Recent studies have significantly advanced our understanding of amyloid-beta (Aβ) and tau pathology in Alzheimer's disease (AD). One notable study utilized focused ultrasound to temporarily open the blood-brain barrier during aducanumab infusions, resulting in a greater reduction of Aβ in treated regions compared to untreated areas (ref: Rezai doi.org/10.1056/NEJMoa2308719/). In a different context, Banerjee et al. provided compelling evidence of iatrogenic Alzheimer's disease through the transmission of Aβ pathology in individuals treated with contaminated growth hormone, highlighting the role of Aβ in disease etiology (ref: Banerjee doi.org/10.1038/s41591-023-02729-2/). Furthermore, the relationship between APOE4 genotype and aging was explored by Millet et al., who identified an exhausted-like microglial state in aged APOE4 carriers, suggesting a link between genetic risk factors and neuroinflammatory responses (ref: Millet doi.org/10.1016/j.immuni.2023.12.001/). This is complemented by findings from Tijms et al., who characterized molecular subtypes of AD using cerebrospinal fluid (CSF) proteomics, revealing distinct genetic risk profiles associated with Aβ and tau pathology (ref: Tijms doi.org/10.1038/s43587-023-00550-7/). Overall, these studies underscore the complex interplay between amyloid and tau pathologies and their implications for diagnostic and therapeutic strategies in AD.

Microglial responses and neuroinflammation are critical components in the pathophysiology of Alzheimer's disease. Tagliatti et al. demonstrated that Trem2 expression in microglia is essential for maintaining neuronal bioenergetics during development, indicating a pivotal role for microglial genes in neuronal health (ref: Tagliatti doi.org/10.1016/j.immuni.2023.12.002/). This is further supported by findings from Cadiz et al., who observed that aducanumab treatment not only reduced Aβ levels but also induced significant microglial activation and a pro-phagocytic transcriptomic signature, suggesting that microglia play a crucial role in the therapeutic response to anti-amyloid therapies (ref: Cadiz doi.org/10.1084/jem.20231363/). Additionally, Yu et al. highlighted the unique profile of microglia at sites of retinal degeneration, emphasizing the role of galectin-3 and Trem2 in modulating neuroinflammatory responses (ref: Yu doi.org/10.1084/jem.20231011/). These findings collectively illustrate the importance of microglial function and neuroinflammation in both the progression of Alzheimer's disease and the response to therapeutic interventions.

The identification of biomarkers for early diagnosis and staging of Alzheimer's disease has seen significant advancements. Tao et al. conducted a large-scale proteomic profiling of CSF and serum, identifying numerous potential biomarkers that could differentiate mild cognitive impairment due to AD from normal cognition, achieving high accuracy with machine learning models (ref: Tao doi.org/10.1016/j.xinn.2023.100544/). Similarly, Ashton et al. evaluated the diagnostic accuracy of a plasma phosphorylated tau 217 immunoassay, demonstrating its utility in detecting AD pathology and establishing reference ranges for abnormal amyloid and tau levels (ref: Ashton doi.org/10.1001/jamaneurol.2023.5319/). Furthermore, the importance of cerebrospinal fluid collection protocols was underscored by Algeciras-Schimnich et al., who highlighted how variations in collection methods could impact diagnostic accuracy (ref: Algeciras-Schimnich doi.org/10.1002/alz.13721/). These studies collectively emphasize the critical role of biomarkers in enhancing diagnostic precision and facilitating early intervention in Alzheimer's disease.

Genetic and proteomic research has provided valuable insights into the mechanisms underlying Alzheimer's disease. The role of the APOE4 allele in disease progression was explored by Li et al., who identified a conserved exhausted-like microglial state in aged APOE4 carriers, linking genetic risk to neuroinflammatory changes (ref: Li doi.org/10.1016/j.immuni.2023.12.015/). Strickland et al. further investigated the structural properties of apolipoprotein E, revealing its formation of antiparallel dimers in discoidal lipoproteins, which may have implications for understanding its function in AD (ref: Strickland doi.org/10.1016/j.neuron.2023.12.018/). Additionally, a study by Zhao et al. demonstrated that microbial infections could exacerbate amyloid pathology in mouse models, suggesting environmental factors may interact with genetic predispositions to influence disease outcomes (ref: Zhao doi.org/10.1038/s41380-024-02428-5/). These findings highlight the multifaceted nature of Alzheimer's disease, where genetic, proteomic, and environmental factors converge to influence disease pathology.

