Do prenatal factors shape the risk for dementia?: A systematic review of the epidemiological evidence for the prenatal origins of dementia.

PURPOSE: Prenatal factors such as maternal stress, infection and nutrition affect fetal brain development and may also influence later risk for dementia. The purpose of this systematic review was to provide an overview of all studies which investigated the association between prenatal factors and later risk for dementia. METHODS: We systematically searched MEDLINE and Embase for original human studies reporting on associations between prenatal factors and dementia from inception to 23 November 2022. Prenatal factors could be any factor assessed during pregnancy, at birth or postnatally, provided they were indicative of a prenatal exposure. Risk of bias was assessed using the Newcastle Ottawa Scale. We followed PRISMA guidelines for reporting. RESULTS: A total of 68 studies met eligibility criteria (including millions of individuals), assessing maternal age (N = 30), paternal age (N = 22), birth order (N = 15), season of birth (N = 16), place of birth (N = 13), prenatal influenza pandemic (N = 1) or Chinese famine exposure (N = 1), birth characteristics (N = 3) and prenatal hormone exposure (N = 4). We observed consistent results for birth in a generally less optimal environment (e.g. high infant mortality area) being associated with higher dementia risk. Lower and higher birth weight and prenatal famine exposure were associated with higher dementia risk. The studies on season of birth, digit ratio, prenatal influenza pandemic exposure, parental age and birth order showed inconsistent results and were hampered by relatively high risk of bias. CONCLUSION: Our findings suggest that some prenatal factors, especially those related to a suboptimal prenatal environment, are associated with an increased dementia risk. As these associations may be confounded by factors such as parental socioeconomic status, more research is needed to examine the potential causal role of the prenatal environment in dementia.

Early life predictors of late life cerebral small vessel disease in four prospective cohort studies.

Development of cerebral small vessel disease, a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socio-economic status or of vascular risk factor exposures. We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, socio-economic status), adult small vessel disease, and brain volumes, using data from four prospective cohort studies: STratifying Resilience And Depression Longitudinally (STRADL) (n = 1080; mean age = 59 years); the Dutch Famine Birth Cohort (n = 118; mean age = 68 years); the Lothian Birth Cohort 1936 (LBC1936; n = 617; mean age = 73 years), and the Simpson's cohort (n = 110; mean age = 78 years). We analysed each small vessel disease feature individually and summed to give a total small vessel disease score (range 1-4) in each cohort separately, then in meta-analysis, adjusted for vascular risk factors and adult socio-economic status. Higher birth weight was associated with fewer lacunes [odds ratio (OR) per 100 g = 0.93, 95% confidence interval (CI) = 0.88 to 0.99], fewer infarcts (OR = 0.94, 95% CI = 0.89 to 0.99), and fewer perivascular spaces (OR = 0.95, 95% CI = 0.91 to 0.99). Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point = 0.99, 95% CI 0.98 to 0.998), fewer infarcts (OR = 0.98, 95% CI = 0.97 to 0.998), fewer lacunes (OR = 0.98, 95% CI = 0.97 to 0.999), and lower total small vessel disease burden (OR = 0.98, 95% CI = 0.96 to 0.999). Low education was associated with more microbleeds (OR = 1.90, 95% CI = 1.33 to 2.72) and lower total brain volume (mean difference = -178.86 cm3, 95% CI = -325.07 to -32.66). Low childhood socio-economic status was associated with fewer lacunes (OR = 0.62, 95% CI = 0.40 to 0.95). Early life factors are associated with worse small vessel disease in later life, independent of each other, vascular risk factors and adult socio-economic status. Risk for small vessel disease may originate in early life and provide a mechanistic link between early life factors and risk of stroke and dementia. Policies investing in early child development may improve lifelong brain health and contribute to the prevention of dementia and stroke in older age.

Prenatal exposure to the Dutch famine is associated with more self-perceived cognitive problems at 72 years of age.

