Distinct spatiotemporal patterns of cortical thinning in Alzheimer's disease-type cognitive impairment and subcortical vascular cognitive impairment.

Previous studies on Alzheimer's disease-type cognitive impairment (ADCI) and subcortical vascular cognitive impairment (SVCI) has rarely explored spatiotemporal heterogeneity. This study aims to identify distinct spatiotemporal cortical atrophy patterns in ADCI and SVCI. 1,338 participants (713 ADCI, 208 SVCI, and 417 cognitively unimpaired elders) underwent brain magnetic resonance imaging (MRI), amyloid positron emission tomography, and neuropsychological tests. Using MRI, this study measures cortical thickness in five brain regions (medial temporal, inferior temporal, posterior medial parietal, lateral parietal, and frontal areas) and utilizes the Subtype and Stage Inference (SuStaIn) model to predict the most probable subtype and stage for each participant. SuStaIn identifies two distinct cortical thinning patterns in ADCI (medial temporal: 65.8%, diffuse: 34.2%) and SVCI (frontotemporal: 47.1%, parietal: 52.9%) patients. The medial temporal subtype of ADCI shows a faster decline in attention, visuospatial, visual memory, and frontal/executive domains than the diffuse subtype (p-value < 0.01). However, there are no significant differences in longitudinal cognitive outcomes between the two subtypes of SVCI. Our study provides valuable insights into the distinct spatiotemporal patterns of cortical thinning in patients with ADCI and SVCI, suggesting the potential for individualized therapeutic and preventive strategies to improve clinical outcomes.

Association of Glycemic Variability With Imaging Markers of Vascular Burden, ß-Amyloid, Brain Atrophy, and Cognitive Impairment.

BACKGROUND AND OBJECTIVE: We aimed to investigate the association between glycemic variability (GV) and neuroimaging markers of white matter hyperintensities (WMH), beta-amyloid (Aß), brain atrophy, and cognitive impairment. METHODS: This was a retrospective cohort study that included participants without dementia from a memory clinic. They all had Aß PET, brain MRI, and standardized neuropsychological tests and had fasting glucose (FG) levels tested more than twice during the study period. We defined GV as the intraindividual visit-to-visit variability in FG levels. Multivariable linear regression and logistic regression were used to identify whether GV was associated with the presence of severe WMH and Aß uptake with DM, mean FG levels, age, sex, hypertension, and presence of APOE4 allele as covariates. Mediation analyses were used to investigate the mediating effect of WMH and Aß uptake on the relationship between GV and brain atrophy and cognition. RESULTS: Among the 688 participants, the mean age was 72.2 years, and the proportion of female participants was 51.9%. Increase in GV was predictive of the presence of severe WMH (coefficient [95% CI] 1.032 [1.012-1.054]; p = 0.002) and increased Aß uptake (1.005 [1.001-1.008]; p = 0.007). Both WMH and increased Aß uptake partially mediated the relationship between GV and frontal-executive dysfunction (GV → WMH → frontal-executive; direct effect, -0.319 [-0.557 to -0.080]; indirect effect, -0.050 [-0.091 to -0.008]) and memory dysfunction (GV → Aß â†’ memory; direct effect, -0.182 [-0.338 to -0.026]; indirect effect, -0.067 [-0.119 to -0.015]), respectively. In addition, increased Aß uptake completely mediated the relationship between GV and hippocampal volume (indirect effect, -1.091 [-2.078 to -0.103]) and partially mediated the relationship between GV and parietal thickness (direct effect, -0.00101 [-0.00185 to -0.00016]; indirect effect, -0.00016 [-0.00032 to -0.000002]). DISCUSSION: Our findings suggest that increased GV is related to vascular and Alzheimer risk factors and neurodegenerative markers, which in turn leads to subsequent cognitive impairment. Furthermore, GV can be considered a potentially modifiable risk factor for dementia prevention.

Transcriptional risk scores in Alzheimer's disease: From pathology to cognition.

