Genetic architecture of brain morphology and overlap with neuropsychiatric traits.

Uncovering the genetic architectures of brain morphology offers valuable insights into brain development and disease. Genetic association studies of brain morphological phenotypes have discovered thousands of loci. However, interpretation of these loci presents a significant challenge. One potential solution is exploring the genetic overlap between brain morphology and disorders, which can improve our understanding of their complex relationships, ultimately aiding in clinical applications. In this review, we examine current evidence on the genetic associations between brain morphology and neuropsychiatric traits. We discuss the impact of these associations on the diagnosis, prediction, and treatment of neuropsychiatric diseases, along with suggestions for future research directions.

Clinical trajectories preceding incident dementia up to 15 years before diagnosis: a large prospective cohort study.

BACKGROUND: Dementia has a long prodromal stage with various pathophysiological manifestations; however, the progression of pre-diagnostic changes remains unclear. We aimed to determine the evolutional trajectories of multiple-domain clinical assessments and health conditions up to 15 years before the diagnosis of dementia. METHODS: Data was extracted from the UK-Biobank, a longitudinal cohort that recruited over 500,000 participants from March 2006 to October 2010. Each demented subject was matched with 10 healthy controls. We performed logistic regressions on 400 predictors covering a comprehensive range of clinical assessments or health conditions. Their evolutional trajectories were quantified using adjusted odds ratios (ORs) and FDR-corrected p-values under consecutive timeframes preceding the diagnosis of dementia. FINDINGS: During a median follow-up of 13.7 [Interquartile range, IQR 12.9-14.2] years until July 2022, 7620 subjects were diagnosed with dementia. In general, upon approaching the diagnosis, demented subjects witnessed worse functional assessments and a higher prevalence of health conditions. Associations up to 15 years preceding the diagnosis comprised declined physical strength (hand grip strength, OR 0.65 [0.63-0.67]), lung dysfunction (peak expiratory flow, OR 0.78 [0.76-0.81]) and kidney dysfunction (cystatin C, OR 1.13 [1.11-1.16]), comorbidities of coronary heart disease (OR 1.78 [1.67-1.91]), stroke (OR 2.34 [2.1-1.37]), diabetes (OR 2.03 [1.89-2.18]) and a series of mental disorders. Cognitive functions in multiple tests also demonstrate decline over a decade before the diagnosis. Inadequate activity (3-5 year, overall time of activity, OR 0.82 [0.73-0.92]), drowsiness (3-5 year, sleep duration, OR 1.13 [1.04-1.24]) and weight loss (0-5 year, weight, OR 0.9 [0.83-0.98]) only exhibited associations within five years before the diagnosis. In addition, serum biomarkers of enriched endocrine, dysregulations of ketones, deficiency of brand-chain amino acids and polyunsaturated fatty acids were found in a similar prodromal time window and can be witnessed as the last pre-symptomatic conditions before the diagnosis. INTERPRETATION: Our findings present a comprehensive temporal-diagnostic landscape preceding incident dementia, which could improve selection for preventive and early disease-modifying treatment trials.

Associations between liver function and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in non-demented adults: The CABLE study.

Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (ß = -0.115, pFDR < 0.001), GLO (ß = -0.184, pFDR < 0.001), and A/G (ß = 0.182, pFDR < 0.001) and CSF ß-amyloid1-42 (Aß1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.

Associations of liver dysfunction with incident dementia, cognition, and brain structure: A prospective cohort study of 431 699 adults.

The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross-sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow-up were included from the UK Biobank; 5542 all-cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR = 0.010), AST to ALT ratio (HR, 1.195; PFDR <0.001), gamma-glutamyl transpeptidase (GGT; HR, 1.066; PFDR <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U-shaped association between Alb and AST and incident ACD (Pnonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR <0.05). In sensitivity analysis, metabolic dysfunction-associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence.

Associations between adiposity and white matter hyperintensities: Cross-sectional and longitudinal analyses of 34,653 participants.