BACKGROUND: Undernutrition during critical periods of neurodevelopment can hinder the developing brain with lasting negative consequences for brain size, structure and function. In this study, we describe self-perceived cognitive problems of men and women who were born around the time of the Dutch famine of 1944-45. METHODS: We compared self-perceived cognitive problems between men and women who had been exposed to the 1944-45 Dutch famine in late, mid or early gestation and those who were born before or conceived after the famine (and had thus not been exposed prenatally). We included 595 participants aged 71-74 years. RESULTS: Women who had been exposed to famine in late gestation more often reported cognitive problems compared to those who had not been exposed (OR 2.2 [95% CI 1.1-4.4]), whereas for men, this was the case for those exposed in early gestation (OR 2.3 [0.9-5.5]). Furthermore, men and women exposed in early gestation more often reported consulting a healthcare practitioner for cognitive problems in the past 12 months (OR 3.2 [1.3-8.1]). Especially men exposed in early gestation reported having consulted a healthcare practitioner more often than unexposed men (OR 4.4 [1.2-16.0]). CONCLUSIONS: These findings suggest that prenatal undernutrition does not only have lasting effects on brain size, but also on its function, with more self-perceived cognitive problems at older age, which also require more medical attention. Also, the effects of undernutrition depend on sex and its timing during gestation.

Lessons learned from 25 Years of Research into Long term Consequences of Prenatal Exposure to the Dutch famine 1944-45: The Dutch famine Birth Cohort.

This paper describes the findings of a historical cohort study of men and women born around the time of the Dutch famine 1944-45. It provided the first direct evidence in humans of the lasting consequences of prenatal undernutrition. The effects of undernutrition depended on its timing during gestation, and the organs and tissues undergoing periods of rapid development at that time. Early gestation appeared to be particularly critical, with the effects of undernutrition being most apparent, even without reductions in size at birth. Undernutrition during gestation affected the structure and function of organs and tissues, altered behaviour and increased risks of chronic degenerative diseases. This demonstrates the fundamental importance of maternal nutrition during gestation as the building blocks for future health.

Psychosocial and peripartum determinants of postpartum depression: Findings from a prospective population-based cohort. The ABCD study.

BACKGROUND: Postpartum depression is prevalent and concerns a serious health problem for women and their families. The current large-scale birth cohort study investigated: (1) the associations of various potential determinants of postpartum depression using a multidimensional approach, and (2) the individual contribution of obstetric and perinatal determinants and pregnancy-specific anxiety to the risk of postpartum depression. METHODS: This study was based on a large-scale birth cohort study in Amsterdam, the Netherlands (ABCD-study). In 5109 women depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (cut-off ≥16 indicating high risk of postpartum depression). Determinants were assessed using self-report or perinatal registries. RESULTS: In the final multivariable model, other-Western and non-Western ethnic background, increased antepartum depressive symptoms, increased antepartum anxiety, increased pregnancy-specific anxiety, being unemployed, poor sleep quality, unwanted pregnancy, abuse, multiparity, and congenital abnormality were all independently related to an increased risk of postpartum depression. The strongest risk factors for postpartum depression were antepartum depressive symptoms (adjusted odds ratio (AOR) = 3.86, 95% confidence interval (CI) 3.02-4.92), having a baby with a congenital abnormality (AOR = 2.33, 95% CI 1.46-3.73), and abuse (AOR = 1.95, 95% CI 1.02-3.73). The final model accounted for 24.5% of the variance. LIMITATIONS: Our dataset did not provide information on social support or maternal and family history of depression. Next to these determinants, future research should include biological factors. CONCLUSIONS: The determinants identified provide opportunities for the development of multidimensional early screening and early intervention strategies for women with an increased risk of postpartum depression.

Daily stair climbing is associated with decreased risk for the metabolic syndrome.

BACKGROUND: Stair climbing can be a vigorous lifestyle physical activity, and is associated with healthier lipoprotein profiles, lower body weight and blood pressure, as well as higher aerobic fitness. The present analysis of data from a cohort of late middle-aged men and women examined the association between daily stair climbing and the metabolic syndrome. METHODS: Data from 782 (423 women) participants (mean (SD) age 58.3 (0.95) years in the Dutch Famine Birth Cohort Study (2002-2004) were used to examine the cross-sectional association between self-reported daily stair climbing and the metabolic syndrome. Stair climbing was assessed by the question 'Do you climb stairs daily?' and the metabolic syndrome was defined using the established five components relating to lipid fractions, blood glucose levels, blood pressure and abdominal obesity. RESULTS: Not climbing stairs daily was associated with an increased incidence of the metabolic syndrome (OR = 1.90, 95% CI = 1.23, 2.92, p = 0.004) and a greater number of its components (F1,780 = 8.48, p = 0.004): these associations were still evident after adjusting for a variety of potential confounders. CONCLUSIONS: The most likely explanation for the current findings is that daily stair climbing may be protective against the metabolic syndrome. This result reinforces public health recommendations for increased stair climbing with evidence from physiological outcomes.