INTRODUCTION: Our previously developed blood-based transcriptional risk scores (TRS) showed associations with diagnosis and neuroimaging biomarkers for Alzheimer's disease (AD). Here, we developed brain-based TRS. METHODS: We integrated AD genome-wide association study summary and expression quantitative trait locus data to prioritize target genes using Mendelian randomization. We calculated TRS using brain transcriptome data of two independent cohorts (N = 878) and performed association analysis of TRS with diagnosis, amyloidopathy, tauopathy, and cognition. We compared AD classification performance of TRS with polygenic risk scores (PRS). RESULTS: Higher TRS values were significantly associated with AD, amyloidopathy, tauopathy, worse cognition, and faster cognitive decline, which were replicated in an independent cohort. The AD classification performance of PRS was increased with the inclusion of TRS up to 16% with the area under the curve value of 0.850. DISCUSSION: Our results suggest brain-based TRS improves the AD classification of PRS and may be a potential AD biomarker. HIGHLIGHTS: Transcriptional risk score (TRS) is developed using brain RNA-Seq data. Higher TRS values are shown in Alzheimer's disease (AD). TRS improves the AD classification power of PRS up to 16%. TRS is associated with AD pathology presence. TRS is associated with worse cognitive performance and faster cognitive decline.

Clinical and Pathological Validation of CT-Based Regional Harmonization Methods of Amyloid PET.

PURPOSE: The CT-based regional direct comparison Centiloid (dcCL) method was developed to harmonize and quantify regional ß-amyloid (Aß) burden. In the present study, we aimed to investigate correlations between the CT-based regional dcCL scales and Aß pathological burdens and to validate the clinical utility using thresholds derived from pathological assessment. PATIENTS AND METHODS: We included a pathological cohort of 63 cases and a clinical cohort of 4062 participants, and obtained modified Consortium to Establish a Registry for Alzheimer's Disease criteria (mCERAD) scores by assessment of neuritic plaque burdens in multiple areas of each cortical region. PET and CT images were processed using the CT-based regional dcCL method to calculate scales in 6 distinct regions. RESULTS: The CT-based regional dcCL scales were correlated with neuritic plaque burdens represented by mCERAD scores, globally and regionally ( r = 0.56~0.76). In addition, striatum dcCL scales reflected Aß involvement in the striatum ( P < 0.001). The regional dcCL scales could predict significant Aß deposition in specific brain regions with high accuracy: area under the receiver operating characteristic curve of 0.81-0.97 with an mCERAD cutoff of 1.5 and area under the receiver operating characteristic curve of 0.88-0.93 with an mCERAD cutoff of 0.5. When applying the dcCL thresholds of 1.5 mCERAD scores, the G(-)R(+) group showed lower performances in memory and global cognitive functions and had less hippocampal volume compared with the G(-)R(-) group ( P < 0.001). However, when applying the dcCL thresholds of 0.5 mCERAD scores, there were no differences in the global cognitive functions between the 2 groups. CONCLUSIONS: The thresholds of regional dcCL scales derived from pathological assessments might provide clinicians with a better understanding of biomarker-guided diagnosis and distinguishable clinical phenotypes, which are particularly useful when harmonizing different PET ligands with only PET/CT.

Distinct effects of cholesterol profile components on amyloid and vascular burdens.

BACKGROUND: Cholesterol plays important roles in ß-amyloid (Aß) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aß and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aß and CSVD burdens in a large, non-demented Korean cohort. METHODS: We enrolled 1,175 non-demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aß PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low-density lipoprotein cholesterol [LDL-c], high-density lipoprotein cholesterol [HDL-c], and triglyceride) level as a predictor and each image marker (Aß uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders. RESULTS: Increased LDL-c levels (ß = 0.014 to 0.115, p = 0.013) were associated with greater Aß uptake, independent of the APOE e4 allele genotype and lipid-lowering medication. Decreased HDL-c levels (ß = - 0.133 to - 0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL-c levels were also associated with decreased hippocampal volume (direct effect ß = - 0.053, p = 0.040), which was partially mediated by Aß uptake (indirect effect ß = - 0.018, p = 0.006). CONCLUSIONS: Our findings highlight that increased LDL-c and decreased HDL-c levels are important risk factors for Aß and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL-c and HDL-c levels is a potential strategy to prevent dementia.

Sex-specific relationship between non-alcoholic fatty liver disease and amyloid-ß in cognitively unimpaired individuals.

