Moreover, the study of subjective cognitive decline (SCD) has gained traction, with investigations into the functional connectome revealing compensatory mechanisms that may mask early cognitive deficits. Using resting-state functional MRI, researchers found altered connectivity patterns in individuals with SCD compared to healthy controls, suggesting that these changes could serve as potential biomarkers for early intervention (ref: Chen doi.org/10.1186/s40035-020-00201-6/). The modulation of oxidative DNA damage repair pathways by HDAC1 in the aging brain also presents a promising therapeutic target, as its activation was shown to mitigate the effects of oxidative stress in mouse models of AD (ref: Pao doi.org/10.1038/s41467-020-16361-y/). Collectively, these findings underscore the multifaceted nature of AD biomarkers, ranging from genetic and proteomic factors to neuroimaging and functional connectivity assessments.

Moreover, the role of metabolic factors such as obesity and diabetes in exacerbating vascular dysfunction and cognitive decline has been highlighted. Elevated circulating amyloid concentrations in individuals with obesity and diabetes were shown to correlate with endothelial dysfunction, further complicating the interplay between metabolic health and neurodegeneration (ref: Meakin doi.org/10.1172/JCI122237/). The exploration of non-amyloid therapeutic strategies has gained momentum, with discussions on targeting tau, neuroinflammation, and other pathways to modify disease progression (ref: Gauthier doi.org/10.14283/jpad.2020.18/). This multifactorial approach to understanding AD pathophysiology emphasizes the need for integrated strategies that address both vascular and neurodegenerative components.

Furthermore, advancements in drug delivery systems, such as dual-sensitive nanomicelles, have shown significant improvements in the systemic delivery of therapeutic antibodies to the brain, enhancing treatment efficacy (ref: Xie doi.org/10.1021/acsnano.9b09991/). However, not all interventions have yielded positive results; for instance, a randomized clinical trial assessing bupropion for treating apathy in AD did not show significant benefits compared to placebo, underscoring the challenges in finding effective treatments (ref: Maier doi.org/10.1001/jamanetworkopen.2020.6027/). These findings reflect the ongoing efforts to develop multifaceted therapeutic strategies that address the complex nature of Alzheimer's disease.

Additionally, the exploration of subjective cognitive decline (SCD) has revealed significant insights into the functional connectome's compensatory mechanisms, which may mask early cognitive impairments. The use of resting-state functional MRI has provided valuable data on connectivity alterations in SCD individuals, suggesting potential biomarkers for early intervention (ref: Chen doi.org/10.1186/s40035-020-00201-6/). Moreover, the integration of lifestyle factors, such as physical exercise combined with cognitive stimulation through 40-Hz light flickering, has shown promise in improving cognitive functions in animal models of AD, indicating that non-pharmacological interventions may play a crucial role in cognitive health (ref: Park doi.org/10.1186/s13195-020-00631-4/). Collectively, these findings highlight the need for comprehensive cognitive assessments and interventions that address both clinical and functional aspects of Alzheimer's disease.

Additionally, the use of in vivo imaging techniques, such as SV2A PET, has emerged as a promising method for measuring synaptic loss in AD, providing insights into the structural correlates of cognitive impairment (ref: Mecca doi.org/10.1002/alz.12097/). The interplay between cancer and AD risk has also been explored, with findings suggesting a small association between cancer history and reduced risk of developing AD, although the mechanisms underlying this relationship remain unclear (ref: Ording doi.org/10.1002/alz.12090/). These studies underscore the complexity of genetic and environmental interactions in the pathogenesis of Alzheimer's disease, emphasizing the need for further research into the multifactorial nature of risk factors.

Furthermore, the relationship between neuroinflammation and other factors, such as HIV-1 Tat-mediated astrocytic amyloidosis, has been investigated, revealing the involvement of the HIF-1α/lncRNA BACE1-AS axis in amyloid pathology associated with HIV (ref: Sil doi.org/10.1371/journal.pbio.3000660/). This intersection of neuroinflammation and viral infections underscores the complexity of AD and the need for a multifaceted approach to understanding its pathophysiology. Overall, the exploration of neuroinflammatory mechanisms provides a promising avenue for developing targeted therapies aimed at modulating the immune response in Alzheimer's disease.

Moreover, the influence of HIV-1 on neurocognitive disorders, particularly in the context of amyloid pathology, has been explored, indicating that lifestyle factors such as viral infections can exacerbate neurodegenerative processes (ref: Sil doi.org/10.1371/journal.pbio.3000660/). These studies highlight the importance of considering environmental and lifestyle factors in the broader context of Alzheimer's disease research, as they may offer insights into preventive strategies and therapeutic interventions aimed at reducing disease risk and improving cognitive outcomes.