychiatric symptom scores than placebo in AD, with somnolence as the main safety concern. Interpretation remains limited by few trials, heterogeneous formulations and outcome instruments, short follow-up, and concentrated statistical weight. Larger randomized trials with formulation-specific protocols, longer follow-up, active comparators, and systematic safety monitoring are needed.

INTRODUCTION: Alzheimer's disease (AD) progresses over decades, yet plasma biomarkers that resolve disease stage rather than simply detect disease remain scarce. This distinction is clinically consequential because effective AD intervention depends on identifying patients before disease biology has progressed beyond a therapeutically responsive stage. METHODS: We used small-molecule-modulated protein corona proteomics to profile plasma from 90 individuals in the Australian Imaging, Biomarker and Lifestyle cohort, stratified by Centiloid (CL) Aβ-amyloid burden (30 amyloid-negative, CL < 15; 30 moderate-to-high, CL 26 to 100; 30 very high, CL > 100). We quantified 3,176 proteins and applied differential abundance and actual causality analyses to identify stage-specific and candidate causal proteins. RESULTS: Differential protein abundance was exclusively captured during the moderate-to-high AD transition, revealing a discrete proteomic "switch." The switch was marked by accumulation of the autophagy receptor CALCOCO1, together with coordinated depletion of the S100A8/S100A9 calprotectin complex and core erythroid-cytoskeletal network structural markers (e.g., SPTA1, SPTB, ANK1). Adhesion G protein-coupled receptor G6 (ADGRG6) showed a significant moderate positive monotonic association with absolute CL burden, providing a proportional molecular anchor for cumulative disease burden. Actual causality analysis identified COL6A2, FOXRED2, P3H1, PRR4, and GOLGA5 as candidate upstream drivers linking matrix remodeling, Golgi trafficking, and collagen processing to AD progression. DISCUSSION: These findings suggest a candidate blood-accessible framework for staging AD by active disease biology, which, if replicated in independent cohorts, may have implications for therapeutic selection and mechanism-guided clinical trials.

BACKGROUND:Glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in managing type 2 diabetes mellitus (T2DM) and provide metabolic and cardiovascular benefits. Their associations with neurocognitive outcomes in clinical populations remain uncertain. METHODS:We conducted a retrospective, population-based cohort study using de-identified electronic health records from the global TriNetX research network, predominantly comprising U.S.-based healthcare organizations. Adults with T2DM who initiated tirzepatide or semaglutide were included. Propensity score matching (1:1) was applied to balance baseline characteristics, including age, sex, race, and cardiometabolic and psychiatric comorbidities. Incident diagnoses of mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD) occurring at least 12 months after treatment initiation were assessed using risk ratios (RRs) and time-to-event analyses with Kaplan-Meier estimators. FINDINGS:A total of 290,606 patients initiated semaglutide and 44,471 initiated tirzepatide. After propensity score matching, each group included 44,470 patients. Compared with semaglutide, initiation of tirzepatide was associated with a lower risk of MCI (RR 0.12; 95% CI 0.06-0.22), dementia (RR 0.15; 95% CI 0.09-0.26), and AD (RR 0.48; 95% CI 0.22-1.01). Absolute risks were low for all outcomes, and separation of survival curves was more consistent for MCI than for dementia or AD. INTERPRETATION:In this real-world observational analysis of adults with T2DM, initiation of tirzepatide was associated with a lower incidence of MCI compared with semaglutide, whereas associations for dementia and AD were less consistent. These findings should be interpreted descriptively and as hypothesis-generating. Prospective randomized trials with longer follow-up and systematic neurocognitive assessment are needed to clarify whether, and under which conditions, incretin-based therapies influence neurocognitive outcomes.

Alzheimer's disease (AD) is a major neurodegenerative disorder affecting more than 7 million Americans. Extensive studies have identified various factors associated with the development of AD, but the actual cause remains unknown. Transgenic mouse model and human studies strongly indicate that oxidative stress precedes amyloid-β plaque formation and tau phosphorylation in AD. GSH loss itself raises the Abeta42/Abeta40 ratio and promotes tau aggregation [5], placing GSH depletion upstream of classical AD pathology. Subsequently, the role of the master antioxidant, glutathione (GSH), came into focus for brain GSH level enrichment through supplementation with γ-glutamylcysteine (GGC), the immediate precursor of GSH. We present that GGC has an excellent safety record and bioavailability. GGC is a strong candidate to investigate for brain GSH enrichment (target engagement hippocampus, anterior cingulate cortex etc.) and subsequent cognitive enhancement for patients with mild cognitive impairment (MCI).

