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American Journal of Epidemiology Advance Access originally published online on February 13, 2007
American Journal of Epidemiology 2007 165(9):993-997; doi:10.1093/aje/kwm033
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American Journal of Epidemiology Copyright © 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

Invited Commentary

Invited Commentary: Lipoproteins and Dementia—Is It the Apolipoprotein A-I?

Nikolaos Scarmeas1,2,3

1 Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY
2 Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY
3 Department of Neurology, Columbia University Medical Center, New York, NY

Correspondence to Dr. Nikolaos Scarmeas, Columbia University Medical Center, 622 West 168th Street, PH 19th Floor, New York, NY, 10032 (e-mail: ns257{at}columbia.edu).

Received for publication November 30, 2006. Accepted for publication December 8, 2006.


   ABSTRACT
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INTRODUCTION
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Because of the aging of the population, dementia has become a major public health problem. There has been growing evidence for a possible association between lipids and dementia. A large body of literature has demonstrated multiple hypothesized biologic links between lipids and neurodegenerative or other biologic pathways connected to dementing processes. However, the epidemiologic associations have been conflicting: dyslipidemia at middle age, but not in later life, seems to be associated with higher dementia risk in some but not all studies. Results from the Honolulu-Asia Aging Study reported by Saczynski et al. (Am J Epidemiol 2007;165:985–92) suggest that lipoprotein constituents, such as apolipoprotein A-I, a major component of the high density lipoprotein, may be more informative in enlightening the association between lipids and dementia. In this commentary, the epidemiology and biology of apolipoprotein A-I in relation to dementia is reviewed.

Alzheimer disease; apolipoproteins; dementia; lipids

Abbreviations: ApoA-I, apolipoprotein A-I; HDL, high density lipoprotein


   INTRODUCTION
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 INTRODUCTION
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Currently, there are an estimated 24 million people worldwide with dementia. Two thirds of them live in developing countries. This figure is set to increase to more than 80 million by 2040. Much of this increase will be in rapidly developing and heavily populated regions such as China, India, and Latin America (http://www.alz.co.uk/alzheimers/faq.html). Alzheimer's disease is by far the commonest cause of dementia in the elderly, being responsible for 65–80 percent of dementia cases (1, 2). Alzheimer's disease is the commonest neurologic disease, and it has become extremely frequent in the developed countries (3–5): more than 4.5 million people suffer from Alzheimer's disease in the United States, and it is estimated that this number will increase threefold, exceeding 13 million by 2050. National direct and indirect annual costs of caring for Alzheimer's disease patients are at least $100 billion, with an average lifetime cost of care for each person with Alzheimer's disease approximating $174,000 (6–8). One in eight men and almost one in four women will develop Alzheimer's disease during their lifetime. In a population-based study of people older than age 65 years, dementia was the strongest risk factor for mortality, surpassing heart disease, stroke, diabetes, and cancer (9).

Despite a previous sharp distinction between vascular and neurodegenerative diseases, evidence linking vascular risk factors and indicators of vascular disease to Alzheimer's disease has accumulated over the past decade, blurring the classic borders and reshaping them into a broader dementia spectrum, from purely vascular to mixed (in different degrees) to purely degenerative. In particular, evidence is growing for a possible association between lipids and Alzheimer's disease or dementia.


   BIOLOGIC LINKS BETWEEN LIPIDS AND DEMENTIA
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The central nervous system is the most lipid-rich organ, and approximately 25 percent of the total amount of cholesterol present in humans is localized in the brain and the central nervous system, mainly in the myelin sheath (i.e., oligodendroglia) and the membranes of astrocytes and neurons (10, 11). Lipoprotein complexes are critical for synaptic maturation and maintenance of synaptic plasticity (12, 13), and synaptic growth, regeneration, and neuritic outgrowth depend greatly on the availability of brain lipids (12–14).

Evidence is growing that lipid-rich membrane microdomains are involved in regulating the trafficking and amyloidegenic processing of amyloid precursor protein (15). ß-amyloid cleaving enzyme, the major ß-secretase in neurons, resides in lipid rafts, and a subset of amyloid precursor protein is subject to amyloidogenic processing by ß-amyloid cleaving enzyme in lipid rafts (the integrity of which is important for this process). Additionally, there is a cholesterol-dependent association of significant amounts of each of the {gamma}-secretase components with lipid rafts (15).

Binding of ß-amyloid to lipids may play an important role in maintaining the peptide in solution and thus be particularly relevant to ß-amyloid's normal and pathologic biochemistry and physiology (16). Elevated dietary cholesterol has been shown to increase amyloid plaque formation in different in vivo models (17, 18), and cholesterol loading and cholesterol depletion have also been shown to affect ß-amyloid generation (19). Dietary cholesterol could induce Alzheimer-like ß-amyloid immunoreactivity in rabbit brains (18), and disruption of cholesterol homeostasis in Alzheimer's disease has been linked to ß-amyloid pathology (20).

