Recent research has significantly advanced our understanding of the genetic and molecular underpinnings of Alzheimer's disease (AD). A genome-wide association study (GWAS) identified over 80 genetic loci associated with Alzheimer's disease and related dementias (ADRD), emphasizing the complexity of neuropathological outcomes that are often overlooked in clinical studies (ref: Shade doi.org/10.1038/s41588-024-01939-9/). Another study highlighted the role of apolipoprotein E (APOE) aggregation in microglia, which initiates Aβ amyloidosis, a key pathological feature of AD. This process is influenced by microglial lipid metabolism and the JAK/STAT signaling pathway, suggesting that APOE aggregation may be a critical trigger for plaque formation (ref: Kaji doi.org/10.1016/j.immuni.2024.09.014/). Additionally, the exploration of transient reprogramming using Yamanaka factors in mice revealed potential protective effects against neurodegeneration, indicating that manipulating cellular identity could offer new therapeutic avenues (ref: Shen doi.org/10.1016/j.stem.2024.09.013/). Furthermore, a comprehensive transcriptomic atlas of brain regions affected by AD has been developed, revealing distinct vulnerabilities and resilience mechanisms across neuronal and glial subtypes, which could inform targeted interventions (ref: Ortí-Casañ doi.org/10.1038/s41392-024-02014-9/). Lastly, advancements in mass spectrometry have underscored the importance of in vivo protein conformation in understanding AD pathology, suggesting that structural changes in proteins may precede expression alterations (ref: Son doi.org/10.1038/s41467-024-53582-x/).

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease, with recent studies elucidating the complex interactions between immune responses and neurodegeneration. The aggregation of apolipoprotein E in microglia has been shown to initiate Aβ amyloidosis, highlighting the importance of microglial lipid metabolism and signaling pathways in this process (ref: Kaji doi.org/10.1016/j.immuni.2024.09.014/). A cross-disease resource profiling human microglia revealed significant heterogeneity among microglial subsets, with specific populations linked to antigen presentation and motility, which could inform therapeutic strategies targeting microglial states (ref: Tuddenham doi.org/10.1038/s41593-024-01764-7/). Additionally, a study mapping cellular vulnerability in AD identified region-specific changes in neuronal and glial subtypes, suggesting that certain brain regions are more susceptible to AD pathology (ref: Ortí-Casañ doi.org/10.1038/s41392-024-02014-9/). Furthermore, the TRPV1 receptor has been implicated in modulating microglial responses and T cell infiltration, particularly in the context of APOE4, the most significant genetic risk factor for sporadic AD (ref: Lu doi.org/10.1186/s40035-024-00445-6/). Lastly, research utilizing electronic health records has indicated that heparin treatment may be associated with delayed diagnoses of AD dementia, suggesting a potential link between anticoagulant therapy and neuroinflammatory processes (ref: Readhead doi.org/10.1038/s41380-024-02757-5/).

Cognitive decline in Alzheimer's disease and related conditions has been a focal point of recent clinical trials and observational studies. A randomized clinical trial demonstrated that cognitive remediation combined with transcranial direct current stimulation (tDCS) effectively slowed cognitive decline in older adults with remitted major depressive disorder or mild cognitive impairment, particularly over a median follow-up of 48.3 months (ref: Rajji doi.org/10.1001/jamapsychiatry.2024.3241/). Additionally, a cohort study in Korea found that maintaining or initiating physical activity after a dementia diagnosis significantly reduced all-cause mortality risk, highlighting the importance of lifestyle factors in managing cognitive health (ref: Park doi.org/10.1136/bjsports-2024-108264/). Furthermore, lesion network mapping has revealed that connectivity to white matter hyperintensities is associated with lower cognitive performance, suggesting that structural brain changes may precede cognitive decline (ref: Petersen doi.org/10.1093/brain/). Research on cerebral amyloid angiopathy (CAA) has shown that cognitive dysfunction can occur even before symptomatic intracerebral hemorrhage, indicating the need for early detection and intervention strategies (ref: van Dort doi.org/10.1002/alz.14171/). Lastly, a study investigating retrotransposable elements at the single-cell level across neurodegenerative diseases has provided insights into cellular heterogeneity and its implications for cognitive decline (ref: Deng doi.org/10.1101/gr.279363.124/).