OBJECTIVES: White matter hyperintensities (WMH) increase the risk of stroke and cognitive impairment. This study aims to determine the cross-sectional and longitudinal associations between adiposity and WMH. METHODS: Participants were enrolled from the UK Biobank cohort. Associations of concurrent, past, and changes in overall and central adiposity with WMH were investigated by linear and nonlinear regression models. The association of longitudinal adiposity and WMH volume changes was determined by a linear mixed model. Mediation analysis investigated the potential mediating effect of blood pressure. RESULTS: In 34,653 participants with available adiposity measures and imaging data, the concurrent obese group had a 25.3% (ß [95% CI] = 0.253 [0.222-0.284]) higher WMH volume than the ideal weight group. Increment in all adiposity measures was associated with a higher WMH volume. Among them, waist circumference demonstrated the strongest effect (ß [95% CI] = 0.113 [0.101-0.125]). Past adiposity also demonstrated similar effects. Among the subset of 2664 participants with available WMH follow-up data, adiposity measures were predictive of WMH change. Regarding changes of adiposity, compared with ideal weight stable group, those who turned from ideal weight to overweight/obese had a 8.1% higher WMH volume (ß [95% CI] = 0.081 [0.039-0.123]), while participants who turned from overweight/obese to ideal weight demonstrated no significant WMH volume change. Blood pressure partly meditates the associations between adiposity and WMH. CONCLUSIONS: Both concurrent and past adiposity were associated with a higher WMH volume. The detrimental effects of adiposity on WMH occurred throughout midlife and in the elderly and may still exist after changes in obesity status.

Echocardiographic measures of the left heart and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: The CABLE study.

INTRODUCTION: This study delineated the interrelationships between subclinical alterations in the left heart, cerebrospinal fluid (CSF), Alzheimer's disease (AD) biomarkers, and cognition. METHODS: Multiple linear regressions were conducted in 1244 cognitively normal participants (mean age = 65.5; 43% female) who underwent echocardiography (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers measurements. Mediating effects of AD pathologies were examined. Differences in cardiac parameters across ATN categories were tested using analysis of variance (ANOVA) and logistic regressions. RESULTS: LA or LV enlargement (characterized by increased diameters and volumes) and LV hypertrophy (increased interventricular septal or posterior wall thickness and ventricular mass) were associated with higher CSF phosphorylated (p)-tau and total (t)-tau levels, and poorer cognition. Tau pathologies mediated the heart-cognition relationships. Cardiac parameters were higher in stage 2 and suspected non-Alzheimer's pathology groups than controls. DISCUSSION: These findings suggested close associations of subclinical cardiac changes with tau pathologies and cognition. HIGHLIGHTS: Various subclinical alterations in the left heart related to poorer cognition. Subclinical cardiac changes related to tau pathologies in cognitively normal adults. Tau pathologies mediated the heart-cognition relationships. Subclinical cardiac changes related to the AD continuum, especially to stage 2. The accumulation of cardiac alterations magnified their damage to the brain.

Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease.

INTRODUCTION: Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. METHODS: Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD dementia (n = 47), mild cognitive impairment (MCI; n = 137), and normal controls (n = 235) from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. DISCUSSION: Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD. HIGHLIGHTS: The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aß) positron emission tomography (PET) burden and Aß-positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aß42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aß PET and brain atrophy mediated the link of ALPS index with cognitive decline.

Incremental value of amyloid PET in a tertiary memory clinic setting in China.

INTRODUCTION: The objective of this study is to investigate the incremental value of amyloid positron emission tomography (Aß-PET) in a tertiary memory clinic setting in China. METHODS: A total of 1073 patients were offered Aß-PET using 18F-florbetapir. The neurologists determined a suspected etiology (Alzheimer's disease [AD] or non-AD) with a percentage estimate of their confidence and medication prescription both before and after receiving the Aß-PET results. RESULTS: After disclosure of the Aß-PET results, etiological diagnoses changed in 19.3% of patients, and diagnostic confidence increased from 69.3% to 85.6%. Amyloid PET results led to a change of treatment plan in 36.5% of patients. Compared to the late-onset group, the early-onset group had a more frequent change in diagnoses and a higher increase in diagnostic confidence. DISCUSSION: Aß-PET has significant impacts on the changes of diagnoses and management in Chinese population. Early-onset cases are more likely to benefit from Aß-PET than late-onset cases. HIGHLIGHTS: Amyloid PET contributes to diagnostic changes and its confidence in Chinese patients. Amyloid PET leads to a change of treatment plans in Chinese patients. Early-onset cases are more likely to benefit from amyloid PET than late-onset cases.