Background: Non-alcoholic fatty liver disease (NAFLD) is known to be associated with a high risk of clinically diagnosed Alzheimer's disease (AD). Additionally, the prevalence of NAFLD and AD is higher in elderly females than in males. However, a sex-specific association between NAFLD and amyloid-beta (Aß) deposition remains unclear. Therefore, we investigated the sex-specific relationship between NAFLD and Aß deposition in a large-sized cohort of cognitively unimpaired (CU) individuals. Methods: We enrolled 673 (410 [60.9%] females and 263 [39.1%] males) CU individuals aged ≥45 years who underwent Aß positron emission tomography (PET). The presence of NAFLD, assessed using the hepatic steatosis index, and the severity of NAFLD, assessed using the Fibrosis-4 index, were considered predictors. Aß deposition on PET was considered as an outcome. Results: Females had a higher frequency of NAFLD than males (48 and 23.2%, p < 0.001). Among females, the presence of NAFLD (ß = 0.216, p < 0.001) was predictive of increased Aß deposition, whereas among males, the presence of NAFLD (ß = 0.191, p = 0.064) was not associated with Aß deposition. Among females, the presence of NAFLD with low (ß = 0.254, p = 0.039), intermediate (ß = 0.201, p = 0.006), and high fibrosis (ß = 0.257, p = 0.027) was predictive of increased Aß deposition. Aß deposition also increased as the severity of NAFLD increased in females (p for trend = 0.001). Conclusion: We highlight the marked influence of NAFLD and its severity on the risk of Aß deposition in relation to sex. Furthermore, our findings suggest that sex-specific strategies regarding the management of NAFLD are necessary for the prevention of Aß deposition.

Clinical effects of novel susceptibility genes for beta-amyloid: a gene-based association study in the Korean population.

Amyloid-beta (Aß) is a pathological hallmark of Alzheimer's disease (AD). We aimed to identify genes related to Aß uptake in the Korean population and investigate the effects of these novel genes on clinical outcomes, including neurodegeneration and cognitive impairments. We recruited a total of 759 Korean participants who underwent neuropsychological tests, brain magnetic resonance imaging, 18F-flutemetamol positron emission tomography, and microarray genotyping data. We performed gene-based association analysis, and also performed expression quantitative trait loci and network analysis. In genome-wide association studies, no single nucleotide polymorphism (SNP) passed the genome-wide significance threshold. In gene-based association analysis, six genes (LCMT1, SCRN2, LRRC46, MRPL10, SP6, and OSBPL7) were significantly associated with Aß standardised uptake value ratio in the brain. The three most significant SNPs (rs4787307, rs9903904, and rs11079797) on these genes are associated with the regulation of the LCMT1, OSBPL7, and SCRN2 genes, respectively. These SNPs are involved in decreasing hippocampal volume and cognitive scores by mediating Aß uptake. The 19 enriched gene sets identified by pathway analysis included axon and chemokine activity. Our findings suggest novel susceptibility genes associated with the uptake of Aß, which in turn leads to worse clinical outcomes. Our findings might lead to the discovery of new AD treatment targets.

Sex differences in the structural rich-club connectivity in patients with Alzheimer's disease.

Background and objectives: Alzheimer's disease (AD) is more prevalent in women than in men; however, there is a discrepancy in research on sex differences in AD. The human brain is a large-scale network with hub regions forming a central core, the rich-club, which is vital to cognitive functions. However, it is unknown whether alterations in the rich-clubs in AD differ between men and women. We aimed to investigate sex differences in the rich-club organization in the brains of patients with AD. Methods: In total, 260 cognitively unimpaired individuals with negative amyloid positron emission tomography (PET) scans, 281 with prodromal AD (mild cognitive impairment due to AD) and 285 with AD dementia who confirmed with positive amyloid PET scans participated in the study. We obtained high-resolution T1-weighted and diffusion tensor images and performed network analysis. Results: We observed sex differences in the rich-club and feeder connections in patients with AD, suggesting lower structural connectivity strength in women than in men. We observed a significant group-by-sex interaction in the feeder connections, particularly in the thalamus. In addition, the connectivity strength of the thalamus in the feeder connections was significantly correlated with general cognitive function in only men with prodromal AD and women with AD dementia. Conclusion: Our findings provide important evidence for sex-specific alterations in the structural brain network related to AD.

Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer's and concomitant cerebrovascular burdens.

