In this population-based study of 5 birth cohorts of women, age 38–60 at baseline and followed for up to 32 years, the relationship between cholesterol and dementia (all-cause and AD) was examined utilizing multiple statistical methodologies that have been previously published in the examination of this relationship. In summary: 1) high cholesterol at baseline in 1968–1969 was not associated with risk of all-cause dementia or AD once age was considered; 2) high cholesterol at baseline in 1968–1969 was more strongly associated (albeit not significant) with incident dementia (all-cause and AD) when only including those who survived to and participated in the 2000–2001 examination compared to the inclusion of all participants and their respective survival times; and 3) a decrease in cholesterol levels over the follow-up was associated with a modest increased risk of dementia.
There is increasing awareness that identification of risk factors for syndromes of late life, such as dementia, need to be considered using a life-course perspective. Throughout life, genetic and environmental (e.g., diet, physical activity, obesity) factors have interactive effects in predisposing a person to dementia. One impediment to the current lifespan approach evaluating the cholesterol–dementia relationship is that most longitudinal studies have only examined this relationship among people that survived to old age. In the present study, we used different methodologies to examine the cholesterol–dementia relationship. We examined the relationship continuously over the middle to late lifespan as well as only among those who survived to old age. A clear difference was demonstrated. When including all persons, there was no association between midlife cholesterol and risk of dementia or AD in multivariate models. In contrast, when only including those who survived to old age, there was a clear trend for high cholesterol to be associated with an increased risk of AD. This difference is likely due to a survival bias and competing mortality,23
and demonstrates that thoughtful consideration of this bias is needed when examining relationships between midlife risk factors and late-life outcomes only among survivors. Including survivors only may lead to an overestimation of association. As loss to follow-up is negligible in this study sample, this consideration is underscored.
Perhaps more importantly, the present study found that decreasing cholesterol between visits was associated with an increased risk of dementia, but not AD, similar to results found in other studies.9,17
Thus, unintended decreases in cholesterol levels (e.g., not via medications or cholesterol-lowering diet) greater than expected due to aging may be more indicative of dementia risk than midlife cholesterol levels and may reflect underlying dementia processes. This pattern is observed for other dementia risk factors, such as BMI23
and blood pressure.26
In these women, we observe declines in both BMI and blood cholesterol levels, yet these observations are statistically independent of each other indicating that decline in each parameter is important. Hypotheses related to observed declines may have to do with regions of the brain affected by amyloid deposition, such as the arcuate nucleus and in general, the hypothalamus, which are areas of homeostatic regulation.27
In addition, consequences of the dementia prodrome such as apathy or reduced olfactory function28,29
may lead to decreased energy intake, which may also affect blood cholesterol levels.
There are some limitations and methodologic factors that need to be addressed. First, it is often difficult to discriminate between AD and VAD. However, our criteria for AD are strict and we exclude all cases with stroke or infarcts on CT. Second, loss of participants due to death or refusal may have influenced the results, particularly in the oldest age groups. While we have information from examinations, close informants, case records, hospital registers, and death certificates, some of these secondary sources are known to underrate dementia. Thus, undiagnosed cases of dementia may be included in the no-dementia group, which would most likely diminish differences between the 2 groups, and lead to conservative estimates of effects. Third, APOE
ε4 genotyping and low-density lipoprotein and high-density lipoprotein cholesterol were not available. However, a recent meta-analysis7
reported no interaction between the APOE
ε4 allele and total cholesterol in predicting dementia risk or an association between high-density lipoprotein and dementia. Finally, the study is composed of women in Sweden and the results may not be generalizable to men or other ethnicities.
Despite these limitations, the present study has several notable strengths. First, among the strengths of this study are the 32 years of follow-up with multiple cholesterol measurements and health information, which has allowed for the lifespan examination of the relationship and temporality between cholesterol and dementia. Second, there was no loss to follow-up because information regarding a dementia diagnosis was obtained for all study participants. Participants who died or refused to take part in the study were traced through several registries and records from hospital systems and homes for the aged. Although case records may underdiagnose the number of dementia cases, this methodologic aspect has a distinct advantage over other longitudinal studies because persons lost to follow-up are not representative of the population in that they are more likely to be ill and/or cognitively impaired. Finally, the study timeframe was 1968–2000; only during the last few years of the study were statins and other lipid-lowering drugs available. Thus, without potential confounding with medications, a true relationship between cholesterol and dementia is observed.
On neither an individual nor population level can we determine whether a person will develop dementia in late life based on a midlife cholesterol level. However, in accordance with heart healthy guidelines, we suggest that midlife cholesterol levels be monitored and treated via diet, exercise, and medication as recommended or required. In addition, we suggest that declines in metabolic parameters, such as blood cholesterol levels, BMI, and blood pressure, be monitored with aging, and that there may be precedent for stabilization of these parameters in relation to lowering dementia risk.