Genome-wide association study of cerebellar white matter microstructure and genetic overlap with common brain disorders.

BACKGROUND: The cerebellum is recognized as being involved in neurocognitive and motor functions with communication with extra-cerebellar regions relying on the white matter integrity of the cerebellar peduncles. However, the genetic determinants of cerebellar white matter integrity remain largely unknown. METHODS: We conducted a genome-wide association analysis of cerebellar white matter microstructure using diffusion tensor imaging data from 25,415 individuals from UK Biobank. The integrity of cerebellar white matter microstructure was measured as fractional anisotropy (FA) and mean diffusivity (MD). Identification of independent genomic loci, functional annotation, and tissue and cell-type analysis were conducted with FUMA. The linkage disequilibrium score regression (LDSC) was used to calculate genetic correlations between cerebellar white matter microstructure and regional brain volumes and brain-related traits. Furthermore, the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was employed to identify the shared genetic basis between cerebellar white matter microstructure and common brain disorders. RESULTS: We identified 11 genetic loci (P < 8.3 × 10-9) and 86 genes associated with cerebellar white matter microstructure. Further functional enrichment analysis implicated the involvement of GABAergic neurons and cholinergic pathways. Significant polygenetic overlap between cerebellar white matter tracts and their anatomically connected or adjacent brain regions was detected. In addition, we report the overall genetic correlation and specific loci shared between cerebellar white matter microstructural integrity and brain-related traits, including movement, cognitive, psychiatric, and cerebrovascular categories. CONCLUSIONS: Collectively, this study represents a step forward in understanding the genetics of cerebellar white matter microstructure and its shared genetic etiology with common brain disorders.

The causal role of circulating amino acids on neurodegenerative disorders: A two-sample Mendelian randomization study.

Potential associations between the risk of neurodegenerative diseases and circulating levels of amino acids have been implied in both experimental research and observational studies. However, because of the confounding and reverse causality, the findings could be biased. We aimed to determine whether circulating amino acid levels have potential effects on the risk of neurodegenerative diseases through a more robust analysis. So, we performed a total of two MR analyses, a discovery two-sample MR analysis, and a replication test, using summary-level genome-wide association study (GWAS) data, both with circulating levels of amino acids as exposure and risk of neurodegenerative diseases as an outcome. The potential causalities between nine amino acids (Glutamine [Glu], Leucine [Leu], Isoleucine [Ile], Phenylalanine [Phe], Valine [Val], Alanine [Ala], Tyrosine [Tyr], Histidine [His], and Glycine [Gly]) and six neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], Multiple sclerosis [MS], Frontotemporal dementia [FTD], Lewy body dementia [DLB], Amyotrophic lateral sclerosis [ALS]) were explored in this study. According to the discovery MR analysis, 1 SD. increase in circulating levels of Gln was genetically determined to result in a 13% lower risk of AD (IVW ORSD [95% CI] = 0.872 [0.822, 0.926]; FDR = 7.46 × 10-5 ) while PD risk was decreased to 63% per SD. increase of circulating Leu levels (IVW ORSD [95% CI] = 0.628 [0.467, 0.843]; FDR = 0.021). Results from the replication test provide further evidence of the potential association between circulating Gln levels and AD risk (IVW ORSD [95% CI] = 0.094 [0.028, 0.311]; FDR = 9.98 × 10-4 ). Meanwhile, sensitivity analysis demonstrated that the significant relationships revealed by our two-sample MR outcomes were reliable. Our analyses provided robust evidence of causal associations between circulating levels of Gln and AD risk as well as circulating Leu levels and risk of PD. However, the underlying mechanisms remain to be further investigated.

