Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-βand Prevents Alzheimer’s Disease-Type Pathology and Cognitive Deficits

Deficiencies in the clearance of peripheral amyloidβ(Aβ)play a crucial role in the progression of Alzheimer’s disease(AD).Previous studies have shown that the ability of blood monocytes to phagocytose Aβis decreased in AD.However,the exact mechanism of Aβclearance dysfunction in AD monocytes remains unclear.In the present study,we found that blood monocytes in AD mice exhibited decreases in energy metabolism,which was accompanied by cellular senescence,a senescence-associated secretory phenotype,and dysfunctional phagocytosis of Aβ.Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβin vivo and in vitro.Moreover,enhancing blood monocyte Aβphagocytosis by improving energy metabolism alleviated brain Aβdeposition and neuroinflammation and eventually improved cognitive function in AD mice.This study reveals a new mechanism of impaired Aβphagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

Association of Polygenic Risk Score with Age at Onset and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease in a Chinese Cohort

To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer’s disease(sAD)and pathological biomarkers in cerebrospinal fluid(CSF),462 sAD patients and 463 age-matched cognitively normal(CN)controls were genotyped for 35 singlenucleotide polymorphisms(SNPs)that are significantly associated with sAD.Then,the alleles found to be associated with sAD were used to build polygenic risk score(PRS)models to represent the genetic risk.Receiver operating characteristic(ROC)analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset.We measured the CSF levels of Aβ42,Aβ42/Aβ40,total tau(T-tau),and phosphorylated tau(P-tau)in a subgroup(60 sAD and 200 CN participants),and analyzed their relationships with the PRSs.We found that 14 SNPs,including SNPs in the APOE,BIN1,CD33,EPHA1,SORL1,and TOMM40 genes,were associated with sAD risk in our cohort.The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls,and were able to predict the incidence rate of sAD and age at onset.Furthermore,the PRSs were correlated with the CSF levels of Aβ42,Aβ42/Aβ40,T-tau,and P-tau.Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD.As genetic risk profiles vary among populations,large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.

Spicy food consumption is associated with cognition and cerebrospinal fluid biomarkers of Alzheimer disease

Background:Recent studies suggest that a healthy diet helps to prevent the development of Alzheimer disease(AD).This study aimed to investigate whether spicy food consumption is associated with cognition and cerebrospinal fluid(CSF)biomarkers of AD in the Chinese population.Methods:We enrolled 55 AD patients and 55 age-and gender-matched cognitively normal(CN)subjects in a case-control study,as well as a cohort of 131 participants without subjective cognitive decline(non-AD)in a cross-sectional study.Spicy food consumption was assessed using the Food Frequency Questionnaire(FFQ).Associations of FFQ scores with cognition and CSF biomarkers of AD were analyzed.Results:In the case-control study,spicy food consumption was lower in AD patients than that in CNs(4.0[4.0-8.0]vs.8.0[4.5-10.0],P<0.001);FFQ scores were positively associated with Mini-Mental Status Examination scores in the total sample(r=0.218,P=0.014).In the cross-sectional study,the association between spicy food consumption and cognition levels was verified in non-AD subjects(r=0.264,P=0.0023).Moreover,higher FFQ scores were significantly associated with higherβ-Amyloid(1-42)(Aβ42)levels and lower phospho-tau/Aβ42 and total tau/Aβ42 ratios in the CSF of non-AD subjects(P<0.05).Conclusion:Spicy food consumption is closely related to higher cognition levels and reversed AD biomarkers in the CSF,suggesting that a capsaicin-rich diet might have the potential to modify the cognitive status and cerebral pathologies associated with AD.