Joseph H Lee

Joseph H Lee
Columbia University | CU · Taub Institute for Research on Alzheimer's Disease and the Aging Brain

DrPH

About

319
Publications
25,870
Reads
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10,307
Citations
Citations since 2017
114 Research Items
4443 Citations
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20172018201920202021202220230200400600800
20172018201920202021202220230200400600800
Introduction
We have 2 main research interests. FIRST, we aim to identify and characterize genetic and nongenetic factors that modify Alzheimer disease (AD) risk and age-related traits. To this end, we study high risk individuals -- PSEN1 carrier families and adults with Down syndrome who carry 3 copies of APP – and ask how some individuals escape AD into old ages. SECOND, we conduct natural experiments to maximize salient biological info, and minimize biases in human studies. We apply multiomic approaches.
Additional affiliations
March 2018 - present
Columbia University
Position
  • Professor (Full)
July 2007 - February 2018
Columbia University
Position
  • Professor (Associate)
September 1999 - June 2007
Columbia University
Position
  • Professor (Assistant)
Education
October 1987 - March 1996
Columbia University
Field of study
  • Genetic Epidemiology
September 1983 - May 1985
University of California, Berkeley
Field of study
  • Epidemiology
February 1982 - May 1983

Publications

Publications (319)
Article
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The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in...
Article
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Background Shortening of chromosomal telomeres is a consequence of cell division and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging. Objective To determine whether shorter telomere length (TL), as measured in human blood samples, is associated with the development of Alzheimer disease and...
Article
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Researchers in anthropology, epidemiology, and human genetics have been investigating the sources of human variation and the etiology of human diseases over the past century, largely independently of one another, using very different methodologies to study environmental factors, infectious agents, genetic variation, and their respective effects on...
Article
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Genetic determinants of Alzheimer disease (AD) have not been comprehensively examined in Caribbean Hispanics, a population in the United States in whom the frequency of AD is higher compared with non-Hispanic whites. To identify variant alleles in genes related to familial early-onset AD among Caribbean Hispanics. Family-based case series conducted...
Article
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The present study identified potential genetic modifiers that may delay or accelerate age at onset of familial Alzheimer disease (AD) by examining age at onset in PSEN1 mutation carrier families, and further investigation of these modifiers may provide insight into the pathobiology of AD and potential therapeutic measures. To identify genetic varia...
Article
Introduction: Vascular aging is characterized by structural and functional changes in blood vessels that lead to reduced perfusion pressure to distal organs and high blood pressure (BP). Cerebrovascular aging is strongly associated with high BP, however, systemic BP is constituted by the steady and pulsatile components. We aimed this study to inves...
Article
Background: Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down s...
Article
Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our...
Article
Background: Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. Objective: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological ag...
Article
Down Syndrome (DS), caused by triplication of human chromosome 21 (Hsa21) is the most common form of intellectual disability worldwide. Recent progress in healthcare has resulted in a dramatic increase in the lifespan of individuals with DS. Unfortunately, most will develop Alzheimer’s disease like dementia (DS-AD) as they age. Understanding simila...
Article
Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our...
Article
Background Leukocyte telomere length (LTL) is a potential genomic marker of biological aging, but its relationship to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability, but that this association would be attenuated by adju...
Article
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Weight loss and increased physical activity may promote beneficial modulation of the metabolome, but limited evidence exists about how very low-level weight loss affects the metabolome in previously non-obese active individuals. Following a weight loss period (21.1 ± 3.1 weeks) leading to substantial fat mass loss of 52% (−7.9 ± 1.5 kg) and low bod...
Article
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Background Twenty-four-hour and nighttime blood pressure (BP) levels are more strongly associated with cardiovascular risk than office or daytime BP measurements. However, it remains undocumented which of the office and ambulatory BP measurements have the strongest association and predictive information in relation to the presence of type I, or art...
Article
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Kazakhstan, the ninth-largest country in the world, is located along the Great Silk Road and connects Europe with Asia. Historically, its territory has been inhabited by nomadic tribes, and modern-day Kazakhstan is a multiethnic country with a dominant Kazakh population. We sequenced and analyzed the genomes of five ethnic Kazakhs at high coverage...
Article
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Extended maternal age has been suggested as marker of delayed age-associated disabilities. We use the Long Life Family Study (LLFS) offspring generation to investigate the association between extended maternal age at last childbirth and healthy-aging endophenotypes. We hypothesize that women with extended maternal age at last childbirth will exhibi...
