Assessing Statins for Alzheimer Disease: Conflicting Evidence

The second report from the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial was recently published, along with several reviews of clinical and laboratory investigations of the statins, in a theme issue of Acta Neurologica Scandinavica. The accumulated data reflect the potential of the agents to affect the onset or course of Alzheimer disease (AD), with contradictory or insufficient evidence of treatment effect.

The first ADCLT report suggested that lowering cholesterol levels with atorvastatin (Lipitor) could reduce cognitive and behavioral deterioration in persons with mild to moderate AD.¹ This second report examined whether the apparent benefit is influenced by severity of cognitive impairment, circulating cholesterol levels, or apolipoprotein E genotype.²

The ADCLT trial is a double-blind controlled study involving 67 patients with mild to moderate AD, randomized to receive 1 year of treatment with atorvastatin (80 mg/d) or placebo. The primary measure is scoring on the Alzheimer's Disease Assessment Scale–Cognitive (ADAS-cog) subscale, with secondary measurement on the Mini-Mental State Examination (MMSE). Prestudy medications for both AD and comorbidities continued throughout the study period.

Both the statin treatment and placebo groups showed deterioration on the ADAS-cog at 3 months, and the placebo group continued to deteriorate by about 1 point per quarter throughout the study period. The ADAS-cog mean score in the statin treatment group was about 3.5 points higher than the mean score of the placebo group at 6 months. The ADCLT investigators reported that the benefit of the statins appeared to be more prominent in those with cholesterol levels above 200 mg/dL, those with the apoE4 allele, and those with higher baseline MMSE scores.

In regard to the latter patient group (those with higher baseline MMSE scores), the investigators commented, “This is consistent with evolving opinion that the earlier the treatment of AD, the better the outcome, and the concept of treating the disorder, clinically presenting as mild cognitive impairment, in advance of transition to clinical impairment consistent with AD.”²

In one of the accompanying commentaries, Kivipelto and colleagues³ note that while most discussion of the cause of AD has centered on the genes and protein patterns in familial-linked onset, most AD emerges sporadically, outside of familial patterns, and presents considerable heterogeneity of risk factors, pathogenesis, and neuropathologic processes.

“In this markedly multifactorial sporadic AD, the involvement of lipids from both plasma and brain should not be underestimated,” they indicate. “It took several decades for data on peripheral lipid metabolism to emerge, and it will again take time to elucidate brain lipid metabolism and the interaction between the two lipid pools.”³

Kivipelto and associates point out that community-based preventive studies in the field of cardiovascular disease began more than 20 years ago and have been continuously modified to focus on areas evidencing potential. To establish epidemiologic evidence of preventive effect they note, “one needs to do the right thing and do enough of it.”³

Kivipelto and colleagues further argue against a fatalistic view of the inevitability of AD onset. Claiming that there are indications of a number of modifiable risk factors they declare, “aetiological treatment may belong to the future, but prevention is now.”³

In a critical view of the evidence for the potential of statins to modify onset and development of AD, Rockwood⁴ points out that initial expectations were based on cross-sectional observational reports, the results of which were not subsequently supported by 2 large clinical trials with cognitive add-on studies. Although these studies were not originally designed to evaluate statin effect, epidemiologic data from the Canadian Study of Health and Aging also presented a mixed picture, he notes.

“The first reports appear to have overestimated the extent of protection,” Rockwood comments, “so that unless there are important effects achievable with specific statins, more than a modest role for statins preventing AD seems unlikely.”⁴

A mixed case for statin mechanisms
Several observations have suggested that the cholesterol-lowering action of the statins might be protective and/or therapeutic in AD. In their review, Wolozin and coauthors⁵ cite that, as an example, the determination that the apoE4 allele of the cholesterol transporter apoE4 is a major risk factor for late-onset AD. A closely following supportive epidemiologic finding is that the risk of AD appears to increase in persons with heart disease.⁶ Wolozin and colleagues⁵ also note cell biology studies that found that the processing of amyloid precursor protein (APP) and production of ß-amyloid (Aß)-a component of the amyloid plaques in AD-are strongly modulated by cholesterol.

In contrast, Höglund and colleagues⁷ point out that more recent epidemiologic studies have not associated lowered cholesterol levels with slowing cognitive decline; both animal⁸ and clinical⁹ studies have had negative findings, they note.

“The intake of cholesterol and other lipids has also been found to be inconsistent when related to the risk of developing dementia,” these authors observe.⁷

Other actions of the statins may be neuroprotective, note Sparks and colleagues,¹⁰ including lipid-independent pleiotropic effects that interfere with Aß production and accumulation. In their review, separate from the ADCLT report, they also note in vitro studies with glioma cells in which pravastatin (Pravachol) reduced interleuken-6 and free radical inflammatory mediators.

In his assessment of the pleiotropic effects of statins, Crisby¹¹ emphasizes that inflammation in the CNS is an early hallmark of many neurodegenerative diseases, including AD. Crisby points out that apoE is involved in the clearance of cholesterol-laden neurodegenerative products following brain injury and that apoE isoforms have been found to exert antioxidant and anti-inflammatory actions.¹⁰

Wolozin and colleagues⁵ note their own recently reported evidence of such effects in a small postmortem comparative study. Brain sections of one group of 10 patients with AD who had not received statins were compared with those of a group of 6 who had received the medication for at least a year. Wolozin and coauthors found a “striking” reduction in microglial activation in the statin-treated patients.

“These results are consistent with prior reports indicating that statins reduce inflammation and dampen the immune response in vivo,” they declare.⁵

Although acknowledging that the benefit and mechanism of action of the statins for AD remain to be elucidated, Kivipelto and colleagues³ indicate that multifaceted therapeutic strategies are appropriate for diseases with complex etiologies. In their view, targeting cholesterol in treatment or prevention of AD remains an appropriate strategy. “Even if the mechanisms involved are not fully known to us at the present,” they conclude, “it seems that minding heart health may protect the brain as well.”

References:

References1. Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin for the treatment of mild-to-moderate Alzheimer's disease: preliminary results: Arch Neurol. 2005;62:753- 757.
2. Sparks DL, Connor DJ, Sabbagh MN, et al. Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer's disease: results of the Alzheimer's Disease Cholesterol-Lowering Treatment (ADCLT) trial. Acta Neurol Scand. 2006;114(suppl 185):3-7.
3. Kivipelto M, Solomon A, Winblad B. Alzheimer's disease: back to the future. Acta Neurol Scand. 2006;114 (suppl 185):119-120.
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10. Sparks DL, Sabbagh MN, Connor DJ, et al. Statin therapy in Alzheimer's disease. Acta Neurol Scand. 2006;114(suppl 185):78-86.
11. Crisby M. The role of pleiotropic effects of statins in dementia. Acta Neurol Scand. 2006;114(suppl 185):115-118.