Baseline participant characteristics were similar between treatment groups (). On average, participants were middle-aged, overweight, prehypertensive, and had lipid values similar to mean levels noted in adults in the United States. (23
) Given their parental history of AD, participants had higher APOE4
allele prevalence (25%), a risk factor for both AD and vascular dysfunction, than is seen in the general population (~15%). Framingham risk scores were low, (16
) yet decreased mean FMD values suggested that participants had impaired endothelial function and increased vascular risk (). (24
Baseline Participant Characteristics
All 16 participants completed the study. Complete ASL-MRI data (baseline and month 4) were available on 13 participants. Technical software problems and poor image quality led to the loss of two baseline images (both in atorvastatin arm) and one at month 4 (placebo arm).
Baseline Perfusion Measures
Evaluation of the baseline relationships between participant characteristics and mean regional CBF measures showed that increasing age, low HDL-C, higher Framingham 10-year CVD risk, and worse endothelial function, as measured by FMD, correlated with reduced regional CBF (). LDL-C was not significantly related to CBF.
Figure 1 A. Baseline age correlated inversely with baseline CBF in the posterior cingulate (shown, r=−0.530, p=0.051), hippocampus (shown, r=−0.541, p=0.046), parahippocampus (r=−0.577, p=0.031), thalamus (−0.546, p=0.043), and (more ...)
Effects of Atorvastatin on Lipoprotein Levels and Arterial Function
Atorvastatin significantly reduced mean serum total cholesterol (−30%), triglycerides (−37%), and LDL-C levels (−49%) (all p<0.03), compared to placebo (). Four months of atorvastatin use did not significantly affect FMD compared to placebo in this pilot study ().
Effects of Atorvastatin vs. Placebo on Changes in Outcome Measures Compared to Baselin
Effects of Atorvastatin on Cerebral Perfusion
Using voxel-wise analyses, participants randomized to atorvastatin showed a greater increase in regional CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to participants on placebo (). Mean global CBF changes at month 4 compared to baseline were not significantly different between the atorvastatin and placebo groups ().
Figure 2 Participants randomized to atorvastatin treatment showed greater increase in regional CBF in bilateral hippocampus, fusiform gyrus, putamen and insular cortices compared to participants on placebo (pvoxel <0.05 with extent threshold for cluster (more ...)
In this pilot clinical trial of asymptomatic middle-aged adults at risk for AD, participants randomized to four months of atorvastatin had greater increases in regional CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to placebo. Other studies have demonstrated relative hypoperfusion in the posterior cingulate, and the parietal and medial temporal lobes in adults with mild cognitive impairment (MCI) (7
), cognitively healthy APOE4
allele carriers (8
), and non-demented persons with memory complaints who later develop AD (25
). Given that cerebrovascular dysregulation is one of the earliest changes in AD pathology, (6
) targeting regional CBF may be a promising prevention strategy to delay or prevent AD. While findings from recent clinical trials suggest that statins have little effect in slowing cognitive decline in AD patients with advanced neurodegeneration, (26
) the role of these medications in preventing or delaying the onset of AD remains promising. Our findings of increased hippocampal perfusion with atorvastatin in asymptomatic adults at risk for AD suggest that further research is warranted in a larger more definitive trial to clarify if statins can not only increase CBF, but also whether such changes in perfusion are associated with cognitive benefits and reduced AD risk.
In addition to possibly improving cerebral perfusion, other studies support that statins have additional pleiotropic effects that could lead to neuroprotection and reduced AD risk, including beneficial changes on β-amyloid (28
), decreased inflammation (30
), and potential direct cognitive benefits. (31
) Studies are underway to clarify the impact of statins on these AD-related processes and whether modifying these potential mechanisms of disease leads to long-term improved cognition and reduced risk for AD.
Other studies targeting different patient populations support our pilot study findings that short-term statin therapy is effective in improving CBF (9
). In two clinical studies, adults with underlying subcortical small vessel disease showed improved CBF in the middle cerebral artery after only 2–3 months of statin therapy (34
). In a trial of healthy adults, improvements in cerebral vasoreactivity were noted after 14 days of statin use (36
). Our findings are consistent with these studies yet expand their findings to a unique population of asymptomatic middle-aged adults at increased risk for AD. The absence of an effect of statin therapy on the markers of endothelial function in our study is likely explained by the small sample size and by our subjects’ normal baseline cholesterol values. Larger studies of longer duration statin therapy are underway to evaluate the relationship between changes in FMD, CBF, and AD risk.
Asymptomatic adult children of persons with AD show early neuropathological changes consistent with AD even in the preclinical phase (14
) and, thus, are an ideal group to study for preventive therapies. Despite having fairly low vascular risk on their Framingham 10-year CVD risk assessment, our participants had reduced FMD suggesting increased risk for future vascular events. (24
) Participants in our study who were older, had lower HDL-C, worse endothelial function, and higher CVD risk scores demonstrated reduced baseline regional CBF in areas of the brain related to memory and learning. These findings suggest that subclinical changes in vascular risk profiles in adult children of persons with AD may influence risk for regional cerebral hypoperfusion and, potentially, risk of clinical AD. Thus, targeting vascular risk factor modification in persons at risk for AD who have average vascular risk profiles may beneficially affect cerebral perfusion and cognitive function. Larger randomized controlled trials are underway in at-risk adults to address these questions. Since middle-aged adults with high cholesterol, diabetes mellitus, or increased CVD risk should already be taking statins for CVD prevention, these drugs will need to be tested in persons at risk for AD who otherwise would not be prescribed statins, such as our study population. Larger more definitive clinical trials are needed to clarify if modifying vascular risk in midlife beneficially alters not only brain perfusion and AD pathology, but also delays clinical onset of cognitive and functional loss.