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With the sustained growth of economy and significant changes in social demographics, the issue of elderly-related diseases has increasingly drawn attention particularly. Alzheimer's disease (AD),as a representative disease of neurodegenerative diseases has become a major challenge, affecting the health and quality of life among the elderly population severely. In recent years, the incidence, prevalence, and mortality rate of AD increase in China, imposing substantial economic burdens on families, society, and the entire healthcare system. To proactively address this challenge and respond to the national 'Healthy China Action' initiative, leading experts from Renji Hospital, Shanghai Jiao Tong University School of Medicine,and Chinese Center for Disease Control and Prevention Chronic Non-communicable Disease Control Center, Fudan University School of Public Health, Shanghai Mental Health Center, Ruijin Hospital,Shanghai Jiao Tong University School of Medicine, Fujian Medical University, and other authoritative institutions, have jointly authored the 'China Alzheimer Disease Report 2024'. Building upon previous editions of 2021, 2022, and 2023, this report updates epidemiological data on AD in China, thoroughly analyzes the latest economic burdens of the disease, and comprehensively evaluates the current status of AD diagnosis and treatment services, as well as the allocation of public health resources in our country. The release of the 'China Alzheimer Disease Report 2024' not only reflects China's progress and efforts in AD research and prevention, but also underscores the social heightened concern for elderly health issues. It aims to provide scientific and technical guidance and robust data support for the prevention, diagnosis, and treatment of AD, offering a professional basis for the government and relevant departments to formulate targeted health policies and intervention measures. Furthermore, it serves as a platform for promoting academic exchanges and cooperation in this field domestically and internationally. Through the dissemination and application of this report, we anticipate it will not only serve as a reference for professionals but also enhance public awareness of AD, promote active participation across various sectors of society, and jointly advance the development of elderly health care in China, empowering us towards achieving 'healthy aging'.

Although aging and apolipoprotein E (APOE) ε4 allele have been documented as two major risk factors for late‐onset Alzheimer's disease (LOAD), their interaction and potential underlying mechanisms remain unelucidated. Using humanized ApoE4‐ and ApoE3‐ target replacement mice, we found the accumulation of senescent neurons and the activation of mTOR and endosome‐lysosome‐autophagy (ELA) system in the hippocampus of aged ApoE4 mice. Further analyses revealed that ApoE4 aggravated the profile change of hippocampal transcription and metabolism in an age‐dependent manner, accompanying with an disruption of metabolism, which is presented with the downregulating activity of citrate synthase, the level of ATP and, most importantly, the level of acetyl coenzyme A (Ac‐CoA); GTA supplement, an Ac‐CoA substrate, reversed the senescent characteristics, decreased the activation of mTOR and ELA system, and enhanced the synaptic structure and increasing level of pre‐/post‐synaptic plasticity‐related protein, leading to cognitive improvement in aged ApoE4 mice. These data suggest that ApoE4 exacerbates neuronal senescence due to a deficiency of acetyl‐CoA, which can be ameliorated by GTA supplement. The findings provide novel insights into the potential therapeutic value of GTA supplement for the cognitive improvement in aged APOE4 carriers. [ABSTRACT FROM AUTHOR]

Background: Language ability differs between the sexes. However, it is unclear how this sex difference is moderated by genetic factors and how the brain interacts with genetics to support this specific language capacity. Previous studies have demonstrated that the sorting protein-related receptor (SORL1) polymorphism influences cognitive function and brain structure differently in males and females and is associated with Alzheimer's disease risk. Objective: The aim of this study was to investigate the effects of sex and the SORL1 rs1699102 (CC versus T carriers) genotype on language. Methods: 103 non-demented Chinese older adults from Beijing Aging Brain Rejuvenation Initiative (BABRI) database were included in this study. Participants completed language tests, T1-weighted structural magnetic resonance imaging (MRI) and resting-state functional MRI. Language test performance, gray matter volume, and network connections were compared between genotype and sex groups. Results: The rs1699102 polymorphism moderated the effects of sex on language performance, with the female having reversed language advantages in T carriers. The T allele carriers had lower gray matter volume in the left precentral gyrus. The effect of sex on language network connections was moderated by rs1699102; male CC homozygotes and female T carriers had higher internetwork connections, which were negatively correlated with language performance. Conclusion: These results suggest that SORL1 moderates the effects of sex on language, with T being a risk allele, especially in females. Our findings underscore the importance of considering the influence of genetic factors when examining sex effects. [ABSTRACT FROM AUTHOR]

