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August 21, 2007; 69 (8) Articles

Incident dementia in women is preceded by weight loss by at least a decade

D. S. Knopman, S. D. Edland, R. H. Cha, R. C. Petersen, W. A. Rocca
First published August 20, 2007, DOI: https://doi.org/10.1212/01.wnl.0000267661.65586.33
D. S. Knopman
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S. D. Edland
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R. H. Cha
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R. C. Petersen
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W. A. Rocca
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Incident dementia in women is preceded by weight loss by at least a decade
D. S. Knopman, S. D. Edland, R. H. Cha, R. C. Petersen, W. A. Rocca
Neurology Aug 2007, 69 (8) 739-746; DOI: 10.1212/01.wnl.0000267661.65586.33

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Abstract

Background: Although several studies reported weight loss preceding the onset of dementia, other studies suggested that obesity in midlife or even later in life may be a risk factor for dementia.

Methods: The authors used the records-linkage system of the Rochester Epidemiology Project to ascertain incident cases of dementia in Rochester, MN, for the 5-year period 1990 to 1994. The authors defined dementia using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Each case was individually matched by age (±1 year) and sex to a person drawn randomly from the same population, and free from dementia in the index year (year of onset of dementia in the matched case). Weights were abstracted from the medical records in the system.

Results: There were no differences in weight between cases and controls 21 to 30 years prior to the onset of dementia. However, women with dementia had lower weight than controls starting at 11 to 20 years prior to the index year, and the difference increased over time through the index year. We found a trend of increasing risk of dementia with decreasing weight in women both at the index year (test for linear trend; p < 0.001) and 9 to 10 years before the index year (test for linear trend; p = 0.001).

Conclusions: Even accounting for delays in diagnosis, weight loss precedes the diagnosis of dementia in women but not in men by several years. This loss may relate to predementia apathy, loss of initiative, and reduced olfactory function.

The evidence for an association between body weight and the risk of dementia remains limited and conflicting. Several studies have shown that weight loss precedes dementia.1–4 Weight loss has also been noted at the time of diagnosis,5,6 and has been shown to occur as the dementia progresses.7 On the other hand, obesity in midlife has been suggested as a risk factor for dementia.8,9 Obesity is associated with diabetes, hypertension, and cardiovascular disease, three recognized risk factors for dementia.10 Therefore, midlife obesity may be a marker for one of those conditions. One study also suggested that late life obesity may be positively associated with an increased risk of dementia.11

To address this conflicting evidence, we used the resources of the Rochester Epidemiology Project to examine weight in the years preceding incident dementia. We first identified all cases of incident dementia in Rochester, MN, in 1990 to 1994 as well as controls of the same age and sex from the same population. We then reviewed medical records for 30 or more years preceding the index year and abstracted weights at specific time points.

METHODS

Cases.

We ascertained cases of dementia through the records-linkage system of the Rochester Epidemiology Project from January 1, 1990, through December 31, 1994, as described previously.12–14 Medical care for the population of Rochester and Olmsted County is provided largely by the Mayo Clinic at the primary, secondary, and tertiary levels and by Olmsted Medical Center. Additional care providers in the community participate in the Rochester Epidemiology Project, which provides the infrastructure for indexing essentially all the medical information of the local population.15 Medical diagnoses, surgical interventions, and other key information from the complete dossier of each resident are routinely abstracted. The abstracted information is coded using the International Classification of Diseases, adapted code for hospitals (H-ICDA) and entered into computerized indices.16 Therefore, each individual in the system can be searched for a given condition through extensive indices of clinical or histologic diagnoses and surgical procedures.

We searched these indices for 132 specific H-ICDA codes that might indicate dementia.14 Any subject with at least one of the study codes was considered as a potential case. Patients with dementia in the general population may remain undetected for a number of years,17,18 but may be eventually diagnosed at some point during their natural history. To increase the likelihood of capturing these individuals, the indices were searched for the study interval and for 6 additional years following the last year of the study interval. Cases of dementia identified in the 6 subsequent years were then reviewed for evidence of dementia onset in the 1990 to 1994 time period. All medical records of each potential case were screened by a specifically trained nurse abstracter. All medical records, including physician and nurse notes, were reviewed and all available data pertinent to the documentation of cognitive symptoms were abstracted, as previously described.12,14,19–21 The primary study neurologists and dementia subspecialist (D.S.K. or R.C.P.) confirmed the presence of dementia, classified the dementia by type, and determined the year of onset. To standardize and operationalize the diagnoses, each cardinal feature required for a diagnosis of dementia (see diagnostic criteria below) was considered and scored separately.

