Association between Alzheimer's disease genes and trajectories of cognitive function decline in Han Chinese in Taiwan.
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ABSTRACT:
SUBMITTER: Hsieh TJ
PROVIDER: S-EPMC8312434 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alzheimer's disease (AD) is characterised by a dynamic process of neurocognitive changes from normal cognition to mild cognitive impairment (MCI) and progression to dementia. However, not all individuals with MCI develop dementia. Predicting whether individuals with MCI will decline (i.e. progressive MCI) or remain stable (i.e. stable MCI) is impeded by patient heterogeneity due to comorbidities that may lead to MCI diagnosis without progression to AD. Despite the importance of early diagnosis of AD for prognosis and personalised interventions, we still lack robust tools for predicting individual progression to dementia. Here, we propose a novel trajectory modelling approach based on metric learning (Generalised Metric Learning Vector Quantization) that mines multimodal data from MCI patients in the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort to derive individualised prognostic scores of cognitive decline due to AD. We develop an integrated biomarker generation- using partial least squares regression- and classification methodology that extends beyond binary patient classification into discrete subgroups (i.e. stable vs. progressive MCI), determines individual profiles from baseline (i.e. cognitive or biological) data and predicts individual cognitive trajectories (i.e. change in memory scores from baseline). We demonstrate that a metric learning model trained on baseline cognitive data (memory, executive function, affective measurements) discriminates stable vs. progressive MCI individuals with high accuracy (81.4%), revealing an interaction between cognitive (memory, executive functions) and affective scores that may relate to MCI comorbidity (e.g. affective disturbance). Training the model to perform the same binary classification on biological data (mean cortical ?-amyloid burden, grey matter density, APOE 4) results in similar prediction accuracy (81.9%). Extending beyond binary classifications, we develop and implement a trajectory modelling approach that shows significantly better performance in predicting individualised rate of future cognitive decline (i.e. change in memory scores from baseline), when the metric learning model is trained with biological (r = -0.68) compared to cognitive (r = -0.4) data. Our trajectory modelling approach reveals interpretable and interoperable markers of progression to AD and has strong potential to guide effective stratification of individuals based on prognostic disease trajectories, reducing MCI patient misclassification, that is critical for clinical practice and discovery of personalised interventions.
| S-EPMC7044529 | biostudies-literature
Project description:ImportanceUnderstanding mechanisms associated with prolonged cognitive health in combination with exceptional longevity might lead to approaches to enable successful aging.ObjectiveTo investigate trajectories of cognitive functioning in centenarians across domains, and to examine the association of these trajectories with factors underlying cognitive reserve, physical health, and postmortem levels of Alzheimer disease (AD)-associated neuropathology.Design, setting, and participantsThis cohort study used neuropsychological test data and postmortem neuropathological reports from Dutch centenarians who were drawn from the 100-plus Study between January 2013 and April 2019. Eligible participants self-reported being cognitively healthy, which was confirmed by a proxy. Data analysis was performed between June 2019 and June 2020.ExposuresAge, sex, APOE ε genotype, factors of cognitive reserve, physical health, and AD-associated neuropathology (ie, amyloid-β, neurofibrillary tangles, and neuritic plaques).Main outcomes and measuresIn annual visits (until death or until participation was no longer possible), centenarians underwent an extensive neuropsychological test battery, from which an mean z score of global cognition, memory, executive functions, verbal fluency, visuospatial functions, and attention/processing speed was calculated. Linear mixed models with a random intercept and time as independent variable were used to investigate cognitive trajectories, adjusted for sex, age, education, and vision and hearing capacities. In a second step, linear mixed models were used to associate cognitive trajectories with factors underlying cognitive reserve, physical health at baseline, and AD-associated neuropathology.ResultsOf the 1023 centenarians approached, 340 were included in the study. We analyzed 330 centenarians for whom cognitive tests were available at baseline (239 [72.4%] women; median [interquartile range] age of 100.5 [100.2-101.7] years), with a mean (SD) follow-up duration of 1.6 (0.8) years. We observed no decline across investigated cognitive domains, with the exception of a slight decline in memory function (β, -0.10 SD per year; 95% CI, -0.14 to -0.05 SD; P < .001). Cognitive performance was associated with factors of physical health (eg, higher Barthel index: β, 0.37 SD per year; 95% CI, 0.24-0.49; P < .001) and cognitive reserve (eg, higher education: β, 0.41 SD per year; 95% CI, 0.29-0.53; P < .001), but none of these factors were associated with the rate of decline. Neuropathological reports were available for 44 participants. While centenarian brains revealed varying loads of postmortem neuropathological hallmarks of AD, this was not associated with cognitive performance or rate of decline.Conclusions and relevanceWhile we observed a slight vulnerability for decline in memory function, centenarians maintained high levels of performance in all other investigated cognitive domains for up to 4 years despite the presence of risk factors of cognitive decline. These findings suggest that mechanisms of resilience may underlie the prolongation of cognitive health until exceptional ages.
