Association of alzheimer disease pathology with abnormal lipid metabolism: the hisayama study
Mascitelli, Luca; Seneff, Stephanie; Goldstein, Mark R.
Responding to the study by Matsuzaki et al., which found an association between high cholesterol levels and Alzheimer disease (AD) pathology, Dr. Mascitelli et al. suggest the alternative interpretation that statin therapy may be responsible for the increased risk of dementia in these patients. The authors counter that, while they did not address this question directly, most other studies on the subject have not found a significant association between statin use and AD risk. Drs. Park and Koltzenburg point out that small sample size and broader inclusion criteria may explain why Burakgazi et al. found that oxaliplatin causes only mild axonal loss, compared to previous studies that showed more significant amplitude reductions. They also comment that the reductions in intraepidermal nerve fiber density are surprising and that these findings should be replicated in a larger population. Authors Klassen and Ahlskog respond to Dr. Rosenbaum's inquiry, clarifying that the normal pressure hydrocephalus patients in their study were assessed with videotaped gait examinations before and about 30 minutes after high-volume lumbar puncture as part of their diagnostic evaluation. Megan Alcauskas, MD, and Robert C. Griggs, MD
Matsuzaki et al.1 found that dyslipidemia may increase the risk of plaque-type pathology, and suggested that adequate control of cholesterol, in addition to the control of diabetes, might contribute to a strategy for the prevention of Alzheimer disease (AD). However, the most significant result reported in this study is that the highest quartiles of low-density lipoprotein (LDL), total cholesterol/ high-density lipoprotein (HDL), LDL/HDL, and non-HDL cholesterol showed increased risk for neuritic plaque compared to the lowest quartiles, where cholesterol status was measured at least 10 years prior to plaque measurement. After correcting for major confounding variables, there was no significant difference for the middle quartiles compared to the lowest. A plausible explanation for this finding might also be that statin therapy, more likely to be used in those with high cholesterol, could be the main cause of the increased risk of dementia. Otherwise, this study is inconsistent with other studies that have shown an inverse relationship between cholesterol levels and mental decline in the elderly.2,3 Furthermore, such an interpretation would confirm the results reported in the Cardiovascular Health Study,4 where “ever used statins” were associated with a 1.21 hazard ratio for dementia, and “previously used statins” were associated with a 2.5-fold increased risk compared to “never used statins.”
Author Response: Kensuke Sasaki, Toru Iwaki, Fukuoka, Japan: Mascitelli et al. question whether statin use could be an important confounding factor for the risk of Alzheimer pathology. They stated that “previously used statins” were associated with a 2.5-fold increased risk compared to “never used statins” in the Cardiovascular Health Study.4 However, most related studies including the Cardiovascular Health Study itself claimed no significant association of statins with a risk of AD.4–6 Moreover, the Rotterdam Study reported that statins are associated with a reduced risk of AD.7 We did not directly evaluate the risk of statin use because it was difficult to determine separately the impact of high cholesterol and statin use in our observational study.1 Currently, we do not know if statin therapy may cause increased risk of AD. It is plausible that adequate control of metabolism and lifestyle modifications may lessen the need for statin therapy and may contribute to a strategy for the prevention of AD. Ongoing analyses in the Hisayama Study for the association between dyslipidemia and AD, in relationship to many confounding factors, may contribute to further clarification.
1. Matsuzaki T, Sasaki K, Hata J, et al.. Association of Alzheimer disease pathology with abnormal lipid metabolism: The Hisayama Study. Neurology 2011; 77: 1068–1075 . [Context Link]
2. Tilvis RS, Valvanne JN, Strandberg TE, Miettinen TA. Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age: a 17-year population study. Ann Med 2011; 43: 292–301 . [Context Link]
3. Presecki P, Muck-Seler D, Mimica N, et al.. Serum lipid levels in patients with Alzheimer's disease. Coll Antropol 2011; 35 (suppl 1): 115–120 . [Context Link]
4. Rea TD, Breitner JC, Psaty BM, et al.. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol 2005; 62: 1047–1051 . [Context Link]
Juliegee wrote:The correlation between cholesterol and Alzheimer's MAY not be as clearcut as the Hisayama Study indicates. I'Here's a few other threads that we've put together on the topic.
Correlation between Cholesterol and Alzheimer's
HDL Plays a Pivotal Role in Preserving Cognition
Hypercholesterolaemia effect on BBB
The relationship between HDLC levels and the risk of NPs was diminished after adjustment for APOE genotype, which suggested that APOE genotype was a confounding factor that had distorted the relationship between HDLC and NPs
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