- Email: [email protected]
Adiposity indices and dementia
Personal View
Adiposity indices and dementia Deborah Gustafson
Indicators of adiposity, such as body-mass index (BMI), may be markers for changes in energy metabolism that influence dementia risk, progression, and ultimately death. Cross-sectional studies show that people with dementia have a lower BMI than those without dementia, which is potentially due to a greater rate of BMI decline occurring during the years immediately preceding dementia onset. However, a high BMI can also increase the risk for dementia when measured before clinical dementia onset, which might be due to vascular disorders or bioactive hormonal compounds that are secreted by adipose tissue. In this personal view, I consider how dementia is associated with BMI by looking at the role of BMI and obesity syndromes, mechanisms associated with adiposity, and the potential for hypothalamic dysregulation during the life course. Understanding the life course of adiposity by use of common surrogate measures, such as BMI, among those who do and do not develop dementia is relevant for understanding the causes of dementia and for shaping possible treatment options.
http://neurology.thelancet.com Vol 5 August 2006
Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, SE 413–45, Göteborg, Sweden; and the Medical College of Wisconsin, Department of Family and Community Medicine, Milwaukee, Wisconsin, USA (D Gustafson PhD) [email protected]
stage of the dementia process, including during early brain development.16 The most common and simple measure of adiposity used in population-based and clinical studies is bodymass index (BMI), which is calculated as weight (kg)/ height (m²). BMI is not a perfect measure of adiposity and is affected by factors such as ethnicity and age—the ratio of fat-free mass to height begins to decrease after age 45 years, particularly among women.17 Waist-to-hip ratio and waist circumference alone, are measures of body fat distribution. Waist circumference seems to be a more sensitive indicator of cardiovascular-disease risk than BMI.18 Better measures of adiposity and its effects are needed—for example, measuring the concentration of an adipocyte hormone in the blood. Biological plausibility for an association between high adiposity and dementia is relevant to the aetiology of the disease and forms a basis for prevention efforts. In this personal view, I focus on how BMI may be associated with dementia by looking at the evidence for a role of high BMI, obesity syndromes, and BMI decline; biological mechanisms associated with adiposity; and the potential for hypothalamic dysregulation during the life course. • Fat and brain development • Adipose-derived factors shape hypothalamus
Age-related changes in body composition
Critical fatness level and menarcheal age and sex hormone levels
BMI
The number of overweight and obese people is reaching epidemic proportions worldwide.1 Over 50% of adults in the USA and Europe are overweight or obese;2,3 with the highest prevalence among women age 50 years and above.2 The prevalence of Alzheimer’s disease is also highest among women and will increase as women live to older ages. One of the most rapidly growing age groups is 85 years and older. At age 85 years, dementia incidence approaches 10% per year4 and prevalence 30%,5 with subsequent prevalence estimates as high as 50% at age 95 years.5 The number of people with Alzheimer’s disease may reach epidemic proportions between 2010 and 2050, when the number of people with the disease might more than double. Many studies suggest that vascular disorders, including being overweight or obese,6–10 are risk factors for Alzheimer’s disease. Because being overweight or obese increases the risk for subsequent vascular disorders,11 these states may be an initial trigger eventually leading to Alzheimer’s disease and vascular forms of dementia, or these states may indicate vascular burden. Although adipose tissue is the largest endocrine organ in the human body, it is commonly overlooked that the effects of being overweight or obese on brain health might be independent of vascular effects and instead be due to adipocyte hormones and cytokines. Although the classification of clinical dementia subtypes is debated in terms of the underlying pathologies,12 before the development of preclinical and clinical dementia symptoms there are both neuropathological and cerebrovascular changes in the brain. Studies in animals have shown that vascular disease and fatty streaks in blood vessels can appear early in the fetus and, in youth, and are associated with dietary fat intake; Alzheimer’s disease plaques and tangles can develop as early as during the third decade.13 A life course approach to understanding the causes of dementia is imperative14,15 because the roles and timing of risk and protective factors are relevant throughout life. Because adipose tissue is a persistent lifetime exposure beginning in utero (figure 1), its influence may be relevant at every
Cognition
Introduction
Lancet Neurol 2006; 5: 713–20
• High BMI may lead to cognitive decline and dementia later in life, and to later brain pathology
Fetus
Early life
Adult life
• High BMI may predict cognitive decline and dementia • Greater decline in BMI may predict dementia • Low BMI may be associated with dementia Late life
Figure 1: Potential trajectories of cognition associated with adipose tissue and stage of life
713
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Baseline Years of age (years) follow-up
Baseline BMI
Gerontological and geriatric population studies, H70 (Sweden)7
70
18
Primary prevention study (Sweden)8
47–55
Kaiser Permanente (USA)9
Dementia assessment
Number with Risk ratio for all dementias (RR, 95% CI)* dementia/total
25·8 (3·8)
Neuropsychiatric interview, key informant interview, medical record review
93/382
In women with dementia age 79–88 years, for each unit (kg/m²) increase in BMI at age 70 years 1·13, 1·04–1·24 for AD 1·36, 1·16–1·59 75 years 1·13, 1·04–1·24 for AD 1·35, 1·19–1·53 79 years 1·15, 1·05–1·26 for AD 1·23, 1·10–1·37
28
25·5 (3·3)
Primary and secondary dementia hospital discharge diagnoses
254/7148
In men, the risk of dementia by BMI level BMI <20 2·43, 1·10–5·29 BMI 20–22·49 1·00 BMI 22·50–27·49 1·49, 0·92–2·41 BMI ≥30 1·98, 1·10–3·56
40–45
27
10% ≥30 36% 25–30; 53% 18·6–25; 1·3% <18·6
ICD-9 criteria
713/10 276
In women and men, the RR of dementia by BMI BMI >30 1·74, 1·34–2·26 BMI 25–30 1·35, 1·14–1·60 Highest quintile of subscapular skinfold thickness 1·72, 1·36–2·18 Highest quintile of triceps skinfold thickness 1·59 1·24–2·04 In women only, the RR of dementia by BMI: BMI >30 2·07, 1·49–2·89 BMI 25–30 1·55, 1·22–1·97
Cardiovascular risk factors, ageing, and dementia, CAIDE (Finland)10
51
21
26·6 (3·7)
Screening, clinical, and differential diagnostic phases
61/1449
In women and men, the risk of dementia with obesity BMI >30: OR=2·09, 1·16–3·77 No significant effect of BMI at lower levels
Personnes ages quid, PAQUID study (France)25
≥65
8
24·6 (3·9)
Screening, clinical, and differential diagnostic phases
221/3557
In women and men, the risk of dementia by BMI level BMI <21 1·48, 1·08–2·04 with inclusion of all dementias over 8 years; 1·19, 0·72–1·96 when individuals developing dementia within 5 years of baseline were excluded No effect of baseline high BMI
Rancho Bernardo study (USA)24
50–79
20
25·0
Screening, clinical, and differential diagnostic phases
60/299
Women and men developing AD experienced a greater decline in bodyweight (≥5 kg) compared with those not developing dementia; men who developed AD had a higher average baseline bodyweight
Honolulu Asia Aging Study, HAAS (USA)26
45–66
32
23·9 (2·7)
Screening, clinical, and differential diagnostic phases
112/1890
In men with incident dementia, during the last 6 years of follow-up, mean weight loss adjusted for age and education –0·58 kg/year compared with –0·22 kg/year among men not developing dementia. No effect of baseline BMI
Average 5·6
27·4 (5·4)
Physicians’ examination, NINCDS-ADRDA criteria for Alzheimer’s disease
151/832
In women and men: risk of dementia per one unit decline in BMI from baseline HR=0·94, 0·91–0·98 Risk of dementia by one unit less BMI at baseline HR=0·73, 0·63–0·85 Similar result when excluding those developing AD during first 4 years
Religious Order Study 77·1 (USA)27
(kg/m², SD)
NINCDS-ADRDA=National Institute of Neurological and Communicative Disease and Stroke-Alzheimer’s Disease and Related Disorders Association; AD=Alzheimer’s disease; RR=relative risk; HR=hazard ratio; ICD-9=International classification of diseases; OR=odds ratio; RR=relative risk. *Unless otherwise stated.