Combining lipidomics and machine learning to measure clinical lipids in dried blood spots.

INTRODUCTION: Blood-based sample collection is a challenge, and dried blood spots (DBS) represent an attractive alternative. However, for DBSs to be an alternative to venous blood it is important that these samples are able to deliver comparable associations with clinical outcomes. To explore this we looked to see if lipid profile data could be used to predict the concentration of triglyceride, HDL, LDL and total cholesterol in DBSs using markers identified in plasma. OBJECTIVES: To determine if DBSs can be used as an alternative to venous blood in both research and clinical settings, and to determine if machine learning could predict 'clinical lipid' concentration from lipid profile data. METHODS: Lipid profiles were generated from plasma (n = 777) and DBS (n = 835) samples. Random forest was applied to identify and validate panels of lipid markers in plasma, which were translated into the DBS cohort to provide robust measures of the four 'clinical lipids'. RESULTS: In plasma samples panels of lipid markers were identified that could predict the concentration of the 'clinical lipids' with correlations between estimated and measured triglyceride, HDL, LDL and total cholesterol of 0.920, 0.743, 0.580 and 0.424 respectively. When translated into DBS samples, correlations of 0.836, 0.591, 0.561 and 0.569 were achieved for triglyceride, HDL, LDL and total cholesterol. CONCLUSION: DBSs represent an alternative to venous blood, however further work is required to improve the combined lipidomics and machine learning approach to develop it for use in health monitoring.

Maternal verbal aggression in early infancy and child's internalizing symptoms: interaction by common oxytocin polymorphisms.

Genetic predisposition of social sensitivity might affect vulnerability to develop psychopathology after early life stress exposure. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin polymorphisms in developing internalizing symptoms at ages 5-6 and 11-12. In the Amsterdam-Born-Children-and-their-Development (ABCD) study, a large observational, population-based birth cohort, maternal verbally aggressive behavior was assessed in the 13th postnatal week by a self-report questionnaire. Internalizing symptoms at age 5-6 were assessed by maternal report (N = 969) and internalizing symptoms at age 11-12 were assessed by self-report (N = 750). Data on oxytocin receptor polymorphisms rs53576 and rs2268498 and oxytocin polymorphisms rs2740210 and rs4813627 were collected. If the child was carrier of rs2740210 CA/AA polymorphism, exposure to maternal verbally aggressive behavior (10.6%) was positively associated with general anxiety at age 5-6 and emotional symptoms at age 11-12 (p for interaction = 0.011 and p = 0.015, respectively). If the child was carrier of rs4813627 GG (wild type), exposure to maternal verbally aggressive behavior was negatively associated with anxiety sensitivity and emotional symptoms at age 11-12 (p for interaction = 0.011 and p = 0.022, respectively). After exposure to maternal verbally aggressive behavior in early infancy, oxytocin polymorphisms may partly determine a child's vulnerability to internalizing symptoms.

Malnutrition and depression in pregnancy and associations with child behaviour and cognitive function: a review of recent evidence on unique and joint effects 1.

Accumulating studies suggest that prenatal experiences can shape a child's neurodevelopment. Malnutrition and depression occur in pregnancy relatively often and may affect child neurodevelopment independently as well as synergistically. We aimed to provide an overview of recent studies that have examined malnutrition and (or) depression in pregnancy and associations with child behavioural problems and cognitive function. We conducted a literature search in PubMed, using the following main search terms: "depression", "nutrition", "BMI", "pregnancy", "offspring", "cognition", and "behaviour". We included studies in human populations published from 2013 onwards. The literature search yielded 1531 articles, of which 55 were included in the current review. We presented the evidence on the associations between prenatal markers of nutritional status and (or) depression and child behaviour and (or) cognitive function. We additionally discussed interventions and mechanisms. Both malnutrition and depression in pregnancy are associated with increased externalizing behavioural problems and attentional deficits, and to some extent with poorer cognitive function in the child, but the evidence is not conclusive. Studies on synergistic effects of both factors on child behaviour and cognitive function are still scarce, and more research is needed. Potential shared mechanisms include the hypothalamic-pituitary-adrenal axis, the immune system, epigenetics, and oxidative stress.

