Statins dementia

There is some evidence that statins can reduce the risk of stroke and even senile dementia. Consequently, there is current clinical discussion as to whether statins should be recommended for all patients with an increased risk of stroke and possibly for protection against senile dementia. 

The statins may lower the risk of CHD by decreasing inflammation, an important component of atherogene-sis. Lovastatin decreased elevated plasma levels of C-reactive protein, a marker for cellular inflammation, and acute coronary events in patients with relatively low plasma cholesterol levels. Recent studies also suggest that use of statins may decrease the risk of stroke, dementia, and Alzheimer s disease and may improve bone... 

Emerging data associate statins with a reduced risk of Alzheimer s disease however, two women had significant cognitive impairment temporally related to statin therapy (18). One took atorvastatin, and the other first took atorvastatin then simvastatin. Cognitive impairment and dementia as potential adverse effects associated with statins has been reviewed (17). 

Jeandel C, Nicolas MB, Dubois F, Nabet-BeUevitle F, Penin F, Cuny G (1989) Fipid peroxidation and free radical scavengers in Alzheimer s disease. Gerontology 35 275-282 Jia Y, Jeng JM, Sensi SL, Weiss JH (2002) Zn2+ currents are mediated by calcium-permeable AMPA/kainate channels in cultured murine hippocampal neurones. J Physiol 543 35-48 Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA (2000) Statins and the risk of dementia. Lancet 356 1627-1631... 

Jick H, Zomberg GL, Jick SS, Seshadri S, Drachman DA. 2000. Statins and the risk of dementia. Lancet 356 1627-31... 

Since the publication of these two early studies, a number of studies have adopted a more prospective cohort approach to the examination of statin use in patients who develop dementia and AD over the course of a set period (usually between 5-10yrs). While many of the subsequent studies described seemingly protective effects in cross-sectional case-control analysis [36,45-51], the majority of prospective cohort analysis failed to identify a reduced risk of dementia in incident cases of dementia or AD [36, 46,47,51[. One notable exception comes from a study that examined a population identified by common AD risk facfors and co-morbidities (e.g., first degree relatives) [52]. In a high AD risk population, statin use was associated with a lowered risk of AD [52]. A summary of the epidemiological findings for stafin use in AD are shown in Table 1. 

Table 1 Summary of risk of AD and dementia associated with statin use ...

Dementia 888 Controls Positive Nested case-control analysis reporting lower risk of dementia in statin users. [44]... 

Dementia (326 AD) 823 Controls Positive Case-control analysis reporting that statins and lipid lowering agents rednced risk of AD in patients less that 80 yrs of age. [48]... 

Dementia out of 655 Positive Case-Control reporting lower prevalence of dementia in statin nsers. [45]... 

Incident dementia (168 Probable AD) 1,496 Controls Negative Cross-section case control analysis noted statin use associated with lower incidence of AD. Prospective cohort study reported no association of statins with AD. [46]... 

Incident dementia (245 AD) out of 2798 Negative Case-control study noted protective effects of statins in dementia. In prospective cohort analysis, statin use was not associated with lower risk or dementia or AD. [47]... 

The Heart Protection and PROSPER results do draw into question preventative effects of statins on dementia. On the other hand, the CHS study raises the possibility that statins may beneficially impact the rate of cognitive changes. Cardiovascular-based studies only indirectly measure the impact on dementia since most cardiovascular studies exclude patients with dementia and cardiovascular trials employ cognitive tests that are relatively insensitive for populations that are not aheady demented. Eurthermore, assessment of cognitive decline in patients aheady suffering from cognitive deficits remains a critical component to the effective treatment of AD. 

Lovastatin is a member of a class of drugs (atorvastatin and simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Recent studies indicate that there may be important secondary effects of statin therapy because some of the medical benefits of statins are too rapid to be a result of decreasing atherosclerotic lesions. Statin therapy has been associated with reduced risks of dementia, Alzheimer disease, ischemic cerebral stroke, and other diseases that are not correlated with high cholesterol levels. Although this is still an active area of research, it appears that the pleiotropic effects of statins may be a result of a reduction in the synthesis of isoprenoid intermediates that are formed in the pathway of cholesterol biosynthesis. 

Vaughan CJ (2003) Prevention of stroke and dementia with statins effects beyond Upid lowering. Am J Cardiol 91 23B-29B... 

McGuinness B, Craig D, Bullock R, Passmore P (2009) Statins for the prevention of dementia. Cochrane Database Syst Rev 2 CD003160... 

Riekse RG, Li G, Petrie EC, Leverenz JB, Vavrek D, Vuletic S, Albers JJ, Montine TJ, Lee VM, Lee M, Seubert P, Galasko D, Schellenberg GD, Hazzard WR, Peskind ER (2006) Effect of statins on Alzheimer s disease biomarkers in cerebrospinal fluid. J Alzheimer Dis 10 399-406 Ridha BH, Josephs KA, Rosser MN (2005) Delusions and hallucinations in dementia with Lewy bodies worsening with memantine. Neurology 65 481 82 Roberts CK, Barnard RJ, Sindhu RK, Jurczak M, Ehdaie A, Vaziri ND (2006) Oxidative stress and dysregulation of NAD(P)H oxidase and antioxidant enzymes in diet-induced metabolic syndrome. Metabolism 55 928—934... 

Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloflf R, et al (1999) f -Secretase cleavage of Alzheimer s amyloid precursor protein by transmembrane aspartic protease BACE. Science 286 735-741 Vaughan CJ (2003) Prevention of stroke and dementia with statins effects beyond lipid lowering. Am J Cardiol 9E23B-29B... 

Dementia Accumulating evidence suggests that cholesterol might be implicated in the pathogenesis of dementia. A double-blind, randomised controlled trial of statins treated for at least 6 months in 748 subjects with a diagnosis of probable or possible dementia showed that statins did not provide any beneficial effect in cognitive behaviours [48]. 

McGuinness B, O Hare J, Craig D, BuUock R, Malouf R, Passmore P. Cochrane review on Statins for the treatment of dementia. Int Geriatr Psychiatry. 2013 28(2) 119-126. 

---