Abstract
We investigated the association between serum level of oxidized low-density lipoprotein (oxLDL) and risk of cognitive impairment (dementia or mild cognitive impairment) among 572 non-demented community-dwelling women from a prospective cohort study of aging. After 5 years of follow-up, 228 (39.9%) developed cognitive impairment; and this did not differ by tertile of baseline oxLDL level (highest compared to lowest tertile 38.2% vs 39.5% OR=0.90; 95% CI: 0.63,1.43). Multivariate adjustment produced similar results (OR: 0.91; 95% CI: 0.60,1.39). These findings suggest that increased levels of serum oxLDL are not associated with a greater risk of incident cognitive impairment in older women.
Keywords: dementia, Alzheimer’s disease, oxidized LDL, inflammation, oxidative stress
1. Introduction
Oxidative stress has been hypothesized to lead to or accompany the neurodegenerative processes seen in dementia. Evidence includes post-mortem studies that have suggested oxidative damage occurs early in the pathogenesis of Alzheimer’s disease (AD) (Nunomura, et al., 2001) and also may be involved in cell death mediated by amyloid-beta (Bruce-Keller, et al., 2010). Therefore, markers of oxidative stress merit further investigation either as predictive or diagnostic tools or as potential causative agents for dementia. To date, we are not aware of any prospective cohort studies that have reported on an association between oxLDL level and incident dementia or cognitive decline. We therefore tested the hypothesis that elevated baseline levels of serum oxidized LDL (a common marker of oxidative stress) would be associated with increased risk of dementia or mild cognitive impairment (MCI).
2. Methods
The participants in this study were enrolled in the Study of Osteoporotic Fractures (SOF), a multi-center, prospective, observational study of older women. Briefly, the present study utilized visit 8 (2002-2004) as baseline, and followed 4,727 women 75 years of age and older for 5 years. 1,040 women had oxLDL measured from visit 8 serum samples using a commercial ELISA kit (Alpco Diagnostics) and inter-assay CV was 4.0%. The primary outcomes of interest were dementia and MCI. Dementia was diagnosed based on the DSM-IV criteria and MCI diagnosed using modified Peterson criteria (Petersen, et al., 2001). A total of 572 women had available data on both oxLDL level and followup cognitive status. Further details on participant recruitment, data collection, and dementia adjudication have been published previously (Yaffe, et al., 2011). Logistic regression models were used to test for any association between tertiles of serum oxLDL and incident dementia or MCI.
3. Results
The 572 non-demented women at baseline had a mean age of 82.6 years and a mean education of 12.9 years. None of the baseline characteristics were significantly different by tertile of oxLDL level. After five years of follow-up, 141 women developed MCI and 87 developed dementia for a total of 228 women with cognitive impairment. Compared to women in the lowest tertile of oxLDL, women in the highest tertile did not have greater risk of cognitive impairment (38.2% vs 39.5%, OR= 0.95, 95% CI: 0.63,1.43), nor did women in the middle tertile (41.9%, OR=1.11, 95% CI: 0.73,1.66) . After adjustment for age, race, and education, results remained similar: the OR was 0.91 (95% CI: 0.60,1.39) for women with the highest tertile, and 1.08 (95% CI: 0.71,1.65) for the middle tertile (Table 1). Secondary analyses of oxLDL as a continuous variable or dementia alone as the outcome produced similar results.
Table 1.
Risk of developing dementia or MCI by level of serum oxidized LDL
| Dementia/MCI | |||
|---|---|---|---|
|
| |||
| Serum oxLDL level | No. of cases/No. at risk | Crude OR (95% CI) | Adjusted OR (95% CI)* |
| Tertile 1 | 75/190 | 1.0 (ref.) | 1.0 (ref.) |
| Tertile 2 | 80/191 | 1.11 (0.73,1.66) | 1.08 (0.71,1.65) |
| Tertile 3 | 73/191 | 0.95 (0.63,1.43) | 0.91 (0.60,1.39) |
adjusted for age, race, and education
4. Discussion
In this longitudinal study of community-dwelling older women, we did not find an association between serum oxLDL level and increased risk of cognitive impairment. Certain characteristics of this study may have prevented us from viewing a true association. First, the study population was relatively homogeneous, comprised of mostly white, all female participants. Second, the mean age of this population was 82.6 years, while previous literature has shown that measures of inflammatory markers at midlife may be a better indicator of cognitive decline compared to those in later life (Schmidt, et al., 2002). Additionally, a single measurement of oxLDL may not be as reliable as multiple measures over time, although oxLDL has been shown to have similar longitudinal stability as total cholesterol or high-sensitivity C-reactive protein (Holvoet, et al., 2006). Lastly, a peripheral marker may not accurately reflect central processes. Indeed, a previous study reported a positive association between CSF antibodies to oxLDL and dementia, but no association between CSF and serum antibodies to oxLDL (Kankaanpaa, et al., 2009). It is also possible that serum oxLDL level is not associated with increased risk of dementia, despite other evidence supporting the oxidative stress hypothesis. As this is the first prospective study to investigate any association between oxLDL and dementia, further studies may be needed to elucidate these findings.
Acknowledgments
Funding
This study was supported in part by grants K24 AG 031155 and R01 AG 026720 from the National Institute of Aging and grant IIRG-08-88872 from the Alzheimer’s Association. The Study of Osteoporotic Fractures (SOF) is supported by the National Institutes of Health. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576.
Footnotes
Disclosure Statement
The authors do not have any conflicts of interest to report.
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References
- Bruce-Keller AJ, Gupta S, Parrino TE, Knight AG, Ebenezer PJ, Weidner AM, LeVine H, 3rd, Keller JN, Markesbery WR. NOX activity is increased in mild cognitive impairment. Antioxid Redox Signal. 2010;12(12):1371–82. doi: 10.1089/ars.2009.2823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holvoet P, Macy E, Landeloos M, Jones D, Jenny NS, Van de Werf F, Tracy RP. Analytical performance and diagnostic accuracy of immunometric assays for the measurement of circulating oxidized LDL. Clin Chem. 2006;52(4):760–4. doi: 10.1373/clinchem.2005.064337. [DOI] [PubMed] [Google Scholar]
- Kankaanpaa J, Turunen SP, Moilanen V, Horkko S, Remes AM. Cerebrospinal fluid antibodies to oxidized LDL are increased in Alzheimer’s disease. Neurobiol Dis. 2009;33(3):467–72. doi: 10.1016/j.nbd.2008.12.001. [DOI] [PubMed] [Google Scholar]
- Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001;60(8):759–67. doi: 10.1093/jnen/60.8.759. [DOI] [PubMed] [Google Scholar]
- Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58(12):1985–92. doi: 10.1001/archneur.58.12.1985. [DOI] [PubMed] [Google Scholar]
- Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol. 2002;52(2):168–74. doi: 10.1002/ana.10265. [DOI] [PubMed] [Google Scholar]
- Yaffe K, Middleton LE, Lui LY, Spira AP, Stone K, Racine C, Ensrud KE, Kramer JH. Mild cognitive impairment, dementia, and their subtypes in oldest old women. Arch Neurol. 2011;68(5):631–6. doi: 10.1001/archneurol.2011.82. [DOI] [PMC free article] [PubMed] [Google Scholar]