Recent research has underscored the importance of biomarkers in diagnosing Alzheimer's disease (AD) at various stages, including preclinical, mild cognitive impairment, and dementia. The National Institute on Aging and Alzheimer’s Association's diagnostic recommendations have been supported by studies demonstrating that imaging and cerebrospinal fluid (CSF) biomarkers correlate with neuropathological changes in AD (ref: Unknown doi.org/10.1038/s41591-023-02477-3/). Notably, cerebrospinal fluid proteomics have elucidated the natural history of autosomal dominant AD, highlighting the early aggregation of amyloid-β (Aβ) and tau proteins as critical pathological processes (ref: Johnson doi.org/10.1038/s41591-023-02476-4/). A multicenter study further revealed that cognitively unimpaired individuals with specific Aβ and tau biomarker profiles are at varying risks for cognitive decline, emphasizing the predictive power of these biomarkers in clinical settings (ref: Unknown doi.org/10.1038/s41591-023-02468-4/). Moreover, tau positron emission tomography (PET) has shown increased uptake in the medial temporal lobe even in the absence of Aβ positivity, suggesting that tau pathology may precede cognitive decline (ref: Costoya-Sánchez doi.org/10.1001/jamaneurol.2023.2560/). This finding is critical as it indicates that tau pathology could serve as an early indicator of cognitive impairment, independent of Aβ levels. The interplay between tau and cognitive decline is further supported by studies linking tau deposition with metabolic dysfunction, which mediates cognitive impairment (ref: Boccalini doi.org/10.1002/alz.13355/).

The pathophysiology of Alzheimer's disease is complex, involving a myriad of genetic, cellular, and molecular interactions. Recent studies have highlighted the role of immune signaling pathways in exacerbating neuropathology, particularly the interaction between T cells and microglia, which may influence the progression of AD (ref: Unknown doi.org/10.1038/s41593-023-01417-1/). Additionally, the regulation of lipid metabolism by neuronal γ-secretase has been shown to link cholesterol levels to synaptic dysfunction, suggesting that alterations in lipid metabolism may contribute to AD pathology (ref: Essayan-Perez doi.org/10.1016/j.neuron.2023.07.005/). Moreover, tau fibrils have been implicated in inducing glial inflammation through the TLR2 pathway, highlighting the inflammatory response as a significant component of AD pathology (ref: Dutta doi.org/10.1172/JCI161987/). This inflammatory response is further exacerbated by neuronal hyperactivity, which is linked to the engulfment of synapses by microglia, indicating a potential mechanism for synaptic loss in AD (ref: Rueda-Carrasco doi.org/10.15252/embj.2022113246/). The multifaceted nature of AD pathology underscores the need for a comprehensive understanding of these mechanisms to develop effective therapeutic strategies.

Therapeutic strategies for Alzheimer's disease are increasingly focusing on lifestyle interventions and pharmacological approaches that target underlying pathophysiological mechanisms. Time-restricted feeding has emerged as a promising intervention, demonstrating the ability to improve memory and reduce amyloid deposition in mouse models of AD without caloric restriction (ref: Whittaker doi.org/10.1016/j.cmet.2023.07.014/). This approach highlights the potential of circadian modulation in mitigating AD pathology. In addition, restoring neuronal chloride extrusion has been shown to reverse cognitive decline associated with AD mutations, indicating that targeting ionic balance in neurons may be a viable therapeutic avenue (ref: Keramidis doi.org/10.1093/brain/). Furthermore, specific inhibitors of quinone reductase 2 have been developed to reduce metabolic stress and reverse AD phenotypes in mice, suggesting that metabolic pathways play a crucial role in AD progression (ref: Gould doi.org/10.1172/JCI162120/). These findings collectively point towards a multifaceted approach to AD treatment, integrating lifestyle modifications with targeted pharmacological interventions.