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Project description:Alzheimer's disease (AD) is the most common cause of dementia. Mitochondrial dysfunction has been widely reported in AD due to its important role in cellular metabolism and energy production. Complex IV (cytochrome c oxidase, COX) of mitochondrial electron transport chain, is particularly vulnerable in AD. Defects of COX in AD have been well documented, but there is little evidence to support the genetic association of the COX-related genes with AD. In this study, we investigated the genetic association between 17 nuclear-encoded COX-related genes and AD in 1572 Han Chinese. The whole exons of these genes were also screened in 107 unrelated AD patients with a high probability of hereditarily transmitted AD. Variants in COX6B1, NDUFA4, SURF1, and COX10 were identified to be associated with AD. An integrative analysis with data of eQTL, expression and pathology revealed that most of the COX-related genes were significantly downregulated in AD patients and mouse models, and the AD-associated variants in COX6B1, SURF1, and COX10 were linked to altered mRNA levels in brain tissues. Furthermore, mRNA levels of Ndufa4, Cox5a, Cox10, Cox6b2, Cox7a2, and Lrpprc were significantly correlated with A? plaque burden in hippocampus of AD mice. Convergent functional genomics analysis revealed strong supportive evidence for the roles of COX6B1, COX10, NDUFA4, and SURF1 in AD. As the result of our comprehensive analysis of the COX-related genes at the genetic, expression, and pathology levels, we have been able to provide a systematic view for understanding the relationships of the COX-related genes in the pathology of AD.
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Project description:Older adults with subjective cognitive decline are at increased risk of future pathological cognitive decline and dementia. Subjective memory decline is an early sign of cognitive decline; preventing or slowing cognitive decline in at-risk populations remains an elusive issue. This study aimed to examine the cognitive trajectories and factors in older adults with subjective memory decline. Latent growth curve models (LGCMs) were fitted to examine the cognitive function trajectories and factors among 1465 older adults (aged 60+ years) with subjective memory decline. Data were obtained from four waves from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018), which is a large nationally representative sample of the Chinese population. The results showed that older adults with better initial cognition had a slower decline rate, which may be accelerated by advanced age, low-level education, a rapid decrease in instrumental activities of daily living (IADL) ability, and rapid increase in depression levels. This study was the first to examine the trajectories of cognitive function and its factors in a high-risk population with subjective memory decline. These findings may guide prevention approaches to tackle the issues of cognitive function decline and dementia.
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Project description:Elevated triglyceride glucose (TyG) index is associated with an increased risk of cardiovascular disease. The current study aimed to investigate whether the TyG index was correlated with renal function decline in patients with hypertension. Han Chinese participants with essential hypertension were included. The TyG index was calculated as ln[fasting triglycerides (mg/dL) * fasting glucose (mg/dL)/2]. Renal function decline was defined as >25% decline in estimated glomerular filtration rate (eGFR). The Cox proportional hazard regression model was used to examine the independent effect of the TyG index on renal events. In total, 548 Han Chinese hypertensive participants with a mean age of 62.1 ± 14.3 years were eligible for enrollment. During a mean follow-up period of 4.7 ± 3.1 years, 97 patients suffered from >25% decline in eGFR. When compared to those without eGFR decline, patients with eGFR decline had higher fasting triglyceride levels (P = .056), fasting glucose levels (P = .014), and TyG indexes (P = .014). The Cox proportional hazard regression model revealed that the TyG index (hazard ratio [HR] = 1.490; 95% confidence interval [CI] = 1.016-2.185, P = .041), office systolic blood pressure (HR = 1.013; 95% CI = 1.000-1.026, P = .047), diabetes mellitus (HR = 1.797, 95% CI = 1.026-3.147, P = .040), and baseline eGFR (HR = 1.015; 95% CI = 1.002-1.028, P = .025) were associated with renal events. In conclusions, an elevated TyG index is independently associated with an increased risk of eGFR decline in hypertensive patients.
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Project description:The trajectory of cognitive decline in patients with late-onset Alzheimer's disease varies widely. Genetic variations in CLU, PICALM, and CR1 are associated with Alzheimer's disease, but it is unknown whether they exert their effects by altering cognitive trajectory in elderly individuals at risk for the disease.The authors developed a Bayesian model to fit cognitive trajectories in a cohort of elderly subjects and test for genetic effects. They first validated the model's ability to detect the previously established effects of APOE ?4 alleles on age at cognitive decline and of psychosis on the rate of cognitive decline in 802 subjects from the Cardiovascular Health Cognition Study who did not have dementia at study entry and developed incident dementia during follow-up. The authors then evaluated the effects of CLU, PICALM, and CR1 on age and rate of decline in 1,831 subjects who did not have dementia at study entry and then did or did not develop incident dementia by study's end.The model generated robust fits to the observed cognitive trajectory data, and validation analysis supported the model's utility. CLU and CR1 were associated with more rapid cognitive decline. PICALM was associated with an earlier age at midpoint of cognitive decline. Associations remained after accounting for the effects of APOE and demographic factors.Evaluation of cognitive trajectories provides a powerful approach to dissecting genetic effects on the processes leading to cognitive deterioration and Alzheimer's disease.
