Recent studies have advanced our understanding of the genetic and molecular underpinnings of Alzheimer's disease (AD). A notable contribution is the development of a new association method called the liability threshold model with family history (LT-FH), which enhances the power of case-control studies by incorporating familial risk factors. This method was applied to analyze genetic data from the UK Biobank, revealing significant insights into the genetic liabilities associated with AD and other diseases (ref: Pedersen doi.org/10.1038/s41588-024-02023-y/). Additionally, the role of microglial lipid phosphatase SHIP1 has been highlighted, showing its enrichment during early brain development and its potential implications for AD risk (ref: Matera doi.org/10.1016/j.immuni.2024.11.003/). Furthermore, tau hyperphosphorylation has been linked to synaptic loss and behavioral changes in models lacking tau seeds, indicating that tau pathology may initiate neurodegenerative processes even in the absence of aggregated tau (ref: Watamura doi.org/10.1038/s41593-024-01829-7/). The exploration of microRNAs has also provided insights into their regulatory roles in neuropsychiatric conditions, with findings suggesting that genetic variations can influence miRNA expression in the brain, thereby affecting brain health and disease (ref: Vattathil doi.org/10.1038/s43587-024-00778-x/). Additionally, the UFMylation pathway has been shown to be impaired in AD, with significant changes correlating with pathological tau, suggesting that this pathway may modify tau pathology (ref: Yan doi.org/10.1186/s13024-024-00784-y/). Lastly, the deficiency of CD2AP has been found to exacerbate AD phenotypes through p38 MAPK activation, linking synaptic impairments and cognitive deficits to this genetic factor (ref: Xue doi.org/10.1186/s40035-024-00454-5/).

Neuroinflammation and the role of microglia in Alzheimer's disease have emerged as critical areas of research. The lipid phosphatase SHIP1 has been shown to limit complement-mediated synaptic pruning in the developing hippocampus, suggesting its protective role in brain health (ref: Matera doi.org/10.1016/j.immuni.2024.11.003/). In contrast, a study demonstrated that homeostatic microglia initially seed amyloid plaques, while activated microglia later reshape these plaques, indicating a dual role in the amyloid cascade (ref: Baligács doi.org/10.1038/s41467-024-54779-w/). This finding is supported by evidence that depletion of microglia prior to amyloid-beta deposition reduces plaque formation, reinforcing their involvement in plaque initiation (ref: Baligács doi.org/10.1038/s41467-024-54779-w/). Moreover, a neurodegenerative cellular stress response linked to dark microglia has been identified, where microglial activation exacerbates neurodegenerative pathologies through the secretion of toxic lipids (ref: Flury doi.org/10.1016/j.neuron.2024.11.018/). This highlights the detrimental effects of microglial activation in AD models. Additionally, a novel mechanism termed digestive exophagy has been uncovered, where microglia degrade amyloid-beta deposits extracellularly, showcasing their role in managing amyloid pathology (ref: Jacquet doi.org/10.1016/j.celrep.2024.115052/). These findings collectively underscore the complex interplay between microglial function and neuroinflammation in the context of Alzheimer's disease.

Recent advancements in the clinical and diagnostic evaluation of Alzheimer's disease have focused on improving diagnostic accuracy and accessibility. A head-to-head comparison of plasma phosphorylated-tau217 (p-tau217) assays revealed that both Lumipulse and SIMOA methods provide reliable diagnostic markers for AD, with implications for clinical practice (ref: Pilotto doi.org/10.1093/brain/). Furthermore, the Alzheimer's Association has developed updated clinical practice guidelines aimed at standardizing the diagnostic evaluation process for cognitive impairment due to AD and related disorders, emphasizing a structured approach suitable for primary care settings (ref: Atri doi.org/10.1002/alz.14335/; ref: Atri doi.org/10.1002/alz.14333/). Additionally, the endo-IP and lyso-IP toolkit has been introduced for profiling endolysosomal function in human-induced neurons, which is crucial for understanding the role of endolysosomal systems in neurodegenerative diseases (ref: Hundley doi.org/10.1073/pnas.2419079121/). The association between cardiorespiratory fitness and cognitive function in older adults has also been highlighted, suggesting that physical fitness may play a role in cognitive health (ref: Oberlin doi.org/10.1136/bjsports-2024-108257/). These developments reflect a growing emphasis on integrating clinical guidelines with innovative diagnostic tools to enhance patient outcomes in Alzheimer's disease.