Genetic factors play a pivotal role in the susceptibility to Alzheimer's disease, with specific genes influencing both familial and sporadic forms of the disease. Mutations in presenilin, which affect γ-secretase activity, are linked to familial AD, while the ApoE4 allele is a significant risk factor for sporadic AD (ref: Essayan-Perez doi.org/10.1016/j.neuron.2023.07.005/). Recent studies have also explored the impact of biological aging on AD, presenting a transcriptome-based model that quantifies aging in various tissues, which may help in understanding the genetic underpinnings of AD (ref: Mao doi.org/10.1101/gr.277491.122/). Moreover, the influence of environmental factors, such as physical inactivity, has been highlighted, with estimates suggesting that a significant proportion of dementia cases may be attributable to this lifestyle factor (ref: Feter doi.org/10.1002/alz.13417/). This interplay between genetic predisposition and lifestyle factors underscores the complexity of AD risk and the necessity for a holistic approach to prevention and intervention.

Neuroinflammation is increasingly recognized as a critical component of Alzheimer's disease pathology, with immune responses contributing to disease progression. Recent studies have shown that infiltrating CD8 T cells and monocytes are more prevalent in AD models, suggesting that peripheral immune cell infiltration may exacerbate neurodegeneration (ref: Jorfi doi.org/10.1038/s41593-023-01415-3/). The activation of microglia in response to tau fibrils has been linked to inflammatory pathways, particularly through TLR2, indicating a mechanism by which tau pathology can drive neuroinflammation (ref: Dutta doi.org/10.1172/JCI161987/). Furthermore, the engulfment of synapses by microglia, mediated by phosphatidylserine exposure, has been shown to ameliorate neuronal hyperactivity in AD models, highlighting the dual role of microglia in both promoting and resolving inflammation (ref: Rueda-Carrasco doi.org/10.15252/embj.2022113246/). These findings emphasize the importance of understanding the immune landscape in AD, as targeting neuroinflammatory processes may offer new therapeutic avenues.

Cognitive decline in Alzheimer's disease is closely linked to the underlying neurodegenerative processes characterized by the accumulation of amyloid-β and tau proteins. Studies have shown that the presence of these proteins correlates with cognitive impairment, with tau deposition being a significant predictor of cognitive decline (ref: Boccalini doi.org/10.1002/alz.13355/). Furthermore, the natural history of AD reveals that pathological changes can occur long before clinical symptoms manifest, emphasizing the need for early detection and intervention (ref: Johnson doi.org/10.1038/s41591-023-02476-4/). Additionally, the relationship between biological aging and cognitive decline has been explored, with new models providing insights into how aging processes may influence neurodegeneration (ref: Mao doi.org/10.1101/gr.277491.122/). These findings collectively highlight the multifactorial nature of cognitive decline in AD, necessitating a comprehensive approach to understanding and addressing the disease.

Circadian rhythms have been implicated in the pathology of Alzheimer's disease, with disruptions in these rhythms potentially exacerbating cognitive decline. Recent research has demonstrated that time-restricted feeding can improve memory and reduce amyloid deposition in mouse models of AD, suggesting that circadian modulation may have therapeutic potential (ref: Whittaker doi.org/10.1016/j.cmet.2023.07.014/). Additionally, increased tau PET signal in the medial temporal lobe has been observed in older individuals, indicating that tau pathology may disrupt circadian rhythms and contribute to cognitive decline (ref: Costoya-Sánchez doi.org/10.1001/jamaneurol.2023.2560/). Moreover, studies have linked aberrant circadian input pathways to sundowning behaviors in AD patients, highlighting the complex interplay between circadian rhythms and neurodegenerative processes (ref: Warfield doi.org/10.1038/s41467-023-40546-w/). These findings underscore the importance of considering circadian factors in the development of therapeutic strategies for AD.

Environmental and lifestyle factors play a significant role in the risk and progression of Alzheimer's disease. Recent systematic reviews have indicated that physical inactivity may account for a notable percentage of dementia cases, emphasizing the need for lifestyle interventions to mitigate risk (ref: Feter doi.org/10.1002/alz.13417/). Additionally, the impact of cardiovascular health and infection burden on dementia incidence has been highlighted, suggesting that maintaining overall health may influence cognitive outcomes (ref: Beydoun doi.org/10.1002/alz.13405/). Furthermore, therapeutic strategies targeting vascular cognitive impairment have been explored, revealing the heterogeneity of this condition and the need for tailored interventions (ref: Masserini doi.org/10.1002/alz.13409/). These findings collectively underscore the importance of integrating lifestyle and environmental considerations into the broader context of Alzheimer's disease prevention and treatment.