Innovative therapeutic approaches are being developed to address Alzheimer's disease, focusing on both drug efficacy and delivery mechanisms. Huang et al. introduced a self-stimulated release hydrogel designed to enhance the therapeutic effects of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in AD, showcasing a novel method for drug delivery that could improve clinical applicability (ref: Huang doi.org/10.1002/adma.202311420/). In a systematic review, Terao et al. compared the efficacy of several anti-amyloid drugs, including donanemab and lecanemab, finding significant improvements in cognitive function over placebo, although the relative effectiveness of these treatments remains to be fully established (ref: Terao doi.org/10.1016/j.arr.2024.102203/). Additionally, Lei et al. developed a brain-targeting nanoparticle system that utilizes mannose to enhance oral delivery of therapeutic agents for AD, addressing the challenges of crossing the blood-brain barrier (ref: Lei doi.org/10.1021/acsnano.3c09715/). These studies reflect a growing emphasis on innovative drug delivery systems and comparative efficacy assessments in the ongoing quest for effective Alzheimer's treatments.

Cognitive impairment in Alzheimer's disease is a complex interplay of neurodegenerative processes and associated comorbidities. Landau et al. examined individuals with low tau burden on the AD pathway, revealing that low tau levels are common and linked to various comorbidities that may contribute to cognitive impairment (ref: Landau doi.org/10.1002/alz.13609/). In a cohort study, Albrecht et al. assessed the impact of Alzheimer's disease and socioeconomic disadvantage on recovery from traumatic brain injury, highlighting how these factors can influence post-injury outcomes (ref: Albrecht doi.org/10.1002/alz.13666/). Additionally, Liu et al. identified blood metabolites associated with AD risk, integrating genomics and metabolomics data to uncover potential biomarkers for early detection (ref: Liu doi.org/10.1038/s41380-023-02400-9/). These findings underscore the multifactorial nature of cognitive decline in Alzheimer's disease, emphasizing the need for comprehensive approaches to diagnosis and management.

Neurovascular dysfunction plays a critical role in the pathophysiology of Alzheimer's disease, particularly in relation to amyloid pathology. Li et al. reported that amyloid protein aggregation leads to endothelial leakiness, which is associated with neurodegeneration and cerebral amyloid angiopathy, suggesting that vascular health is integral to AD pathology (ref: Li doi.org/10.1038/s41467-024-44814-1/). Furthermore, the spatial transcriptomic patterns underlying amyloid and tau pathology were linked to cognitive dysfunction, indicating that neurovascular integrity may influence cognitive outcomes in AD (ref: Yu doi.org/10.1016/j.celrep.2024.113691/). The study by Capstick et al. on digital remote monitoring for urinary tract infections in dementia patients also highlights the importance of monitoring health conditions that can exacerbate neurovascular dysfunction (ref: Capstick doi.org/10.1038/s41746-023-00995-5/). These studies collectively emphasize the interconnectedness of vascular health, neuroinflammation, and cognitive function in Alzheimer's disease.

Environmental and lifestyle factors significantly influence the risk and progression of Alzheimer's disease. Damsgaard et al. mapped morbidity patterns in young-onset Alzheimer's disease (YOAD) patients, revealing a higher burden of psychiatric morbidity up to 10 years prior to diagnosis, suggesting that early intervention may be crucial for this demographic (ref: Damsgaard doi.org/10.1002/alz.13681/). Additionally, the study by Algeciras-Schimnich et al. on cerebrospinal fluid collection protocols emphasizes the importance of standardized practices in accurately diagnosing Alzheimer's disease, which can be influenced by environmental factors (ref: Algeciras-Schimnich doi.org/10.1002/alz.13721/). These findings highlight the need for a holistic approach to Alzheimer's disease that considers both biological and environmental determinants of health.