Article
Objective: 24-h and nighttime blood pressure (BP) levels are the strongest BP measurements associated with cardiovascular risk. However, it remains undocumented which of the ambulatory BP measurements have the strongest association and predictive information in relation to the presence of cerebral small vessel diseases (CSVD). Design and method:...
Article
Full-text available
We determined the extent to which obstructive sleep apnea (OSA) is associated with increased cerebrovascular disease and amyloid burden, and the relation of the two processes across clinical Alzheimer’s disease (AD) diagnostic groups in adults with Down syndrome (DS). Adults with DS from the Biomarkers of Alzheimer’s Disease in Down Syndrome (ADDS)...
Article
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The left ventricular assist device (LVAD) is one of the alternative treatments for heart failure (HF) patients. However, LVAD support is followed by thrombosis, and bleeding complications which are caused by high non-physiologic shear stress and antithrombotic/anticoagulant therapy. A high risk of complications occurs in the presence of the genotyp...
Article
Background: Mean arterial pressure (MAP) drives ocular perfusion. Excessive 24-h MAP variability relates to glaucoma, however, whether this is due to dips or increases in the blood pressure (BP) is undocumented. We investigated the association of open-angle glaucoma (OAG) in relation to the five largest MAP dips/increases over 24-h, henceforth cal...
Article
Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia‐related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS....
Preprint
Full-text available
We conducted a genome-wide association study (GWAS) of Digit Symbol Substitution Test (DSST) scores administered in 4207 family members of the Long Life Family Study (LLFS). Genotype data were imputed to the HRC panel of 64,940 haplotypes resulting in ~15M genetic variants with quality score > 0.7. The results were replicated using genetic data imp...
Chapter
Down syndrome (DS) is one of the most common genetic diseases, and adults with DS show neuropathological signs of Alzheimer's disease (AD) starting at age 40 years of age, and nearly one-half will develop dementia by age 60, owing to triplication and overexpression of the APP gene on chromosome 21. Beyond the amyloid precursor protein (APP) gene lo...
Article
Full-text available
The apolipoprotein ε4 (APOE4) is the most prevalent genetic risk factor for late-onset Alzheimer’s Disease (AD). Here we assessed the metabolomic profile differences between APOE4 carriers who develop AD vs. who do not in a sample of 142 participants, aged 65-99 years in the Long Life Family Study (LLFS). Of 7,321 metabolites, we applied a generali...
Article
Full-text available
Leukocyte telomere length (LTL) is a potential marker of biological aging, but its relationship to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability. Two generations of participants (N=1,997; 309 probands, 1,688 offspring)...
Article
Full-text available
Adiponectin is involved in regulating insulin resistance (IR) and is a potential regulator of healthy aging and lifespan. To identify novel variants associated with adiponectin, we further assessed our previously identified linkage peak on 16q23.2 (LODs=3.8). We used sequence data of 632 participants (age, 24-110 years) from 47 families of European...
Article
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Objectives Kazakhstan is a Central Asian crossroad of European and Asian populations situated along the way of the Great Silk Way. The territory of Kazakhstan has historically been inhabited by nomadic tribes and today is the multi-ethnic country with the dominant Kazakh ethnic group. We sequenced and analyzed the whole-genomes of five ethnic healt...
Article
Plasma neurofilament light (NfL) and total tau (t‐tau) are emerging as promising biomarkers of Alzheimer’s disease (AD) in adults with Down Syndrome (DS). Sex may influence the levels of these biomarkers however, research on sex differences in these biomarkers is limited. In this study, we examined whether sex influences plasma levels and clinical...
Article
Full-text available
The NIA Long Life Family Study (LLFS) is a longitudinal, multicenter, multi-national, population-based multi-generational family study of the genetic and non-genetic determinants of exceptional longevity and healthy aging. The Visit 1 in-person evaluation (2006-2009) recruited 4,953 individuals from 539 two-generation families, selected from the up...
Article
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Purpose: To examine the benefits and feasibility of a mobile, real-time, community-based, teleophthalmology program for detecting eye diseases in the New York metro area. Design: Single site, nonrandomized, cross-sectional, teleophthalmologic study. Methods: Participants underwent a comprehensive evaluation in a Wi-Fi-equipped teleophthalmolog...
Article
Background Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to comp...
Chapter
Although there is a growing interest in improving cognitive abilities in older adults, there has been considerable variation in how different cognitive domains have been conceptualized over time. Broadly, neuropsychology assumes that cognitive processes are fundamentally similar across humankind (Nell, 1999), and as such, the manner in which cognit...
