Francine Grodstein

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (235)2122.24 Total impact

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    ABSTRACT: Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
    Nature 07/2015; DOI:10.1038/nature14618 · 42.35 Impact Factor
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    ABSTRACT: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37.
    Molecular Psychiatry 04/2015; DOI:10.1038/mp.2015.37 · 15.15 Impact Factor
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    Molecular Psychiatry 04/2015; · 15.15 Impact Factor
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    ABSTRACT: Dietary flavonoids have been related to lower risks of various chronic diseases, but it is unclear whether flavonoid intake in midlife helps to maintain good health and wellbeing in aging. We examined the relation of flavonoid intake in midlife with the prevalence of healthy aging. We included 13,818 women from the Nurses' Health Study with dietary data and no major chronic diseases in 1984-1986 when they were aged in their late 50s (median age: 59 y); all women provided information on multiple aspects of aging an average of 15 y later. Intakes of 6 major flavonoid subclasses in midlife were ascertained on the basis of averaged intakes of flavonoid-rich foods from 2 food-frequency questionnaires (1984-1986). We defined healthy compared with usual aging as of age 70 y; healthy aging was based on survival to ≥70 y with maintenance of 4 health domains (no major chronic diseases or major impairments in cognitive or physical function or mental health). Of women who survived until ≥70 y of age, 1517 women (11.0%) met our criteria for healthy aging. Compared with women in the lowest quintile of intake, women in the highest quintile of intake of several flavonoid subclasses at midlife had greater odds of healthy aging. After multivariable adjustment, ORs were as follows: flavones, 1.32 (95% CI: 1.10, 1.58); flavanone, 1.28 (95% CI: 1.08, 1.53); anthocyanin, 1.25 (95% CI: 1.04, 1.50); and flavonol, 1.18 (95% CI: 0.98, 1.42) (all P-trend ≤ 0.02). Consistently, greater intakes of major sources of these flavonoids (i.e., oranges, berries, onions, and apples) were associated with increased odds of healthy aging. We showed no association with flavan-3-ol monomers (P-trend = 0.80) or polymers (P-trend = 0.63). Higher intake of flavonoids at midlife, specifically flavones, flavanones, anthocyanins, and flavonols, is associated with greater likelihood of health and wellbeing in individuals surviving to older ages. © 2014 American Society for Nutrition.
    American Journal of Clinical Nutrition 12/2014; 100(6):1489-97. DOI:10.3945/ajcn.114.085605 · 6.92 Impact Factor
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    ABSTRACT: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: Background Subjective cognitive concerns may represent a simple method to assess likelihood of memory decline among apolipoprotein E (APOE) ε4 carriers. Methods We examined the relationship of self-reported subjective cognitive concerns, using seven specific cognitive concerns, with memory and memory decline over 6 years among APOE ε4 carriers and non-carriers from the Nurses' Health Study. Results In both groups, increasing subjective cognitive concern score predicted worse baseline memory and faster rates of subsequent memory decline, after adjustment for age, education and depression. The relation with baseline memory appeared statistically stronger in APOE ε4 carriers (P-interaction = 0.03). For memory decline, mean differences in slopes of episodic memory (95% CI) for 4 to 7 versus no concern = −0.05 (−0.10, 0.01) standard units in APOE ε4 carriers, and −0.04 (−0.08, −0.01) standard units in non-carriers. Conclusions APOE ε4 carriers with self-assessed cognitive concerns appear to have worse memory, and possibly accelerated memory decline.