Table 1: Prospective studies of BMI and dementia
Is high BMI a risk factor for dementia? In the past, studies reported that a low BMI or being underweight were risk factors for dementia19–22 and agerelated brain changes, such as atrophy.23 These observations, however, were based on cross-sectional or case-control studies, and there was a lack of prospective analyses. Several prospective reports7–10,24–27 have assessed BMI in association with dementia (table 1). When assessing prospective studies it is important to note the study populations, age of the participants at baseline, BMI measurement, and the length and completeness of follow-up to dementia onset. In general, these studies assess BMI among those who have survived to about age 70 years and therefore have not died due to other consequences of higher BMI levels and are now at risk of dementia. 714
The longest study of BMI and dementia so far published has 32 years of follow-up.26 emphasising the importance of taking a life-course approach to studying adiposity in dementia. A life-course approach has been pursued for other age-related diseases such as breast cancer28 and cardiovascular disease.29 Factors such as birthweight, age at menarche, recalled weight at different stages of physical maturation, and weight cycling have been used to assess adiposity and disease. In addition, there are no published reports on the longitudinal BMI–dementia association that take into account the role of APOE ε4— the major susceptibility allele for dementia. There are numerous reports on the association between cognitive performance, BMI, and other adiposity measures;30–36 however, comparison of these studies is difficult because most are cross-sectional, have small http://neurology.thelancet.com Vol 5 August 2006
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Baseline age (years,SD)
Years of follow-up
Baseline BMI (kg/m²,SD)
Cognitive assessment
Number with poor performance/ total n
Risk of poor cognitive ability (OR, 95% CI)*
Cluster sample (South Korea)34
≥65
0
21·6% with BMI ≥25
K-MMSE
175/467 with K-MMSE <19
In women and men: BMI ≥25 +abdominal obesity (≥90 cm in men and ≥80 cm in women) 2·79, 1·12–6·96 BMI 23–25 +no abdominal adiposity 0·32, 0·12–0·86 multivariate-adjusted
EPIDOS (France)30
≥75
0
25·3
SPSMQ
782/7105 with a SPSMQ score <8 defined as cognitive impairment
In women: First quartile of fat-free soft tissue mass 1·43, 1·07–1·91 First quartile of fat mass: 1·35, 1·01–1·79
The Framingham Heart Study (USA)35
65·7 (6·9) in men 67·2 (7·3) for women
4–8
26·3 (3·2) in men 25·3 (3·8) in women
Neuropsychological 61 obese men, 95 obese test battery women/1423 (obese is BMI ≥30)
Men with average obesity over 16 years showed low ability in visual reproductions, digit span backward, and global composite No associations in women Diabetes associated with low cognition in men and women combined
Prospective epidemiological 63·8 (postmenopausal risk factors, PERF study women only) (Denmark)31
7·3
baseline weight 67·1 kg
Short Blessed test
222/5607 with short Blessed test score ≥9
In women greater change in weight (–0·15±1·0) and lower central fat mass and central fat mass-toperipheral fat mass ratio with short Blessed test score ≥9; not reported in women >80 years
CERAD-NAB
97/531 had poor cognitive performance, defined as 2 or more of 11 tests ≤1·5 standard deviation of normative mean
In women and men: weight loss and gain related to poor cognitive performance: 50% higher odds of poor cognitive performance associated with an annual decrease of 0·5 kg/m²or increase of +0·3 kg/m² BMI
Basel study cohort (Switzerland)32
59·4 (7·8)
10
25·2 (3·1)
Community-based sample of women with Down’s syndrome (USA)33
40–60
0
21/38 premenopausal Neuropsychological Postmenopausal obese obese; 32/78 test battery had lower mean test postmenopausal scores obese (obese is BMI ≥30)
Obese postmenopausal women had better performance in verbal memory and an omnibus test of neuropsychological function; adjustment for serum oestrone attenuated the association No associations in premenopausal women
Community-based sample of middle-aged and older adults (USA)36
54–81
0
27·5 (5·1)
In women and men interaction of high waist circumference or high BMI and high blood pressure associated with motor speed, manual dexterity, and executive function
Neuropsychological Correlational analyses assessment
CERAD=Consortium to establish a registry for Alzheimer’s disease; NAB=neurosychological assessment battery; OR=odds ratio; K-MMSE=Korean mini-mental state examination; SPSMQ= short portable mental status questionnaire.
Table 2: Selected studies on adiposity and cognition
sample sizes, use different methods to measure cognitive function and adiposity, and inconsistently define poor or low cognitive performance (table 2). Additionally, many of these studies do not screen for other mental health outcomes, such as depression or medication use, which may affect these reported associations of BMI and cognitive performance. More research is needed on adiposity and preclinical symptoms of dementia or cognitive impairment to determine at what point adiposity may have an effect or when the influence of adiposity changes direction.