Childhood adversity and women's cardiometabolic health in adulthood: associations with health behaviors, psychological distress, mood symptoms, and personality.

BACKGROUND: We tested whether childhood adversity is associated with poor cardiometabolic health in adulthood among a sample of overweight or obese Dutch women of reproductive age. Health behaviors, psychological distress, mood symptoms, or personality traits were included as potential mediators. METHODS: Data came from a follow-up visit (N = 115), carried out in 2016/2017, of a randomized controlled lifestyle intervention trial in 577 obese infertile women. The associations between total adversity exposure score and cardiometabolic health were tested with regression models. Sleep, smoking and eating behavior, symptoms of depression, anxiety and stress, and personality traits were potential mediators. RESULTS: Childhood adversity scores were not associated with cardiometabolic outcomes but were associated with poorer sleep quality score (M = 7.2 (SD = 3.5) for those with ≥2 types of events versus 4.8 (2.9) for those with no events; p = 0.022), higher external eating score (26.4 (8.7) versus 21.8 (10.3); p = 0.038), higher perceived stress score (17.1 (6.8) versus 12.3 (4.5); p = 0.016), post-traumatic stress score (1.9 (1.5) versus 0.6 (1.1); p < 0.001), and lower agreeableness score (28.2 (4.2) versus 30.3 (3.1); p = 0.035). CONCLUSION: Childhood adversity was associated with poorer health behaviors including sleep and eating behavior, and more stress-related symptoms, but not with women's cardiometabolic health.

Premature brain aging in humans exposed to maternal nutrient restriction during early gestation.

BACKGROUND: Prenatal exposure to undernutrition is widespread in both developing and industrialized countries, causing irreversible damage to the developing brain, resulting in altered brain structure and decreased cognitive function during adulthood. The Dutch famine in 1944/45 was a humanitarian disaster, now enabling studies of the effects of prenatal undernutrition during gestation on brain aging in late adulthood. METHODS: We hypothesized that study participants prenatally exposed to maternal nutrient restriction (MNR) would demonstrate altered brain structure resembling premature brain aging in late adulthood, expecting the effect being stronger in men. Utilizing the Dutch famine birth cohort (n = 118; mean age: 67.5 ± 0.9 years), this study implements an innovative biomarker for individual brain aging, using structural neuroimaging. BrainAGE was calculated using state-of-the-art pattern recognition methods, trained on an independent healthy reference sample, then applied to the Dutch famine MRI sample, to evaluate the effects of prenatal undernutrition during early gestation on individual brain aging in late adulthood. RESULTS: Exposure to famine in early gestation was associated with BrainAGE scores indicative of an older-appearing brain in the male sample (mean difference to subjects born before famine: 4.3 years, p < 0.05). Furthermore, in explaining the observed variance in individual BrainAGE scores in the male sample, maternal age at birth, head circumference at birth, medical treatment of hypertension, history of cerebral incidences, actual heart rate, and current alcohol intake emerged to be the most influential variables (adjusted R2 = 0.63, p < 0.01). INTERPRETATION: The findings of our study on exposure to prenatal undernutrition being associated with a status of premature brain aging during late adulthood, as well as individual brain structure being shaped by birth- and late-life health characteristics, are strongly supporting the critical importance of sufficient nutrient supply during pregnancy. Interestingly, the status of premature brain aging in participants exposed to the Dutch famine during early gestation occurred in the absence of fetal growth restriction at birth as well as vascular pathology in late-life. Additionally, the neuroimaging brain aging biomarker presented in this study will further enable tracking effects of environmental influences or (preventive) treatments on individual brain maturation and aging in epidemiological and clinical studies.

Invited Commentary: A Matter of Survival-The Detrimental Consequences of Adverse Early-Life Conditions.