    Alzheimer's and Dementia 09/2014; 10(6). DOI:10.1016/j.jalz.2014.06.012 · 17.47 Impact Factor
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    ABSTRACT: Dementia or other significant cognitive impairment (SCI) are often comorbid with other chronic diseases. To promote collaborative research on the intersection of these conditions, we compiled a systematic inventory of major data resources.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 09/2014; 11(6). DOI:10.1016/j.jalz.2014.07.002 · 17.47 Impact Factor
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    ABSTRACT: Background: The frequency of soda consumption remains high in the United States. Soda consumption has been associated with poor bone health in children, but few studies have examined this relation in adults, and to our knowledge, no study has examined the relation of soda consumption with risk of hip fractures. Objective: We examined the association of soda, including specific types of soda, and risk of hip fracture in postmenopausal women. Design: An analysis was conducted in postmenopausal women from the Nurses' Health Study cohort (n = 73,572). Diet was assessed at baseline by using a semiquantitative food-frequency questionnaire and updated approximately every 4 y. In <= 30 y of follow-up, we identified 1873 incident hip fractures: We computed RRs for hip fractures by the amount of soda consumption by using Cox proportional hazards models with adjustment for potential confounders. Results: In multivariable models, each additional serving of total soda per day was associated with a significant 14% increased risk of hip fracture (RR: 1.14; 95% CI: 1.06, 1.23). The attributable risk in our cohort for total soda consumption was 12.5%. Risk was significantly elevated in consumers of both regular soda (RR: 1.19; 95% CI: 1.02, 1.38) and diet soda (RR: 1.12; 95% CI: 1.03, 1.21) and also did not significantly differ between colas and noncolas or sodas with or without caffeine. The association between soda and hip fractures did not differ by body mass index or diagnosis of diabetes. Conclusion: Increased soda consumption of all types may be associated with increased risk of hip fracture in postmenopausal women; however, a clear mechanism was not apparent on the basis of these observational data.
    American Journal of Clinical Nutrition 08/2014; 100(3). DOI:10.3945/ajcn.114.083352 · 6.92 Impact Factor
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    ABSTRACT: Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain. Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging. Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)–type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals). Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: −0.054 ± 0.004 and −0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: −0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: −0.01; 95% CI: −0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: −0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment. Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.
    American Journal of Clinical Nutrition 06/2014; 100(2). DOI:10.3945/ajcn.113.076349 · 6.92 Impact Factor
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    ABSTRACT: Background. Microvascular and macrovascular abnormalities are frequently found on noninvasive tests performed in older adults. Their prognostic implications on disability and life expectancy have not been collectively assessed.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 05/2014; 69(12). DOI:10.1093/gerona/glu074 · 4.98 Impact Factor
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    ABSTRACT: Objective: Nuts contain nutrients that may benefit brain health; thus, we examined long-term intake of nuts in relation to cognition in older women. Design: Population-based prospective cohort study. Setting: Academic research using data from the Nurses' Health Study. Participants: Nut intake was assessed in a food-frequency questionnaire beginning in1980, and approximately every four years thereafter. Between 1995-2001, 16,010 women age 70 or older (mean age = 74 years) without a history of stroke were administered 4 repeated telephone-based cognitive interviews over 6 years. Our final sample included 15,467 women who completed an initial cognitive interview and had complete information on nut intake. Main Outcome Measures: The Telephone Interview for Cognitive Status (TICS), a global score averaging the results of all tests (TICS, immediate and delayed verbal recall, category fluency, and attention), and a verbal memory score averaging the results of tests of verbal recall. Results: In multivariable-adjusted linear regression models, higher long-term total nut intake was associated with better average cognitive status for all cognitive outcomes. For the global composite score combining all tests, women consuming at least 5 servings of nuts/week had higher scores than non-consumers (mean difference=0.08 standard units, 95% confidence interval 0.00-0.15; p-trend=0.003). This mean difference of 0.08 is equivalent to the mean difference we find between women 2 years apart in age. Long-term intake of nuts was not associated with rates of cognitive decline. Conclusions: Higher nut intake may be related to better overall cognition at older ages, and could be an easily-modifiable public health intervention.