How might excess adiposity increase risk of dementia? Adipose tissue is the largest endocrine organ in the human body and secretes hormones, cytokines, and growth factors, which directly interact with blood vessels,37,38 cross the blood–brain barrier,39 and contribute to homoeostasis. Adipose tissue is particularly important in elderly people—illustrated by the classic example of adipose being the primary site of oestrogen synthesis in postmenopausal women, which is modulated by http://neurology.thelancet.com Vol 5 August 2006
environmental factors.40 In addition, adipose tissue secretes various bioactive metabolites, such as insulinlike growth factor-I, transforming growth factor β, tumour necrosis factor α, angiotensin II, leptin, neurotrophins, growth factors, cytokines, fatty acids, and many other factors that may cross the blood–brain barrier39,41 and affect brain health and subsequent dementia (figure 2). These compounds are important as exemplified by published reports that a high BMI or more adiposity is independently associated with dementia, even after adjustment for multiple vascular factors. In terms of vascular effects, the association between BMI and dementia could be due to effects of excess adiposity on blood pressure, blood lipids, cardiovascular disease, and general health of the vasculature. Obesity is also associated with carotidartery-wall thickening,37 vascular and coronary endothelial dysfunction,38,42,43 peripheral resistance, arterial stiffness, ventricular hypertrophy, increased sympathetic activity, increased intravascular volume, high cardiac output, and increased platelet aggregation.44,45 The association between BMI, body-fat distribution, and dementia might 715
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Vascular effects Ischaemia and toxic events Carotid-artery-wall thickening Coronary endothelial dysfunction Peripheral resistance Arterial stiffness Ventricular hypertrophy Increased sympathetic activity Increased intravascular volume Increased cardiac output Platelet aggregation
Adipose-derived Leptin Sex hormones Interleukins Neurotrophins Growth factors Adipocytokines
Adipose-associated Insulin Satiety factors Sex hormones
Background Age Sex Genes
Figure 2: Adipose tissue and the brain
be the result of underlying brain pathologies associated with dementia, such as cerebral atrophy and white-matter lesions. This association would therefore implicate the detrimental involvement of higher adiposity in the early stages of dementia. In addition, disturbance of the blood–brain barrier is common in those with dementia and vascular diseases,46 thus affecting transfer of adiposederived compounds to the brain. Cerebral atrophy is a symptom of neuronal degeneration and contributes to cognitive decline and dementia.47,48 Atrophy of the temporal lobe, an area that is highly susceptible to effects of ischaemia and other vascular insults to the brain,49 may be an early hallmark of Alzheimer’s disease. Among women age 62–84 years, atrophy of the temporal lobe measured with CT was associated with higher BMI at four examinations where the women were followed up for 24 years (starting when the women were age 38–60 years).50 After adjustment for multiple vascular factors, the odds of temporal atrophy were 13–16% higher per 1·0 kg/m² increase in BMI. This finding was replicated in a cross-sectional study of women and men age 40–66 years, among whom higher BMI was associated with lower global-brain volume on MRI;51 but was not replicated in another.23 A high waist-to-hip ratio was inversely associated with hippocampal volume measured with MRI, in a subsample of the Sacramento Area Latino Study on Aging (SALSA).52 Waist-to-hip ratio was not associated with temporal atrophy in the prospective population study of women in Sweden.50 The Austrian Stroke Prevention Study showed that a high BMI predicted a high rate of progression of brain atrophy on serial MRI.53 Vascular factors, primarily hypertension, are implicated in the cause and progression of white-matter lesions, and 716
these lesions lead to cognitive decline and dementia.6,54 In one study, the presence and severity of white-matter lesions at age 85–88 years were associated with high BMI up to 18 years before.55 Women with high BMI had two times greater risk of white-matter lesions later in life than women without. The SALSA study showed a 27% increase in white-matter hyperintensities on MRI associated with a higher waist-to-hip ratio.52 The effects of adiposity on brain health in late life cannot perhaps be completely assessed without considering cognitive reserve or level of intelligence. However, measurement of this variable is uncommon or unavailable in many epidemiological studies of dementia; the level of education is commonly used as a surrogate marker of intelligence or cognitive reserve and often adjusted for in multivariate models. Intelligence may be the single largest influence of health behaviours.56 Lower childhood intelligence quotient scores are associated with later adiposity, smoking, high blood pressure, cardiovascular disease, and mortality; however, the level of education achieved may “correct” potential influences of low intelligence quotients.57 The directionality and absolute effect of obesity–intelligence associations are difficult to assess because there are many factors that interact to affect cognitive and physical health, such as environmental stimulation, socioeconomic status, parental nutrition, hypothalamic programming, metabolic imprinting, genetics, vascular risk factors, educational attainment, diet, and physical activity.57
Is an obesity syndrome associated with dementia? Whether there is an association between old-age metabolic or obesity syndrome and Alzheimer’s disease and dementia is still unknown, although a high BMI rarely exists in isolation.58,59 As many as one in five adults has a clinically characterised obesity syndrome.1 The ubiquity of adipose tissue means that this syndrome potentially affects various adjacent organ systems and is a primary mediator of obesity-associated syndromes. Therefore, syndromes in the periphery may be associated with syndromes in the ageing brain. The Honolulu-Asia Aging Study showed that clustering of cardiovascular risk factors was associated with vascular dementia in Japanese American men.59 BMI was part of this cluster and a one standard deviation increase in BMI was associated with a 21% higher risk of vascular dementia. The Health, Aging and Body Composition study showed a 20% increased risk of cognitive impairment among white and black people age 74 years with a clinically diagnosed metabolic syndrome.58 This risk tripled among those with high concentrations of C-reactive protein and interleukin 6.58 The cardiovascular risk factors, ageing, and dementia (CAIDE) study reported that the accumulation of vascular risk factors, notably obesity, systolic hypertension, and hyperhttp://neurology.thelancet.com Vol 5 August 2006
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cholesterolaemia during midlife was associated with increased odds of dementia.10 Diabetes—a metabolic and vascular dysregulator—can also increase dementia risk.60,61 Memory impairment is related to poor glycaemic control,62 and low cognition to insulin resistance.63 However, the Framingham Heart Study showed that obesity (independent of diabetes status) was associated with lower cognitive ability among men than in women.35 Given the increasing occurrence of type 2 diabetes among young adults and the role of insulin, insulin resistance, and related genes, diabetes may become increasingly important in the cause of cognitive decline and dementia. When assessing components of an obesity or metabolic syndrome, it is difficult to pinpoint the trigger event. In an obese person, blood supply to adipose tissue can reach 15–30% of cardiac output, which can lead to hypertension and other haemodynamic changes. However, temporality is not clear.64 Hypertension syndrome (obesity, hypertension, salt sensitivity, and insulin resistance)45 and metabolic syndrome (obesity, high waist circumference, hypertension, glucose intolerance, and hyperlipidaemia)65 are both characterised by symptom clusters without clear indication of temporality and point to a general increase in sympathetic activity. In rapidly ageing developed societies, if obesity increases dementia risk then public health implications of the obesity epidemic are more severe than previously estimated and extend to those age 85 years and older.