OBJECTIVES: Alzheimer's disease (AD) is characterised by amyloid-beta accumulation (A), tau aggregation (T) and neurodegeneration (N). Vascular (V) burden has been found concomitantly with AD pathology and has synergistic effects on cognitive decline with AD biomarkers. We determined whether cognitive trajectories of AT(N) categories differed according to vascular (V) burden. METHODS: We prospectively recruited 205 participants and classified them into groups based on the AT(N) system using neuroimaging markers. Abnormal V markers were identified based on the presence of severe white matter hyperintensities. RESULTS: In A+ category, compared with the frequency of Alzheimer's pathological change category (A+T-), the frequency of AD category (A+T+) was significantly lower in V+ group (31.8%) than in V- group (64.4%) (p=0.004). Each AT(N) biomarker was predictive of cognitive decline in the V+ group as well as in the V- group (p<0.001). Additionally, the V+ group showed more severe cognitive trajectories than the V- group in the non-Alzheimer's pathological changes (A-T+, A-N+; p=0.002) and Alzheimer's pathological changes (p<0.001) categories. CONCLUSION: The distribution and longitudinal outcomes of AT(N) system differed according to vascular burdens, suggesting the importance of incorporating a V biomarker into the AT(N) system.

Circulating lipid profiles are associated with cross-sectional and longitudinal changes of central biomarkers for Alzheimer's disease.

Investigating the association of lipidome profiles with central Alzheimer's disease (AD) biomarkers, including amyloid/tau/neurodegeneration (A/T/N), can provide a holistic view between the lipidome and AD. We performed cross-sectional and longitudinal association analysis of serum lipidome profiles with AD biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort (N=1,395). We identified lipid species, classes, and network modules that were significantly associated with cross-sectional and longitudinal changes of A/T/N biomarkers for AD. Notably, we identified the lysoalkylphosphatidylcholine (LPC(O)) as associated with "A/N" biomarkers at baseline at lipid species, class, and module levels. Also, GM3 ganglioside showed significant association with baseline levels and longitudinal changes of the "N" biomarkers at species and class levels. Our study of circulating lipids and central AD biomarkers enabled identification of lipids that play potential roles in the cascade of AD pathogenesis. Our results suggest dysregulation of lipid metabolic pathways as precursors to AD development and progression.

Identifying genetic variants for amyloid ß in subcortical vascular cognitive impairment.

Background: The genetic basis of amyloid ß (Aß) deposition in subcortical vascular cognitive impairment (SVCI) is still unknown. Here, we investigated genetic variants involved in Aß deposition in patients with SVCI. Methods: We recruited a total of 110 patients with SVCI and 424 patients with Alzheimer's disease-related cognitive impairment (ADCI), who underwent Aß positron emission tomography and genetic testing. Using candidate AD-associated single nucleotide polymorphisms (SNPs) that were previously identified, we investigated Aß-associated SNPs that were shared or distinct between patients with SVCI and those with ADCI. Replication analyses were performed using the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Rush Memory and Aging Project cohorts (ROS/MAP). Results: We identified a novel SNP, rs4732728, which showed distinct associations with Aß positivity in patients with SVCI (P interaction = 1.49 × 10-5); rs4732728 was associated with increased Aß positivity in SVCI but decreased Aß positivity in ADCI. This pattern was also observed in ADNI and ROS/MAP cohorts. Prediction performance for Aß positivity in patients with SVCI increased (area under the receiver operating characteristic curve = 0.780; 95% confidence interval = 0.757-0.803) when rs4732728 was included. Cis-expression quantitative trait loci analysis demonstrated that rs4732728 was associated with EPHX2 expression in the brain (normalized effect size = -0.182, P = 0.005). Conclusion: The novel genetic variants associated with EPHX2 showed a distinct effect on Aß deposition between SVCI and ADCI. This finding may provide a potential pre-screening marker for Aß positivity and a candidate therapeutic target for SVCI.

Clinical outcomes of increased focal amyloid uptake in individuals with subthreshold global amyloid levels.