    The Journal of Nutrition Health and Aging 05/2014; 18(5):496-502. DOI:10.1007/s12603-014-0014-6 · 2.66 Impact Factor
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    ABSTRACT: Objectives To evaluate associations between sleep duration at midlife and later life and change in sleep duration over time and cognition in older women.DesignParticipants reported sleep duration in 1986 and 2000, and a subgroup of older participants began cognitive testing in 1995 to 2001; follow-up testing was conducted three times, at 2-year intervals.SettingProspective Nurses' Health Study cohort.ParticipantsFemale nurses aged 70 and older free of stroke and depression at the initial cognitive assessment (N = 15,385).MeasurementsValidated, telephone-based cognitive battery to measure cognitive function; four repeated assessments over 6 years were averaged to estimate overall cognition at older ages, and trajectories of cognitive change were evaluated over follow up.ResultsExtreme sleep durations in later life were associated with worse average cognition (P < .001 for the quadratic term for a global score averaging all six cognitive tests). For example, women sleeping 5 h/d or less had worse global cognition than those sleeping 7 h/d, as did women sleeping 9 h/d or more; differences were equivalent to nearly 2 additional years of age. Associations were similar, although slightly attenuated, for sleep duration in midlife. Women whose sleep duration changed by 2 h/d or more over time had worse cognition than women with no change in sleep duration (e.g., for the global score, P < .001 for the quadratic term). Sleep duration was not associated with trajectories of cognitive function over 6 years, which might be attributable to short follow-up for detecting cognitive decline.Conclusion Extreme sleep durations at midlife and later life and extreme changes in sleep duration over time appear to be associated with poor cognition in older women.
    Journal of the American Geriatrics Society 04/2014; 62(6). DOI:10.1111/jgs.12790 · 4.22 Impact Factor
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    ABSTRACT: Background Vitamin D may play a role in preserving cognitive function. However, there is a paucity of prospective studies on the relationship between vitamin D and cognition with aging. The aim of this study was to examine the association between plasma levels of vitamin D and subsequent cognitive function. Methods This is a prospective study including 1,185 women aged 60–70 years from the Nurses’ Health Study, who had plasma 25-hydroxy-vitamin D levels measured in 1989–1990 and completed an initial Telephone Interview of Cognitive Status approximately 9 years later. Subsequently, three follow-up cognitive assessments were conducted at 1.5–2.0 years intervals. We used multivariable-adjusted linear regression to model initial cognitive function, and mixed linear regression to model change in cognitive function over time. Results Lower vitamin D levels were associated with significantly worse cognitive function 9 years later. For example, the mean global composite score averaging all the cognitive tests was 0.20 lower (95% Confidence Interval (CI):−0.33,−0.08; p-trend=0.009) in women in the lowest quintile (median=14.1 ng/mL) compared with women in the highest quintile of vitamin D (median=38.4 ng/mL). The observed differences were equivalent to the effect estimates we found for women who were approximately 4–6 years apart in age. However, vitamin D levels were not significantly associated with subsequent cognitive decline during 6 years of follow-up. Conclusions Higher levels of plasma vitamin D in women aged 60–70 years were associated with better cognitive function about a decade later but were not associated with cognitive decline during 6 years of follow-up.