Links with dementia biology have not been demonstrated for total cholesterol only. High density lipoprotein (HDL) cholesterol prevents aggregation and polymerization of ß-amyloid (16). HDL cholesterol may also influence dementia risk through its antiinflammatory (21) and antioxidant (22) effects. Additionally, in a brain imaging study, lower HDL cholesterol was associated with lower hippocampal volume, even in nondemented subjects and irrespective of apolipoprotein E status and coexisting cerebrovascular disease (23). This finding was in contrast to the absence of correlations between total and low density lipoprotein cholesterol and brain atrophy.


   EPIDEMIOLOGIC LINKS BETWEEN LIPIDS AND DEMENTIA
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Epidemiologic data on the relation between lipids and Alzheimer's disease or dementia have been conflicting. Some longitudinal studies report that dyslipidemia is a risk factor (24–28); some others report either a negative association or no association at all (28–36). Regarding HDL cholesterol in particular, in cross-sectional studies, lower HDL cholesterol levels have been associated with lower Mini-Mental State Examination scores (37) and with higher dementia (23, 37, 38) and Alzheimer's disease (39) risks. However, most longitudinal studies have failed to detect similar associations: HDL cholesterol levels have not been associated with Alzheimer's disease (29–33, 35), vascular dementia (29, 31, 33), or dementia (33).

A possible explanation for the contradictory findings in the literature is that lipid levels tend to change as people become older (40). This pattern can be partly explained by physiologic aging, unintentional or voluntary changes in lifestyle (due to increased public health awareness and initiation of interventional programs meant to lower cholesterol levels), selective mortality, or clinical-subclinical disease (41). For example, in a Finnish cohort, compared with those for the nondemented, serum cholesterol levels declined more rapidly for subjects who subsequently developed Alzheimer's disease, who had lower cholesterol levels 5 years before the diagnosis was established (42). In a Swedish study, low cholesterol level was associated with dementia even 9 or more years before diagnosis (36). In another study, although high levels of cholesterol at midlife represented a risk factor for Alzheimer's disease, there was no detectable difference in cholesterol levels in late life (25).

That midlife (and not late life) lipids are somehow related to Alzheimer's disease–type pathology is also supported by at least two autopsy studies (43, 44). In a previous report from the Honolulu-Asia Aging Study, low midlife total cholesterol level was associated with a lower number of neuritic, amyloid plaques and neurofibrillary tangles (the characteristic pathologic changes of Alzheimer's disease), while late-life total cholesterol and low density lipoprotein cholesterol levels were not associated with any of the neuropathologic markers (43). In another study in which a clinic-based sample was used, the association between total cholesterol level and presence of amyloid deposition was examined separately for young and older age groups (44). Although the calculated odds of developing amyloid deposits almost tripled with only a 10 percent increase in total cholesterol level in the younger group, no association between total cholesterol and amyloid deposition was present at older ages.

However, at least two prospective studies with long follow-up before assessment of Alzheimer's disease/dementia incidence did not find a significant association for abnormal lipid levels. In the Framingham Study, there was no relation between high serum total cholesterol or serum HDL cholesterol and subsequent Alzheimer's disease (35). In a Swedish study that included subjects evaluated up to 18 years before dementia occurred, a negative association between baseline cholesterol levels and later Alzheimer's disease diagnosis was noted, whereas triglyceride levels were not associated with dementia (36).


   EPIDEMIOLOGY AND BIOLOGY OF APOLIPOPROTEIN A-I IN RELATION TO DEMENTIA
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Another possible explanation for the conflicting epidemiologic associations between lipids and dementia is that other lipoprotein constituents may be more biologically relevant in Alzheimer's disease or vascular dementia pathology and may therefore represent a more accurate dementia risk factor. Apolipoprotein A-I (ApoA-I), a major component of HDL, may be such a factor. So far, the association between ApoA-I and dementia has been looked at only cross-sectionally.

In a case-control study of 44 late-onset Alzheimer's disease and 43 vascular dementia patients, as compared with those for controls, ApoA-I levels were decreased in Alzheimer's disease patients but especially so in those with vascular dementia (45). In another case-control study of 45 Alzheimer's disease patients and 79 controls, levels of ApoA-I were lower in Alzheimer's disease patients (46). The reductions in ApoA-I levels were observed in both carriers and noncarriers of the {varepsilon}4 allele. Finally, in a case-control study of 98 Alzheimer's disease patients and 59 elderly controls, serum ApoA-I levels were significantly lower in Alzheimer's disease patients (39). An ApoA-I cutoff value of 1.50 g/liter could distinguish between the two groups with a sensitivity of 71 percent and a specificity of 69 percent. ApoA-I levels were highly correlated with Mini-Mental State Examination scores and were significantly and consistently lower in Alzheimer's disease patients, independent of {varepsilon}4 status.