Is anorexia of ageing a marker for dementia? One of the first studies to report a decline in bodyweight preceding a dementia diagnosis was the Rancho Bernardo study24 and there have been at least two other published studies of BMI decline (table 1).26,27 Therefore, among some individuals, weight loss may be a potential preclinical marker for Alzheimer’s disease, particularly when measured 6–10 years before a clinical diagnosis. Low bodyweight or low BMI also predicts mortality among those with dementia.66 Temporal changes in bodyweight and BMI may be biomarkers for changes in energy metabolism that may influence the risk of Alzheimer’s disease, progression, and ultimately death. The brain, in particular the hypothalamus, regulates energy homoeostasis through the control of hunger and satiety, the regulation of energy expenditure, and the release of hormones that increase use of energy stores.67 The neuropathology that precedes and accompanies Alzheimer’s disease may be a cause of or exacerbate disruptions in energy metabolism. Memory impairment might be an initial symptom in Alzheimer’s disease; individuals with memory impairments may forget to eat, and thus experience declines in bodyweight. There are numerous hypotheses associating memory, hippocampal function, control of energy intake, and hypothalamic function.68,69 http://neurology.thelancet.com Vol 5 August 2006
Hypothalamic dysregulation from cradle to grave Reports of pronounced anorexia in elderly people with dementia may suggest early onset of variation and potential dysregulation in brain centres responsible for feeding behaviour, bodyweight control and set-points, and energy metabolism. Hormones secreted by adipose (eg, leptin, sex hormones), the gut (eg, cholecystokinin, peptide YY, glucagon-like peptide 1), pancreas (eg, insulin), and liver (eg, glucagon) as well as a host of neuropeptides interact with brain centres to induce physiological responses associated with energy intake and expenditure.67 These are obvious pieces of the puzzle underlying individual susceptibility for various diseases associated with energy metabolism. Along with this is the role of genetic variation, which also shapes our responses to and interactions with environmental factors, aspects of our phenotype, and other products of gene expression. Although hypothalamic variation or dysregulation is difficult to characterise during the life course, it is interesting nonetheless to formulate a few hypotheses. This viewpoint will address leptin as an example. Adipose-derived factors, such as leptin, affect the function of the hypothalamus and learning and memory processes controlled by the hippocampus.68 Common hormone receptors, such as the leptin receptor, in the hippocampus, hypothalamus, amygdala, cerebellum, and brainstem indicate potentially linked regulatory mechanisms.68,70 Recent experimental data show that compounds secreted by adipose tissue, such as leptin and adiponectin, interact directly with hypothalamic nuclei and regulate energy expenditure and hyperphagic responses.71,72 Leptin may even shape the hypothalamus during the earliest stages of development and improve cognition.70 The data on adiposity and dementia provide strong evidence for a fat–brain axis73 or hypothalamic– pituitary–adipose axis,74 concepts that have recently been proposed. As is the case for other regulatory axes, environmental or phenotypic influences may be reported early in life. The hypothalamic–pituitary–gonadal axis, for example, may be influenced by attainment of critical levels of adiposity in association with onset of ovulation in prepubertal females.75 Evidence of this process can be seen in the delayed menarche reported in lean athletes and ballet dancers; also the mean age at onset of menarche has become younger over time in developed societies as levels of adiposity and nutrition have increased.76 One hypothesis linking the establishment of bodyweight set-points and feeding behaviour to bodyweight disturbances in Alzheimer’s disease is involvement of hippocampal formations—eg, CA1 (cornu ammonis)—in both. In early Alzheimer’s disease neuropathological lesions seem to be selectively located in medial temporal lobe structures, including the 717
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transentorhinal cortex, entorhinal cortex, and CA1 area of the hippocampal formation.77 The CA1 nucleus is directly affected by adipose-derived hormones, such as leptin. Direct administration of leptin into the hippocampus improves memory processing in mice and increases expression of NMDA receptors.70 However, other roles of leptin and associated adipose-derived factors in the Alzheimer’s diseased brain are not clear.78,79 One case-control study (n=24) showed that patients with dementia, particularly Alzheimer’s disease, with a low BMI (<20 kg/m²) had lower concentrations of leptin than healthy people of normal weight (BMI 20–25 kg/m²). As expected, a positive association between BMI and leptin was reported within the entire study sample.80 However, no prospective reports on leptin and dementia are available. Thus, more clinical and epidemiological research is needed to understand the role of adiposederived compounds in dementia and Alzheimer’s disease. Another question to consider is whether early variations in energy metabolism contribute to Alzheimer’s disease. Alzheimer’s disease is associated with loss of cerebral metabolism, particularly in the temporoparietal cortices, and affects mitochondrial enzymes.81 These enzymes regulate energy metabolism, and uncoupling of the electron transport system, for example, leads to lack of ATP generation and heat production (futile cycling). This uncoupling is a primary feature of brown adipose tissue. Changes in energy metabolism in Alzheimer’s disease could be remnant markers of changes in energy metabolism occurring very early, for example in mitochondrial DNA or as a result of hypothalamic imprinting.73 In one study, high (not overweight or obese) mid-life BMI was associated with temporal atrophy 24 years later,50 which suggests that BMI levels in healthy people when they are younger affect atrophy of the brain later in life. However, the possibility that some level of atrophy or susceptibility to atrophy is already present among those with a high BMI, and that these very early symptoms of temporallobe atrophy contribute to dysregulatory events leading to high levels of BMI throughout life, cannot be excluded.
Conclusion Is Alzheimer’s disease the disease of a lifetime instead of a disease of late life? A lifetime pattern of BMI reported in association with dementia has begun to emerge. Being overweight (≥25 kg/m²) or obese (≥30 kg/m²) seems to be a risk factor for dementia as early as midlife, whereas variation within the healthy range of BMI (18·5–24·9 kg/ m²) during midlife may not be. Assessment of risk among women age 70 years may yield a different picture, where the average BMI is more likely to be slightly overweight (25–26 kg/m²) and those who develop dementia might either be even more overweight or on a path of BMI decline among those with low BMI (eg, 718
21 kg/m²). These risk associations that are modified by stage of life and BMI may indicate potential underlying variations in hypothalamic axes that could have been initiated very early in life and affected by environmental factors, genes, and length of survival, thus causing, accelerating, increasing susceptibility to, or exacerbated by Alzheimer’s disease or Alzheimer’s disease neuropathology. This relatively simple scenario is complicated by changes in glucose metabolism, altered insulin signalling and insulin resistance, high blood leptin concentrations and leptin resistance; the involvement of numerous neuropeptides influencing feeding behaviour and regulation of satiety; and the influence of meal content (percentage fat, amount of energy) and meal patterning on brain responses.67 Excess adiposity represents a persistent exposure, particularly in elderly people, thus compounding potentially adverse vascular and non-vascular effects. There are several steps that can be taken to improve knowledge of the role of adiposity in late-life disease. First, the current secular pattern of high obesity rates,2 against a backdrop of improved blood lipids, blood pressure, and smoking profiles among obese people,82 should lead to better characterisation of adipose tissue effects. Second, as cohorts come of age it will become possible to track secular changes in obesity rates against changes in dementia prevalence and incidence and will allow better characterisation of temporal associations with dementia, brain changes, risk and genetic factors, and mortality across early, mid, and late life. Third, continued identification of adiposity-associated biomarkers that are more sensitive than BMI in indicating the amount of adipose tissue present are needed to determine the effect of this important tissue. These biomarkers might be identified in blood or other biological fluids, involve the use of advanced imaging techniques, or be associated with the development of more sophisticated, but easy to use, body composition instruments for use in clinical and epidemiological studies. Fourth, rigorous investigation of putative factors secreted by adipose tissue that are involved in brain health and age-related brain changes and cognitive decline is essential. Is Alzheimer’s disease a disease of lifetime instead of a disease of late life? Understanding the role of adipose tissue may provide some important clues. Conflicts of interest I have no conflicts of interest. Acknowledgments Supported by grants from The Alzheimer’s Association (IIRG-03-6168 and ZEN-01-3151), the Swedish Brain Power Project, and National Institutes of Health/National Institutes on Aging 1R03AG026098 - 01A1. References 1 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination survey. JAMA 2002; 287: 356–59. 2 Flegal KM. Epidemiologic aspects of overweight and obesity in the United States. Physiol Behav 2005; 86: 599–602.
