👤 Members of the Alzheimers Disease Neuroimaging Initiative

Sex hormone-binding globulin (SHBG), which regulates androgen and estrogen bioavailability, has been linked to cognitive decline, but its relationship with temporal lobe changes-an area vulnerable in early Alzheimer's disease (AD)-remains unclear. This study aimed to investigate whether plasma SHBG levels are associated with temporal lobe volume and cognitive performance across the cognitive spectrum from normal aging to AD. Participants included individuals with AD (n = 85), mild cognitive impairment (MCI; n = 304), and cognitively normal controls (CN; n = 50). Cognitive performance was assessed using the ADAS-Cog 11, MMSE, and CDR-SB. Temporal lobe volumes were derived from MRI scans using tensor-based morphometry (TBM), and plasma SHBG levels were measured using a validated immunoassay. Multiple regression analyses adjusted for age, sex, education, handedness, and APOE ε4 status were conducted, followed by mediation analysis to test indirect effects through temporal lobe volume. After covariate adjustment, elevated plasma SHBG levels were significantly associated with reduced temporal lobe volume in the MCI group. Across both MCI and AD participants, greater temporal lobe volume correlated with better cognitive performance on all tests. Mediation analysis indicated that in MCI, the relationship between higher plasma SHBG and poorer cognitive outcomes was significantly mediated by reduced temporal lobe volume. These findings suggest that elevated SHBG may contribute to early cognitive impairment in MCI through its impact on temporal lobe integrity, highlighting SHBG as a potential target in the prodromal stages of AD. Show less

Cost-effectiveness of Lipoprotein(a) [Lp(a)] testing is not established. We aimed to evaluate the cost-effectiveness of Lp(a) testing in the cardiovascular disease (CVD) primary prevention population from healthcare and societal perspectives. We constructed and validated a multi-state microsimulation Markov model for a population of 10,000 individuals aged between 40 and 69 years without CVD, selected randomly from the UK Biobank. The model evaluated Lp(a) testing in individuals not initially classified as high-risk based on age, diabetes status, or the SCORE-2 algorithm. Those with an Lp(a) level ≥105 nmol/L (50 mg/dL) were treated as high risk (initiation of a statin plus blood pressure lowering). The Lp(a) testing intervention was compared to standard of care. The primary analyses were conducted from the Australian and UK healthcare perspectives in 2023AUD/GBP. A cost adaptation method estimated cost-effectiveness in multiple European countries, Canada, and the USA. Among 10,000 individuals, 1,807 had their treatment modified from Lp(a) testing. This led to 217 and 255 quality-adjusted life years gained in Australia and the UK, respectively, with corresponding incremental cost-effectiveness ratios of 12,134 (cost-effective) and -3,491 (cost-saving). From a societal perspective, Lp(a) testing saved $85 and £263 per person in Australia and the UK, respectively. Lp(a) testing was cost-saving among all countries tested in the cost adaptation analysis. Lp(a) testing in the primary prevention population to reclassify CVD risk and treatment is cost-saving and warranted to prevent CVD. Show less

Posttraumatic stress disorder (PTSD) has been linked to an increased risk of cognitive impairment and dementia, with neuroinflammation, metabolic dysfunction, and neuropathologic markers such as β-amyloid and τ implicated as potential mechanisms. However, the roles of altered functional connectivity and amyloid deposition as biomarkers in the progression of cognitive impairment among patients with PTSD remain unclear, with limited and often conflicting evidence from existing neuroimaging studies. This study examines these neuroimaging markers in patients with PTSD with and without cognitive impairment to better understand the neurobiologic pathways contributing to cognitive decline in PTSD. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Department of Defense (DOD) databases. A cohort of 178 age-matched male subjects was divided into 4 groups: posttraumatic stress disorder with cognitive impairment (PTSD-CI); posttraumatic stress disorder and cognitively normal (PTSD-CN); non-posttraumatic stress disorder with cognitive impairment (NPTSD-CI); and non-posttraumatic stress disorder and cognitively normal (NPTSD-CN). All subjects underwent resting-state functional MRI and amyloid PET imaging, with PTSD diagnosis and cognitive impairment (CI) confirmed through clinical assessments. Functional connectivity was analyzed by using the CONN Toolbox, and amyloid burden was quantified via standardized uptake value ratios. Analyses controlled for demographic and genetic factors, including age, education, Compared with the NPTSD-CN group, the PTSD-CI group showed significantly increased amyloid uptake in the temporal and parietal lobes, with corresponding functional connectivity increase between the bilateral temporal lobes and parietal operculum. In contrast, PTSD-CN patients exhibited no significant amyloid increase but showed increased connectivity between the salience network, postcentral gyri, and sensorimotor areas, and decreased connectivity between the sensorimotor network and anterior cingulate cortex. These distinct patterns suggest differing neurobiologic profiles between PTSD-CI and PTSD-CN patients. The findings suggest that elevated amyloid and altered connectivity patterns are associated with cognitive impairment in PTSD, particularly in the temporal and parietal regions. In contrast, PTSD without cognitive decline was associated with functional connectivity changes in salience and sensorimotor networks but no increased amyloid deposition. This study underscores the importance of neuroimaging biomarkers in understanding PTSD-related cognitive decline and suggests avenues for further investigation into the mechanistic pathways involved. Show less