Associations of circulating metabolites with cerebral white matter hyperintensities.

White matter hyperintensities (WMH) are the most compelling risk factors of stroke, dementia, and early mortality. We aimed to investigate the associations between WMH and circulating metabolites. We studied up to 8190 individuals from the UK Biobank, who have both measurements of 249 plasma metabolites and WMH volume. Linear regression models were applied in pooled samples, and age-stratified and sex-stratified subsamples to estimate the associations between WMH and metabolomic measures. We conducted three analytic models. In the basic model, we identified 45 metabolomic measures associated with WMH after multiple testing correction (p < 0.0022), 15 of which remained significant in additional adjustments, but no metabolites passed the full adjustment in pooled samples. The 15 WMH-related metabolites were subfractions of various sizes of high-density lipoprotein (HDL), fatty acids, and glycoprotein acetyls. Among them, one fatty acid metabolite and 12 HDL-related traits showed significant negative associations with WMH. Higher glycoprotein acetyls were associated with large WMH. Strong age and sex specificities were observed indicating distinct metabolomic features accompany WMH in different samples. More metabolites were identified in males and adults under 50 years old. Circulating metabolites showed remarkably widespread associations with WMH. Population specificities may shed light on the different pertinent implications of WMH.

Circulating metabolites and risk of incident dementia: A prospective cohort study.

Identifying circulating metabolites associated with dementia, cognition, and brain volume may improve the understanding of dementia pathogenesis and provide novel insights for preventive and therapeutic interventions. This cohort study included a total of 87 885 participants (median follow-up of 9.1 years, 54% female) without dementia at baseline from the UK Biobank. A total of 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Cox proportional regression was used to examine the associations of each metabolite with incident dementia (cases = 1134), Alzheimer's disease (AD; cases = 488), and vascular dementia (VD; cases = 257) during follow-up. Dementia-associated metabolites were further analyzed for association with cognitive deficits (N = 87 885) and brain volume (N = 7756) using logistic regression and linear regression. We identified 26 metabolites associated with incident dementia, of which 6 were associated with incident AD and 5 were associated with incident VD. These 26 dementia-related metabolites were subfractions of intermediate-density lipoprotein, large low-density lipoprotein (L-LDL), small high-density lipoprotein (S-HDL), very-low-density lipoprotein, fatty acids, ketone bodies, citrate, glucose, and valine. Among them, the cholesterol percentage in L-LDL (L-LDL-C%) was associated with lower risk of AD (HR [95% CI] = 0.92 [0.87-0.97], p = 0.002), higher brain cortical (ß = 0.047, p = 3.91 × 10-6 ), and hippocampal (ß = 0.043, p = 1.93 × 10-4 ) volume. Cholesteryl ester-to-total lipid ratio in L-LDL (L-LDL-CE%) was associated with lower risk of AD (HR [95% CI] = 0.93 [0.90-0.96], p = 1.48 × 10-4 ), cognitive deficits (odds ratio = 0.98, p = 0.009), and higher hippocampal volume (ß = 0.027, p = 0.009). Cholesteryl esters in S-HDL (S-HDL-CE) were associated with lower risk of VD (HR [95% CI] = 0.81 [0.71-0.93], p = 0.002), but not AD. Taken together, circulating levels of L-LDL-CE% and L-LDL-C% were robustly associated with risk of AD and AD phenotypes, but not with VD. S-HDL-CE was associated with lower risk of VD, but not with AD or AD phenotypes. These metabolites may play a role in the advancement of future intervention trials. Additional research is necessary to gain a complete comprehension of the molecular mechanisms behind these associations.

Systematic assessment of plasma biomarkers in spinocerebellar ataxia.