To be included in the study, patients with dementia were required to reside in Rochester in the year of onset of dementia and for at least one preceding year. Patients with dementia who moved to Rochester for the management of a pre-existing dementing illness were excluded. The age at onset of the dementia was determined according to information collected in the medical record at the time of diagnosis. An attempt was made to retrodate the onset of symptoms as far back as supported by clinical history details.

Diagnostic criteria.

The principal sources of diagnostic information were the medical history, neurologic examinations, neuroimaging studies, and laboratory studies as recorded historically in the patient dossier of the records-linkage system (as per routine medical care). The diagnostic criteria for dementia of the Diagnostic and Statistic Manual for Mental Disorders, fourth edition (DSM-IV) were applied retrospectively.22 The criteria for dementia in DSM-IV include the following features: memory impairment as a prominent early feature; at least one of the following: aphasia, apraxia, agnosia, or disturbance of executive function; and loss of function sufficient to interfere with social or occupational activities. Furthermore, there must be evidence in the medical record for all of the following: decline from a previous level of cognitive functioning, interference with work or usual social activities, presumed not due to psychiatric disorder, and preserved alertness. The diagnostic criteria were scored separately, and the diagnosis of dementia was made only if all of the requirements for the diagnosis were fulfilled. However, we were unable to estimate the severity of dementia through our retrospective chart review.

We defined Alzheimer disease (AD) using the DSM-IV criteria.22 Vascular dementia was defined by the presence of one of the following two criteria: 1) clear evidence for the onset or worsening of dementia within 3 months of a clinical stroke, or 2) bilateral gray matter infarcts shown by imaging and judged to be critical.20 Dementia with PD was defined by the presence of both an extrapyramidal disorder and dementia, and by the exclusion of cerebrovascular disease. We defined primary dementia to include patients with AD, vascular dementia, dementia with PD, or any other neurodegenerative dementia. Patients with dementia caused by a nondegenerative and nonvascular condition were excluded from the case-control study.14

Controls.

Patients with primary dementia were individually matched by age (±1 year) and sex to a general population control subject, drawn randomly from the list of all persons residing in Rochester, MN, and free from dementia in the index year (year of onset of dementia in the matched case). The list of all Rochester residents from which potential controls were drawn was provided by the records-linkage system, and was based on the enumeration of all individuals in contact with the system at least once in the 3 years after the index year.15 Potential control subjects were selected randomly among all residents fulfilling the matching criteria. Control subjects were judged free from dementia if review of their medical record revealed no mention of cognitive impairment or loss of function prior to the index year. In addition, we excluded potential controls who were found to have cognitive impairment after the index year, whenever there was evidence suggesting that the onset of the cognitive impairment preceded the index year.13

Ethical considerations.

All study procedures were reviewed and approved by the Mayo Clinic and the Olmsted Medical Center institutional review boards. No written consent form was requested for this study; however, persons obtaining medical care within the Rochester Epidemiology Project are given the opportunity to deny access to their medical records for research purposes.23 Thirty-six subjects were excluded from our study for this reason, and their dementia status remains unknown.

Documentation of weight and height.

Body weights were abstracted from the medical records in the records-linkage system at six time points starting with the year of dementia onset (the index year), and moving backward to 5 to 6, 9 to 10, 11 to 20, 21 to 30, and more than 30 years prior to the index year. When more than one weight measure was available for a person in a given time interval, we used the median value for that interval. Height at or around age 40 years was also abstracted from medical records.

Data analysis.

We compared the distribution by weight in cases and controls using median and quartiles, and tested differences using Wilcoxon signed rank tests at each time point (matched pair analysis). In addition, we computed ORs and 95% CIs comparing the first, second, and third quartile to the fourth quartile of the distribution by weight (in cases and controls combined) at the index year and at 9 to 10 years before the index year. All statistical testing was done two-tailed at the conventional alpha level of 0.05 using the SAS package version 8.2 (SAS Institute, Cary, NC).

RESULTS

Overall analyses.