Gabapentinoids, particularly gabapentin and pregabalin, are widely prescribed for neuropathic pain and other chronic conditions, including in populations at risk for cognitive decline. Their long-term cognitive safety and potential association with Alzheimer’s disease and related dementias (ADRD) remain uncertain. We examined whether gabapentinoid use is associated with ADRD risk and assessed between-study heterogeneity and potential study-level modifiers. PubMed, Embase, and the Cochrane Library were searched from inception through November 2025. We included observational studies comparing gabapentinoid users with non-users or non-gabapentinoid comparators and reporting incident ADRD. Risk of bias was assessed using ROBINS-E. A random-effects meta-analysis was performed using odds ratios. Subgroup and meta-regression analyses explored study-level modifiers. Certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). The protocol was registered in PROSPERO (CRD420251240055). Five observational studies (325,245 participants) were included. Gabapentinoid use was associated with modestly higher estimated odds of ADRD (odds ratio, 1.28; 95

BACKGROUND:Alzheimer's disease (AD) is the most prevalent cause of dementia and has been closely linked to βSupplemental data for this article can be accessed online at ht tps://doi.org/-amyloid accumulation. However, the efficacy and safety of anti-β-amyloid monoclonal antibodies remain debated. METHODS:We systematically searched PubMed, Embase, and Cochrane databases for RCTs comparing anti-β-amyloid monoclonal antibodies with placebo in early-stage AD. Eligible trials enrolled participants with biomarker-supported AD and reported global, cognitive, or safety outcomes, including the CDR-SB, ADAS-Cog 13/14, ARIA, and brain volumetric measures. RESULTS:Six RCTs including 7837 participants were analyzed. Mean age ranged from 69.8 to 75.4 years, and 57.4% were APOE ε4 carriers. Anti-β-amyloid therapy was associated with small differences in global and cognitive outcomes, best described as a modest slowing of decline on the CDR-SB and ADAS-Cog scales. Treatment was associated with increased risks of ARIA-E (RR, 9.40; 95% CI, 6.98-12.66) and ARIA-H (RR, 2.40; 95% CI, 2.08-2.78), as well as greater ventricular enlargement and hippocampal atrophy. CONCLUSION:In early AD, anti-β-amyloid monoclonal antibodies are associated with modest slowing of decline accompanied by increased ARIA risk and unfavorable structural brain changes, limiting clinical applicability. PROTOCOL REGISTRATION:www.crd.york.ac.uk/prospero identifier is CRD420251071393.

Sensory decline is a common feature of aging and an early sign of a high risk of developing neurodegenerative diseases. Abnormal protein deposits of tau are also observed in sensorial areas in early stages of Alzheimer’s disease and related dementia (ADRD), indicating that these two features are associated with common neuropathological changes in the affected brain areas. Alterations in taste and smell are evident in subjects with cognitive decline, but sensory decline is perceived in olfaction, vision, hearing (at early times of degeneration), and even touch, which correlates with disease progression. Consequently, affected individuals may suffer from varying altered behaviors that emerge from the declined capability to process and perceive information, suggesting that differences in sensory perception of the environment may play a key role in explaining these behavioral variations in subjects with cognitive impairment. This commentary discusses some of the alterations in sensory functionality and how these could contribute to the development of neurodegenerative disorders, such as ADRD.

Abstract Industrialization has been identified as the single biggest factor driving global microbiome diversity. While many studies examining gut microbiomes attribute these shifts to dietary increases in fat and reductions in protein, oral microbiome responses to industrialization remains debated. The oral microbiome is more resilient due to long-standing coevolution with host tissues and biofilm stability. However, limited geographic and historical representation has constrained our understanding of how these transitions unfolded globally in the oral microbiomes. Here, we investigate oral microbiome variation in Batwa rainforest hunter-gatherers and neighboring Bakiga subsistence farmers from southwestern Uganda, comparing them with publicly available data from Tanzanian, Venezuelan, and industrialized populations from North America, Europe, and Australia. Using 16S rRNA gene sequencing, we characterized salivary microbiota and evaluated differences in local and global diversity, composition, and differential abundance. Ugandan populations contained significant compositional differences but similar levels of diversity, suggesting that shared environments and dietary overlap may shape microbial assemblages despite distinct cultural histories. Globally, strong continental and industrialization effects were observed in the oral microbiome, with all industrial populations clustering separately from people living in other locations. African populations also clustered separately from non-African groups. Oral microbiome diversity was highest in Ugandan individuals and lowest in industrialized populations, mirroring patterns previously observed in the gut microbiome. Together, these findings demonstrate that both geography and subsistence strategy structure global oral microbiome variation. They also clarify the position that oral microbial communities record biocultural transitions and highlight the need to better understand the industrial mechanisms that shape microbial diversity in the oral cavity.

We propose five recommendations to make AI-based research studies more suitable for a clinical readership. First, authors should justify the added value of complex and potentially more opaque AI approaches. Second, rigorous description of input data, diagnostic criteria, and preprocessing is essential to avoid biased or clinically irrelevant outcomes. Third, benchmarking against clinically relevant performance thresholds should be established a priori. Fourth, method sections should combine an accessible lay summary with detailed technical supplement. Fifth, model explainability is encouraged to mitigate opacity. These recommendations aim to support AI research that is methodologically robust and interpretable for AD researchers.

