Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial

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Numerous clinical studies suggest a link between elevated cholesterol and increased risk of Alzheimer disease (AD), and the preponderance of data suggests that statin therapy may reduce the risk of AD later in life. The first clinical investigation of statin therapy in patients with AD, the AD Cholesterol-Lowering Treatment (ADCLT) trial, found that atorvastatin 80 mg/day was associated with improvements relative to placebo on some, but not all, cognitive measures after 6 months and 1 year of therapy. We report here findings from a pilot ADCLT substudy showing a nonsignificant reduction in total hippocampal volume with 1 year of atorvastatin therapy compared with placebo, driven by a highly significant reduction in right hippocampal volume with atorvastatin therapy.



Alzheimer disease (AD) is a degenerative disorder characterized by a gradual deterioration in memory. In its clinically overt stages, obvious signs of neural degeneration on magnetic resonance imaging (MRI) appear as global cerebral atrophy. Even in the earliest stages of the disease, regional cell loss can be observed, particularly in the mesial temporal lobe regions, specifically the hippocampus and entorhinal cortex.1–3

MRI is used primarily as a diagnostic tool to rule out conditions other than AD. However, MRI may be useful in understanding whether the underlying processes that are associated with these cognitive changes can be attributed to general or specific effects of the disease process. Volumetric changes observed with MRI in the hippocampal region have been correlated with disease progression4,5 and predict development of AD in individuals with isolated memory impairment,6 suggesting that neuroimaging quantification may serve as a useful measure of brain integrity in patients with AD.

New treatments for AD are emerging, and assessing their efficacy is of critical importance. The rationale for testing statin drugs as a therapy for AD was bolstered by ever-mounting preclinical animal and human data suggesting that elevated circulating cholesterol exacerbates AD-like pathology and that statin treatment, in part, reverses the effect of cholesterol. This article surveys current evidence on the association between cholesterol and AD as well as between statin use and AD risk. We conclude by focusing on results from the first clinical investigation of statin therapy in patients with AD and present new results of a substudy of this trial examining the morphologic effects of statin therapy in AD patients.


Early epidemiologic surveys suggested an association between a high-fat/high-cholesterol diet and increased risk of AD,7–10 and this suggestion has been supported by more recent investigations.11,12 Cholesterol levels are increased in the blood of AD patients,7,13–16 and increased cholesterol has been observed in the AD brain as a function of the apolipoprotein E allotype.8,17

Numerous clinical studies suggest a link between elevated cholesterol and increased risk of AD,17–23 with one study reporting a threefold increase in the risk of AD with elevated serum cholesterol, even after adjusting for age and presence of the apolipoprotein E4 allele.19 Another study indicates that persistently elevated cholesterol levels in midlife increase the risk of AD.23 A retrospective analysis of the Framingham Study suggested, however, that there is no relationship between total cholesterol levels and risk of incident AD.24 A more recent report indicated that language performance in elderly subjects without dementia declined faster among those individuals with higher cholesterol levels, but this effect did not remain significant after accounting for multiple comparisons.25 In contrast, the Three-City Study, a population-based cohort investigation of 9,294 subjects in France, demonstrated a significant increase in the risk of dementia among subjects who had hyperlipidemia (odds ratio [OR] = 1.43; 95% confidence interval [CI], 1.03 to 1.99).12


The preponderance of clinical data suggests that statin therapy may reduce the risk of AD later in life. Since the initial epidemiologic investigation assessing the effect of statin use on later risk of AD in the elderly, there have been 13 additional studies; all but two of these studies have reported benefit with cholesterol-lowering therapy.

In the two earliest epidemiologic studies, Wolozin et al demonstrated benefit with the use of lovastatin and pravastatin, but not with simvastatin or non-statin therapy,26 and Jick et al showed benefit associated with cholesterol-lowering therapy, but not specifically with statin use.27 Five epidemiologic studies published in 2002 suggested that prior statin use reduced the risk of dementia or AD.28–32 Meta-analysis of these first seven retrospective studies suggested a significant reduction in the risk of later cognitive impairment with statin use (relative risk = 0.43; 95% CI, 0.31 to 0.62), but the risk reduction with lipid-lowering agents collectively (not just statins) was not statistically significant.33

In 2004, Zamrini et al reported a 39% reduction in the risk of AD in statin users compared with nonusers (OR = 0.61; 95% CI, 0.42 to 0.87).34 That same year, Li et al suggested that there was no association between statin use and a reduced incidence of probable AD using a time-dependent proportional hazards model, but if the data were analyzed (inappropriately) as a case-control study, a significant protective effect was identified.35

Data from the Cache County Study cohort demonstrated no significant reduction in the risk of AD with statin use but allowed for the possibility that some benefit could be provided with longer-term statin therapy.36 In constrast, the Three-City Study of 9,294 individuals in France identified a significant reduction in the risk of AD with statin use (OR = 0.61; 95% CI, 0.41 to 0.91).12 Rea et al reported that prior statin use did not decrease the risk of dementia or AD, but when they included in their analysis individuals currently using a statin, there was a significant reduction in the hazard ratios for AD and for all-cause dementia.37 The two most recent epidemiologic studies both suggest that statin therapy slows cognitive decline in AD.38,39


A retrospective cohort study that assessed intelligence and cognition at a young age and again when subjects were in their 80s indicated that statin use had a significant beneficial effect on cognitive ability.40

In contrast, two very large prospective studies published in 2002 suggested that statins produce no positive effect on cognition in younger individuals at risk for heart disease.41,42 The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) found that the mean Mini-Mental State Examination (MMSE) score, which was assessed only at subjects’ last on-treatment clinical visit, was comparable between the study’s pravastatin and placebo groups.41 Likewise, the Medical Research Council/British Heart Foundation (MRC/BHF) Heart Protection Study, which used the Telephone Interview for Cognitive Status questionnaire at the end of the investigation, reported that simvastatin had no positive effect on cognitive performance compared with placebo, but this finding was obtained in the absence of baseline data.42 Given the limited cognitive assessments performed in these two studies, no firm conclusions should be drawn.

A more recent prospective comparison of atorvastatin and placebo in younger subjects did include baseline and follow-up assessment of cognitive function, and it identified significantly superior performance in the statin-treated population on the MMSE and on tests of attention, psychomotor speed, mental flexibility, working memory, and memory retrieval.43

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