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Davidson TL, Kanoski SE, Walls EK, Jarrard LE. Memory inhibition and energy regulation. Physiol Behav 2005; 86: 731–46. Tracy AL, Jarrard LE, Davidson TL. The hippocampus and motivation revisited: appetite and activity. Behav Brain Res 2001; 127: 13–23. Harvey J, Shanley LJ, O’Malley D, Irving AJ. Leptin: a potential cognitive enhancer? Biochem Soc Trans 2005; 33: 1029–32. Kishi T, Elmquist JK. Body weight is regulated by the brain: a link between feeding and emotion. Mol Psychiatry 2005; 10: 132–46. Qi Y, Takahashi N, Hileman SM, et al. Adiponectin acts in the brain to decrease body weight. Nat Med 2004; 10: 524–29. Elmquist JK, Flier JS. Neuroscience. The fat-brain axis enters a new dimension. Science 2004; 304: 63–64. Schäffler A, Binart N, Scholmerich J, Buchler C. Hypothesis paper. Brain talks with fat: evidence for a hypothalamic-pituitary-adipose axis? Neuropeptides 2005; 39: 363–67. Frisch RE, McArthur JW. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 1974; 185: 949–51. Biro FM, Khoury P, Morrison JA. Influence of obesity on timing of puberty. Int J Androl 2006; 29: 272–77. Welsh-Bohmer KA, Hulette C, Schmechel D, Burke J, Saunders A. Neuropsychological detection of preclinical Alzheimer’s disease: results of a neuropathological series of ‘normal’ controls. In: Iqbal K, Sisodia SS, Winblad B, eds. Alzheimer’s disease: advances in etiology, Pathogenesis and Treatment. New York: John Wiley & Sons, 2001: 111–28. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. Obesity-related leptin regulates Alzheimer’s Abeta. FASEB J 2004; 18: 1870–78. Olsson T, Nasman B, Rasmuson S, Ahren B. Dual relation between leptin and cortisol in humans is disturbed in Alzheimer’s disease. Biol Psychiatry 1998; 44: 374–76. Power DA, Noel J, Collins R, O’Neill D. Circulating leptin levels and weight loss in Alzheimer’s disease patients. Dement Geriatr Cogn Disord 2001; 12: 167–70. Sullivan PG, Brown MR. Mitochondrial aging and dysfunction in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 407–10. Gregg EW, Cheng YJ, Cadwell BL, et al. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA 2005; 293: 1868–74.
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Adiposity indices and dementia Deborah Gustafson
Indicators of adiposity, such as body-mass index (BMI), may be markers for changes in energy metabolism that influence dementia risk, progression, and ultimately death. Cross-sectional studies show that people with dementia have a lower BMI than those without dementia, which is potentially due to a greater rate of BMI decline occurring during the years immediately preceding dementia onset. However, a high BMI can also increase the risk for dementia when measured before clinical dementia onset, which might be due to vascular disorders or bioactive hormonal compounds that are secreted by adipose tissue. In this personal view, I consider how dementia is associated with BMI by looking at the role of BMI and obesity syndromes, mechanisms associated with adiposity, and the potential for hypothalamic dysregulation during the life course. Understanding the life course of adiposity by use of common surrogate measures, such as BMI, among those who do and do not develop dementia is relevant for understanding the causes of dementia and for shaping possible treatment options.
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Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, SE 413–45, Göteborg, Sweden; and the Medical College of Wisconsin, Department of Family and Community Medicine, Milwaukee, Wisconsin, USA (D Gustafson PhD) [email protected]
stage of the dementia process, including during early brain development.16 The most common and simple measure of adiposity used in population-based and clinical studies is bodymass index (BMI), which is calculated as weight (kg)/ height (m²). BMI is not a perfect measure of adiposity and is affected by factors such as ethnicity and age—the ratio of fat-free mass to height begins to decrease after age 45 years, particularly among women.17 Waist-to-hip ratio and waist circumference alone, are measures of body fat distribution. Waist circumference seems to be a more sensitive indicator of cardiovascular-disease risk than BMI.18 Better measures of adiposity and its effects are needed—for example, measuring the concentration of an adipocyte hormone in the blood. Biological plausibility for an association between high adiposity and dementia is relevant to the aetiology of the disease and forms a basis for prevention efforts. In this personal view, I focus on how BMI may be associated with dementia by looking at the evidence for a role of high BMI, obesity syndromes, and BMI decline; biological mechanisms associated with adiposity; and the potential for hypothalamic dysregulation during the life course. • Fat and brain development • Adipose-derived factors shape hypothalamus
Age-related changes in body composition
Critical fatness level and menarcheal age and sex hormone levels
BMI
The number of overweight and obese people is reaching epidemic proportions worldwide.1 Over 50% of adults in the USA and Europe are overweight or obese;2,3 with the highest prevalence among women age 50 years and above.2 The prevalence of Alzheimer’s disease is also highest among women and will increase as women live to older ages. One of the most rapidly growing age groups is 85 years and older. At age 85 years, dementia incidence approaches 10% per year4 and prevalence 30%,5 with subsequent prevalence estimates as high as 50% at age 95 years.5 The number of people with Alzheimer’s disease may reach epidemic proportions between 2010 and 2050, when the number of people with the disease might more than double. Many studies suggest that vascular disorders, including being overweight or obese,6–10 are risk factors for Alzheimer’s disease. Because being overweight or obese increases the risk for subsequent vascular disorders,11 these states may be an initial trigger eventually leading to Alzheimer’s disease and vascular forms of dementia, or these states may indicate vascular burden. Although adipose tissue is the largest endocrine organ in the human body, it is commonly overlooked that the effects of being overweight or obese on brain health might be independent of vascular effects and instead be due to adipocyte hormones and cytokines. Although the classification of clinical dementia subtypes is debated in terms of the underlying pathologies,12 before the development of preclinical and clinical dementia symptoms there are both neuropathological and cerebrovascular changes in the brain. Studies in animals have shown that vascular disease and fatty streaks in blood vessels can appear early in the fetus and, in youth, and are associated with dietary fat intake; Alzheimer’s disease plaques and tangles can develop as early as during the third decade.13 A life course approach to understanding the causes of dementia is imperative14,15 because the roles and timing of risk and protective factors are relevant throughout life. Because adipose tissue is a persistent lifetime exposure beginning in utero (figure 1), its influence may be relevant at every
Cognition
Introduction
Lancet Neurol 2006; 5: 713–20
• High BMI may lead to cognitive decline and dementia later in life, and to later brain pathology
Fetus
Early life
Adult life
• High BMI may predict cognitive decline and dementia • Greater decline in BMI may predict dementia • Low BMI may be associated with dementia Late life
Figure 1: Potential trajectories of cognition associated with adipose tissue and stage of life
713
Personal View
Baseline Years of age (years) follow-up
Baseline BMI
Gerontological and geriatric population studies, H70 (Sweden)7
70
18
Primary prevention study (Sweden)8
47–55
Kaiser Permanente (USA)9
Dementia assessment
Number with Risk ratio for all dementias (RR, 95% CI)* dementia/total
25·8 (3·8)
Neuropsychiatric interview, key informant interview, medical record review
93/382
In women with dementia age 79–88 years, for each unit (kg/m²) increase in BMI at age 70 years 1·13, 1·04–1·24 for AD 1·36, 1·16–1·59 75 years 1·13, 1·04–1·24 for AD 1·35, 1·19–1·53 79 years 1·15, 1·05–1·26 for AD 1·23, 1·10–1·37
28
25·5 (3·3)
Primary and secondary dementia hospital discharge diagnoses
254/7148
In men, the risk of dementia by BMI level BMI <20 2·43, 1·10–5·29 BMI 20–22·49 1·00 BMI 22·50–27·49 1·49, 0·92–2·41 BMI ≥30 1·98, 1·10–3·56
40–45
27
10% ≥30 36% 25–30; 53% 18·6–25; 1·3% <18·6
ICD-9 criteria
713/10 276
In women and men, the RR of dementia by BMI BMI >30 1·74, 1·34–2·26 BMI 25–30 1·35, 1·14–1·60 Highest quintile of subscapular skinfold thickness 1·72, 1·36–2·18 Highest quintile of triceps skinfold thickness 1·59 1·24–2·04 In women only, the RR of dementia by BMI: BMI >30 2·07, 1·49–2·89 BMI 25–30 1·55, 1·22–1·97
Cardiovascular risk factors, ageing, and dementia, CAIDE (Finland)10
51
21
26·6 (3·7)
Screening, clinical, and differential diagnostic phases
61/1449
In women and men, the risk of dementia with obesity BMI >30: OR=2·09, 1·16–3·77 No significant effect of BMI at lower levels
Personnes ages quid, PAQUID study (France)25
≥65
8
24·6 (3·9)
Screening, clinical, and differential diagnostic phases
221/3557
In women and men, the risk of dementia by BMI level BMI <21 1·48, 1·08–2·04 with inclusion of all dementias over 8 years; 1·19, 0·72–1·96 when individuals developing dementia within 5 years of baseline were excluded No effect of baseline high BMI
Rancho Bernardo study (USA)24
50–79
20
25·0
Screening, clinical, and differential diagnostic phases
60/299
Women and men developing AD experienced a greater decline in bodyweight (≥5 kg) compared with those not developing dementia; men who developed AD had a higher average baseline bodyweight
Honolulu Asia Aging Study, HAAS (USA)26
45–66
32
23·9 (2·7)
Screening, clinical, and differential diagnostic phases
112/1890
In men with incident dementia, during the last 6 years of follow-up, mean weight loss adjusted for age and education –0·58 kg/year compared with –0·22 kg/year among men not developing dementia. No effect of baseline BMI
Average 5·6
27·4 (5·4)
Physicians’ examination, NINCDS-ADRDA criteria for Alzheimer’s disease
151/832
In women and men: risk of dementia per one unit decline in BMI from baseline HR=0·94, 0·91–0·98 Risk of dementia by one unit less BMI at baseline HR=0·73, 0·63–0·85 Similar result when excluding those developing AD during first 4 years
Religious Order Study 77·1 (USA)27
(kg/m², SD)
NINCDS-ADRDA=National Institute of Neurological and Communicative Disease and Stroke-Alzheimer’s Disease and Related Disorders Association; AD=Alzheimer’s disease; RR=relative risk; HR=hazard ratio; ICD-9=International classification of diseases; OR=odds ratio; RR=relative risk. *Unless otherwise stated.