The identification and validation of biomarkers for Alzheimer's disease have gained momentum, with several studies providing insights into diagnostic tools and their clinical significance. A comprehensive comparison of plasma phosphorylated tau 217 biomarker tests revealed that plasma %p-tau217WashU outperformed other immunoassays in predicting Aβ-PET status, indicating its potential as a reliable diagnostic marker (ref: Warmenhoven doi.org/10.1093/brain/). Additionally, a novel deep learning framework utilizing retinal imaging has been proposed for early detection of Alzheimer's disease, demonstrating the feasibility of using non-invasive methods for diagnosing early-onset Alzheimer's and mild cognitive impairment (ref: Hao doi.org/10.1038/s41746-024-01292-5/). Furthermore, cerebrospinal fluid (CSF) analyses have shown that complement proteins are elevated in prodromal to moderate Alzheimer's disease, suggesting their role in the disease's pathophysiology (ref: Sandoval doi.org/10.1002/alz.14271/). Another study clarified the association of CSF biomarkers with AT(N) stages, revealing significant increases in pathological markers during disease progression (ref: Lehmann doi.org/10.1186/s13024-024-00755-3/). Lastly, the psychological outcomes of dementia risk estimation in mild cognitive impairment patients highlighted the importance of counseling and biomarker testing in managing patient expectations and treatment pathways (ref: Rostamzadeh doi.org/10.1002/alz.14226/).

Innovative therapeutic approaches for Alzheimer's disease are being explored, focusing on both symptom management and disease modification. A novel intranasal carrier-free nanomodulator has been developed, which combines donepezil and simvastatin for direct nose-to-brain delivery, showing promise in addressing both the symptoms and underlying pathology of Alzheimer's disease (ref: Yang doi.org/10.1021/acsnano.4c09449/). Additionally, research on cannabidiol has demonstrated its potential to ameliorate cognitive decline in a mouse model of Alzheimer's disease, primarily through enhancing the function of extrasynaptic glycine receptors (ref: Jin doi.org/10.1038/s41380-024-02789-x/). Furthermore, the study of accelerated amyloid-β aggregation on fibril surfaces has provided insights into the mechanisms of fibril formation, which could inform future therapeutic strategies aimed at inhibiting this process (ref: Nirmalraj doi.org/10.1126/sciadv.adp5059/). A study on post-stroke incident ischemic lesions highlighted their association with cognitive and functional impairments, suggesting that addressing these lesions may improve outcomes for patients with Alzheimer's disease (ref: Fang doi.org/10.1002/alz.14274/). Lastly, the role of brain microRNAs in cognitive trajectory and Alzheimer's disease has been investigated, revealing a significant number of differentially expressed miRNAs that may contribute to cognitive decline (ref: Vattathil doi.org/10.1007/s00401-024-02818-7/).

Neuroanatomical and imaging studies have provided critical insights into the structural changes associated with Alzheimer's disease. A recent study focused on differentiating visceral sensory ganglion organoids from induced pluripotent stem cells, which may enhance our understanding of the gut-brain axis and its implications for neurological disorders (ref: Ahn doi.org/10.1038/s41592-024-02455-8/). Additionally, the application of Yamanaka factors in vivo has shown potential for expanding the neocortex and protecting against neurodegeneration, suggesting that cellular reprogramming could be a viable strategy for mitigating Alzheimer's pathology (ref: Shen doi.org/10.1016/j.stem.2024.09.013/). High-speed atomic force microscopy has been utilized to observe single-molecule interactions between antibodies and amyloid-β fibrils, providing a refined understanding of fibril assembly and potential therapeutic targets (ref: Yagi-Utsumi doi.org/10.1021/jacs.4c08841/). Moreover, research on accelerated forgetting has indicated its association with amyloid deposition and brain atrophy, suggesting that this phenomenon may serve as a sensitive marker for cognitive changes in preclinical Alzheimer's disease (ref: Lu doi.org/10.1093/brain/). Lastly, the exploration of terminal lucidity in Alzheimer's patients has raised intriguing questions about the brain's capacity for functional reorganization, even in advanced stages of the disease (ref: Lin doi.org/10.1186/s13024-024-00761-5/).

Environmental and lifestyle factors have emerged as significant contributors to the risk and progression of Alzheimer's disease. A cohort study utilizing the National Health Insurance Service Database in Korea found that maintaining regular physical activity after a dementia diagnosis was associated with a reduced risk of all-cause mortality, emphasizing the importance of lifestyle interventions in managing dementia (ref: Park doi.org/10.1136/bjsports-2024-108264/). Additionally, the Framingham Stroke Risk Profile was shown to be significantly associated with incident dementia and Alzheimer's disease, particularly highlighting female vulnerability to these conditions (ref: Yuan doi.org/10.1002/ana.27108/). Furthermore, a study on nursing home residents with Alzheimer's disease indicated that they had higher odds of avoidable hospital transfers, suggesting that improved management strategies could mitigate unnecessary hospitalizations (ref: Powell doi.org/10.1002/alz.14292/). The AAIC 2024 conference preview highlighted the potential for integrating blood tests and cognitive assessments at the primary care level to expedite Alzheimer's diagnoses and treatment eligibility (ref: Unknown doi.org/10.1002/alz.14325/). Lastly, cognitive dysfunction associated with cerebral amyloid angiopathy was noted even before symptomatic intracerebral hemorrhage, indicating the need for early intervention strategies (ref: van Dort doi.org/10.1002/alz.14171/).