The relationship between cognitive decline and various risk factors has been a focal point of recent research. A systematic review and meta-analysis revealed that adverse pregnancy outcomes are associated with an increased risk of cognitive impairment and dementia in women, highlighting the long-term impact of pregnancy-related health issues (ref: Miller doi.org/10.1016/j.lanhl.2024.100660/). Additionally, peripheral risk factors have been shown to correlate with plasma biomarkers associated with dementia, suggesting that these factors may reflect broader health issues beyond the brain (ref: Hu doi.org/10.1002/alz.14293/). Furthermore, the POINTER Imaging study has characterized baseline data linking multimodal neuroimaging biomarkers with cardiovascular health and cognition, revealing that cardiovascular risk factors are independently related to cognitive decline (ref: Harrison doi.org/10.1002/alz.14399/). In a community-based study in Chongqing, common risk factors for mild cognitive impairment and dementia were identified, including age, gender, and medical history, emphasizing the need for targeted interventions (ref: Kang doi.org/10.1002/alz.14443/). These findings underscore the multifaceted nature of cognitive decline and the importance of addressing both biological and lifestyle factors in prevention strategies.

Innovative therapeutic strategies for Alzheimer's disease are being explored, with a focus on novel drug delivery systems and treatment modalities. One promising approach involves the use of a lysosome-targeting nano-chimera designed to enhance the degradation of the receptor for advanced glycation end products (RAGE), a key player in AD pathology (ref: Wang doi.org/10.1002/adma.202411061/). This method aims to improve the efficacy of therapeutic interventions by facilitating precise drug delivery to affected neurons. Additionally, a systematic review and meta-analysis of monoclonal therapy with lecanemab demonstrated its efficacy in slowing cognitive decline in mild AD, although it was associated with an increased risk of amyloid-related imaging abnormalities (ARIA) (ref: Arroyo-Pacheco doi.org/10.1016/j.arr.2024.102620/). The role of social activity as a potential community-level intervention for reducing dementia risk has also been emphasized, suggesting that engaging in social activities may contribute to cognitive health (ref: Chen doi.org/10.1002/alz.14316/). These therapeutic advancements reflect a growing understanding of the need for multifaceted approaches to address the complexities of Alzheimer's disease.

Research into the pathological features and biomarkers of Alzheimer's disease has revealed critical insights into the disease's underlying mechanisms. A study identified isoAsp7-Aβ as a significant variant in Alzheimer's disease and other dementias, suggesting that specific post-translational modifications of amyloid-beta may contribute to the pathogenic profiles of different dementia types (ref: Schrempel doi.org/10.1007/s00401-024-02824-9/). Additionally, neurodegeneration in the cortical sulcus has been linked to chronic traumatic encephalopathy, with findings indicating that the duration of contact sports play correlates with neuronal loss and cortical thinning (ref: Nicks doi.org/10.1007/s00401-024-02833-8/). Moreover, the role of microglia in the amyloid cascade has been further elucidated, with evidence supporting their involvement in both the initiation and remodeling of amyloid plaques (ref: Baligács doi.org/10.1038/s41467-024-54779-w/). The association between cardiorespiratory fitness and cognitive function has also been highlighted, suggesting that physical health may influence cognitive decline (ref: Oberlin doi.org/10.1136/bjsports-2024-108257/). These findings collectively enhance our understanding of the pathological features and potential biomarkers for Alzheimer's disease, paving the way for improved diagnostic and therapeutic strategies.

The impact of environmental and lifestyle factors on Alzheimer's disease has garnered significant attention in recent research. A systematic analysis of disease burden in the USA highlighted disparities in health outcomes across states, emphasizing the role of lifestyle factors such as diet and physical activity in influencing health (ref: doi.org/10.1016/S0140-6736(24)01446-6/). Additionally, the association of VEGF family genes with Alzheimer's disease endophenotypes has been explored, revealing that specific gene expressions are linked to amyloid-beta load and cognitive performance (ref: Wu doi.org/10.1002/alz.14419/). Moreover, the role of microglia in the amyloid cascade has been further elucidated, with evidence supporting their involvement in both the initiation and remodeling of amyloid plaques (ref: Baligács doi.org/10.1038/s41467-024-54779-w/). These findings collectively enhance our understanding of the pathological features and potential biomarkers for Alzheimer's disease, paving the way for improved diagnostic and therapeutic strategies.

The neurodegenerative disease spectrum, particularly the overlap between Alzheimer's disease and other conditions such as dementia with Lewy bodies (DLB), has been a focus of recent studies. Research has shown that patients with DLB who exhibit high tau levels display distinct proteome profiles, suggesting a complex interplay between tau and alpha-synuclein pathologies (ref: Greally doi.org/10.1186/s13024-024-00782-0/). This highlights the need for a nuanced understanding of how these neurodegenerative diseases may share underlying mechanisms and clinical features. Additionally, the deficiency of CD2AP has been linked to aggravated Alzheimer's disease phenotypes through p38 MAPK activation, further illustrating the interconnectedness of various neurodegenerative processes (ref: Xue doi.org/10.1186/s40035-024-00454-5/). Furthermore, a risk variant associated with African ancestry has been identified in the GBA1 gene, which has implications for both Parkinson's disease and Alzheimer's disease, emphasizing the genetic factors that contribute to the neurodegenerative disease spectrum (ref: Álvarez Jerez doi.org/10.1038/s41594-024-01423-2/). These findings underscore the importance of considering the broader context of neurodegenerative diseases when investigating their pathophysiology and potential therapeutic targets.