Studies across different species have shown that moderate dietary restriction is associated with a longer life span. Surprisingly, however, when diet is restricted in prenatal life, the effect is completely the opposite. Animal studies and human epidemiologic data have shown that undernutrition in utero negatively affects health in later life and reduces life span considerably. In this issue of the Journal, Schoeps et al. (Am J Epidemiol. 2018;187(10):2085-2092) provide new evidence that variations in nutritional conditions during pregnancy relate to the future health of the unborn child. In a detailed analysis of data from Muslim and non-Muslim pregnant women in Burkina Faso, they showed that the occurrence of Ramadan in early life was strongly associated with mortality rates among children under 5 years of age. Mortality rates were highest when Ramadan had occurred in the preconception period or during the first trimester. That nutritional conditions in early life can have such profound consequences for child mortality is both astonishing and extremely relevant from a public health perspective.

Prenatal stress and models explaining risk for psychopathology revisited: Generic vulnerability and divergent pathways.

The present review revisits three hypothesized models that potentially could explain how prenatal maternal stress influences fetal development, birth outcomes, and subsequent developmental psychopathology. These models were mostly based on animal models, and new evidence for these models from human studies is evaluated. Furthermore, divergent trajectories from prenatal exposure to adversities to offspring affected outcomes are reviewed, including the comparison of studies on prenatal maternal stress with research on maternal substance use and maternal malnutrition during pregnancy. Finally, new directions in research on the mechanism underlying prenatal stress effects on human offspring is summarized. While it is concluded that there is abundant evidence for the negative associations between prenatal maternal stress and offspring behavioral, brain, and psychopathological outcomes in humans, there is no consistent evidence for specific mechanisms or specific outcomes in relation to stress exposure in utero. Rather, principles of multifinality and equifinality best describe the consequences for the offspring, suggesting a generic vulnerability and different pathways from prenatal adversities to developmental psychopathology, which complicates the search for underlying mechanisms. New and promising directions for research are provided to get a better understanding of how prenatal stress gets under the skin to affect fetal development.

Prenatal famine exposure has sex-specific effects on brain size.

Early nutritional deprivation might cause irreversible damage to the brain. Prenatal exposure to undernutrition has been shown to be associated with increased central nervous system anomalies at birth and decreased cognitive function in adulthood. Little is known about the potential effect on the brain in older age. We investigated brain size and structure at age 68 years after prenatal famine exposure. T1-weighted structural magnetic resonance images of the brain were made in 118 Dutch famine birth cohort members. Of these 118 (44% male, age range 65-69 years), 41 had been exposed to famine in early gestation and 77 had been prenatally unexposed. Structural volumes were automatically assessed using FreeSurfer. Diffusion tensor imaging was performed and anisotropy and diffusivity were computed. Fluid attenuated inversion recovery was performed to assess white matter hyperintensities. Exposure to famine in early gestation was associated with smaller intracranial volume in males, but not females. Volumes of total brain, grey and white matter were also smaller in early exposed males, but these differences disappeared after adjusting for intracranial volume. Prenatally exposed males but not females, had a smaller intracranial and total brain volume compared to unexposed subjects. Our findings show that prenatal undernutrition permanently affected brain size.media-1vid110.1093/brain/aww132_video_abstractaww132_video_abstract.

Prenatal Undernutrition and Autonomic Function in Adulthood.

OBJECTIVES: Early-life adversity has been shown to be associated with cardiovascular disease and mortality in later life, but little is known about the mechanisms that underlie this association. Prenatal undernutrition, a severe early-life stressor, is associated with double the risk of coronary heart disease and increased blood pressure responses to psychological stress. In the present study, we tested the hypothesis that prenatal undernutrition induces alterations in the autonomic nervous system, which may increase the risk of developing heart disease. METHODS: We studied autonomic function in 740 men and women (mean [SD] age, 58 [0.9] years) who were members of the Dutch famine birth cohort. We compared those exposed to famine during early (n = 64), mid (n = 107), or late gestation (n = 127) to those unexposed to famine in utero (n = 442). Participants underwent a series of 3 psychological stressors (Stroop, mirror tracing, and speech) while their blood pressure and heart rate were recorded continuously. RESULTS: Data had sufficient quality in 602 participants for derivation of autonomic function indices by spectral analysis. The stress protocol led to significant sample-level changes in systolic blood pressure, heart rate, and all cardiovascular control measures (all p values < .001). None of the autonomic function parameters, at rest or in response to stress, differed significantly (all p values > .050) according to prenatal famine exposure. CONCLUSIONS: Prenatal undernutrition was not associated with autonomic function in late adulthood. We conclude that altered autonomic function does not seem to explain our previous findings of increased coronary heart disease risk among those exposed to famine prenatally.

