Research into the genetic and epigenetic factors influencing Alzheimer's disease (AD) has revealed significant insights into its complex etiology. A study integrating single-cell epigenomic and transcriptomic profiles from 3.5 million cells across 384 postmortem brain samples identified over 1 million candidate cis-regulatory elements (cCREs) organized into 123 regulatory modules across 67 cell subtypes, highlighting the intricate epigenetic rewiring associated with AD progression and cognitive resilience (ref: Liu doi.org/10.1016/j.cell.2025.06.031/). Additionally, the interplay between genetic predisposition, plasma metabolome, and dietary factors was examined in a large cohort, revealing that the associations of 57 metabolites with dementia risk varied significantly by APOE4 genotype, emphasizing the importance of personalized approaches in understanding AD risk (ref: Liu doi.org/10.1038/s41591-025-03891-5/). Furthermore, the protective APOE-Christchurch variant was shown to suppress microglial responses and enhance clearance of pathological tau aggregates, suggesting a potential therapeutic target for mitigating AD pathology (ref: Akay doi.org/10.1016/j.immuni.2025.07.019/). These findings collectively underscore the multifaceted genetic landscape of AD and the potential for targeted interventions based on genetic profiles. However, the identification of high-throughput methods for screening tau aggregation remains a critical area for future research, as current probes lack the ability to discriminate between amyloid fibril polymorphs (ref: Carroll doi.org/10.1038/s41557-025-01889-7/).

The exploration of biomarkers for Alzheimer's disease has gained momentum, particularly focusing on plasma phosphorylated tau (p-tau) as a diagnostic tool. A systematic review and meta-analysis demonstrated that plasma p-tau205 exhibited a sensitivity of 76.76% and specificity of 86.70% for identifying biologically defined AD, with an area under the receiver operating characteristic curve (AUROC) of 85.71% (ref: Therriault doi.org/10.1016/S1474-4422(25)00227-3/). This highlights the potential of p-tau biomarkers to transform clinical management by providing accessible diagnostic options. Additionally, a study measuring various tau peptides in plasma across independent cohorts proposed a blood biomarker-based staging system for AD, which could enhance diagnosis and prognosis (ref: Montoliu-Gaya doi.org/10.1038/s43587-025-00951-w/). Concurrently, research indicated that changes in plasma p-tau217 levels correlated with cognitive decline in preclinical AD, suggesting that these biomarkers could serve as indicators of disease progression (ref: Insel doi.org/10.1001/jamaneurol.2025.2974/). However, the role of chronic inflammation, as evidenced by Toxoplasma gondii infection driving cognitive deficits through IL-1 signaling, adds complexity to the interpretation of biomarkers in the context of neuroinflammation (ref: Belloy doi.org/10.1038/s41593-025-02041-x/).

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease, with recent studies elucidating various mechanisms involved. Midkine (MDK), a protein upregulated in AD brains, was found to attenuate amyloid-beta fibril assembly and plaque formation in mouse models, suggesting its potential as a therapeutic target (ref: Zaman doi.org/10.1038/s41594-025-01657-8/). Additionally, RABGAP1 was identified as a crucial sensor facilitating the sorting and processing of amyloid precursor protein, highlighting the importance of protein trafficking in AD progression (ref: Eden doi.org/10.1038/s44318-025-00530-0/). The contribution of peripheral monocytes to neuroinflammation was further explored using human cortical organoid microphysiological systems, revealing their significant role in AD pathogenesis (ref: Tian doi.org/10.1126/sciadv.adu2708/). Moreover, the NMDAR/TRPM4 death complex was implicated in promoting disease progression in mouse models, linking glutamate signaling to neurodegeneration (ref: Yan doi.org/10.1038/s41380-025-03143-5/). These findings collectively underscore the intricate interplay between neuroinflammation and AD pathology, suggesting that targeting immune responses may offer novel therapeutic avenues.

The investigation of amyloid and tau pathology remains central to understanding Alzheimer's disease. Recent advancements include the development of a transferrin receptor-targeted anti-amyloid antibody that enhances brain delivery and mitigates amyloid-related imaging abnormalities (ARIA), addressing a significant safety concern in anti-amyloid therapies (ref: Pizzo doi.org/10.1126/science.ads3204/). Furthermore, the discovery of high-throughput fluoroprobes capable of recognizing distinct amyloid fibril polymorphs marks a significant step forward in studying tau aggregation, which is critical for understanding neurodegenerative tauopathies (ref: Carroll doi.org/10.1038/s41557-025-01889-7/). Research also identified genetic mutations in microglial genes, such as MS4A6A, that correlate with altered AD risk and increased beta-amyloid levels in cerebrospinal fluid, emphasizing the role of microglial function in AD pathology (ref: Jiao doi.org/10.1186/s13024-025-00887-0/). Moreover, early intervention with anti-Aβ immunotherapy demonstrated a robust reduction in amyloid plaque pathology and microglial activation, suggesting that timely therapeutic strategies could significantly alter disease progression (ref: de Weerd doi.org/10.1186/s13024-025-00878-1/). Collectively, these studies highlight the critical need for targeted therapies that address both amyloid and tau pathologies in the pursuit of effective AD treatments.