Alzheimer's disease (AD) is a highly heritable disease. The morphological changes of cortical cortex (such as, cortical thickness and surface area) in AD always accompany by the change of the functional connectivity to other brain regions and influence the short- and long-range brain network connections, causing functional deficits of AD. In this study, the first hypothesis is that genetic variations might affect morphology-based brain networks, leading to functional deficits; the second hypothesis is that protein-protein interaction (PPI) between the candidate proteins and known interacting proteins to AD might exist and influence AD. 600 470 variants and structural magnetic resonance imaging scans from 175 AD patients and 214 healthy controls were obtained from the Alzheimer's Disease Neuroimaging Initiative-1 database. A co-sparse reduced-rank regression model was fit to study the relationship between non-synonymous mutations and morphology-based brain networks. After that, PPIs between selected genes and BACE1, an enzyme that was known to be related to AD, are explored by using molecular dynamics (MD) simulation and co-immunoprecipitation (Co-IP) experiments. Eight genes affecting morphology-based brain networks were identified. The results of MD simulation showed that the PPI between TGM4 and BACE1 was the strongest among them and its interaction was verified by Co-IP. Hence, gene variations influence morphology-based brain networks in AD, leading to functional deficits. This finding, validated by MD simulation and Co-IP, suggests that the effect is robust. Show less

Contralateral brain structures represent a unique, within-patient reference element for disease, and asymmetries can provide a personalized measure of the accumulation of past disease processes. Neuroanatomical shape asymmetries have recently been associated with the progression of Alzheimer's disease (AD), but the biological basis of asymmetric brain changes in AD remains unknown. We investigated genetic influences on brain asymmetry by identifying associations between magnetic resonance imaging-derived measures of asymmetry and candidate single nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies for AD diagnosis and for brain subcortical volumes. For analyzing longitudinal neuroimaging data (1241 individuals, 6395 scans), we used a mixed effects model with interaction between genotype and diagnosis. Significant associations between asymmetry of the amygdala, hippocampus, and putamen and SNPs in the genes BIN1, CD2AP, ZCWPW1, ABCA7, TNKS, and DLG2 were found. The associations between SNPs in the genes TNKS and DLG2 and AD-related increases in shape asymmetry are of particular interest; these SNPs have previously been associated with subcortical volumes of amygdala and putamen but have not yet been associated with AD pathology. For AD candidate SNPs, we extend previous work to show that their effects on subcortical brain structures are asymmetric. This provides novel evidence about the biological underpinnings of brain asymmetry as a disease marker. Show less

We implemented least absolute shrinkage and selection operator (LASSO) regression to evaluate gene effects in genome-wide association studies (GWAS) of brain images, using an MRI-derived temporal lobe volume measure from 729 subjects scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sparse groups of SNPs in individual genes were selected by LASSO, which identifies efficient sets of variants influencing the data. These SNPs were considered jointly when assessing their association with neuroimaging measures. We discovered 22 genes that passed genome-wide significance for influencing temporal lobe volume. This was a substantially greater number of significant genes compared to those found with standard, univariate GWAS. These top genes are all expressed in the brain and include genes previously related to brain function or neuropsychiatric disorders such as MACROD2, SORCS2, GRIN2B, MAGI2, NPAS3, CLSTN2, GABRG3, NRXN3, PRKAG2, GAS7, RBFOX1, ADARB2, CHD4, and CDH13. The top genes we identified with this method also displayed significant and widespread post hoc effects on voxelwise, tensor-based morphometry (TBM) maps of the temporal lobes. The most significantly associated gene was an autism susceptibility gene known as MACROD2. We were able to successfully replicate the effect of the MACROD2 gene in an independent cohort of 564 young, Australian healthy adult twins and siblings scanned with MRI (mean age: 23.8 ± 2.2 SD years). Our approach powerfully complements univariate techniques in detecting influences of genes on the living brain. Show less