BACKGROUND AND OBJECTIVES: Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), phosphorylated-tau (p-tau), and ß-amyloid (Aß) have emerged as promising markers in several neurodegenerative disorders, but whether they can be used as biomarkers in spinocerebellar ataxias (SCA) is yet to be determined. This study aimed to identify sensitive plasma markers for SCA and investigate their effectiveness in tracking ataxia severity, cognition, non-motor symptoms, and brain atrophy. METHODS: This observational study recruited consecutive participants from Huashan Hospital and the CABLE study from November 2019. Patients with SCA were genetically diagnosed, grouped according to the ataxia severity, and compared with healthy older individuals and patients with multiple system atrophy type C (MSA-C). Plasma NfL, GFAP, p-tau, and Aß levels were measured by Simoa in all participants. Analysis of covariance, Spearman correlation, and multivariable regression were used to explore candidate markers in SCA. RESULTS: A total of 190 participants (60 SCA, 56 MSA-C, and 74 healthy controls) were enrolled. Plasma NfL level increased early in the pre-ataxic stage of SCA (32.23 ± 3.07 vs. 11.41 ± 6.62 pg/mL in controls), was positively associated with the ataxia severity (r = 0.45, P = 0.005) and CAG repeat length (r = 0.51, P = 0.001), varied among the different SCA subtypes (39.57 ± 13.50 pg/mL in SCA3, which was higher than 28.17 ± 8.02 pg/mL in SCA2, 17.08 ± 6.78 pg/mL in SCA8, and 24.44 ± 18.97 pg/mL in rare SCAs; P < 0.05), and was associated with brainstem atrophy. NfL alone (area under the curve [AUC] 0.867) or combined with p-tau181 and Aß (AUC 0.929), showed excellent performance in discriminating SCA patients from controls. Plasma GFAP distinguished SCA from MSA-C with moderate accuracy (AUC > 0.700) and correlated with cognitive performance and cortical atrophy. Changes in levels of p-tau181 and Aß were observed in SCA patients compared to controls. They were both correlated with cognition, while Aß was also associated with non-motor symptoms, such as anxiety and depression. DISCUSSION: Plasma NfL may serve as a sensitive biomarker for SCA, and its level is elevated in the pre-ataxic stage. The different performance of NfL and GFAP indicates differences in the underlying neuropathology of SCA and MSA-C. Moreover, amyloid markers may be useful for detecting memory dysfunction and other non-motor symptoms in SCA.

Multipredictor risk models for predicting individual risk of Alzheimer's disease.

BACKGROUND: Early prevention of Alzheimer's disease (AD) is a feasible way to delay AD onset and progression. Information on AD prediction at the individual patient level will be useful in AD prevention. In this study, we aim to develop risk models for predicting AD onset at individual level using optimal set of predictors from multiple features. METHODS: A total of 487 cognitively normal (CN) individuals and 796 mild cognitive impairment (MCI) patients were included from Alzheimer's Disease Neuroimaging Initiative. All the participants were assessed for clinical, cognitive, magnetic resonance imaging and cerebrospinal fluid (CSF) markers and followed for mean periods of 5.6 years for CN individuals and 4.6 years for MCI patients to ascertain progression from CN to incident prodromal stage of AD or from MCI to AD dementia. Least Absolute Shrinkage and Selection Operator Cox regression was applied for predictors selection and model construction. RESULTS: During the follow-up periods, 139 CN participants had progressed to prodromal AD (CDR ≥ 0.5) and 321 MCI patients had progressed to AD dementia. In the prediction of individual risk of incident prodromal stage of AD in CN individuals, the AUC of the final CN model was 0.81 within 5 years. The final MCI model predicted individual risk of AD dementia in MCI patients with an AUC of 0.92 within 5 years. The models were also associated with longitudinal change of Mini-Mental State Examination (p < 0.001 for CN and MCI models). An Alzheimer's continuum model was developed which could predict the Alzheimer's continuum for individuals with normal AD biomarkers within 3 years with high accuracy (AUC = 0.91). CONCLUSIONS: The risk models were able to provide personalized risk for AD onset at each year after evaluation. The models may be useful for better prevention of AD.

Plasma Glial Fibrillary Acidic Protein in the Alzheimer Disease Continuum: Relationship to Other Biomarkers, Differential Diagnosis, and Prediction of Clinical Progression.