Cognitive function and behavioral changes in Alzheimer's disease have been the focus of several recent studies, revealing important associations with various factors. A study examining menstrual cycle irregularities in premenopausal women found that long and irregular cycles were linked to a greater risk of premature mortality, suggesting that hormonal factors may influence cognitive health (ref: Heller doi.org/10.1038/s41591-025-03879-1/). Additionally, sex differences in mortality and healthcare utilization post-dementia diagnosis were highlighted, with male patients showing a higher hazard of death and hospitalization, indicating a need for tailored healthcare strategies for different sexes (ref: Lusk doi.org/10.1001/jamaneurol.2025.2236/). Furthermore, research on lipoprotein(a) levels across large cohorts found no significant association with the risk of Alzheimer's or vascular-related dementia, challenging previous assumptions about lipid profiles and cognitive decline (ref: Thomas doi.org/10.1093/eurheartj/). The potential of human pluripotent stem cell-derived pericytes for neuroprotection and vascular repair in AD was also explored, demonstrating promising therapeutic avenues through extracellular vesicle mechanisms (ref: Liu doi.org/10.1016/j.ymthe.2025.08.024/). These findings collectively emphasize the multifactorial nature of cognitive decline in AD and the importance of considering diverse biological and environmental influences.

Therapeutic approaches for Alzheimer's disease are evolving, with recent studies focusing on innovative strategies to address the underlying pathophysiology. One study identified significant transcriptional changes in ex vivo human microglia associated with various AD phenotypes, suggesting that targeting microglial function could be a viable therapeutic strategy (ref: Kosoy doi.org/10.1038/s41593-025-02020-2/). Additionally, a phase 2 trial evaluated the safety and efficacy of rotigotine in patients with frontotemporal dementia, demonstrating the importance of exploring pharmacological interventions beyond traditional AD therapies (ref: Koch doi.org/10.1016/j.lanepe.2025.101409/). The role of innate immune cell variations in relation to epigenetic clocks and health outcomes was also investigated, indicating that understanding immune system heterogeneity could inform therapeutic strategies (ref: Guo doi.org/10.1002/advs.202505922/). Moreover, the spreading of MAPT/Tau pathology was linked to neurodegeneration, emphasizing the need for therapies targeting tau aggregation and its cellular pathways (ref: Sandhof doi.org/10.1080/15548627.2025.2551676/). These studies collectively highlight the potential for novel therapeutic interventions that address both the immune response and the molecular underpinnings of AD.

Environmental and lifestyle factors are increasingly recognized for their role in Alzheimer's disease risk and progression. A study examining the interplay of genetic predisposition, plasma metabolome, and dietary habits found that associations between metabolites and dementia risk varied significantly by APOE4 genotype, underscoring the importance of personalized dietary interventions (ref: Liu doi.org/10.1038/s41591-025-03891-5/). Conversely, a large cohort analysis revealed that lipoprotein(a) levels did not correlate with the risk of Alzheimer's or vascular-related dementia, challenging the notion that lipid profiles are significant risk factors (ref: Thomas doi.org/10.1093/eurheartj/). Additionally, research on early intervention with anti-Aβ immunotherapy demonstrated a reduction in microglial activation and amyloid plaque pathology, suggesting that lifestyle factors influencing inflammation may also impact disease progression (ref: de Weerd doi.org/10.1186/s13024-025-00878-1/). Furthermore, variations in innate immune cell subtypes were found to correlate with epigenetic clocks and health outcomes, indicating that lifestyle factors affecting immune function could influence cognitive health (ref: Guo doi.org/10.1002/advs.202505922/). These findings collectively highlight the multifaceted nature of Alzheimer's disease, emphasizing the need for comprehensive approaches that integrate genetic, environmental, and lifestyle factors.

The relationship between neurodegeneration, aging, and Alzheimer's disease is a critical area of research, with studies revealing significant insights into shared risk factors and biological mechanisms. A randomized controlled trial demonstrated that genetic scores for Alzheimer's and cardiovascular disease were associated with cognitive changes, indicating that shared genetic risk factors may influence cognitive decline in aging populations (ref: Saadmaan doi.org/10.1093/brain/). Furthermore, the role of ribosome-associated quality control in counteracting aging and age-associated pathologies was explored, revealing that defects in this process could contribute to neurodegeneration (ref: Lee doi.org/10.1073/pnas.2505217122/). The therapeutic potential of intravenously injected human pluripotent stem cell-derived pericytes for neuroprotection and vascular repair was also investigated, highlighting innovative approaches to mitigate age-related cognitive decline (ref: Liu doi.org/10.1016/j.ymthe.2025.08.024/). Additionally, variations in innate immune cell subtypes were shown to correlate with epigenetic clocks and health outcomes, suggesting that understanding immune system dynamics could provide insights into aging and neurodegeneration (ref: Guo doi.org/10.1002/advs.202505922/). Collectively, these studies underscore the importance of addressing both aging and neurodegenerative processes in the quest for effective Alzheimer's disease interventions.