Background: DNA methylation is expected to become a kind of new diagnosis and treatment method of Alzheimer's disease (AD). Neuroinflammation- and immune-related pathways represent one of the major genetic risk factors for AD.Objective: We aimed to investigate DNA methylation levels of 7 key immunologic-related genes in peripheral blood and appraise their applicability in the diagnosis of AD.Methods: Methylation levels were obtained from 222 participants (101 AD, 72 MCI, 49 non-cognitively impaired controls). Logistic regression models for diagnosing AD were established after least absolute shrinkage and selection operator (LASSO) and best subset selection (BSS), evaluated by respondent working curve and decision curve analysis for sensitivity.Results: Six differentially methylated positions (DMPs) in the MCI group and 64 in the AD group were found, respectively. Among them, there were 2 DMPs in the MCI group and 30 DMPs in the AD group independent of age, gender, and APOE4 carriers (p <  0.05). AD diagnostic prediction models differentiated AD from normal controls both in a training dataset (LASSO: 8 markers, including methylation levels at ABCA7 1040077, CNR1 88166293, CX3CR1 39322324, LRRK2 40618505, LRRK2 40618493, NGFR 49496745, TARDBP 11070956, TARDBP 11070840 area under the curve [AUC] = 0.81; BSS: 2 markers, including methylation levels at ABCA7 1040077 and CX3CR1 39322324, AUC = 0.80) and a testing dataset (AUC = 0.84, AUC = 0.82, respectively).Conclusion: Our work indicated that methylation levels of 7 key immunologic-related genes (ABCA7, CNR1, CX3CR1, CSF1R, LRRK2, NGFR, and TARDBP) in peripheral blood was altered in AD and the models including methylation of immunologic-related genes biomarkers improved prediction of AD. [ABSTRACT FROM AUTHOR]

Biomarker testing is recommended for the accurate and timely diagnosis of Alzheimer's disease (AD). Using illustrative case narratives we consider how cerebrospinal fluid (CSF) biomarker tests may be used in different presentations of cognitive impairment to facilitate timely and differential diagnosis, improving diagnostic accuracy, providing prognostic information, and guiding personalized management in diverse scenarios. Evidence shows that (1) CSF ratios are superior to amyloid beta (Aβ)1‐42 alone; (2) concordance of CSF ratios to amyloid positron emission tomography (PET) is better than Aβ1‐42 alone; and (3) phosphorylated tau (p‐tau)/Aβ1‐42 ratio is superior to p‐tau alone. CSF biomarkers are recommended for the exclusion of AD as the underlying cause of cognitive impairment, diagnosis of AD at an early stage, differential diagnosis of AD in individuals presenting with other neuropsychiatric symptoms, accurate diagnosis of AD in an atypical presentation, and for clinical trial enrichment. Highlights: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker testing may be underused outside specialist centers.CSF biomarkers improve diagnostic accuracy, guiding personalized management of AD.CSF ratios (amyloid beta [Aβ]1‐42/Aβ1‐40 and phosphorylated tau/Aβ1‐42) perform better than single markers.CSF ratios produce fewer false‐negative and false‐positive results than individual markers.CSF biomarkers should be included in diagnostic work‐up of AD and mild cognitive impairment due to AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease ( AD) is characterized by early impairments in memory and progressive neurodegeneration. Disruption of synaptic plasticity processes that underlie learning and memory contribute partly to this pathophysiology. Tripchlorolide (T4), an extract from a traditional Chinese herbal Tripterygium wilfordii Hook F, has been shown to be neuroprotective in animal models of Parkinson's disease and to improve cognitive deficits in senescence-accelerated mouse P8. In this study, we investigated the effect of T4 on cognitive decline and synaptic plasticity in five times familial AD (5 XFAD) mice co-expressing mutated amyloid precursor protein and presenilin-1. Five-month-old 5 XFAD mice and wild type littermates were intraperitoneally injected with T4, 5 μg/kg or 25 μg/kg, every other day for 60 days. T4 treatment significantly improved spatial learning and memory, alleviated synaptic ultrastructure degradation, up-regulated expression of synapse-related proteins, including synaptophysin, post-synaptic density-95, N-methyl-D-aspartate receptor subunit 1, phosphorylation of calcium/calmodulin dependent protein kinase II α, and phosphorylation of cyclic AMP-response element binding protein, and promoted activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway in 5 XFAD mice. Accumulation of amyloid β (Aβ) may contribute to synapse dysfunction and memory impairment in AD. We found that T4 treatment significantly reduced cerebral Aβ deposits and lowered Aβ levels in brain homogenates. These effects coincided with a reduction in cleavage of β-carboxyl-terminal amyloid precursor protein ( APP) fragment, levels of soluble APPβ, and protein expression of β-site APP cleaving enzyme 1. Taken together, our findings identify T4 as a potent negative regulator of brain Aβ levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD. [ABSTRACT FROM AUTHOR]

