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

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Statistical analyses

Mean differences between the atorvastatin and placebo groups were evaluated using two-tailed Student t tests. Correlation between changes in cognitive measures and changes in the hippocampal volume for the total population and for the treatment groups was determined using Pearson’s r coefficient. Significance was defined as a P value less than .05; a P value between .05 and .10 was deemed a trend.


There was no difference in age or in years of education between the atorvastatin and the placebo groups (Table 1).

In contrast to other studies,54–58 we found in this pilot study that right hippocampal volume was slightly less than left hippocampal volume (2,015 ± 141 mm3 vs 2,135 ± 183 mm3).

Mean changes in performance on the ADAS-cog and MMSE were less pronounced in the atorvastatin group than in the placebo group, but not significantly so (Table 1). However, there was a trend toward superiority in the atorvastatin group on performance on the free word-recall subscale of the ADAS-cog.

Figure 2. Differential effects of placebo and atorvastatin therapy on size of the right hippocampus in a pilot substudy of the Alzheimer’s Disease Cholesterol-Lowering Treatment trial of patients with mild to moderate Alzheimer disease. In placebo patient 3 from Table 1 (panel A), the right hippocampus is slightly larger after 1 year of treatment with placebo relative to baseline. In contrast, in atorvastatin patient 2 from Table 1 (panel B), the right hippocampus is much smaller after 1 year of treatment with atorvastatin.
The reduction in total hippocampal volume was greater in the atorvastatin group than in the placebo group (Table 1), but the difference was not statistically significant. This effect seems to have been driven by the highly significant reduction in right hippocampal volume in the atorvastatin group relative to the placebo group (P =.008), as illustrated in Figure 2.

No significant correlations were found between change in cognitive performance and change in hip-pocampal volume.


The preponderance of evidence clearly indicates that hippocampal volume is reduced in patients with AD compared with individuals with normal cognitive ability for their age. There is also evidence indicating that as cognitive performance deteriorates in AD patients, there are concurrent further reductions in hippocampal volume.54 Many studies reported that there was no significant volume difference between the right and left hippocampi, but most suggested that the left hip-pocampus was slightly smaller than the right.54–58 We identified no significant difference in volume between the sides, but we did find that the right hippocampus was smaller than the left in a very limited population of subjects with mild to moderate AD.

The major finding of this pilot study flies in the face of conventional wisdom in that there seems to be significant shrinkage of the right hippocampus with atorvastatin therapy compared with placebo in a randomized AD treatment trial that demonstrated clinical benefit with atorvastatin therapy.44 A similar finding was reported from the beta-amyloid immunization (AN1792) treatment trial in AD.59 In that study the active immunization was associated with significant clinical benefit, reduced beta-amyloid load, and reduced hippocampal volume.59 The authors suggested that removal of beta-amyloid and/or other protein constituents from the tissue might have caused a “fluid shift” out of the tissue, resulting in shrinkage.

Based on our previous finding of reduced brain tissue density in AD patients compared with age-matched normal controls,48 an alternative explanation can be proposed. Neuronal loss in the hippocampus may be accompanied by increased fluid balance (reduced density) in an attempt to retain the previous volume at the expense of function. Accordingly, as the hippocampus shrinks, it approaches a more normal density for the remaining neuronal complement, and cognitive function improves.

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