Table 1: Prospective studies of BMI and dementia
Is high BMI a risk factor for dementia? In the past, studies reported that a low BMI or being underweight were risk factors for dementia19–22 and agerelated brain changes, such as atrophy.23 These observations, however, were based on cross-sectional or case-control studies, and there was a lack of prospective analyses. Several prospective reports7–10,24–27 have assessed BMI in association with dementia (table 1). When assessing prospective studies it is important to note the study populations, age of the participants at baseline, BMI measurement, and the length and completeness of follow-up to dementia onset. In general, these studies assess BMI among those who have survived to about age 70 years and therefore have not died due to other consequences of higher BMI levels and are now at risk of dementia. 714
The longest study of BMI and dementia so far published has 32 years of follow-up.26 emphasising the importance of taking a life-course approach to studying adiposity in dementia. A life-course approach has been pursued for other age-related diseases such as breast cancer28 and cardiovascular disease.29 Factors such as birthweight, age at menarche, recalled weight at different stages of physical maturation, and weight cycling have been used to assess adiposity and disease. In addition, there are no published reports on the longitudinal BMI–dementia association that take into account the role of APOE ε4— the major susceptibility allele for dementia. There are numerous reports on the association between cognitive performance, BMI, and other adiposity measures;30–36 however, comparison of these studies is difficult because most are cross-sectional, have small http://neurology.thelancet.com Vol 5 August 2006
Personal View
Baseline age (years,SD)
Years of follow-up
Baseline BMI (kg/m²,SD)
Cognitive assessment
Number with poor performance/ total n
Risk of poor cognitive ability (OR, 95% CI)*
Cluster sample (South Korea)34
≥65
0
21·6% with BMI ≥25
K-MMSE
175/467 with K-MMSE <19
In women and men: BMI ≥25 +abdominal obesity (≥90 cm in men and ≥80 cm in women) 2·79, 1·12–6·96 BMI 23–25 +no abdominal adiposity 0·32, 0·12–0·86 multivariate-adjusted
EPIDOS (France)30
≥75
0
25·3
SPSMQ
782/7105 with a SPSMQ score <8 defined as cognitive impairment
In women: First quartile of fat-free soft tissue mass 1·43, 1·07–1·91 First quartile of fat mass: 1·35, 1·01–1·79
The Framingham Heart Study (USA)35
65·7 (6·9) in men 67·2 (7·3) for women
4–8
26·3 (3·2) in men 25·3 (3·8) in women
Neuropsychological 61 obese men, 95 obese test battery women/1423 (obese is BMI ≥30)
Men with average obesity over 16 years showed low ability in visual reproductions, digit span backward, and global composite No associations in women Diabetes associated with low cognition in men and women combined
Prospective epidemiological 63·8 (postmenopausal risk factors, PERF study women only) (Denmark)31
7·3
baseline weight 67·1 kg
Short Blessed test
222/5607 with short Blessed test score ≥9
In women greater change in weight (–0·15±1·0) and lower central fat mass and central fat mass-toperipheral fat mass ratio with short Blessed test score ≥9; not reported in women >80 years
CERAD-NAB
97/531 had poor cognitive performance, defined as 2 or more of 11 tests ≤1·5 standard deviation of normative mean
In women and men: weight loss and gain related to poor cognitive performance: 50% higher odds of poor cognitive performance associated with an annual decrease of 0·5 kg/m²or increase of +0·3 kg/m² BMI
Basel study cohort (Switzerland)32
59·4 (7·8)
10
25·2 (3·1)
Community-based sample of women with Down’s syndrome (USA)33
40–60
0
21/38 premenopausal Neuropsychological Postmenopausal obese obese; 32/78 test battery had lower mean test postmenopausal scores obese (obese is BMI ≥30)
Obese postmenopausal women had better performance in verbal memory and an omnibus test of neuropsychological function; adjustment for serum oestrone attenuated the association No associations in premenopausal women
Community-based sample of middle-aged and older adults (USA)36
54–81
0
27·5 (5·1)
In women and men interaction of high waist circumference or high BMI and high blood pressure associated with motor speed, manual dexterity, and executive function
Neuropsychological Correlational analyses assessment
CERAD=Consortium to establish a registry for Alzheimer’s disease; NAB=neurosychological assessment battery; OR=odds ratio; K-MMSE=Korean mini-mental state examination; SPSMQ= short portable mental status questionnaire.
Table 2: Selected studies on adiposity and cognition
sample sizes, use different methods to measure cognitive function and adiposity, and inconsistently define poor or low cognitive performance (table 2). Additionally, many of these studies do not screen for other mental health outcomes, such as depression or medication use, which may affect these reported associations of BMI and cognitive performance. More research is needed on adiposity and preclinical symptoms of dementia or cognitive impairment to determine at what point adiposity may have an effect or when the influence of adiposity changes direction.