Background: Although the standardized uptake value ratio (SUVR) method is objective and simple, cut-off optimization using global SUVR values may not reflect focal increased uptake in the cerebrum. The present study investigated clinical and neuroimaging characteristics according to focally increased ß-amyloid (Aß) uptake and global Aß status. Methods: We recruited 968 participants with cognitive continuum. All participants underwent neuropsychological tests and 498 18F-florbetaben (FBB) amyloid positron emission tomography (PET) and 470 18F-flutemetamol (FMM) PET. Each PET scan was assessed in 10 regions (left and right frontal, lateral temporal, parietal, cingulate, and striatum) with focal-quantitative SUVR-based cutoff values for each region by using an iterative outlier approach. Results: A total of 62 (6.4%) subjects showed increased focal Aß uptake with subthreshold global Aß status [global (-) and focal (+) Aß group, G(-)F(+) group]. The G(-)F(+) group showed worse performance in memory impairment (p < 0.001), global cognition (p = 0.009), greater hippocampal atrophy (p = 0.045), compared to those in the G(-)F(-). Participants with widespread Aß involvement in the whole region [G(+)] showed worse neuropsychological (p < 0.001) and neuroimaging features (p < 0.001) than those with focal Aß involvement G(-)F(+). Conclusion: Our findings suggest that individuals show distinctive clinical outcomes according to focally increased Aß uptake and global Aß status. Thus, researchers and clinicians should pay more attention to focal increased Aß uptake in addition to global Aß status.

Novel CYP1B1-RMDN2 Alzheimer's disease locus identified by genome-wide association analysis of cerebral tau deposition on PET.

Determining the genetic architecture of Alzheimer's disease (AD) pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we performed a genome-wide association study of cortical tau quantified by positron emission tomography in 3,136 participants from 12 independent studies. The CYP1B1-RMDN2 locus was associated with tau deposition. The most significant signal was at rs2113389, which explained 4.3% of the variation in cortical tau, while APOE4 rs429358 accounted for 3.6%. rs2113389 was associated with higher tau and faster cognitive decline. Additive effects, but no interactions, were observed between rs2113389 and diagnosis, APOE4 , and Aß positivity. CYP1B1 expression was upregulated in AD. rs2113389 was associated with higher CYP1B1 expression and methylation levels. Mouse model studies provided additional functional evidence for a relationship between CYP1B1 and tau deposition but not Aß. These results may provide insight into the genetic basis of cerebral tau and novel pathways for therapeutic development in AD.

Classification and prediction of cognitive trajectories of cognitively unimpaired individuals.

Objectives: Efforts to prevent Alzheimer's disease (AD) would benefit from identifying cognitively unimpaired (CU) individuals who are liable to progress to cognitive impairment. Therefore, we aimed to develop a model to predict cognitive decline among CU individuals in two independent cohorts. Methods: A total of 407 CU individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 285 CU individuals from the Samsung Medical Center (SMC) were recruited in this study. We assessed cognitive outcomes by using neuropsychological composite scores in the ADNI and SMC cohorts. We performed latent growth mixture modeling and developed the predictive model. Results: Growth mixture modeling identified 13.8 and 13.0% of CU individuals in the ADNI and SMC cohorts, respectively, as the "declining group." In the ADNI cohort, multivariable logistic regression modeling showed that increased amyloid-ß (Aß) uptake (ß [SE]: 4.852 [0.862], p < 0.001), low baseline cognitive composite scores (ß [SE]: -0.274 [0.070], p < 0.001), and reduced hippocampal volume (ß [SE]: -0.952 [0.302], p = 0.002) were predictive of cognitive decline. In the SMC cohort, increased Aß uptake (ß [SE]: 2.007 [0.549], p < 0.001) and low baseline cognitive composite scores (ß [SE]: -4.464 [0.758], p < 0.001) predicted cognitive decline. Finally, predictive models of cognitive decline showed good to excellent discrimination and calibration capabilities (C-statistic = 0.85 for the ADNI model and 0.94 for the SMC model). Conclusion: Our study provides novel insights into the cognitive trajectories of CU individuals. Furthermore, the predictive model can facilitate the classification of CU individuals in future primary prevention trials.

Different effects of cardiometabolic syndrome on brain age in relation to gender and ethnicity.

