Atorvastatin for the Treatment of Mild to Moderate Alzheimer Disease

Sparks, David L.; Sabbagh, Marwan N.; Connor, Donald J.; Lopez, Jean; Launer, Lenore J.; Browne, Patrick; Wasser, Dawn; Johnson-Traver, Sherry; Lochhead, Jeffrey J.; Ziolwolski, Chuck

doi:10.1001/archneur.62.5.753

Cited by 388 publications

(245 citation statements)

References 26 publications

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“…Several epidemiological studies also show that lipid levels are lower in persons who develop AD, not higher (57). Perhaps the most encouraging evidence, albeit preliminary, is the apparent ability of atorvastatin to slow progression of dementia in AD (58). The publication of this report and the results of a large National Institute on Aging-sponsored prevention trial of statins are eagerly anticipated.…”

Section: What Is the Role Of Cholesterol In Ad?mentioning

confidence: 79%

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

Gandy¹

2005

Journal of Clinical Investigation

139

151

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For approximately 80 years following Alzheimer's description of the disease that bears his name, a gulf divided researchers who believed that extracellular deposits of the amyloid β (Aβ) peptide were pathogenic from those who believed that the deposits were secondary detritus. Since 1990, the discoveries of missense mutations in the Aβ peptide precursor (APP) and the APP-cleaving enzyme presenilin 1 (PS1) have enabled much progress in understanding the molecular, cellular, and tissue pathology of the aggregates that accumulate in the interstices of the brains of patients with autosomal dominant familial Alzheimer disease (AD). Clarification of the molecular basis of common forms of AD has been more elusive. The central questions in common AD focus on whether cerebral and cerebrovascular Aβ accumulation is (a) a final neurotoxic pathway, common to all forms of AD; (b) a toxic by-product of an independent primary metabolic lesion that, by itself, is also neurotoxic; or (c) an inert by-product of an independent primary neurotoxic reaction. Antiamyloid medications are entering clinical trials so that researchers can evaluate whether abolition of cerebral amyloidosis can mitigate, treat, or prevent the dementia associated with common forms of AD. Successful development of antiamyloid medications is critical for elucidating the role of Aβ in common AD.

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Section: What Is the Role Of Cholesterol In Ad?mentioning

confidence: 79%

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

Gandy¹

2005

Journal of Clinical Investigation

139

151

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“…[12][13][14][15] All had placebo rather than standard care comparators. RCTs (reported in 23 publications [13][14][15][36][37][38][39][40][41][42][43][44][45][46][47][48][50][51][52]55,56,62,64 ) enrolled subjects with normal cognition at baseline, four RCTs (reported in seven publications 12,54,[57][58][59][60][61] ) enrolled patients with AD, and three RCTs enrolled other cognitively impaired subjects (traumatic brain injury, 53,63 and neurofibromatosis type 1 49 ). Simvastatin (eight trials), pravastatin (eight trials), and lovastatin (six trials) were most frequently utilized in the statin RCTs.…”

Section: Assessment Of Heterogeneity and Meta-regression Analysesmentioning

confidence: 99%

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

et al. 2015

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BACKGROUND:In 2012, the United States Food and Drug Administration (FDA) issued a warning regarding potential adverse effects of HMG-CoA reductase inhibitors (statins) on cognition, based on the Adverse Events Reporting System and a review of the medical literature. We aimed to synthesize randomized clinical trial (RCTs) evidence on the association between statin therapy and cognitive outcomes. METHODS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL through December 2012, and reviewed published systematic reviews of statin treatment. We sought RCTs that compared statin treatment versus placebo or standard care, and reported at least one cognitive outcome (frequency of adverse cognitive events or measurements using standard neuropsychological cognitive test scores). Studies reporting sufficient information to calculate effect sizes were included in metaanalyses. Standardized and unstandardized mean differences were calculated for continuous outcomes for global cognition and for pre-specified cognitive domains. The main outcome was change in cognition measured by neuropsychological tests; an outcome of secondary interest was the frequency of adverse cognitive events observed during follow-up. RESULTS: We identified 25 RCTs (all placebo-controlled) reporting cognitive outcomes in 46,836 subjects, of which 23 RCTs reported cognitive test results in 29,012 participants. Adverse cognitive outcomes attributable to statins were rarely reported in trials involving cognitively normal or impaired subjects. Furthermore, meta-analysis of cognitive test data (14 studies; 27,643 participants) failed to show significant adverse effects of statins on all tests of cognition in either cognitively normal subjects (standardized mean difference 0.01, 95 % confidence interval, CI, −0.01 to 0.03, p=0.42) or Alzheimer's disease subjects (standardized mean difference −0.05, 95 % CI −0.19 to 0.10, p=0.38). CONCLUSIONS: Statin therapy was not associated with cognitive impairment in RCTs. These results raise questions regarding the continued merit of the FDA warning about potential adverse effects of statins on cognition.

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“…By 2050, 115 million people worldwide are predicted to have AD . Available treatments amount to several drugs that provide temporary relief or slow progression (Sparks et al 2005;Kehoe and Wilcock 2007;Relkin et al 2009). Risk of AD may be reduced, however, by antioxidants (Grundman and Denaney 2002;Holmquist et al 2007;Cole and Frautschy 2010), healthy diets (Gu et al 2010), environmental enrichment (Jankowski et al 2005;Herring et al 2008), and exercise (Adlard et al 2005).…”

Section: Introductionmentioning

confidence: 99%

A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice

Aksenov

Long

Liu

et al. 2011

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We developed a complex dietary supplement designed to offset five key mechanisms of aging and tested its effectiveness in ameliorating age-related cognitive decline using a visually cued Morris water maze test. All younger mice (<1 year old) learned the task well. However, older untreated mice (>1 year) were unable to learn the maze even after 5 days, indicative of strong cognitive decline at older ages. In contrast, no cognitive decline was evident in older supplemented mice, even when ∼2 years old. Supplemented older mice were nearly 50% better at locating the platform than age-matched controls. Brain weights of supplemented mice were significantly greater than controls, even at younger ages. Reversal of cognitive decline in activity of complexes III and IV by supplementation was significantly associated with cognitive improvement, implicating energy supply as one possible mechanism. These results represent proof of principle that complex dietary supplements can provide powerful benefits for cognitive function and brain aging.

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Atorvastatin for the Treatment of Mild to Moderate Alzheimer Disease

Cited by 388 publications

References 26 publications

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice

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