Our understanding of Alzheimer’s disease (AD) is changing as we get more information about the natural history of the disease. It turns out that AD not only results in cognitive dysfunction, but may also have a variety of other symptoms, depending on which brain regions are affected.
Weight loss, especially unintentional, is not a normal part of aging and usually represents an underlying disease process Citation[1] and leads to poor health outcomes. Weight loss is a frequent complication of AD and occurs in 30–40% of patients at all stages Citation[2]. It is associated with faster progression of dementia and with nursing home placement Citation[3].
The link between body mass index (BMI) and dementia may be separately considered in two different periods of life. High BMI in middle age seems to be associated with higher dementia risk Citation[4,5]. Cournot et al. reports a significant association between cognitive decline at follow-up and a higher BMI at inclusion in a cohort of 2223 healthy workers aged 32–62 years at baseline Citation[6]. Cardiovascular disease and diabetes, frequently associated with obesity, may be one of the reasons for increased risk of dementia with obesity in middle age Citation[4,7]. Biological plausibility for this association is relevant to the etiology of the disease and forms a basis for prevention efforts.
In studies that compared weight changes in elderly people who eventually develop AD versus those who remain without dementia, decreasing bodyweight increased the risk for dementia. One of the first studies to report a decline in bodyweight preceding a dementia diagnosis was the Rancho Bernardo study Citation[8]. Weight was measured at three clinic visits between 1972 and 1993 in a sample of older community-dwelling people. Participants were classified as having probable or possible AD or being cognitively intact at the third visit. In age-adjusted analyses, both men and women who were later diagnosed with AD had a significant decrease in weight after the baseline visit, but there was no significant weight loss in individuals who remained cognitively intact Citation[8].
Other studies suggest that low BMI increases the risk of incident AD and may precede the onset of dementia. In a sample of clinically well-characterized older adults who were cognitively healthy at enrollment, an acceleration in the rate of weight loss was a harbinger of the change from nondemented status to AD Citation[9]. Luchsinger et al. also reported a relation between weight loss and a higher dementia risk in an elderly sample (hazard ratio: 1.8; 95% confidence interval: 1.2–2.9) Citation[10]. For Morris et al., individuals who eventually develop dementia (preclinical AD) have already lost a significant amount of weight 4–6 years before diagnosis Citation[11]. The onset of dementia exaggerates mild weight loss, doubling its rate in the year before the clinical detection of the mildest behavioral symptoms. Therefore, among elderly individuals, weight loss may be a potential preclinical marker for AD Citation[12,13]. Buchman and colleagues suggest that a decline in BMI predates the onset of clinically diagnosed AD Citation[13]. For these authors, a more likely explanation is that factors associated with the development of AD also lead to loss of body mass, and weight loss could be a phenotypic marker that can be apparent prior to the onset of clinical dementia. In our study, low reported BMI predicted the onset of dementia within 5 years of follow-up, but we were not able to substantiate this finding in a large study after excluding from our analyses the participants who developed AD early in the study Citation[12].
The mechanisms responsible for these findings are unknown. One of the hypotheses is that individuals with cognitive impairment forget to eat. However, this seems unlikely given that weight loss starts before the onset of symptoms; the presence of a caregiver for most participants is unrelated to weight loss in most studies. Caregiver burden outstripping the ability to prepare food for the individual with dementia seems unlikely for the same reasons. Individuals who develop AD could also be more depressed, but in studies controlled for depressive symptoms, no association was found Citation[8,13,14]. Impaired olfaction associated with very mild AD could be a possible factor underlying this link Citation[15]. Future investigation of weight loss during the preclinical stage may shed light on the pathogenesis of AD.
Bias due to attrition is an important consideration in longitudinal studies. Weight loss is associated with increased mortality in older populations. Cognitive impairment has also been found to be associated with nonresponse Citation[16]. Selective attrition is therefore more likely to have obscured than exaggerated the association between weight loss and dementia in cohort studies.
In conclusion, the exact course of weight loss and its temporal relationship to the onset of AD remain unknown. Data regarding the association of BMI with the risk of developing dementia are sparse and contradictory. These paradoxical findings could be explained by different age groups in different studies. Being overweight in midlife seems to be a risk factor for dementia, whereas weight loss in later life may reflect disease processes, and this change in BMI might be a clinical predictor of the development of AD. Weight loss and now cognitive impairment without dementia are part of the concept of frailty syndrome in the elderly Citation[17]. Frailty is a commonly used term indicating older persons at increased risk for adverse outcomes, such as onset of disability, morbidity and mortality, or who experience a failure to integrate adequate responses in the face of stress. At its initial stages, frailty syndrome could be reversible. Our hypothesis is that weight loss before AD may be part of frailty syndrome and future preventive trials have to target frail elderly persons.
An important consideration arising from research is the extent to which weight loss may be prevented or minimized.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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