BACKGROUND:Whether low-dose lithium lowers dementia incidence in older adults, relative to an active comparator, is unestablished in real-world data. We compared incident dementia in older adults receiving low-dose lithium versus valproate using a target trial emulation of multicenter electronic health record data. METHODS:Adults aged ≥60 years receiving lithium carbonate (all serum measurements ≤0.40 mmol/L) or valproate between 2015 and 2025 in the TriNetX network, free of prior dementia, mild cognitive impairment, bipolar disorder, Parkinson's disease, or related neurological conditions, were eligible. Cohorts were balanced by 1:1 propensity score matching on 23 covariates. The primary outcome was incident all-cause dementia at 730 days; secondary outcomes were mortality and hospitalization. Cause-specific hazard ratios (HRs), Aalen-Johansen cumulative incidence, and an E-value were computed, with prespecified sensitivity analyses. RESULTS:After matching, 853 patients per cohort remained (all standardized mean differences <0.10). All-cause dementia occurred in 25/795 (3.1%) lithium versus 69/832 (8.3%) valproate users (HR, 0.38; 95% CI, 0.24-0.60; P < .001). Mortality was lower with lithium (HR, 0.56; 95% CI, 0.39-0.80), whereas hospitalization did not differ (HR, 0.81; 95% CI, 0.58-1.13). The E-value was 4.69 (2.71 for the upper bound). Sensitivity analyses (90-day lag, 0.36; 180-day lag, 0.40; non-AD subtype, 0.23; 3-year follow-up, 0.47) were directionally consistent. CONCLUSION:Low-dose lithium was associated with a lower observed incidence of dementia diagnoses than valproate. These observational findings cannot distinguish a direct effect from prescribing or surveillance bias, depletion of susceptibles, or differential healthcare engagement; they are hypothesis-generating, and randomized trials are required before causal interpretation.

Neurobiobanks focused on the study of major cognitive impairment constitute a strategic infrastructure for translational research and personalized medicine in the neurosciences. In Mexico and the Dominican Republic, the National Dementia Biobank (BND) at the Universidad Politécnica de Pachuca and the National Brain Bank at the Universidad Nacional Pedro Henríquez Ureña (BNC-UNPHU) have developed integrated mechanisms for the collection, processing, and preservation of human brain tissue, as well as other tissues such as kidney, liver, intestine, pancreas, and skin, intended exclusively for biomedical research. Both institutions share research lines centered on the molecular pathological study of the tau protein and the amyloid-β peptide, key markers of Alzheimer's disease and other dementias. Protocols for immunohistochemistry, silver staining, single and multiple immunofluorescences, as well as staining with fluorochromes such as thiazine red and thioflavin-S, have been standardized for the precise detection of neuropathological lesions. Transgenic animal models, including the triple transgenic mouse with mutations in presenilin-1, amyloid-β protein precursor, and tau, have served as complementary tools to dissect the temporal sequence of protein aggregation. In parallel, both institutions have implemented sustained scientific outreach programs, including a traveling museum of neurodegenerative diseases, Brain Awareness Week, Alzheimer's fairs, and media campaigns, aimed at reducing stigma, promoting altruistic tissue donation, and building public trust. Collectively, these neurobiobanks represent an emerging model of research contextualized within Latin American populations, with the potential to integrate into regional and international networks that contribute to reducing knowledge gaps in neurodegeneration.

Purpose Epilepsy and early-onset Alzheimer disease (AD) are both common in adults with Down syndrome (DS), and their temporal relationship remains unclear. We examined whether a recorded diagnosis of epilepsy was associated with higher subsequent recording of all-cause dementia, AD, non-Alzheimer dementia, and mortality among adults with DS aged 40 years or older. Methods Retrospective cohort study using deidentified electronic health records from the TriNetX Global Collaborative Network. Adults with DS (ICD-10-CM Q90; age ≥40 years; 2010–2025) were classified as having epilepsy (G40 recorded before any dementia code) or not; secondary seizures were excluded. Cohorts were balanced by 1:1 propensity score matching. Outcomes were assessed from 90 to 730 days after the index date using hazard ratios (HRs) and Kaplan-Meier analyses. Results After matching, 1,812 patients per cohort were retained (mean [SD] age, 54.3 [7.0] vs 54.2 [7.4] years). Epilepsy was associated with higher subsequent recording of all-cause dementia (12.9% vs 6.5%; HR, 2.03 [95% CI, 1.59–2.60]), AD (6.1% vs 3.2%; HR, 1.97 [1.41–2.76]), non-Alzheimer dementia (12.9% vs 6.3%; HR, 2.08 [1.63–2.65]), and mortality (12.8% vs 5.1%; HR, 2.55 [2.00–3.24]). Estimates were similar by age and sex, and when exposure required an antiseizure medication prescription alongside the diagnostic code. Conclusion Epilepsy was associated with higher subsequent recording of dementia and mortality over 2 years. No biomarker, neuroimaging, or neuropathological measure was available; the estimates describe the order in which diagnoses were documented and do not establish that epilepsy marks the underlying neurodegenerative process. Differential ascertainment and residual confounding remain plausible contributors.