Article
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Background: Sex differences in the risk of Alzheimer's Disease (AD) in adults with Down Syndrome (DS) have not been extensively investigated, and existing studies have found conflicting results. This study examined the effect of sex on the risk of AD in adults with DS, adjusted for covariates. Methods: Adults with DS were assessed longitudinally...
Article
Hypoperfusion of the optic nerve might be involved in the pathogenesis of normal-tension glaucomatous optic neuropathy (GON). Mean arterial pressure (MAP) drives ocular perfusion, but no previous studies have addressed the risk of GON in relation to blood pressure (BP) variability, independent of BP level. In a cross-sectional study, 93 residents o...
Article
Background - Polygenic risk scores (PRS) for coronary heart disease (CHD) may contribute to assess the overall risk of CHD. We evaluated how PRS may influence CHD risk when the distribution of age-at-onset, sex, and family health history differ significantly. Methods - Our study included three family-based ascertainments: Long Life Family Study (LL...
Article
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Background Venezuela is in the throes of a complex humanitarian crisis that is one of the worst in decades to impact any country outside of wartime. This case analysis describes the challenges faced by the ongoing Maracaibo Aging Study (MAS) during the deteriorating conditions in Venezuela. When the MAS began in 1997, it focused on memory-related d...
Article
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Background: Very few studies have investigated the association between total plasma homocysteine (tHcy) and depressive symptoms in older Hispanics. Objective: To test the hypothesis that high tHcy associate with depressive symptoms in older Hispanics. Methods: A total of 1,418 participants .55 years old from the Maracaibo Aging Study (MAS) und...
Article
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The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed f...
Article
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Background Ventricular tachycardia (VT) is a major cause of sudden cardiac death (SCD). Clinical investigations can sometimes fail to identify the underlying cause of VT and the event is classified as idiopathic (iVT). VT contributes significantly to the morbidity and mortality in patients with coronary artery disease (CAD) and dilated cardiomyopat...
Article
Background: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such bio...
Article
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The Long Life Family Study (LLFS) has longitudinally measured key aging phenotypes on 4,953 participants (539 pedigrees) in the USA and Denmark selected for exceptional familial longevity. On average, both generations of the LLFS sample are healthier than average for their age/sex, for many phenotypes. However, the pedigrees are heterogeneous, with...
Article
Cerebral small vessel diseases (CSVD) is a forerunner of cognitive decline, vascular dementia, Alzheimer’s disease, and stroke. Which BP index is closest associated with CVSD remains unclear. We aimed this study to examine the association of BP levels, measured by the office and ambulatory BP monitoring (ABPM), with CSVDs, and to determine which BP...
Article
The value of plasma neurofilament light (NfL), a marker of neurodegeneration, in Alzheimer’s Disease (AD) has been reported in the general population. However, evidence for NfL as a predictive marker of neurodegeneration in adults with Down Syndrome (DS) is limited. The small number of longitudinal studies have short follow‐up periods. Thus, the va...
Article
Adults with Down syndrome (DS) develop Alzheimer’s disease (AD) brain changes, including excess Aβ42, Aβ40, and tau aggregates, generally by the fifth decade of life, and with time ultimately develop a dementia syndrome. Here we examine the relationship of baseline plasma biomarkers Aβ42, Aβ40, and tau, to dementia status, in adults with DS from a...
Article
Objectives: Adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology by their fifth decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. W...
Article
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Introduction: Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments. Methods:...
Article
Background: Dementia of the Alzheimer's type (DAT) impacts Hispanics disproportionately, with almost a twofold elevated risk of developing DAT, as well as earlier onset of the disease, than in non-Hispanic Whites. However, the role of main risk factors for DAT, such as APOE ɛ4 and blood pressure (BP) levels, remains uncertain among Hispanics. Obj...
Article
Full-text available
Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer’s disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS. Methods: CSF concentration...
Article
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Introduction: Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD) and its associated dementia, warranting the development of strategies to improve early detection when prevention is possible. Methods: Using a broad battery of neuropsychological assessments, informant interviews, and clinical record review, we...
Article
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Introduction: Previously generated serum and plasma proteomic profiles were examined among adults with Down syndrome (DS) to determine whether these profiles could discriminate those with mild cognitive impairment (MCI-DS) and Alzheimer's disease (DS-AD) from those cognitively stable (CS). Methods: Data were analyzed on n = 305 (n = 225 CS; n =...