How might excess adiposity increase risk of dementia? Adipose tissue is the largest endocrine organ in the human body and secretes hormones, cytokines, and growth factors, which directly interact with blood vessels,37,38 cross the blood–brain barrier,39 and contribute to homoeostasis. Adipose tissue is particularly important in elderly people—illustrated by the classic example of adipose being the primary site of oestrogen synthesis in postmenopausal women, which is modulated by http://neurology.thelancet.com Vol 5 August 2006
environmental factors.40 In addition, adipose tissue secretes various bioactive metabolites, such as insulinlike growth factor-I, transforming growth factor β, tumour necrosis factor α, angiotensin II, leptin, neurotrophins, growth factors, cytokines, fatty acids, and many other factors that may cross the blood–brain barrier39,41 and affect brain health and subsequent dementia (figure 2). These compounds are important as exemplified by published reports that a high BMI or more adiposity is independently associated with dementia, even after adjustment for multiple vascular factors. In terms of vascular effects, the association between BMI and dementia could be due to effects of excess adiposity on blood pressure, blood lipids, cardiovascular disease, and general health of the vasculature. Obesity is also associated with carotidartery-wall thickening,37 vascular and coronary endothelial dysfunction,38,42,43 peripheral resistance, arterial stiffness, ventricular hypertrophy, increased sympathetic activity, increased intravascular volume, high cardiac output, and increased platelet aggregation.44,45 The association between BMI, body-fat distribution, and dementia might 715
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Vascular effects Ischaemia and toxic events Carotid-artery-wall thickening Coronary endothelial dysfunction Peripheral resistance Arterial stiffness Ventricular hypertrophy Increased sympathetic activity Increased intravascular volume Increased cardiac output Platelet aggregation
Adipose-derived Leptin Sex hormones Interleukins Neurotrophins Growth factors Adipocytokines
Adipose-associated Insulin Satiety factors Sex hormones
Background Age Sex Genes
Figure 2: Adipose tissue and the brain
be the result of underlying brain pathologies associated with dementia, such as cerebral atrophy and white-matter lesions. This association would therefore implicate the detrimental involvement of higher adiposity in the early stages of dementia. In addition, disturbance of the blood–brain barrier is common in those with dementia and vascular diseases,46 thus affecting transfer of adiposederived compounds to the brain. Cerebral atrophy is a symptom of neuronal degeneration and contributes to cognitive decline and dementia.47,48 Atrophy of the temporal lobe, an area that is highly susceptible to effects of ischaemia and other vascular insults to the brain,49 may be an early hallmark of Alzheimer’s disease. Among women age 62–84 years, atrophy of the temporal lobe measured with CT was associated with higher BMI at four examinations where the women were followed up for 24 years (starting when the women were age 38–60 years).50 After adjustment for multiple vascular factors, the odds of temporal atrophy were 13–16% higher per 1·0 kg/m² increase in BMI. This finding was replicated in a cross-sectional study of women and men age 40–66 years, among whom higher BMI was associated with lower global-brain volume on MRI;51 but was not replicated in another.23 A high waist-to-hip ratio was inversely associated with hippocampal volume measured with MRI, in a subsample of the Sacramento Area Latino Study on Aging (SALSA).52 Waist-to-hip ratio was not associated with temporal atrophy in the prospective population study of women in Sweden.50 The Austrian Stroke Prevention Study showed that a high BMI predicted a high rate of progression of brain atrophy on serial MRI.53 Vascular factors, primarily hypertension, are implicated in the cause and progression of white-matter lesions, and 716
these lesions lead to cognitive decline and dementia.6,54 In one study, the presence and severity of white-matter lesions at age 85–88 years were associated with high BMI up to 18 years before.55 Women with high BMI had two times greater risk of white-matter lesions later in life than women without. The SALSA study showed a 27% increase in white-matter hyperintensities on MRI associated with a higher waist-to-hip ratio.52 The effects of adiposity on brain health in late life cannot perhaps be completely assessed without considering cognitive reserve or level of intelligence. However, measurement of this variable is uncommon or unavailable in many epidemiological studies of dementia; the level of education is commonly used as a surrogate marker of intelligence or cognitive reserve and often adjusted for in multivariate models. Intelligence may be the single largest influence of health behaviours.56 Lower childhood intelligence quotient scores are associated with later adiposity, smoking, high blood pressure, cardiovascular disease, and mortality; however, the level of education achieved may “correct” potential influences of low intelligence quotients.57 The directionality and absolute effect of obesity–intelligence associations are difficult to assess because there are many factors that interact to affect cognitive and physical health, such as environmental stimulation, socioeconomic status, parental nutrition, hypothalamic programming, metabolic imprinting, genetics, vascular risk factors, educational attainment, diet, and physical activity.57
Is an obesity syndrome associated with dementia? Whether there is an association between old-age metabolic or obesity syndrome and Alzheimer’s disease and dementia is still unknown, although a high BMI rarely exists in isolation.58,59 As many as one in five adults has a clinically characterised obesity syndrome.1 The ubiquity of adipose tissue means that this syndrome potentially affects various adjacent organ systems and is a primary mediator of obesity-associated syndromes. Therefore, syndromes in the periphery may be associated with syndromes in the ageing brain. The Honolulu-Asia Aging Study showed that clustering of cardiovascular risk factors was associated with vascular dementia in Japanese American men.59 BMI was part of this cluster and a one standard deviation increase in BMI was associated with a 21% higher risk of vascular dementia. The Health, Aging and Body Composition study showed a 20% increased risk of cognitive impairment among white and black people age 74 years with a clinically diagnosed metabolic syndrome.58 This risk tripled among those with high concentrations of C-reactive protein and interleukin 6.58 The cardiovascular risk factors, ageing, and dementia (CAIDE) study reported that the accumulation of vascular risk factors, notably obesity, systolic hypertension, and hyperhttp://neurology.thelancet.com Vol 5 August 2006
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cholesterolaemia during midlife was associated with increased odds of dementia.10 Diabetes—a metabolic and vascular dysregulator—can also increase dementia risk.60,61 Memory impairment is related to poor glycaemic control,62 and low cognition to insulin resistance.63 However, the Framingham Heart Study showed that obesity (independent of diabetes status) was associated with lower cognitive ability among men than in women.35 Given the increasing occurrence of type 2 diabetes among young adults and the role of insulin, insulin resistance, and related genes, diabetes may become increasingly important in the cause of cognitive decline and dementia. When assessing components of an obesity or metabolic syndrome, it is difficult to pinpoint the trigger event. In an obese person, blood supply to adipose tissue can reach 15–30% of cardiac output, which can lead to hypertension and other haemodynamic changes. However, temporality is not clear.64 Hypertension syndrome (obesity, hypertension, salt sensitivity, and insulin resistance)45 and metabolic syndrome (obesity, high waist circumference, hypertension, glucose intolerance, and hyperlipidaemia)65 are both characterised by symptom clusters without clear indication of temporality and point to a general increase in sympathetic activity. In rapidly ageing developed societies, if obesity increases dementia risk then public health implications of the obesity epidemic are more severe than previously estimated and extend to those age 85 years and older.