Abstract: There has been no extensive characterization of the effects of Ginsenoside Rg1, a pharmacological active component purified from the nature product ginseng, in an Alzheimer''s disease mouse model. The well-characterized transgenic Alzheimer disease (AD) mice over expressing amyloid precursor protein (APP)/Aβ (Tg mAPP) and nontransgenic (nonTg) littermates at age of 6 and 9months were treated with Rg 1 for three months via intraperitoneal injection. Mice were then evaluated for changes in amyloid pathology, neuropathology and behavior. Tg mAPP treated with Rg1 showed a significant reduction of cerebral Aβ levels, reversal of certain neuropathological changes, and preservation of spatial learning and memory, as compared to vehicle-treated mice. Rg1 treatment inhibited activity of γ-secretase in both Tg mAPP mice and B103-APP cells, indicating the involvement of Rg1 in APP regulation pathway. Furthermore, administration of Rg1 enhanced PKA/CREB pathway activation in mAPP mice and in cultured cortical neurons exposed to Aβ or glutamate-mediated synaptic stress. Most importantly, the beneficial effects on attenuation of cerebral Aβ accumulation, improvement in neuropathological and behavioral changes can be extended to the aged mAPP mice, even to 12–13months old mice that had extensive amyloid pathology and severe neuropathological and cognitive malfunction. These studies indicate that Rg1 has profound multi-faced and neuroprotective effects in an AD mouse model. Rg1 induces neuroprotection through ameliorating amyloid pathology, modulating APP process, improving cognition, and activating PKA/CREB signaling. These findings provide a new perspective for the treatment of AD and demonstrate potential for a new class of drugs for AD treatment. [Copyright &y& Elsevier]

• Hippocampal T2 relaxation time was decreased in 2-, 3-, and 5-month-old 5XFAD mice. • The dorsal hippocampal T2 was decreased earlier than that in ventral hippocampus. • Cognitive behavior was associated with the dorsal hippocampal T2 in 5XFAD mice. T2 relaxation time (T2) alterations may serve as markers for early detection and disease progression monitoring by reflecting brain microstructural integrity in Alzheimer's disease (AD). However, the characteristics of T2 alterations during the early stage of AD remain elusive. We explored T2 alterations and their possible correlations with cognitive function in 5XFAD mice at early ages (1, 2, 3, and 5 months of age). Voxel-based analysis (VBA) and region of interest (ROI) analysis showed a decreased T2 in the hippocampus of 2-, 3-, and 5-month-old 5XFAD mice compared to those of controls. The dorsal hippocampal T2 decreased earlier than the ventral hippocampus T2. A significant correlation was observed between Morris water maze (MWM) test cognitive behavior and the dorsal hippocampus T2 in 5XFAD mice. These results indicated that the microstructural integrity of brain tissues, particularly the hippocampus, was impaired early and the impairment became more extensive and severe during disease progression. Furthermore, the dorsal hippocampus is a crucial component involved in spatial cognition impairment in young 5XFAD mice. [ABSTRACT FROM AUTHOR]

Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer's disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density of the complexes was associated with lower deposition of C3 but higher amounts of synaptic proteins. In mice expressing mutant human tau, Trem2 haploinsufficiency increased complement-mediated microglial engulfment of synapses and accelerated synaptic loss. Administration of a 41-amino-acid TREM2 peptide, which we identified to be responsible for TREM2 binding to C1q, rescued synaptic impairments in AD mouse models. We thus demonstrate a critical role for microglial TREM2 in restricting complement-mediated synaptic elimination during neurodegeneration, providing mechanistic insights into the protective roles of TREM2 against AD pathogenesis. [Display omitted] • TREM2 interacts with C1q in vitro and in vivo • TREM2 suppresses the classical complement cascade by binding to C1q • Trem2 insufficiency increases complement-mediated synaptic loss in AD mice models • A TREM2 peptide that binds to C1q rescues synaptic impairments in AD mouse models TREM2 is strongly linked to Alzheimer's disease risk, but its functions are not fully understood. Zhong et al. discovered that TREM2 suppresses complement activity and synaptic loss by binding to C1q. They identified a 41-amino-acid TREM2 peptide that restricts complement-mediated synaptic elimination during neurodegeneration. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated myelin deficits in Alzheimer’s disease (AD). However, it is still unclear whether myelin deficits occur at early stage of AD. Our study aimed to investigate myelin deficits in 5XFAD mice dynamically in different cognition-associated brain regions at early stage of AD. Transmission electron microscopy (TEM) was applied to detect myelin changes in late-myelinating regions such as prelimbic area (PrL), retrosplenial granular cortex (Rsg), field CA1 of hippocampus (CA1) and entorhinal cortex (ERC) respectively at different stages (1, 2, 3 and 5 months of age) in 5XFAD mouse model. In addition, we assessed spatial learning and memory with Morris water maze (MWM) in 5XFAD mice. Myelin deficits in 5XFAD mice started from 1 month of age and this deterioration continued during ageing, whereas the same myelin abnormality could only be observed in 5-month-old wild-type mice. Additionally, the g-ratio (an index associated with myelin thickness) was increased in 1-month-old 5XFAD mice in the regions including PrL, CA1 and ERC, compared to wild-type mice. As animals aged, the increased g-ratio in 5XFAD appeared in more regions of the brain. Moreover, 5XFAD mice showed spatial memory deficits from 1 month of age and spatial learning deficits from 2 months of age. In conclusion, myelin deficits occurred at an early stage and progressed with ageing in 5XFAD mouse model. Notably, a sequential myelin change was detected in cognition-associated brain regions. Combined with cognitive examinations, this study suggests that myelin changes might contribute to cognitive dysfunction. [ABSTRACT FROM AUTHOR]