This is the first study to specifically investigate the relationship between midlife serum total cholesterol levels and the risk of AD and VaD 3 decades later in a large and very diverse cohort of both women and men. After controlling for a wide range of confounders, midlife cholesterol was associated with both AD and VaD in late life. Testing of interaction terms by race/ethnic group and sex showed that effects were not statistically different for men and women or by race/ethnic group.
High cholesterol levels as defined by the 2002 ATP III guidelines (≥240 mg/dl) [12
] represented a significant risk factor for AD as well, besides the well-known connection to cardiovascular disease risk. Cholesterol values >250 mg/dl have been previously linked to an increased risk of dementia/AD in the Finnish population (CAIDE study, Finnish cohorts of the Seven Countries Study) [2
]. The results of the present study point to an even lower threshold, as additional analyses with cholesterol levels categorized into quartiles indicated that midlife cholesterol values >220 mg/dl increase the risk of developing AD 3 decades later. Therefore, even moderately elevated cholesterol in midlife was associated with an increased risk of AD.
No relationship between midlife serum total cholesterol and the risk of AD was found in the HAAS study, although clustering of cardiovascular metabolic risk factors (including total cholesterol) at midlife increased the risk of dementia in general [4
]. The differences in findings could be due to differences in study population characteristics, since HAAS included Japanese-American men only, while our results are based on a multi-ethnic population of women and men. In the Framingham study, long-term (30 years) average serum total cholesterol was not related to AD development [5
]. This approach does not reflect the influence of cholesterol at midlife as a risk factor for subsequent AD. Since the exact onset of AD (long before it shows itself as Alzheimer's dementia) cannot be diagnosed with current methods and criteria, relating the average of multiple cholesterol measurements over 30 years to AD may mix the influence of cholesterol on AD with the influence of clinically-silent undiagnosed AD on cholesterol. As the CAIDE and HAAS studies have shown, the pattern of change in cholesterol levels after midlife is also important; a decline in serum total cholesterol after midlife may be associated with early stages in the development of dementia [13
Several mechanisms may lie behind the cholesterol-AD association. One hypothesis would indicate the vascular pathway, since high serum cholesterol is related to cardiovascular and cerebrovascular conditions, which have been linked to AD. However, the relation between high midlife serum total cholesterol and AD was significant in our study even after controlling for several vascular factors and conditions, suggesting that there might be other mechanisms as well. A key component for brain function, cholesterol turnover has also been associated with neurodegenerative diseases [15
]. Due to the blood-brain barrier, serum and brain cholesterol are 2 separate pools, but they do interact, for example through 24- and 27-hydroxycholesterol [15
Borderline cholesterol levels as defined by the 2002 ATP III guidelines (200–239 mg/dl) [12
] significantly increased the risk of developing VaD 3 decades later. High cholesterol levels (≥240 mg/dl) tended to increase VaD risk as well, but the association did not reach statistical significance. One reason for this could be the small sample size of VaD (127 persons in total, 39 with high cholesterol).
VaD represents a markedly heterogeneous group of disorders [16
]. Despite its strong link with coronary artery disease, elevated serum cholesterol has a less straightforward relation with stroke, since stroke subtypes are not accounted for in many studies [17
]. Moreover, persons with stroke do not always get dementia, and VaD may also be the result of small and clinically silent infarcts. Risk factor profiles may be slightly different for different types of lesions contributing to VaD: atherosclerosis in larger brain vessels is thought to be related primarily to blood pressure and secondarily to blood lipids; atherosclerosis in smaller vessels is thought to be related to blood pressure alone and not affected by blood lipids [18
]. Since our cohort included fewer VaD cases, and since current diagnostic criteria (including ICD-9 CM) are not able to differentiate the main VaD subtypes (such as multi-infarct dementia, strategic infarct dementia, or subcortical ischemic VaD) [16
], more refined conclusions on cholesterol and VaD are difficult to formulate.
Strengths and Limitations of the Study
To date, this is the largest longitudinal study to investigate the link between midlife serum total cholesterol, AD and VaD. It has comprehensive health examinations at midlife, a long follow-up period, and a multiethnic representative sample including both men and women with equal access to medical care. Also, because cholesterol was measured in people aged 40–45 years, it is highly unlikely that subclinical dementia was present at baseline; thus, the temporality of the associations is clear.
About 60–70% of the total serum cholesterol is typically represented by LDL cholesterol, the major atherogenic lipoprotein [12
]. However, the role of LDL as a risk factor for AD or VaD could not be investigated in this study because data on LDL levels in 1964–1973 were not available.
Since AD and VaD diagnoses were obtained electronically from chart diagnoses, which may be insensitive, a portion of our sample may have had undiagnosed dementia. It is also likely that some AD or VaD cases were missed in participants who died prior to 1994, the onset of the ascertainment. However, this would tend to bias the results toward an underestimation of the true effect of midlife cholesterol on AD or VaD. Information on lipid-lowering treatments, which have been suggested to decrease dementia risk [19
], was not available for this study. Due to the study design, it was only possible to assess AD/VaD status in those who were still Kaiser members at the time of the ascertainment. Post hoc analyses revealed no significant differences in any of the midlife cardiovascular risk factors by health plan membership status in 1994.
Neuropathological data regarding the diagnoses of AD and VaD in our cohort was not available. Diagnostic criteria used in current clinical practice are known to have a bias towards AD due to the emphasis on memory impairment in dementia diagnosis [20
]. As a result, some VaD cases may have been labeled as AD. Also, current diagnostic criteria define AD and VaD as entirely separated from one another, at the cost of mixed dementia etiologies [20
]. Although our cohort does not include persons with mixed dementia as recognized by ICD-9 CM, the concomitant presence of neurodegenerative and vascular pathologies in a portion of the sample cannot be excluded.