In addition to the vascular and inflammatory components, genetic factors play a significant role in AD pathophysiology. Yang et al. conducted a genome-wide screen identifying variants that regulate gene expression in the aging brain, particularly focusing on TDP-43 proteinopathy, which is implicated in neurodegeneration (ref: Yang doi.org/10.1016/j.neuron.2020.05.010/). This work complements findings from Kang et al., who reported that elevated neurofilament light chain (NFL) concentrations in cerebrospinal fluid correlate with reduced grey matter density in AD-vulnerable regions, suggesting that NFL may serve as a biomarker for neurodegeneration (ref: Kang doi.org/10.1038/s41380-020-0818-1/). Collectively, these studies illustrate the multifactorial nature of AD, where genetic predispositions, amyloid pathology, and neuroinflammatory responses converge to drive disease progression.

Moreover, the role of microglial function in AD has been underscored by Andreone et al., who demonstrated that PLCγ2 is essential for TREM2 signaling in microglia, linking genetic variants to inflammatory responses and cellular survival (ref: Andreone doi.org/10.1038/s41593-020-0650-6/). This connection between genetic factors and immune response mechanisms is crucial for understanding the pathogenesis of AD. In contrast, Puzzo et al. provided evidence that tau suppression does not protect against Aβ-induced synaptic impairments, challenging the traditional view of tau's role in AD pathology (ref: Puzzo doi.org/10.1172/JCI137040/). These findings collectively emphasize the complexity of genetic and molecular interactions in AD, suggesting that a multifaceted approach is necessary for effective therapeutic development.

In addition to pharmacological approaches, the identification of biomarkers is crucial for early diagnosis and monitoring of disease progression. Van Steenoven et al. utilized a proteomic approach to identify cerebrospinal fluid biomarkers for dementia with Lewy bodies, achieving an accuracy of 82% in differentiating between clinical groups (ref: van Steenoven doi.org/10.1186/s13024-020-00388-2/). This underscores the importance of biomarker discovery in enhancing diagnostic precision. Furthermore, the study by Kang et al. demonstrated that elevated neurofilament light chain levels correlate with brain atrophy in AD, suggesting its potential as a biomarker for neurodegeneration (ref: Kang doi.org/10.1038/s41380-020-0818-1/). Together, these studies illustrate the dynamic landscape of clinical research in AD, where novel therapeutic strategies and biomarker identification are critical for improving patient outcomes.

Additionally, Lutz et al. explored the shared genetic etiology between late-onset Alzheimer's disease (LOAD) and posttraumatic stress disorder (PTSD), suggesting that neuropsychiatric symptoms may be interconnected and highlighting the potential for genetic screening in identifying at-risk individuals (ref: Lutz doi.org/10.1002/alz.12128/). This research indicates that understanding the genetic and environmental risk factors associated with cognitive decline can inform preventive strategies. Moreover, Lingler et al. conducted a randomized controlled trial examining the impact of amyloid PET results disclosure on individuals with mild cognitive impairment, finding that such disclosures can influence patients' understanding and coping strategies (ref: Lingler doi.org/10.1002/alz.12129/). Collectively, these studies illustrate the multifactorial nature of cognitive decline and the importance of addressing both genetic and psychosocial factors in developing effective interventions.

Moreover, the study by Bi et al. proposed a novel hypothesis regarding GABAergic dysfunction and its role in the excitatory/inhibitory imbalance associated with AD pathogenesis, suggesting that alterations in GABAergic signaling may serve as a potential biomarker for disease progression (ref: Bi doi.org/10.1002/alz.12088/). These findings collectively emphasize the importance of integrating biomarker research with clinical practice, as they hold promise for improving diagnostic accuracy and informing therapeutic strategies in AD.

Furthermore, Cajamarca et al. explored the molecular mechanisms underlying CAA, showing that mutations in Aβ promote fibrin deposits, contributing to vascular dysfunction in AD (ref: Cajamarca doi.org/10.1073/pnas.1921327117/). This highlights the interplay between amyloid pathology and neuroinflammation in driving disease progression. The findings from these studies collectively emphasize the need for a deeper understanding of neuroinflammatory processes in AD, as they may offer novel therapeutic targets and biomarkers for disease management.

Moreover, Lutz et al. investigated the shared genetic etiology between late-onset Alzheimer's disease (LOAD) and posttraumatic stress disorder (PTSD), indicating that lifestyle factors associated with PTSD may also influence the risk of developing AD (ref: Lutz doi.org/10.1002/alz.12128/). This highlights the importance of addressing psychological and lifestyle factors in the context of AD prevention. Additionally, Lingler et al. conducted a randomized controlled trial examining the impact of amyloid PET results disclosure on individuals with mild cognitive impairment, finding that such disclosures can influence patients' understanding and coping strategies (ref: Lingler doi.org/10.1002/alz.12129/). Together, these studies underscore the multifactorial nature of AD, where lifestyle factors, genetic predispositions, and psychological well-being intersect to influence disease risk and progression.

In addition, Andreone et al. demonstrated that PLCγ2 is a critical signaling node for TREM2 function in microglia, linking genetic variants to inflammatory responses and cellular survival (ref: Andreone doi.org/10.1038/s41593-020-0650-6/). This connection between genetic factors and immune response mechanisms is crucial for understanding the pathogenesis of AD. Furthermore, Cajamarca et al. explored the molecular mechanisms underlying CAA, showing that mutations in Aβ promote fibrin deposits, contributing to vascular dysfunction in AD (ref: Cajamarca doi.org/10.1073/pnas.1921327117/). Collectively, these findings emphasize the need for a comprehensive understanding of the interplay between genetic, vascular, and inflammatory factors in neurodegenerative disease mechanisms.