    The Journal of Nutrition Health and Aging 04/2014; 18(4). DOI:10.1007/s12603-013-0409-9 · 2.66 Impact Factor
  • The FASEB Journal 04/2014; 28(1). · 5.48 Impact Factor
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    ABSTRACT: Background Higher long-term cumulative lead exposure predicts faster cognitive decline in older men, but evidence of an association in women is lacking. Objective To determine if there is an association between lead exposure and cognitive decline in women. Methods This study considers a sample of 584 women from the Nurses' Health Study who live in or near Boston, Massachusetts. We quantified lead exposure using biomarkers of lead exposure assessed in 1993–2004 and evaluated cognitive decline by repeated performance on a telephone battery of cognitive tests primarily assessing learning, memory, executive function, and attention completed in 1995–2008. All cognitive test scores were z-transformed for use in analyses. We used linear mixed models with random effects to quantify the association between each lead biomarker and change in cognition overall and on each individual test. Results Consideration of individual tests showed greater cognitive decline with increased tibia lead concentrations, a measure of long-term cumulative exposure, for story memory and category fluency. The estimated excess annual decline in overall cognitive test z-score per SD increase in tibia bone lead concentration was suggestive, although the confidence intervals included the null (0.024 standard units, 95% confidence interval: −0.053, 0.004 – an additional decline in function equivalent to being 0.33 years older). We found little support for associations between cognitive decline and patella or blood lead, which provide integrated measures of exposure over shorter timeframes. Conclusions Long-term cumulative lead exposure may be weakly associated with faster cognitive decline in community-dwelling women, at least in some cognitive domains.
    Environmental Research 02/2014; 129:69–75. DOI:10.1016/j.envres.2013.12.010 · 3.95 Impact Factor
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    ABSTRACT: Worldwide, over 35 million people suffer from Alzheimer's disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Although observational research has some unavoidable limitations, its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.
    02/2014; 1(2):117-123.
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    ABSTRACT: Previous studies report higher prevalence of depression among women with urgency (UUI) or mixed (MUI) urinary incontinence than those with stress UI (SUI). UUI is the dominant type among black women, whereas SUI is the predominant type among white women. Thus, UI-related mental health issues could be a key consideration among black women. We hypothesized that the association between UI and depression might be stronger in black versus white women. These cross-sectional analyses assessed 934 black and 71,161 white women aged 58-83 in the Nurses' Health Study, which was established among women living in the USA. Depressive symptoms were assessed using the ten-item Center for Epidemiologic Studies Depression Scale (CESD-10). Multivariate adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) for high depressive symptoms (CESD-10 score ≥ 10) according to self-reported UI frequency, severity, and type were calculated using logistic regression models. Although point estimates for associations of UI frequency, severity, and type with high depressive symptoms were higher in black women, differences in ORs between black versus white women were not statistically significant. For example, the OR for at least weekly UI compared with no UI was 2.29 (95 % CI 1.30-4.01) in black women and 1.58 (95 % CI 1.49-1.68) in white women (p interaction = 0.4). We found no statistically significant differences in UI frequency, severity, and type with high depressive symptoms in black versus white women. However, the small number of black women in this study with high depressive symptoms limited statistical power to detect significant interactions. Thus, these results should be interpreted with caution.
    International Urogynecology Journal 01/2014; 25(6). DOI:10.1007/s00192-013-2309-2 · 2.16 Impact Factor
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    ABSTRACT: Alzheimer's disease is the public health crisis of the 21st century. There is a clear need for a widely available, inexpensive and reliable method to diagnosis Alzheimer's disease in the earliest stages, track disease progression, and accelerate clinical development of new therapeutics. One avenue of research being explored is blood based biomarkers. In April 2012, the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened top scientists from around the world to discuss the state of blood based biomarker development. This manuscript summarizes the meeting and the resultant discussion, including potential next steps to move this area of research forward.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 01/2014; 10(1):109-14. DOI:10.1016/j.jalz.2013.10.007 · 17.47 Impact Factor

Publication Stats

13k Citations
2,122.24 Total Impact Points

Institutions

  • 1995–2015
    • Brigham and Women's Hospital
      • • Channing Division of Network Medicine
      • • Department of Medicine
      • • Department of Radiology
      Boston, Massachusetts, United States
  • 1995–2014
    • Harvard University
      • • Department of Epidemiology
      • • Department of Nutrition
      • • Department of Health Policy and Management
      Cambridge, Massachusetts, United States
  • 1993–2014
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Neurology
      Boston, Massachusetts, United States
  • 2011
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2002
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States
  • 1997
    • Massachusetts General Hospital
      Boston, Massachusetts, United States