We identified 564 persons who developed dementia between January 1, 1990, and December 31, 1994. Among them, 488 persons (86.5%) were considered affected by a primary dementia (dementia with presumed vascular or degenerative etiology). Among primary dementia cases, 355 (72.7%) were women and 133 (27.3%) were men. Of these 488 patients, seven could not be matched to an adequate control; therefore, 481 patients were included in the study. The distribution of the primary dementia cases by age at onset included 6.1% under age 70 years, 75.6% ages 70 to 89 years, and 18.2% age 90 years or older. The patient sample was previously described in more detail elsewhere.14

Table 1 shows the weights in cases and controls at the index year and at five additional preceding time points. Weights were available at the year of dementia onset for 430 (89.4%) cases and at the index year for 377 (78.4%) controls; however, only 295 pairs of cases and controls had complete information. Fewer cases and controls had weight information at earlier time points, although 366 (76.1%) cases and 381 (79.2%) controls had recorded weights at a point 21 to 30 years prior to the index year (table 1).

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Table 1 Distribution of body weight in pounds in patients with incident primary dementia and in their matched controls

Cases and controls weighed the same both 21 to 30 years and more than 30 years prior to the index year. The cases and controls were also the same height at age 40 years (data not shown). Among the controls, weight loss of approximately 7.5 pounds (median) occurred in the 9 to 10 years prior to the index year. However, individuals with primary dementia weighed 12.0 pounds (median) less than controls at the index year, and weighed less than controls as far as 9 to 10 years earlier (table 1).

Table 2 shows our case-control analyses. We found a trend of increasing risk of dementia with decreasing weight both at the index year (test for linear trend in log odds; p < 0.001) and 9 to 10 years before the index year (test for linear trend in log odds; p = 0.001).

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Table 2 Association between primary dementia and body weight in pounds at index year and at 9 to 10 years before onset

Stratified analyses.

We examined men and women separately (table 1). There was no significant difference in weight in men at any time, including at the index year. By contrast, in women, the difference in weight between cases and controls was present at the index year and for up to 11 to 20 preceding years; however, there was no difference further back (e.g., at 21 to 30 years and more than 30 years prior to the index year). In the decade preceding the index year, control women lost approximately 2.0 pounds (median), while case women lost almost 8.0 pounds (median). Analyses limited to AD cases showed a similar pattern although the difference between cases and controls extended only 5 to 6 years prior to the index year (data not shown).

We found a trend of increasing risk of dementia with decreasing weight in women both at the index year (test for linear trend in log odds; p < 0.001) and 9 to 10 years before the index year (test for linear trend in log odds; p = 0.001). By contrast, the results for men did not show an association between decreasing weight and risk of dementia (table 2).

To study possible differences in the association between body weight and dementia by age at onset of dementia, we stratified women using a median split. Both the younger and the older strata of women with primary dementia showed the same pattern of weight loss at the index years. In women with younger onset, the difference between cases and controls extended back 3 to 4 years prior to the index year. By contrast, in women with older onset, the difference was significant back to 11 to 20 years prior to the index year (data not shown).

Sensitivity analyses.

We performed sensitivity analyses in the sample restricted to cases and controls who had no recorded diagnoses of diabetes mellitus. The results were consistent with those obtained including diabetic subjects. The figure shows the distribution of weight by time preceding index year in nondiabetic women with dementia (figure, A) and in nondiabetic women with AD (figure, B) compared to controls. Results were also essentially the same in analyses restricted to complete pairs (cases and controls who both had weight data at a particular time point as shown in table 1) and in analysis including incomplete pairs (data not shown).

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Figure Distribution of body weight in pounds over time preceding the index year in case women (white box) and control women (gray box) without a diagnosis of diabetes mellitus

(A) Cases with primary dementia compared to matched controls. (B) Cases with Alzheimer disease compared to matched controls.

DISCUSSION

We found that women destined to develop dementia began to lose weight relative to nondemented control subjects as long as 11 to 20 years prior to the year of onset of their dementia. The case-control differences in weight were present across the spectrum by age at onset of dementia. By contrast, weight loss was not evident in case men compared to control men. The lag time between the detection of weight loss and the estimated dementia onset must be interpreted in the context of the uncertainty of the actual onset of mild dementia in our series. We may have overestimated the duration of the predementia interval.

One possible explanation for the weight loss is the development of apathy and loss of initiative in the prodromal stages of dementia.24,25 Another possible explanation is the loss of olfactory function that accompanies the prodromal stages of mild cognitive impairment and AD.26,27 As food became less tasty, individuals destined to develop dementia may have been less motivated to eat. Similar changes in affect and olfaction also occur with Lewy body disease.28 Finally, apathy and loss of initiative are frequently described in vascular dementia.29 The combination of apathy, loss of initiative, and loss of olfaction may have rendered women at risk less likely to prepare nutritious meals, more likely to miss meals, and more likely to lose interest in food in general. Anecdotal observations by the authors suggest that underweight patients with dementia are able to gain weight when meals are prepared for them and they are encouraged to eat.