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Project description:It has been proposed that immune abnormalities may be implicated with pathophysiology of schizophrenia. The nod-like receptor pyrin domain-contraining protein 3 (NLRP3) can trigger immune-inflammatory cascade reactions. In this study, we intended to identify the role of gene encoding NLRP3 (NLRP3) in susceptibility to schizophrenia and its clinical features. For the NLRP3 mRNA expression analysis, 53 drug-naïve patients with first-episode schizophrenia and 56 healthy controls were enrolled. For the genetic study, a total of 823 schizophrenia patients and 859 controls were recruited. Among them, 239 drug-naïve patients with first-episode schizophrenia were enrolled for clinical evaluation. There is no significant difference in NLRP3 mRNA levels between patients with schizophrenia and healthy controls (p = 0.07). We did not observe any significant differences in allele and genotype frequencies of rs10754558 polymorphism between the schizophrenia and control groups. We noticed significant differences in the scores of RBANS attention and total scores between the patients with different genotypes of rs10754558 polymorphism (p = 0.001 and p < 0.01, respectively). Further eQTL analysis presented a significant association between the rs10754558 polymorphism and NLRP3 in frontal cortex (p = 0.0028, p = 0.028 after Bonferroni correction). Although our findings did not support NLRP3 confer susceptibility to schizophrenia, NLRP3 may be a risk factor for cognitive impairment, especially attention deficit in this disorder.
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Project description:The association of dementia-related pathologies with cognition is hypothesized to decrease as age advances. We examined this in 413 persons without cognitive impairment at baseline who completed annual cognitive evaluations during a mean of 10.4 years. After death, neuropathologic examinations quantified beta amyloid plaque load, neurofibrillary tangles, and transactive response DNA-binding protein 43 pathology, and identified Lewy bodies, hippocampal sclerosis, and gross and microscopic cerebral infarcts. We tested whether age at death modified associations of these neuropathologies with the nonlinear trajectory of cognitive decline using mixed-effects change point models. The rate of global cognitive decline was gradual at first and then increased approximately 10-fold in the last 3 years of life. After adjustment for all other pathologic indices, tangle density, gross infarcts, Lewy bodies, and transactive response DNA-binding protein 43 were associated with global cognitive decline. However, the deleterious association of dementia-related pathologies with cognitive decline did not systematically vary by age. This suggests that the neuropathologic mechanisms underlying late-life cognitive decline do not substantially differ across the spectrum of age.
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Project description:The sortilin-related receptor 1 (SORL1) gene, regulating the trafficking and recycling of amyloid precursor protein, has been related to Alzheimer's disease (AD) and mild cognitive impairment (MCI). The aim of the present study was to investigate the relationship between SORL1 polymorphisms, plasma concentrations of amyloid-beta (A?) isoforms, and AD and MCI susceptibility for a Han Chinese population in Taiwan.Eight single-nucleotide polymorphisms (SNPs) in SORL1 and the apolipoprotein E gene (APOE) ?4 alleles were genotyped in 798 patients with AD, 157 patients with MCI, and 401 control subjects. Plasma concentrations of A?42, A?40, and neuropsychiatric tests for six different cognitive domains were examined.Among the eight tested SNPs, SORL1 rs1784933 was most significantly associated with AD and MCI in our population. The G allele of rs1784933 exerted a protective effect and was associated with a reduced risk of AD (odds ratio [OR]?=?0.75, p?=?0.004) and MCI (OR?=?0.69, p?=?0.013). The significance remained after we adjusted for age, sex, and APOE ?4 alleles. For the overall participants, the plasma concentrations of A?42 were nominally significant for subjects carrying the rs1784933 G allele having a lower level than those without the G allele (p?=?0.046). There was a similar trend for the G allele carriers to have a lower plasma A?40 level than noncarriers, but this was not significant. The nonsynonymous SNP rs2298813 was also related to a lower disease risk when AD and MCI were combined as a group (OR?=?0.76, p?=?0.035). However, there was no association between SORL1 genotypes and any of the six cognitive tests.Findings from our study provide support for the effect of SORL1 gene on the disease risks and pathognomonic surrogates of AD/MCI. The interaction between SORL1 polymorphisms and A? formation requires further study.
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