Statins and therapy of Alzheimer's disease: questions of efficacy versus trial design

Recent trials of statins produced no benefit for subjects with Alzheimer's disease. These negative studies add to a growing list of negative clinical trials. These data point to a need for reevaluating the pathophysiology of late-onset Alzheimer's disease. Late-onset Alzheimer's disease might result from the cumulative effects of at least four different factors: β-amyloid accumulation, cardiovascular disease, aging and the associated loss of synaptic plasticity, and inflammation. Successful therapy of subjects with overt dementia might require approaches targeting all four pathophysiological domains.

Th is negative trial adds to an increasing string of negative clinical trials observed for treatments whose effi cacy was hypothesized on the basis of either animal studies or epidemiological studies (reviewed by Kivipelto and colleagues [14]). Th is group includes γ-secretase inhibitors (semagacestat), γ-secretase modulators (r-fl urbiprofen), vaccines (AN1792), non-steroidal anti-in fl ammatory drugs, anti-oxidants (vitamin E), a mito chon drial directed agent (Dimebon; Pfi zer Inc, New York, NY, USA), anti-aggregation agents (Alzhemed; Neuro chem Inc., now part of Bellus Health Inc., Laval, QC, Canada), and many other medications. In the case of the simvastatin trial, biomarker data suggest that simva statin achieves the desired cholesterol-reducing actions. Th e trial did not measure 24-hydroxycholesterol, which is a biomarker for cholesterol turnover in the brain, but multiple studies have demonstrated that simvastatin does lower 24-hydroxycholesterol in humans and in animal models [15].
Part of the answer explaining the negative results might lie in an incomplete conceptualization of the pathophysiology of AD. Th e simplest model for AD assumes that the disease results primarily from the accumulation of β-amyloid (Aβ) and the resulting toxicity. Th is hypothesis applies best to familial AD cases, which result from mutations in proteins directly linked to the Aβ metabolism (amyloid precursor protein and presenilins), and the disease commonly presents in patients who are much younger than those with classic late-onset AD.
Discussions of late-onset AD typically divide the disease course into at least three phases: prodromal, mild cognitive impairment, and overt dementia. To understand how these stages might impact on therapy, we need to think mechanistically. Integrating the breadth of research in AD suggests that late-onset AD might actually result from multiple factors rather than simply from the accumulation of Aβ. Th ese include at least four general factors: 1. Aβ: Th e accumulation of Aβ is clearly relevant to lateonset AD because of the strong presence of amyloid and tau pathology in late-onset AD combined with the

Abstract
Recent trials of statins produced no benefi t for subjects with Alzheimer's disease. These negative studies add to a growing list of negative clinical trials. These data point to a need for reevaluating the pathophysiology of late-onset Alzheimer's disease. Late-onset Alzheimer's disease might result from the cumulative eff ects of at least four diff erent factors: β-amyloid accumulation, cardiovascular disease, aging and the associated loss of synaptic plasticity, and infl ammation. Successful therapy of subjects with overt dementia might require approaches targeting all four pathophysiological domains.
strong data implicating amyloid precursor protein and presenilins in the pathophysiology of familial AD. How ever, Aβ does not appear to be acutely toxic in vivo. Many subjects exhibit Aβ accumulation without experiencing dementia, and this raises the possibility that Aβ levels might exert an infl uence that is only partly causative. Genetic considerations emphasize the issue of incomplete causation. Genetic data for genes linked to late-onset AD, aside from apolipoprotein E (ApoE), all exhibit modest eff ects. 2. Cardiovascular disease: Mid-life cardiovascular risk factors, such as high cholesterol, high blood pressure, diabetes, and obesity, all are associated with increased risk of late-onset AD. Patients with AD consistently exhibit reduced levels of cerebral blood fl ow, which no doubt lead to reduced cognitive reserve. Reduced cerebral blood fl ow could result from vascular disease associated with cardiovascular disease and diabetes and aggravated by deposition of Aβ around the cerebral microvasculature. In a sense, this reduction of cerebral blood fl ow can be reclassifi ed as end-organ disease of the brain for subjects with cardiovascular disease. Th e epidemiological data suggesting a protective benefi t of statin use might easily refl ect moderation of cardiovascular disease and increasing cerebral blood fl ow. 3. Aging, plasticity, and regeneration: Aging leads to reduced plasticity and impaired proteostasis. ApoE4 is the major risk factor for late-onset AD. Much attention has been focused on the tendency of ApoE to promote Aβ aggregation and accumulation; however, ApoE4 is equally notable because it leads to reduced plasticity and regeneration. 4. Infl ammation: Neurodegeneration and aging both stimu late strong infl ammatory responses. Frank dementia occurs late in the disease course at a point when all four factors are impacting on the brain and have impacted on the brain for years. Statins are outstanding medications that can prevent further cardiovascular damage and even improve cardiovascular function but are not regenerative medicines. Statins are unable to restore the function of an end-organ tissue back to the function before cardiovascular disease was present. By analogy, if dementia results from long-term cardiovascular disease, then statins might be unable to benefi t subjects once overt dementia is apparent. Th e window of opportunity for statins might require that treatment begin at mid-life, when statins can function as a protective factor rather than as a treatment that actively reduces dementia once it has occurred. Th e same set of considera tions might apply to anti-amyloid strategies because Aβ accumulation also occurs over a long time frame.
Most clinical trial designs focus on subjects who already have dementia, which represents a late stage in disease if we consider dementia to be analogous to endorgan disease. If dementia results from the interaction of these four factors, then treatment strategies might need to target each factor to be eff ective. Treatments will need to prevent further damage by inhibiting cardiovascular disease and increasing cerebral blood fl ow. In this context, medicines such as angiotensin receptor blockers might be useful because they appear to particularly benefi t those suff ering from dementia [16].
At the same time, treatments will need to reduce the ongoing toxicity resulting from the presence of protein aggregates, including Aβ, tau, and other proteins. Increasing data suggest that multiple pathological proteins in addition to Aβ are secreted in AD; these proteins include oligomeric forms of tau and perhaps α-synuclein. Th us, although anti-amyloid antibody therapy has yet to show promise, concurrent administration of antibodies against oligomeric Aβ and tau might be eff ective. Th e associated infl ammation will need to be dampened. Nonsteroidal anti-infl ammatory drugs could be helpful, but novel anti-infl ammatory drugs, termed resolvins, might prove even more eff ective [17]. Finally, the underlying defi cits in regeneration, resulting from aging and ApoE4, will need to be addressed. Whether SirT1 agonists, such as resveratrol or its analogues, will prove eff ective in the brain remains to be determined. Th e only therapeutic targets that might actually lead to a dramatic improvement in subjects with dementia are those targeting regeneration and plasticity, because only those therapies would elicit an actively benefi cial response in older patients.

Competing interests
BW holds a patent for use of statins in therapy of Alzheimer's disease.