Is anorexia of ageing a marker for dementia? One of the first studies to report a decline in bodyweight preceding a dementia diagnosis was the Rancho Bernardo study24 and there have been at least two other published studies of BMI decline (table 1).26,27 Therefore, among some individuals, weight loss may be a potential preclinical marker for Alzheimer’s disease, particularly when measured 6–10 years before a clinical diagnosis. Low bodyweight or low BMI also predicts mortality among those with dementia.66 Temporal changes in bodyweight and BMI may be biomarkers for changes in energy metabolism that may influence the risk of Alzheimer’s disease, progression, and ultimately death. The brain, in particular the hypothalamus, regulates energy homoeostasis through the control of hunger and satiety, the regulation of energy expenditure, and the release of hormones that increase use of energy stores.67 The neuropathology that precedes and accompanies Alzheimer’s disease may be a cause of or exacerbate disruptions in energy metabolism. Memory impairment might be an initial symptom in Alzheimer’s disease; individuals with memory impairments may forget to eat, and thus experience declines in bodyweight. There are numerous hypotheses associating memory, hippocampal function, control of energy intake, and hypothalamic function.68,69 http://neurology.thelancet.com Vol 5 August 2006
Hypothalamic dysregulation from cradle to grave Reports of pronounced anorexia in elderly people with dementia may suggest early onset of variation and potential dysregulation in brain centres responsible for feeding behaviour, bodyweight control and set-points, and energy metabolism. Hormones secreted by adipose (eg, leptin, sex hormones), the gut (eg, cholecystokinin, peptide YY, glucagon-like peptide 1), pancreas (eg, insulin), and liver (eg, glucagon) as well as a host of neuropeptides interact with brain centres to induce physiological responses associated with energy intake and expenditure.67 These are obvious pieces of the puzzle underlying individual susceptibility for various diseases associated with energy metabolism. Along with this is the role of genetic variation, which also shapes our responses to and interactions with environmental factors, aspects of our phenotype, and other products of gene expression. Although hypothalamic variation or dysregulation is difficult to characterise during the life course, it is interesting nonetheless to formulate a few hypotheses. This viewpoint will address leptin as an example. Adipose-derived factors, such as leptin, affect the function of the hypothalamus and learning and memory processes controlled by the hippocampus.68 Common hormone receptors, such as the leptin receptor, in the hippocampus, hypothalamus, amygdala, cerebellum, and brainstem indicate potentially linked regulatory mechanisms.68,70 Recent experimental data show that compounds secreted by adipose tissue, such as leptin and adiponectin, interact directly with hypothalamic nuclei and regulate energy expenditure and hyperphagic responses.71,72 Leptin may even shape the hypothalamus during the earliest stages of development and improve cognition.70 The data on adiposity and dementia provide strong evidence for a fat–brain axis73 or hypothalamic– pituitary–adipose axis,74 concepts that have recently been proposed. As is the case for other regulatory axes, environmental or phenotypic influences may be reported early in life. The hypothalamic–pituitary–gonadal axis, for example, may be influenced by attainment of critical levels of adiposity in association with onset of ovulation in prepubertal females.75 Evidence of this process can be seen in the delayed menarche reported in lean athletes and ballet dancers; also the mean age at onset of menarche has become younger over time in developed societies as levels of adiposity and nutrition have increased.76 One hypothesis linking the establishment of bodyweight set-points and feeding behaviour to bodyweight disturbances in Alzheimer’s disease is involvement of hippocampal formations—eg, CA1 (cornu ammonis)—in both. In early Alzheimer’s disease neuropathological lesions seem to be selectively located in medial temporal lobe structures, including the 717
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transentorhinal cortex, entorhinal cortex, and CA1 area of the hippocampal formation.77 The CA1 nucleus is directly affected by adipose-derived hormones, such as leptin. Direct administration of leptin into the hippocampus improves memory processing in mice and increases expression of NMDA receptors.70 However, other roles of leptin and associated adipose-derived factors in the Alzheimer’s diseased brain are not clear.78,79 One case-control study (n=24) showed that patients with dementia, particularly Alzheimer’s disease, with a low BMI (<20 kg/m²) had lower concentrations of leptin than healthy people of normal weight (BMI 20–25 kg/m²). As expected, a positive association between BMI and leptin was reported within the entire study sample.80 However, no prospective reports on leptin and dementia are available. Thus, more clinical and epidemiological research is needed to understand the role of adiposederived compounds in dementia and Alzheimer’s disease. Another question to consider is whether early variations in energy metabolism contribute to Alzheimer’s disease. Alzheimer’s disease is associated with loss of cerebral metabolism, particularly in the temporoparietal cortices, and affects mitochondrial enzymes.81 These enzymes regulate energy metabolism, and uncoupling of the electron transport system, for example, leads to lack of ATP generation and heat production (futile cycling). This uncoupling is a primary feature of brown adipose tissue. Changes in energy metabolism in Alzheimer’s disease could be remnant markers of changes in energy metabolism occurring very early, for example in mitochondrial DNA or as a result of hypothalamic imprinting.73 In one study, high (not overweight or obese) mid-life BMI was associated with temporal atrophy 24 years later,50 which suggests that BMI levels in healthy people when they are younger affect atrophy of the brain later in life. However, the possibility that some level of atrophy or susceptibility to atrophy is already present among those with a high BMI, and that these very early symptoms of temporallobe atrophy contribute to dysregulatory events leading to high levels of BMI throughout life, cannot be excluded.
Conclusion Is Alzheimer’s disease the disease of a lifetime instead of a disease of late life? A lifetime pattern of BMI reported in association with dementia has begun to emerge. Being overweight (≥25 kg/m²) or obese (≥30 kg/m²) seems to be a risk factor for dementia as early as midlife, whereas variation within the healthy range of BMI (18·5–24·9 kg/ m²) during midlife may not be. Assessment of risk among women age 70 years may yield a different picture, where the average BMI is more likely to be slightly overweight (25–26 kg/m²) and those who develop dementia might either be even more overweight or on a path of BMI decline among those with low BMI (eg, 718
21 kg/m²). These risk associations that are modified by stage of life and BMI may indicate potential underlying variations in hypothalamic axes that could have been initiated very early in life and affected by environmental factors, genes, and length of survival, thus causing, accelerating, increasing susceptibility to, or exacerbated by Alzheimer’s disease or Alzheimer’s disease neuropathology. This relatively simple scenario is complicated by changes in glucose metabolism, altered insulin signalling and insulin resistance, high blood leptin concentrations and leptin resistance; the involvement of numerous neuropeptides influencing feeding behaviour and regulation of satiety; and the influence of meal content (percentage fat, amount of energy) and meal patterning on brain responses.67 Excess adiposity represents a persistent exposure, particularly in elderly people, thus compounding potentially adverse vascular and non-vascular effects. There are several steps that can be taken to improve knowledge of the role of adiposity in late-life disease. First, the current secular pattern of high obesity rates,2 against a backdrop of improved blood lipids, blood pressure, and smoking profiles among obese people,82 should lead to better characterisation of adipose tissue effects. Second, as cohorts come of age it will become possible to track secular changes in obesity rates against changes in dementia prevalence and incidence and will allow better characterisation of temporal associations with dementia, brain changes, risk and genetic factors, and mortality across early, mid, and late life. Third, continued identification of adiposity-associated biomarkers that are more sensitive than BMI in indicating the amount of adipose tissue present are needed to determine the effect of this important tissue. These biomarkers might be identified in blood or other biological fluids, involve the use of advanced imaging techniques, or be associated with the development of more sophisticated, but easy to use, body composition instruments for use in clinical and epidemiological studies. Fourth, rigorous investigation of putative factors secreted by adipose tissue that are involved in brain health and age-related brain changes and cognitive decline is essential. Is Alzheimer’s disease a disease of lifetime instead of a disease of late life? Understanding the role of adipose tissue may provide some important clues. Conflicts of interest I have no conflicts of interest. Acknowledgments Supported by grants from The Alzheimer’s Association (IIRG-03-6168 and ZEN-01-3151), the Swedish Brain Power Project, and National Institutes of Health/National Institutes on Aging 1R03AG026098 - 01A1. References 1 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination survey. JAMA 2002; 287: 356–59. 2 Flegal KM. Epidemiologic aspects of overweight and obesity in the United States. Physiol Behav 2005; 86: 599–602.
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