The association between weight loss and dementia restricted to women may be mediated by hormonal factors. Women with lesser amounts of adipose tissue may have lower circulating levels of estrogen because the adipose tissue participates in the conversion of endogenous steroids to estrogen. Lower levels of estrogen in early menopause may increase the risk of neurodegenerative or vascular brain lesions.30

Similarly, the lack of association between weight loss and risk of dementia in men may be related to hormonal factors such as testosterone levels; however, a social explanation seems equally plausible. Middle aged and elderly men were less likely to be involved in meal preparation. Either their spouses or adult children prepared meals for them, mitigating the neuropsychiatric and sensory deficits that were emerging.

There are other neurobiological explanations for weight loss preceding dementia. Loss of limbic and hypothalamic function occurs in AD and contributes to an altered sense of satiety.31,32 Subtle changes in automaticity of swallowing, chewing, or even dominant arm and hand function might result in reduced food consumption. It is also possible that increased activity levels could result in weight loss; however, that is not consistent with clinical observations of decreased involvement in prior pastimes and interests of women in the prodromal stages of dementia.33–35

Other non-neurologic and non-psychiatric problems such as alterations in insulin sensitivity, or some other age-related regulatory change in carbohydrate metabolism, could either co-occur with brain AD pathology, or could be a trigger.36 Similarly, a primary gastroenterologic disorder that led to malabsorption could also have been responsible for the weight loss. For example, one study showed that patients with AD are more likely to have antibodies to Helicobacter pylori.37

The present findings of weight loss preceding dementia are consistent with findings from other studies1–4; however, our study is unique in showing that the findings were restricted to women. The Honolulu Asia Aging Study included only men,3 but the other studies included both men and women.1,2,4 Another study found a difference in weight preceding dementia only in the few years prior to the diagnosis and not over a long preclinical period.6 However, our findings contrast several other studies that showed an association between midlife obesity and dementia.8,9,11 The reasons for these discrepant findings concerning dementia remain unknown. Considering cognitive performance rather than dementia, a recent multicenter study involving 2,684 persons showed higher cognitive performance in overweight persons compared to persons with normal weight.38

This study has several strengths. In particular, we included incident cases of dementia and age- and sex-matched controls from a geographically defined population. In addition, a large number of subjects had weight measurements at multiple time points in the 30 or more years preceding dementia. Finally, we had a large enough sample to stratify the analyses by age at onset of dementia and gender.

On the other hand, this study has some limitations. First, it is possible that we missed cases of mild dementia. In addition, we were unable to characterize the initial severity of the dementia because formal cognitive testing was not available for all patients. For these same reasons, the time of recognition of dementia may have been delayed to moderate or severe stages, and thus, we may have overestimated the time between onset of weight loss and onset of dementia. Second, the weight measurements were available only within certain time ranges, and over a third of our subjects had no measurements at all. However, weight data were collected historically before the onset of dementia; therefore, the distribution of missing data is expected to be similar for cases and controls. In addition, lack of weight measurements in the medical record is expected to have occurred more frequently in persons within the second and third quartiles of the distribution rather than in persons particularly thin or obese.

Third, although we had measurements of height at or around age 40 years on a number of individuals, we could not perform analyses using body mass index at the index year or in the 10 years preceding the index year. Both women and men lose approximately 0.2 to 0.3 cm/year between the ages of 70 and 90 years39; however, the loss is not increased in persons with cognitive impairment.40 Finally, our findings were based on a case-control study design, and unknown biases or confounding effects may remain.

ACKNOWLEDGMENT

The authors thank Virginia Hanson for abstracting medical records and Barbara J. Balgaard for typing the manuscript.

Footnotes

  • Supported by NIA grants U01 AG06786 and P50 AG16574, and made possible by the Rochester Epidemiology Project (R01 AR30582).

    Disclosure: Dr. Knopman has been a consultant to GE HealthCare, GlaxoSmithKline, and Myriad Pharmaceuticals and has served on a Data Safety monitoring board for Neurochem Pharmaceuticals and Sanofi-Aventis. The latter involves the drug rimonabont and its effects on cardiovascular disease; one of its actions is weight loss. He is also an investigator in a clinical trial sponsored by Elan Pharmaceuticals. Dr. Petersen has been a consultant to GE HealthCare, Servier, and Elan Pharmaceuticals. The remaining authors report no conflicts of interest.

    Received November 9, 2006. Accepted in final form March 23, 2007.

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