Alzheimer’s disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to the involvement of lipid dysregulation in the development of AD. Nevertheless, the precise lipidomic landscape and the mechanistic roles of lipids in disease pathology remain poorly understood. This review aims to highlight the significance of lipidomics and lipid-targeting approaches in the diagnosis and treatment of AD. We summarized the connection between lipid dysregulation in the human brain and AD at both genetic and lipid species levels. We briefly introduced lipidomics technologies and discussed potential challenges and areas of future advancements in the lipidomics field for AD research. To elucidate the central role of lipids in converging multiple pathological aspects of AD, we reviewed the current knowledge on the interplay between lipids and major AD features, including amyloid beta, tau, and neuroinflammation. Finally, we assessed the progresses and obstacles in lipid-based therapeutics and proposed potential strategies for leveraging lipidomics in the treatment of AD.

Innate immune activation plays a crucial role in the pathogenesis of Alzheimer's disease (AD) and related dementias (ADRD). The cytosolic DNA sensing pathway, involving cGAMP synthase (cGAS) and Stimulator of Interferon Genes (STING), has emerged as a key mediator of neurodegenerative diseases. However, the precise mechanisms through which cGAS activation influences AD progression remain poorly understood. In this study, we observed significant up‐regulation of cGAS‐STING signaling pathway in AD. Notably, this increase is primarily attributed to microglia, rather than non‐microglial cell types. Using an inducible, microglia‐specific cGAS knockout mouse model in the 5xFAD background, we demonstrated that deleting microglial cGAS at the onset of amyloid‐β (Aβ) pathology profoundly restricts plaque accumulation and protects mice from Aβ‐induced cognitive impairment. Mechanistically, our study revealed cGAS promotes plaque‐associated microglia accumulation and is essential for inflammasome activation. Moreover, we showed that restricting cGAS‐mediated innate immunity is crucial for preserving inter‐cellular communication in the brain and induces pleiotrophin, a neuroprotective factor. These findings offer novel insights into the specific roles of the innate immune system in AD employing a cell‐type‐specific approach. The conclusions provide a foundation for targeted interventions to modulate the microglial cGAS‐STING signaling pathway, offering promising therapeutic strategy for AD treatment.

OBJECTIVE: To evaluate changes in prescription stimulant dispensing to children aged 5 to 17 years associated with the COVID-19 pandemic and the shortage of immediate-release mixed amphetamine salts (Adderall), which was announced in October 2022. METHODS: We analyzed the 2017 to 2023 IQVIA Longitudinal Prescription Database, which captures 92% of US prescriptions. Using an interrupted time series design, we evaluated level and slope changes in the monthly stimulant-dispensing rate (number of children with stimulant dispensing per 100 000 children) in March 2020 and October 2022. RESULTS: In March 2020, the monthly stimulant-dispensing rate to children declined −454.9 children per 100 000 (95% CI, −572.6 to −337.2), an 18.8% decrease relative to January 2017. After March 2020, this rate increased to 12.7 children per 100 000 per month (95% CI, 6.6–18.8). In October 2022, there was no level change (−39.7 children per 100 000; 95% CI, −189.9 to 110.5) or slope change (−12.1 children per 100 000 per month; 95% CI, −27.5 to 3.3), although estimates were negative. During October 2022, there was a level decrease in the monthly dispensing rate for immediate-release mixed amphetamine salts and a level increase in the monthly dispensing rate for dexmethylphenidate. CONCLUSIONS: Stimulant dispensing to children declined after the pandemic began. Dispensing may also have declined after October 2022, but estimates were not significant, partly because decreased dispensing of immediate-release mixed amphetamine salts was offset by increased dispensing of other stimulants. Findings suggest the shortage may have prompted children to switch to alternative stimulants. Future research should evaluate whether any switches led to adverse events.

Innate immune activation plays a vital role in the development of Alzheimer’s disease (AD) and related dementias (ADRD). Among which, the DNA sensing cyclic GMP-AMP synthase (cGAS)- STING pathway has been implicated in diverse aspects of AD progression. In the current study, we showed that the cGAS-STING signaling was up-regulated in AD and this elevation was mainly contributed by the microglial population other than non-microglial cell types in the brain. By establishing an inducible, microglia-specific cGAS knockout mouse model in 5xFAD background, we found that deleting microglial cGAS at the onset of amyloid-β (Aβ) pathology significantly limited plaque formation, and protected mice from Aβ-induced cognitive impairment. Mechanistically, we found cGAS was necessary for plaque-associated microglial enrichment potentially driven by IRF8, and was indispensable for the development of disease-associated microglia (DAM) phenotype. Meanwhile, the loss of microglial cGAS reduced the levels of dystrophic neurites which led to preserved synaptic integrity and neuronal function. Our study provides new insights in understanding the effects of innate immune in AD via a cell-type specific manner, and lays the foundation for potential targeted intervention of the microglial cGAS-STING pathway toward the improvement of AD.

Background: Despite being a brain disorder, Alzheimer's disease (AD) is often accompanied by peripheral organ dysregulations (e.g., loss of bladder control in late‐stage AD), which highly rely on spinal cord coordination. However, the causal factor(s) for peripheral organ dysregulation in AD remain elusive.Methods: The central nervous system (CNS) is enriched in lipids. We applied quantitative shotgun lipidomics to determine lipid profiles of human AD spinal cord tissues. Additionally, a CNS sulfatide (ST)‐deficient mouse model was used to study the lipidome, transcriptome and peripheral organ phenotypes of ST loss.Results: We observed marked myelin lipid reduction in the spinal cord of AD subjects versus cognitively normal individuals. Among which, levels of ST, a myelin‐enriched lipid class, were strongly and negatively associated with the severity of AD. A CNS myelin‐specific ST‐deficient mouse model was used to further identify the causes and consequences of spinal cord lipidome changes. Interestingly, ST deficiency led to spinal cord lipidome and transcriptome profiles highly resembling those observed in AD, characterized by decline of multiple myelin‐enriched lipid classes and enhanced inflammatory responses, respectively. These changes significantly disrupted spinal cord function and led to substantial enlargement of urinary bladder in ST‐deficient mice.Conclusions: Our study identified CNS ST deficiency as a causal factor for AD‐like lipid dysregulation, inflammation response and ultimately the development of bladder disorders. Targeting to maintain ST levels may serve as a promising strategy for the prevention and treatment of AD‐related peripheral disorders.

The interconnection between obesity and central nervous system (CNS) neurological dysfunction has been widely appreciated. Accumulating evidence demonstrates that obesity is a risk factor for CNS neuroinflammation and cognitive impairment. However, the extent to which CNS disruption influences peripheral metabolism remains to be elucidated. We previously reported that myelin-enriched sulfatide loss leads to CNS neuroinflammation and cognitive decline. In this study, we further investigated the impact of CNS sulfatide deficiency on peripheral metabolism while considering sex- and age-specific effects. We found that female sulfatide-deficient mice gained significantly more body weight, exhibited higher basal glucose levels, and were glucose-intolerant during glucose-tolerance test (GTT) compared to age-matched controls under a normal diet, whereas male sulfatide-deficient mice only displayed glucose intolerance at a much older age compared to female sulfatide-deficient mice. Mechanistically, we found that increased body weight was associated with increased food intake and elevated neuroinflammation, especially in the hypothalamus, in a sex-specific manner. Our results suggest that CNS sulfatide deficiency leads to sex-specific alterations in energy homeostasis via dysregulated hypothalamic control of food intake.