Article
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Introduction: We sought to determine if proteomic profiles could predict risk for incident mild cognitive impairment (MCI) and Alzheimer's disease (AD) among adults with Down syndrome (DS). Methods: In a cohort of 398 adults with DS, a total of n = 186 participants were determined to be non-demented and without MCI or AD at baseline and througho...
Article
Objective Leukocyte telomere length (LTL) is a widely hypothesized biomarker of biological aging. Persons with shorter LTL may have a greater likelihood of developing dementia. We investigate whether LTL is associated with cognitive function, differently for individuals without cognitive impairment versus individuals with dementia or incipient deme...
Article
Full-text available
Introduction: We sought to determine if a proteomic profile approach developed to detect Alzheimer's disease (AD) in the general population would apply to adults with Down syndrome (DS). Methods: Plasma samples were obtained from 398 members of a community-based cohort of adults with DS. A total of n = 186 participants were determined to be non-...
Article
Objective To test the hypotheses that hypertension and nocturnal blood pressure are related to white matter hyperintensity (WMH) volume, an MRI marker of small vessel cerebrovascular disease, and that WMH burden statistically mediates the association of hypertension and dipping status with memory functioning, we examined the relationship of hyperte...
Article
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Background: Phenotypic expression of pathogenic variants in individuals with no family history of inherited disorders remains unclear. Methods: We evaluated the prevalence of pathogenic variants in 25 genes associated with Mendelian-inherited disorders in 3015 participants from 485 families in the Long Life Family Study (LLFS). Boot-strapping an...
Article
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Recently, Mahalanobis distance (DM) was suggested as a statistical measure of physiological dysregulation in aging individuals. We constructed DM variants using sets of biomarkers collected at the two visits of the Long Life Family Study (LLFS) and performed joint analyses of longitudinal observations of DM and follow-up mortality in LLFS using joi...
Chapter
Human life span is a complex phenotype involving multiple biological processes. In the absence of malnutrition, caloric restriction or following healthy dietary patterns are the major dietary modifications that could potentially prolong life span. Twin and family studies estimate heritability of life span to be nearly 30%. Large-scale genome-wide s...
Article
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Chronic kidney disease (CKD) is a global major public health problem. Almost all of previous studies evaluating the prevalence of CKD focused on adults, while studies among the elderly were relatively rare, especially in China. The aim of this study was to investigate the prevalence and associated risk factors of CKD among the elderly in Qingdao, C...
Article
Full-text available
Exceptional aging has heritable components. One genetic risk factor for cognitive aging may be Apolipoprotein E (APOE), but it is unclear to what extent APOE relates to cognitive aging versus risk of Alzheimer’s disease. Cognitive aging may also be influenced by leukocyte telomere length (LTL), posited to be a marker of “biological age”. We examine...
Article
Background and aims: Atherosclerosis develops with age and is partially controlled by genetics. Research to date has identified common variants with small effects on atherosclerosis related traits. We aimed to use family-based genome-wide linkage analysis to identify chromosomal regions potentially harboring rare variants with larger effects for a...
Article
Background: SNPs in the first intron of the Fat Mass and Obesity-Associated (FTO) gene represent the strongest genome-wide associations with adiposity (BMI); the molecular basis for these associations is under intense investigation. In European populations - the focus of most GWAS conducted to date - the SNPs have indistinguishable associations du...
Article
HbA1c, an index of chronic glycemic status relevant to IR and T2D, is associated with aging, cognitive performance and mortality. To identify epistatic interactions, we assessed 65 published SNPs associated with levels of HbA1c (n=4,090) and change in HbA1c levels over time (n=2,054) among nondiabetic participants of European ancestry who had compl...
Article
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Exercise and exercise-induced weight loss have a beneficial effect on overall health, including positive effects on molecular pathways associated with immune function, especially in overweight individuals. The main aim of our study was to assess how energy deprivation (i.e., “semi-starvation”) leading to substantial fat mass loss affects the immune...
Article
Background: Long-lived individuals and their offspring have healthier metabolic characteristics than expected, such as more favorable levels of fasting glucose, insulin, and lipids than controls without longevity. Dysregulation in metabolic pathways has also shown to predict accelerated aging. Using information from the Long Life Family Study (LLF...
Article
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Background Imputation has become a standard approach in genome-wide association studies (GWAS) to infer in silico untyped markers. Although feasibility for common variants imputation is well established, we aimed to assess rare and ultra-rare variants’ imputation in an admixed Caribbean Hispanic population (CH). Methods We evaluated imputation acc...