Biology subjects

Tan, C. H.

Publications and source records attributed to Tan, C. H..

3 recordsLinked to original sources

bioRxiv2018

Lipid associated polygenic enrichment in Alzheimer’s disease

Cardiovascular (CV) and lifestyle associated risk factors (RFs) are increasingly recognized as important for Alzheimers disease (AD) pathogenesis. Beyond the [isin]4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV associated genes also increase risk for AD (genetic pleiotropy). Using large genome-wide association studies (GWASs) (total n > 500,000 cases and controls) and validated tools to quantify genetic pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 57 SNPs on 19 different chromosomes that were jointly associated with AD and CV outcomes including APOA4, ABCA1, ABCG5, LIPG, and MTCH2/SPI1. We found that common genetic variants influencing AD are associated with multiple CV RFs, at times with a different directionality of effect. Expression of these AD/CV pleiotropic genes was enriched for lipid metabolism processes, over-represented within astrocytes and vascular structures, highly co-expressed, and differentially altered within AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid associated RFs. Rather than a single causal link between genetic loci, RF and the outcome, we found that common genetic variants influencing AD are associated with multiple CV RFs. Our collective findings suggest that a network of genes involved in lipid biology also influence Alzheimers risk.

genetics↗

bioRxiv2017

Polygenic hazard score: an enrichment marker for Alzheimer’s associated amyloid and tau deposition

BackgroundThere is an urgent need for the early identification of nondemented individuals at the highest risk of progressing to Alzheimers disease (AD) dementia for early therapeutic interventions. Our goal was to evaluate whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo CSF or PET biomarkers of amyloid or tau pathology to prospectively predict cognitive decline and clinical progression to AD dementia in nondemented older individuals.\n\nMethodsWe evaluated 347 cognitive normal (CN) and 599 mild cognitively impaired (MCI) individuals. We first investigated whether PHS can predict CSF or PET amyloid and tau deposition. We evaluated differences in positive and negative predictive values of biomarker status, as a function of PHS risk. Next, we used linear mixed-effects (LME) to examine if PHS and biomarker status in conjunction, best predict longitudinal cognitive and clinical progression. Lastly, we used survival analysis to investigate whether a combination of PHS and biomarker positivity predicts progression to AD dementia better than using PHS or biomarker positivity alone.\n\nFindingsIn CN and MCI individuals, we found that amyloid and total tau positivity systematically varies as a function of PHS. For individuals in greater than the 50th percentile PHS, the positive predictive value for amyloid approached 100%. Similarly, for individuals in less than the 25th percentile PHS, the negative predictive value for total tau approached 85%. Beyond APOE, high PHS individuals with amyloid and tau pathology showed the fastest rate of longitudinal cognitive decline and time to AD dementia progression. Among the CN subgroup, we similarly found that PHS was strongly associated with amyloid positivity and the combination of PHS and biomarker status significantly predicted longitudinal clinical progression.\n\nInterpretationAmong asymptomatic and mildly symptomatic older individuals, PHS considerably improves the predictive value of CSF or PET amyloid and tau biomarkers. Beyond APOE, PHS may be useful for risk stratification and cohort enrichment for MCI and preclinical AD therapeutic trials.

genetics↗

bioRxiv2017

Polygenic hazard scores in preclinical Alzheimer’s disease

Identifying asymptomatic older individuals at elevated risk for developing Alzheimers disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE {varepsilon}4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high CERAD (amyloid) and Braak (tau) scores at autopsy, even among APOE {varepsilon}4 non-carriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimers neurodegeneration.

genetics↗