Andrew J Saykin

Andrew J Saykin
Indiana University School of Medicine | IUSOM · Department of Radiology and Imaging Sciences

PsyD

About

1,325
Publications
149,991
Reads
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52,060
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Introduction
I serve as director of the IU Center for Neuroimaging and the Indiana Alzheimer's Disease Research Center and lead the ADNI Genetics Core. My research focuses on the use of MRI and PET, genetics and other biomarkers to better understand disease mechanisms affecting cognition with the goals of earlier detection, therapeutic target discovery and enhanced treatment monitoring as applied to prodromal AD, non-CNS cancer, brain injury, psychosis and other disorders affecting cognition.
Additional affiliations
November 2006 - present
Indiana University School of Medicine
Position
  • Raymond C. Beeler Professor of Radiology and Imaging Sciences
November 2006 - present
Indiana University-Purdue University Indianapolis
Position
  • Professor (Full)
November 2006 - present
Indiana University School of Medicine
Position
  • Raymond C. Beeler Professor of Radiology and Imaging Sciences

Publications

Publications (1,325)
Article
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Purpose Older cancer patients are susceptible to long-term effects of chemotherapy, including cancer-related cognitive decline and impairments to quality of life. Taxane-based chemotherapies are associated with physical declines among older women and may negatively impact cognitive performance. We sought to examine whether changes in objective and...
Article
Brain imaging genetics is an emerging research field aiming to reveal the genetic basis of brain traits captured by imaging data. Inspired by heritability analysis, the concept of morphometricity was recently introduced to assess trait association with whole brain morphology. In this study, we extend the concept of morphometricity from its original...
Article
Brain imaging genetics, an emerging and rapidly growing research field, studies the relationship between genetic variations and brain imaging quantitative traits (QTs) to gain new insights into the phenotypic characteristics and genetic mechanisms of the brain. Heritability is an important measurement to quantify the proportion of the observed vari...
Article
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Introduction: Analyses of off-label use of acetylcholinesterase inhibitors (AChEIs) in mild cognitive impairment (MCI) has produced mixed results. Post hoc analyses of observational cohorts, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported deleterious effects in AChEI-treated subjects (AChEI+). Here, we used neuroimagi...
Article
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The Worldwide Alzheimer's Disease Neuroimaging Initiative (WW-ADNI) is a collaborative effort to investigate imaging and biofluid markers that can inform Alzheimer's disease treatment trials. It is a public-private partnership that spans North America, Argentina, Australia, Canada, China, Japan, Korea, Mexico, and Taiwan. In 2004, ADNI researchers...
Article
Background Elevated blood pressure variability (BPV) is predictive of dementia, independent of average blood pressure levels, but neuropathological mechanisms remain unclear. We examined whether BPV in older adults is related to tau accumulation in brain regions vulnerable to Alzheimer disease and whether relationships are modified by apoϵ4 carrier...
Preprint
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Blood-brain barrier (BBB) dysfunction is well-known in Alzheimer’s disease (AD), but the precise molecular changes contributing to its pathophysiology are unclear. To understand the transcriptional changes in brain vascular cells, we performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains resulting i...
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Importance Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with persistent neurocognitive impairment (NCI) among children in Africa. Identifying blood biomarkers of acute brain injury that are associated with future NCI could allow early interventions to prevent or reduce NCI in survivors of severe malaria. Objective To inves...
Article
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Heterogeneity of brain diseases is a challenge for precision diagnosis/prognosis. We describe and validate Smile-GAN (SeMI-supervised cLustEring-Generative Adversarial Network), a semi-supervised deep-clustering method, which examines neuroanatomical heterogeneity contrasted against normal brain structure, to identify disease subtypes through neuro...
Article
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Klotho-VS heterozygosity (KL-VS het ) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VS het is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VS het and levels of beta-amyloid, a key...
Article
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Background The combinatorial effect of multiple genetic factors calculated as a polygenic risk score (PRS) has been studied to predict disease progression to Alzheimer’s disease (AD) from mild cognitive impairment (MCI). Previous studies have investigated the performance of PRS in the prediction of disease progression to AD by including and excludi...
Article
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Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of A...
Article
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Background Identifying biomarkers associated with Alzheimer’s disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between...
Article
Racial/ethnic differences in cross‐sectional assessment of cognitive test performance are well known. However, longitudinal studies of differences in cognitive decline have been mixed. The purpose of this study was to examine racial/ethnic differences in baseline and longitudinal change on the Uniform Data Set (UDS) version 3 of the NIA Alzheimer’s...
Article
Identifying biomarkers associated with Alzheimer’s disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome‐wide association studies (EWAS) have revealed correlations between DNA methylation level at cytosine‐phosphate‐guanine (CpG) sites and AD pathology in the brain or diagnosis in peripheral blood. We...
Article
Alzheimer’s disease (AD) related neurodegeneration has been correlated with metabolic dysfunction. Sphingomyelins (SM), a class of lipids found in the cell membranes especially myelin sheath, have been shown to be disrupted in AD and in other neurodegenerative diseases. Ceramides, the simplest of the sphingolipids, are known to be associated with A...
