The accumulation of amyloid precursor protein (APP) C-terminal fragments has been implicated in endolysosomal dysfunction, a hallmark of early AD pathology. Inhibiting γ-secretase led to significant endolysosomal collapse in neuronal models, emphasizing the role of APP metabolism in neurodegenerative processes (ref: Bretou doi.org/10.1016/j.devcel.2024.03.030/). Additionally, adaptive immune changes have been associated with clinical progression in AD, with a comprehensive mapping of peripheral immune alterations in patients revealing significant differences compared to controls (ref: van Olst doi.org/10.1186/s13024-024-00726-8/). Seizures, affecting approximately 22% of AD patients, were shown to exacerbate excitatory-inhibitory imbalances in both human patients and 5XFAD mice, indicating that seizure management may be a viable therapeutic target in AD (ref: Barbour doi.org/10.1093/brain/).

The accumulation of APP C-terminal fragments has been linked to endolysosomal dysfunction, which is an early change in AD. Inhibiting γ-secretase in neuronal models resulted in significant endolysosomal collapse, indicating the importance of APP metabolism in AD pathology (ref: Bretou doi.org/10.1016/j.devcel.2024.03.030/). Additionally, a study evaluating the effects of AD-related biomarker changes on clinical features in patients with corticobasal syndrome and progressive supranuclear palsy highlighted the need for understanding how these biomarkers correlate with brain atrophy and cognitive decline (ref: Garcia-Cordero doi.org/10.1002/ana.26930/).

The contribution of environmental chemicals to neurodegenerative diseases has gained attention, with a systematic approach proposed to assess the chemical exposome's impact on conditions like Alzheimer's and Parkinson's diseases (ref: Lefèvre-Arbogast doi.org/10.1038/s41593-024-01627-1/). Additionally, clinicopathologic heterogeneity in Alzheimer's disease was examined, revealing the importance of understanding individual variability in disease presentation and progression (ref: Kouri doi.org/10.1001/jamaneurol.2024.0784/).

In addition to novel drug delivery systems, the role of locus coeruleus integrity in predicting cortical tau accumulation and cognitive decline has been emphasized. Longitudinal imaging studies demonstrated that changes in locus coeruleus integrity precede tau deposition in the medial temporal lobe, suggesting its potential as a biomarker for early intervention (ref: Bueichekú doi.org/10.1038/s43587-024-00626-y/). Furthermore, the identification of senescent microglia expressing TREM2 in AD models has opened avenues for targeting neuroinflammation as a therapeutic strategy (ref: Rachmian doi.org/10.1038/s41593-024-01620-8/).

Anxiety has also been identified as a significant factor in cognitive decline among Alzheimer's disease models, with studies showing that anxiety-like behavior in TgF344-AD rats is influenced by age, genotype, and exercise, but does not correlate with memory performance (ref: Lopez doi.org/10.1002/alz.13813/). Furthermore, long-term sleep duration has been associated with lower odds of neurodegenerative changes in the oldest-old, suggesting that sleep may play a protective role against cognitive decline (ref: Melikyan doi.org/10.1002/alz.13798/).

Moreover, the regulation of microglial gene expression through RNAase-H active antisense oligonucleotides has shown promise in modifying microglial responses to amyloid-β plaques in vivo, indicating a potential therapeutic avenue for targeting neuroinflammation in AD (ref: Vandermeulen doi.org/10.1186/s13024-024-00725-9/). Additionally, astrocyte-derived extracellular vesicles have been implicated in HIV-associated neurocognitive disorders, suggesting that neuroinflammation may also play a role in comorbid conditions affecting cognitive health (ref: Chemparathy doi.org/10.1002/jev2.12439/).

Additionally, the identification of senescent microglia expressing TREM2 in aging and AD models has provided insights into the inflammatory processes contributing to neurodegeneration (ref: Rachmian doi.org/10.1038/s41593-024-01620-8/). The clinicopathologic heterogeneity observed in AD, as examined through the corticolimbic index, underscores the importance of individualized approaches in understanding disease progression and tailoring interventions (ref: Kouri doi.org/10.1001/jamaneurol.2024.0784/).

Moreover, the relationship between sleep duration and neurodegenerative changes was explored in the oldest-old, revealing that longer self-reported sleep was associated with lower odds of Alzheimer's disease neuropathologic changes (ref: Melikyan doi.org/10.1002/alz.13798/). Additionally, neighborhood racial and ethnic segregation has been linked to increased dementia risk among older adults with kidney failure, highlighting the importance of social and environmental factors in cognitive health (ref: Li doi.org/10.1681/ASN.0000000000000359/).