In this issue of the Journal, Saczynski et al. (47) add a longitudinal component to the ApoA-I story. In a population sample of Japanese-American men, lower ApoA-I levels were associated with increased dementia risk more than a decade later. The associations seemed similar for Alzheimer's disease and vascular dementia and were present over and above adjustments for HDL cholesterol and triglyceride levels. Low ApoA-I levels were a dementia risk factor for both {varepsilon}4 and non-{varepsilon}4 carriers.

Strengths of their study (47) include, among others, its community character, the long follow-up, and consideration of the effect of multiple potential covariates. At the same time, the authors carefully outline many of the potential limitations and cautions to consider when interpreting their findings. Because of the multiple steps and long time from initiation of the Honolulu Heart Program to the Cooperative Lipoprotein Study and to the Honolulu-Asia Aging Study, the participants for whom both lipoprotein and cognitive assessments were available may not be as representative as the original random population sample selected in 1965. Inclusion of only Japanese-American men results in limited external validity. Despite the use of standard criteria that have a clinical diagnostic sensitivity of about 81 percent with a specificity of approximately 70 percent (48), there is always the possibility of disease misclassification bias, which may be even larger with the use of screening neuropsychological instruments rather than full batteries of tests. There may also exist exposure measurement error stemming from either the lack of repeated ApoA-I measurements or technical limitations relating to long-term storage effects and laboratory assessment inaccuracies.

ApoA-I is the major protein component of HDL and plays an important role in reverse cholesterol transfer (49). It has been implicated in several antiatherogenic functions, including protection against thrombosis and oxidation (50). HDL contains two major proteins, ApoA-I and ApoA-II, comprising about 70 percent and 20 percent of the total HDL protein mass, respectively. HDL exists in human plasma in two main forms, one containing ApoA-I with ApoA-II (ApoA-I/ApoA-II-HDL) and another containing ApoA-I without ApoA-II (ApoA-I-HDL). After an atherogenic diet in mice, despite similar total cholesterol and HDL cholesterol concentrations, the area of atherogenic lesions in the ApoA-I/ApoA-II mice was 15-fold greater than in the ApoA-I animals. These studies show that ApoA-I-HDL is more antiatherogenic than ApoA-I/ApoA-II-HDL (51). ApoA-I levels have been inversely associated with coronary heart disease risk (52–54).

The cerebrospinal fluid contains very low quantities of low density lipoprotein or very low density lipoprotein, whereas ApoA-I is found in cerebrospinal fluid HDL particles (55–57). Cerebrospinal fluid levels of ApoA-I have been shown to significantly correlate with plasma ApoA-I levels, suggesting a role of plasma ApoA-I in central nervous system lipoprotein metabolism and hence possibly ß-amyloid (58). However, in contrast to differences in plasma ApoA-I between patients and controls, no significant difference in ApoA-I brain expression (59) or in cerebrospinal fluid levels have been found between Alzheimer's disease patients and controls (60). This finding could be explained by an increase in either ApoA-I passage to the cerebrospinal fluid or the housekeeping function of the blood-brain barrier. An increase in ApoA-I passage to the cerebrospinal fluid may be driven by an increased need for central nervous system ApoA-I during either nervous system regeneration (61) or cerebral injury secondary to infection (in degrees correlating with those of histologic neurologic damage and inflammation) (61).

ApoA-I could be involved in the pathology of Alzheimer's disease in multiple ways (39). First, ApoA-I may directly participate in the amyloidogenesis process by binding to ß-amyloid (62) or by forming amyloid-like fibrils (63). Expression of ApoA-I has been reported in the brain of Alzheimer's disease patients with ApoA-I immunostaining of amyloid plaques in Alzheimer's disease cortex (59). Second, it may play a role in neuronal maintenance since it has been implicated in postinjury neuronal regeneration processes (61). Third, ApoA-I may contribute to Alzheimer's disease pathogenesis via its association with other proteins such as apolipoprotein J (64): changes in ApoA-I levels may affect apolipoprotein J structure and/or function in Alzheimer's disease, especially with regard to maintaining the solubility of ß-amyloid and/or affecting its transport across the blood-brain barrier (65–67).

Overall, lipoproteins may influence the risk of dementia not only via Alzheimer's disease–related pathologic mechanisms but also through antiinflammatory processes (21, 68), antioxidative mechanisms (22, 69, 70), and reduction of vascular injury (22, 71). The study by Saczynski et al. (47) suggests there may be merit in investigating further the apolipoprotein components of lipoprotein metabolism, but the exact biologic mechanisms by which ApoA-I impacts dementia risk is far from being fully understood.


   ACKNOWLEDGMENTS
 
Conflict of interest: none declared.


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