Article
A large number of genetic variations have been identified to be associated with Alzheimer’s disease (AD) and related traits. But the downstream biology through which they exert effect on the development of AD remains unknown. Leveraging genomic, transcriptomic and proteomic data, and various biological networks, we proposed a modularity‐constrained...
Article
The retinal nerve fiber layer (RNFL) is an extension of the brain that often reflects changes seen in the brain in neurodegenerative diseases. The purpose of this study was to examine the relationship of RNFL thickness measured using optical coherence tomography (OCT) with temporal lobe neurodegeneration in older adults along the Alzheimer’s diseas...
Article
The relationship between amyloid and tau deposition and episodic memory‐related brain activity is understudied. Our goal was to determine the association between brain activation on fMRI during encoding of complex scenes and amyloid and tau deposition on PET. 91 individuals from the Indiana Memory and Aging Study (36 cognitively normal (CN), 27 sub...
Article
There is increasing interest in early metabolic changes in dementia, which may reflect the effects of genetic determinants of dementia, medical history and co‐morbidity, environmental risk factors, and aging. We studied the relation of blood‐based metabolites to the risk of dementia. The analyses are conducted in 121,389 participants of the UK Biob...
Poster
The overarching goal of the Longitudinal Early‐onset Alzheimer Disease study (LEADS) is to optimally characterize early‐onset AD (EOAD) and establish an EOAD clinical trials network. Here we report the baseline demographic and imaging biomarker comparisons of the LEADS cohort to late‐onset AD (LOAD) subjects from the Alzheimer’s Disease Neuroimagin...
Article
Genome‐wide association study (GWAS) designs are widely used to identify genetic loci associated with Alzheimer’s disease (AD) by performing a statistical test for each single‐nucleotide polymorphism (SNP). This creates a significant multiple testing challenge. Deep learning has demonstrated remarkable ability to identify non‐linear patterns using...
Article
Large‐scale genome wide association studies (GWASs) have identified many genetic variants associated with Alzheimer’s disease (AD) and related traits. While many GWAS findings were found to co‐localize with expression quantitative trait loci (eQTL), it is of great interest to investigate the functional effect of GWAS hits on the downstream transcri...
Article
The Alzheimer’s Disease Neuroimaging Initiative includes cognitive assessments at every study visit. We have had the opportunity to use modern psychometric approaches including confirmatory factor analysis (CFA) and item response theory (IRT) with these rich data. Here we discuss lessons learned from analyses of memory, executive functioning, langu...
Article
Precision medicine is designed to resolve heterogeneity in complex diseases such as Alzheimer’s (AD) to deliver timely and tailored treatment. Using ADNI data, we developed endophenotype‐specific polygenic risk scores (PRS) to assess the AD risk and to identify distinct genetic risk profiles among the converters. We used ADNI genetic, clinical and...
Article
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Established genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal...
Article
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Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer’s diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer’s pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET wer...
Article
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Background The interaction between the brain and periphery might play a crucial role in the development of Alzheimer’s disease (AD). Methods Using blood transcriptomic profile data from two independent AD cohorts, we performed expression quantitative trait locus ( cis -eQTL) analysis of 29 significant genetic loci from a recent large-scale genome-...
Article
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PurposeOlder cancer survivors required medical care during the COVID-19 pandemic, but there are limited data on medical care in this age group.Methods We evaluated care disruptions in a longitudinal cohort of non-metastatic breast cancer survivors aged 60–98 from five US regions (n = 321). Survivors completed a web-based or telephone survey from Ma...
Article
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Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD‐specific met...
Article
The advances in technologies for acquiring brain imaging and high-throughput genetic data allow the researcher to access a large amount of multi-modal data. Although the sparse canonical correlation analysis is a powerful bi-multivariate association analysis technique for feature selection, we are still facing major challenges in integrating multi-...
Preprint
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Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity would aid in elucidating etiological mechanisms and pave the road to precision and individualized medicine. We sought to delineate, cross-sectionally and longitudinally, disease-related heterogeneity in LLD linked to ne...
Article
Objective The cognitive reserve hypothesis has been proposed as a key mechanism explaining the link between social networks and cognitive function but has rarely been empirically tested using neuroimaging data. This study examines whether social network attributes moderate the association between amygdalar volume and cognitive function. Methods Da...
Article
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Introduction: Amyloid beta (Aβ), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression. Methods: Within 248 Aβ-positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to ass...
Article
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Background Accumulating evidence suggests that BMI1 confers protective effects against Alzheimer’s disease (AD). However, the mechanism remains elusive. Based on recent pathophysiological evidence, we sought for the first time to identify genetic variants in BMI1 as associated with AD biomarkers, including amyloid-β. Methods We used genetic, longi...
Article
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Alzheimer’s disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- β (Aβ) peptide. The p-tau tangle unit is a posttranslational modificatio...