BACKGROUND: A growing body of evidence shows differences in the prevalence of cardiometabolic syndrome (CMS) and dementia based on gender and ethnicity. However, there is a paucity of information about ethnic- and gender-specific CMS effects on brain age. We investigated the different effects of CMS on brain age by gender in Korean and British cognitively unimpaired (CU) populations. We also determined whether the gender-specific difference in the effects of CMS on brain age changes depending on ethnicity. METHODS: These analyses used de-identified, cross-sectional data on CU populations from Korea and United Kingdom (UK) that underwent brain MRI. After propensity score matching to balance the age and gender between the Korean and UK populations, 5759 Korean individuals (3042 males and 2717 females) and 9903 individuals from the UK (4736 males and 5167 females) were included in this study. Brain age index (BAI), calculated by the difference between the predicted brain age by the algorithm and the chronological age, was considered as main outcome and presence of CMS, including type 2 diabetes mellitus (T2DM), hypertension, obesity, and underweight was considered as a predictor. Gender (males and females) and ethnicity (Korean and UK) were considered as effect modifiers. RESULTS: The presence of T2DM and hypertension was associated with a higher BAI regardless of gender and ethnicity (p < 0.001), except for hypertension in Korean males (p = 0.309). Among Koreans, there were interaction effects of gender and the presence of T2DM (p for T2DM*gender = 0.035) and hypertension (p for hypertension*gender = 0.046) on BAI in Koreans, suggesting that T2DM and hypertension are each associated with a higher BAI in females than in males. In contrast, among individuals from the UK, there were no differences in the effects of T2DM (p for T2DM*gender = 0.098) and hypertension (p for hypertension*gender = 0.203) on BAI between males and females. CONCLUSIONS: Our results highlight gender and ethnic differences as important factors in mediating the effects of CMS on brain age. Furthermore, these results suggest that ethnic- and gender-specific prevention strategies may be needed to protect against accelerated brain aging.

Contribution of clinical information to the predictive performance of plasma ß-amyloid levels for amyloid positron emission tomography positivity.

Background: Early detection of ß-amyloid (Aß) accumulation, a major biomarker for Alzheimer's disease (AD), has become important. As fluid biomarkers, the accuracy of cerebrospinal fluid (CSF) Aß for predicting Aß deposition on positron emission tomography (PET) has been extensively studied, and the development of plasma Aß is beginning to receive increased attention recently. In the present study, we aimed to determine whether APOE genotypes, age, and cognitive status increase the predictive performance of plasma Aß and CSF Aß levels for Aß PET positivity. Methods: We recruited 488 participants who underwent both plasma Aß and Aß PET studies (Cohort 1) and 217 participants who underwent both cerebrospinal fluid (CSF) Aß and Aß PET studies (Cohort 2). Plasma and CSF samples were analyzed using ABtest-MS, an antibody-free liquid chromatography-differential mobility spectrometry-triple quadrupole mass spectrometry method and INNOTEST enzyme-linked immunosorbent assay kits, respectively. To evaluate the predictive performance of plasma Aß and CSF Aß, respectively, logistic regression and receiver operating characteristic analyses were performed. Results: When predicting Aß PET status, both plasma Aß42/40 ratio and CSF Aß42 showed high accuracy (plasma Aß area under the curve (AUC) 0.814; CSF Aß AUC 0.848). In the plasma Aß models, the AUC values were higher than plasma Aß alone model, when the models were combined with either cognitive stage (p < 0.001) or APOE genotype (p = 0.011). On the other hand, there was no difference between the CSF Aß models, when these variables were added. Conclusion: Plasma Aß might be a useful predictor of Aß deposition on PET status as much as CSF Aß, particularly when considered with clinical information such as APOE genotype and cognitive stage.

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's disease related proteins.

BACKGROUND: Alzheimer's disease (AD) is neuropathologically characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The main protein components of these hallmarks include Aß40, Aß42, tau, phosphor-tau, and APOE. We hypothesize that genetic variants influence the levels and solubility of these AD-related proteins in the brain; identifying these may provide key insights into disease pathogenesis. METHODS: Genome-wide genotypes were collected from 441 AD cases, imputed to the haplotype reference consortium (HRC) panel, and filtered for quality and frequency. Temporal cortex levels of five AD-related proteins from three fractions, buffer-soluble (TBS), detergent-soluble (Triton-X = TX), and insoluble (Formic acid = FA), were available for these same individuals. Variants were tested for association with each quantitative biochemical measure using linear regression, and GSA-SNP2 was used to identify enriched Gene Ontology (GO) terms. Implicated variants and genes were further assessed for association with other relevant variables. RESULTS: We identified genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD-related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. CONCLUSIONS: Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

Integrative Co-methylation Network Analysis Identifies Novel DNA Methylation Signatures and Their Target Genes in Alzheimer's Disease.