BACKGROUND: Plasma glial fibrillary acidic protein (GFAP) has emerged as a promising biomarker in neurological disorders, but further evidence is required in relation to its usefulness for diagnosis and prediction of Alzheimer disease (AD). METHODS: Plasma GFAP was measured in participants with AD, non-AD neurodegenerative disorders, and controls. Its diagnostic and predictive value were analyzed alone or combined with other indicators. RESULTS: A total of 818 participants were recruited (210 followed). Plasma GFAP was significantly higher in AD than in non-AD dementia and non-demented individuals. It increased in a stepwise pattern from preclinical AD, through prodromal AD to AD dementia. It effectively distinguished AD from controls [area under the curve (AUC) > 0.97] and non-AD dementia (AUC > 0.80) and distinguished preclinical (AUC > 0.89) and prodromal AD (AUC > 0.85) from Aß-normal controls. Adjusted or combined with other indicators, higher levels of plasma GFAP displayed predictive value for risk of AD progression (adjusted hazard radio= 4.49, 95%CI, 1.18-16.97, P = 0.027 based on the comparison of those above vs below average at baseline) and cognitive decline (standard-ß=0.34, P = 0.002). Additionally, it strongly correlated with AD-related cerebrospinal fluid (CSF)/neuroimaging markers. CONCLUSIONS: Plasma GFAP effectively distinguished AD dementia from multiple neurodegenerative diseases, gradually increased across the AD continuum, predicted the individual risk of AD progression, and strongly correlated with AD CSF/neuroimaging biomarkers. Plasma GFAP could serve as both a diagnostic and predictive biomarker for AD.

Application of the Amyloid/Tau/Neurodegeneration Framework in Cognitively Intact Adults: The CABLE Study.

OBJECTIVES: The amyloid/tau/neurodegeneration (AT[N]) framework has conceptualized the Alzheimer's disease (AD) continuum as a continuum of disease with evidence of amyloid-related pathologies independent of clinical manifestation. Based on this framework, it is necessary to reveal the distribution and risk factors of AD continuum in the cognitively intact population among different cohorts and races, including the northern Chinese Han population. METHODS: This study classified cognitively intact Chinese Alzheimer's Biomarker and LifestylE (CABLE) participants through the AT(N) scheme. Gaussian mixture models were used to identify the cutoff values of cerebrospinal fluid biomarkers, which distinguished AD continuum ( A + T-N-, A + T + N-, A + T-N + and A + T + N +) from 1,005 participants (mean age 61 years; 40% female). Multivariable logistic regressions and Cochran-Armitage trend tests were used to test neuropsychological performance and risk factors for AD continuum. RESULTS: Approximately one-third of individuals (33.7%) belonged to the AD continuum. Four potential modifiable risk factors, including hypertension, thyroid diseases, social isolation, and minimal depression symptoms, were identified for the AD continuum (OR ranging 1.68-6.90). A trend toward higher prevalence of the AD continuum was associated with a larger number of risk factors (p for trend <0.0001). The risk of AD continuum increased by approximately twofold for each additional modifiable risk factor (OR 1.9, 95% CI 1.65-2.24, p < 0.0001). INTERPRETATION: This study revealed the distribution and potential risk factors of the AD continuum in a cognitively intact Han population in northern China, which filled the gap in the area about the performance of the AT(N) framework in the Asian population. ANN NEUROL 2022;92:439-450.

Plasma Biomarkers and Positron Emission Tomography Tau Pathology in Progressive Supranuclear Palsy.