Article
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Whether the deleterious effects of APOE4 are restricted to the Alzheimer’s disease (AD) spectrum or cause cognitive impairment irrespectively of the development of AD is still a matter of debate, and the focus of this study. Our analyses included APOE4 genotype, neuropsychological variables, amyloid-βeta (Aβ) and Tau markers, FDG-PET values, and hi...
Preprint
Background: Self and informant (proxy or study partner) reports of everyday cognitive functioning have been shown to be associated with incipient neurodegenerative disease. The 20-item Cognitive Change Index (CCI) and the 39-item Measurement of Everyday Cognition (ECog) were each developed to characterize early subjective changes in cognitive funct...
Preprint
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INTRODUCTION: Embedding single-omics disease associations into the wider context of multi-level molecular changes in Alzheimer's disease (AD) remains one central challenge in AD research. METHODS: Results from numerous AD-specific omics studies from AMP-AD, NIAGADS, and other initiatives were integrated into a comprehensive network resource and com...
Article
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A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic...
Article
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Tau neurofibrillary tangles have a central role in the pathogenesis of Alzheimer’s Disease (AD). Mounting evidence indicates that the propagation of tau is assisted by brain connectivity with weakened white-matter integrity along the propagation pathways. Recent advances in tau positron emission tomography tracers and diffusion magnetic resonance i...
Article
The accelerated approval of aducanumab (AduhelmTM) by the US FDA is a momentous event. For the first time, a therapeutic agent that targets the neurobiology of Alzheimer’s disease (AD) is available for clinical use (1, 2). In addition to the FDA approval of aducanumab, the FDA has also provided “Breakthrough therapy designation” for Lilly’s Donanem...
Article
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Introduction: Alzheimer's disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments. Meth...
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Introduction: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020. Methods: We identified 1442 publications us...
Preprint
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We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species that are putatively in the mechanistic pathway to coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 phenotyped individuals from the Busselton Health Study. In our...
Article
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Introduction: Head injuries (HI) are a risk factor for dementia, but the underlying etiology is not fully known. Understanding whether tau might mediate this relationship is important. Methods: Cognition and tau deposition were compared between 752 individuals with (impaired, n = 302) or without cognitive impairment (CN, n = 450) with amyloid an...
Preprint
Introduction: Genetic association analysis of key Alzheimer's disease (AD) endophenotypes may provide insight into molecular mechanisms and genetic contributions. Methods: Major AD endophenotypes based on the A/T/N (Amyloid-beta, Tau, and Neurodegeneration) biomarkers and cognitive performance were selected from Alzheimer's Disease Neuroimaging Ini...
Article
Importance The practice of oncology will increasingly involve the care of a growing population of individuals with midlife and late-life cancers. Managing cancer in these individuals is complex, based on differences in biological age at diagnosis. Biological age is a measure of accumulated life course damage to biological systems, loss of reserve,...
Article
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DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neur...
Article
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Alzheimer’s disease (AD) is a complex and heterogeneous disease that can be affected by various genetic factors. Although the cause of AD is not yet known and there is no treatment to cure this disease, its progression can be delayed. AD has recently been recognized as a brain-specific type of diabetes called type 3 diabetes. Several studies have s...
Preprint
Deep learning is a promising tool that uses nonlinear transformations to extract features from high-dimensional data. Deep learning is challenging in genome–wide association studies (GWAS) with high-dimensional genomic data. Here we propose a novel three-step approach (SWAT-CNN) for identification of genetic variants using deep learning to identify...
Preprint
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Dysregulation of sphingomyelin (SM) and ceramide metabolism have been implicated in Alzheimer’s Disease (AD). Genome-wide and transcriptome wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with AD. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to...
Article
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Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment. Methods: We cr...
Article
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Metabolomics in the Alzheimer’s Disease Neuroimaging Initiative cohort provides a powerful tool for mapping biochemical changes in Alzheimer’s disease, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-β deposition in Alzheimer’s disease. We examined 140 serum metabolites and their assoc...
Article
The pathology of Alzheimer disease (AD) damages structural and functional brain networks, resulting in cognitive impairment. The results of recent connectomics studies have now linked changes in structural and functional network organization in AD to the patterns of amyloid-β and tau accumulation and spread, providing insights into the neurobiologi...
Article
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Neuroinflammation is associated with Alzheimer’s disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-r...
Article
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Caspase-6 (Casp6) is implicated in Alzheimer disease (AD) cognitive impairment and pathology. Hippocampal atrophy is associated with cognitive impairment in AD. Here, a rare functional exonic missense CASP6 single nucleotide polymorphism (SNP), causing the substitution of asparagine with threonine at amino acid 73 in Casp6 (Casp6N73T), was associat...