BACKGROUND: DNA methylation is a key epigenetic marker, and its alternations may be involved in Alzheimer's disease (AD). CpGs sharing similar biological functions or pathways tend to be co-methylated. METHODS: We performed an integrative network-based DNA methylation analysis on 2 independent cohorts (N = 941) using brain DNA methylation profiles and RNA-sequencing as well as AD pathology data. RESULTS: Weighted co-methylation network analysis identified 6 modules as significantly associated with neuritic plaque burden. In total, 15 hub CpGs including 3 novel CpGs were identified and replicated as being significantly associated with AD pathology. Furthermore, we identified and replicated 4 target genes (ATP6V1G2, VCP, RAD52, and LST1) as significantly regulated by DNA methylation at hub CpGs. In particular, VCP gene expression was also associated with AD pathology in both cohorts. CONCLUSIONS: This integrative network-based multiomics study provides compelling evidence for a potential role of DNA methylation alternations and their target genes in AD.

Gender-specific relationship between thigh muscle and fat mass and brain amyloid-ß positivity.

BACKGROUND: The relationship of specific body composition in the thighs and brain amyloid-beta (Aß) deposition remained unclear, although there were growing evidence that higher muscle and fat mass in thighs had a protective effect against cardiometabolic syndromes. To determine whether muscle mass and fat mass in the thighs affected amyloid-beta (Aß) positivity differently in relation to gender, we investigated the association of muscle mass and fat mass with Aß positivity using positron emission tomography (PET) in individuals without dementia. METHODS: We recruited 240 participants (134 [55.8%] males, 106 [44.2%] females) without dementia ≥45 years of age who underwent Aß PET, bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA) scans of the hip in the health promotion center at Samsung Medical Center in Seoul, Korea. Lower extremity skeletal muscle mass index (LASMI) was measured using BIA, and gluteofemoral fat percentage (GFFP) was estimated using DEXA scans of the hip. We investigated the associations of LASMI and GFFP with Aß positivity using logistic regression analyses after controlling for age, APOE4 genotype, and cognitive stage. RESULTS: Higher muscle mass in the thighs, measured as LASMI (odds ratio [OR]=0.27, 95% confidence interval [CI] 0.08 to 0.84, p=0.031) was associated with a lesser risk of Aß positivity in only females. Higher fat mass in the thighs, measured as GFFP (OR=0.84, 95% CI 0.73 to 0.95, p=0.008) was associated with a lesser risk of Aß positivity in only males. However, the association between LAMSI (p for interaction= 0.810), GFFP (p for interaction= 0.075) and Aß positivity did not significantly differ by gender. Furthermore, LAMSI only negatively correlated with centiloid (CL) values in females (r=-0.205, p=0.037), and GFFP only negatively correlated with CL values only in males (r=-0.253, p=0.004). CONCLUSIONS: Our findings highlight the importance of recognizing that gender differences exist with respect to the specific body composition to potentially protect against Aß deposition. Therefore, our results may help in designing gender-specific strategies for controlling body composition to prevent Aß deposition.

Predicting conversion of brain ß-amyloid positivity in amyloid-negative individuals.

BACKGROUND: Cortical deposition of ß-amyloid (Aß) plaque is one of the main hallmarks of Alzheimer's disease (AD). While Aß positivity has been the main concern so far, predicting whether Aß (-) individuals will convert to Aß (+) has become crucial in clinical and research aspects. In this study, we aimed to develop a classifier that predicts the conversion from Aß (-) to Aß (+) using artificial intelligence. METHODS: Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort regarding patients who were initially Aß (-). We developed an artificial neural network-based classifier with baseline age, gender, APOE ε4 genotype, and global and regional standardized uptake value ratios (SUVRs) from positron emission tomography. Ten times repeated 10-fold cross-validation was performed for model measurement, and the feature importance was assessed. To validate the prediction model, we recruited subjects at the Samsung Medical Center (SMC). RESULTS: A total of 229 participants (53 converters) from the ADNI dataset and a total of 40 subjects (10 converters) from the SMC dataset were included. The average area under the receiver operating characteristic values of three developed models are as follows: Model 1 (age, gender, APOE ε4) of 0.674, Model 2 (age, gender, APOE ε4, global SUVR) of 0.814, and Model 3 (age, gender, APOE ε4, global and regional SUVR) of 0.841. External validation result showed an AUROC of 0.900. CONCLUSION: We developed prediction models regarding Aß positivity conversion. With the growing recognition of the need for earlier intervention in AD, the results of this study are expected to contribute to the screening of early treatment candidates.