BACKGROUND: Development of disease-modifying therapeutic trials of progressive supranuclear palsy (PSP) urges the need for sensitive fluid biomarkers. OBJECTIVES: The objectives of this study were to explore the utility of plasma biomarkers in the diagnosis, differential diagnosis, and assessment of disease severity, brain atrophy, and tau deposition in PSP. METHODS: Plasma biomarkers were measured using a single-molecule array in a cohort composed of patients with PSP, Parkinson's disease (PD), multiple system atrophy with predominant parkinsonism (MSA-P), and healthy controls (HCs). RESULTS: Plasma neurofilament light chain (NfL) outperformed other plasma makers (ie, glial fibrillary acidic protein [GFAP], phosphorylated-tau 181 [p-tau181], amyloid-ß 1-40, amyloid-ß 1-42) in identifying PSP from HC (area under the curve [AUC] = 0.904) and from MSA-P (AUC = 0.711). Plasma GFAP aided in distinguishing PSP from HC (AUC = 0.774) and from MSA-P (AUC = 0.832). It correlated with brainstem atrophy and higher regional tau accumulation. However, plasma p-tau181 neither helped in diagnosis nor was it associated with clinical or neuroimaging measures. CONCLUSIONS: Plasma NfL and GFAP showed different values in differentiating PSP from HC or controls with other forms of neurodegenerative parkinsonism and detecting disease severity, brain atrophy, or tau deposition in PSP. © 2023 International Parkinson and Movement Disorder Society.

Lung function and risk of incident dementia: A prospective cohort study of 431,834 individuals.

BACKGROUND: Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms. METHODS: This population-based cohort included 43,1834 non-demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen-carrying indices, metabolites, and brain structures. FINDINGS: During a follow-up of 3,736,181 person-years (mean follow-up 8.65 years), 5,622 participants (1.30 %) developed all-cause dementia, which consisted of 2,511 Alzheimer's dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all-cause dementia (forced expiratory volume in 1 s [liter]: hazard ratio [HR, 95 %CI], 1.24 [1.14-1.34], P = 1.10 × 10-07; forced vital capacity [liter]: 1.16 [1.08-1.24], P = 2.04 × 10-05; peak expiratory flow [liter/min]: 1.0013 [1.0010-1.0017], P = 2.73 × 10-13). Low lung function generated similar hazard estimates for AD and VD risks. As underlying biological mechanisms, systematic inflammatory markers, oxygen-carrying indices, and specific metabolites mediated the effects of lung function on dementia risks. Besides, brain grey and white matter patterns mostly affected in dementia were substantially changed with lung function. INTERPRETATION: Life-course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention.

Identifying causal genes for depression via integration of the proteome and transcriptome from brain and blood.

Genome-wide association studies (GWASs) have identified numerous risk genes for depression. Nevertheless, genes crucial for understanding the molecular mechanisms of depression and effective antidepressant drug targets are largely unknown. Addressing this, we aimed to highlight potentially causal genes by systematically integrating the brain and blood protein and expression quantitative trait loci (QTL) data with a depression GWAS dataset via a statistical framework including Mendelian randomization (MR), Bayesian colocalization, and Steiger filtering analysis. In summary, we identified three candidate genes (TMEM106B, RAB27B, and GMPPB) based on brain data and two genes (TMEM106B and NEGR1) based on blood data with consistent robust evidence at both the protein and transcriptional levels. Furthermore, the protein-protein interaction (PPI) network provided new insights into the interaction between brain and blood in depression. Collectively, four genes (TMEM106B, RAB27B, GMPPB, and NEGR1) affect depression by influencing protein and gene expression level, which could guide future researches on candidate genes investigations in animal studies as well as prioritize antidepressant drug targets.

Peripheral immunity is associated with the risk of incident dementia.

Central immunity components especially microglia in dementia have been well studied and corresponding immunotherapy gradually caught the attention. However, few studies focused on peripheral immunity and dementia. To address the issue, we examined the longitudinal association between incident dementia and peripheral immunity markers encompassing immune cell counts, and their derived ratios including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR), utilizing data of 361,653 participants from the UK Biobank (UKB). During a median follow-up of 8.99 years, 4239 participants developed dementia. The results revealed that increased innate immunity markers were associated with higher dementia risk (per SD increment hazard ratio [HR]; 95% confidence interval [CI] 1.14; 1.09-1.19 for neutrophils, 1.16; 1.11-1.20 for NLR and 1.11; 1.07-1.16 for SII), while increased adaptive immunity markers were associated with lower dementia risk (0.93; 0.90-0.97 for lymphocytes and 0.94; 0.90-0.98 for LMR). Our study pinpoints the differential role of innate and adaptive immunity in dementia incidence, which may provide some new perspectives in etiology and therapy of dementia.