Famines in the last 100 years: implications for diabetes.

Overnutrition is a major cause of diabetes. The contrary situation of undernutrition has also been suggested to increase the risk of the disease. Especially undernutrition during prenatal life has been hypothesized to program the structure and physiology of the fetus in such a way that it is more prone to develop diabetes in later life. Famines over the last 100 years have provided historical opportunities to study later-life health consequences of poor nutritional circumstances in early life. The majority of studies based on famine exposure during prenatal life clearly show that diabetes risk is increased. Postnatal famine exposure in childhood, adolescence, or young adulthood also seems to raise risk for diabetes, although prenatal famine effects seem to be more substantial. These study results not only have implications for the consequences of famines still happening but also for pregnancies complicated by factors mimicking poor nutritional situations.

Prenatal Exposure to the 1944-45 Dutch Famine and Risk for Dementia up to Age 75: An Analysis of Primary Care Data.

BACKGROUND: A poor prenatal environment adversely affects brain development. Studies investigating long-term consequences of prenatal exposure to the 1944-45 Dutch famine have shown that those exposed to famine in early gestation had poorer selective attention, smaller brain volumes, poorer brain perfusion, older appearing brains, and increased reporting of cognitive problems, all indicative of increased dementia risk. OBJECTIVE: In the current population-based study, we investigated whether dementia incidence up to age 75 was higher among individuals who had been prenatally exposed to famine. METHODS: We included men (n=6,714) and women (n=7,051) from the Nivel Primary Care Database who had been born in seven cities affected by the Dutch famine. We used Cox regression to compare dementia incidence among individuals exposed to famine during late (1,231), mid (1,083), or early gestation (601) with those unexposed (born before or conceived after the famine). RESULTS: We did not observe differences in dementia incidence for those exposed to famine in mid or early gestation compared to those unexposed. Men and women exposed to famine in late gestation had significantly lower dementia rates compared to unexposed individuals (HR 0.52 [95%CI 0.30-0.89]). Sex-specific analyses showed a lower dementia rate in women exposed to famine in late gestation (HR 0.39 [95%CI 0.17-0.86]) but not in men (HR 0.68 [95%CI 0.33-1.41]). CONCLUSION: Although prenatal exposure to the Dutch famine has previously been associated with measures of accelerated brain aging, the present population-based study did not show increased dementia incidence up to age 75 in those exposed to famine during gestation.

Aging, sex, metabolic and life experience factors: Contributions to neuro-inflammaging in Alzheimer's disease research.

Alzheimer's disease (AD) is prevalent around the world, yet our understanding of the disease is still very limited. Recent work suggests that the cornerstone of AD may include the inflammation that accompanies it. Failure of a normal pro-inflammatory immune response to resolve may lead to persistent central inflammation that contributes to unsuccessful clearance of amyloid-beta plaques as they form, neuronal death, and ultimately cognitive decline. Individual metabolic, and dietary (lipid) profiles can differentially regulate this inflammatory process with aging, obesity, poor diet, early life stress and other inflammatory factors contributing to a greater risk of developing AD. Here, we integrate evidence for the interface between these factors, and how they contribute to a pro-inflammatory brain milieu. In particular, we discuss the importance of appropriate polyunsaturated fatty acids (PUFA) in the diet for the metabolism of specialised pro-resolving mediators (SPMs); raising the possibility for dietary strategies to improve AD outlook.

Prenatal undernutrition and cognitive function in late adulthood.

At the end of World War II, a severe 5-mo famine struck the cities in the western part of The Netherlands. At its peak, the rations dropped to as low as 400 calories per day. In 1972, cognitive performance in 19-y-old male conscripts was reported not to have been affected by exposure to the famine before birth. In the present study, we show that cognitive function in later life does seem affected by prenatal undernutrition. We found that at age 56 to 59, men and women exposed to famine during the early stage of gestation performed worse on a selective attention task, a cognitive ability that usually declines with increasing age. We hypothesize that this decline may be an early manifestation of an accelerated cognitive aging process.