In a population-based sample of 216 participants with incident AD followed in a prospective longitudinal manner for a mean of 3.14 years, the use of statins and beta-blockers at baseline was associated with a slower rate of functional decline as measured by the CDR-Sum. CDR-Sum increased 1.69 points annually overall indicating that the typical course of AD in this cohort was progressive functional decline. This rate of decline was slower than the 2.9 point annual decline reported by Bhargava et al.32
and the 2.17 point annual decline reported by Pavlik et al.,27
both for referral clinic cohorts. These differences are not surprising: the DPS cohort was older and derived from population-based sampling, which are both factors associated with a more benign course of disease. Our results with MMSE as an alternative outcome were significant only for protective effect of statins, which is expected given that MMSE is a less sensitive measure of change than CDR-Sum.
Statins appeared protective, slowing the rate of increase in CDR-Sum by approximately 0.75 points annually (44% decrease in rate of functional decline). To our knowledge this is the first cohort study to report a protective effect of statins in established AD and extends the results reported from longitudinal studies of AD incidence and clinical trials. There are several potential protective mechanisms of statin treatment. Statins may alter the cholesterol content of lipid rafts in the neuronal membrane which can then alter the activity of β
-secretase, shifting the metabolism of amyloid precursor protein from β
- to α
Excess dietary cholesterol has been shown to lead to amyloid-β
accumulation in mouse models,36
and statin treatment could mediate this effect. Statin treatment improved learning, memory, and hippocampal long-term potentiation in transgenic mice overexpressing human familial autosomal dominant genes for AD.37
In addition, statins have numerous biologic effects other than alteration of cholesterol metabolism, including anti-inflammatory and antioxidant effects.38
One trial of atorvastatin has reported positive effects on cognition and mood in mild to moderate AD,16
and a community-based observational study reported that premortem statin use was associated with less evidence of AD-like pathologic changes at autopsy.39
The Alzheimer Disease Cooperative Study trial of simvastatin for secondary prevention in AD should directly address the efficacy of statins for delaying progression of AD.
Beta-blockers had a similarly protective effect, reducing the increase in CDR-Sum by 0.68 units annually (40% decrease in rate of functional decline). To our knowledge this is a novel finding in the published literature on AD progression. This finding did not appear to be solely due to adequate control of systolic blood pressure since the interaction between beta-blocker use and systolic blood pressure did not significantly affect CDR-Sum. There are published clinical trials reporting the effect of beta-blockers on dementia incidence, but none reporting effect on dementia progression. The Systolic Hypertension in the Elderly Program used atenolol as second-step treatment, and reported no effect on dementia incidence.40
The Honolulu, Hawaii, Asia Aging Study found that a longer duration of hypertensive treatment was associated with reduced incidence of dementia,41
but did not distinguish between different antihypertensive classes. There are several possible mechanisms for neuroprotection in AD by beta-blockers. The beta-blocker carvedilol reduced infarct size and neurologic deficits in a rat model of transient focal stroke, and this neuroprotection was associated with decreased apoptosis and in brain levels of the proinflammatory cytokines TNF-α
Since there is increasing evidence that neurotoxicity in AD is mediated through release of proinflammatory cytokines by activated microglia,43
it is possible that beta-blockers are acting as anti-inflammatory agents in the AD brain. Another possible mechanism is that beta-blockers improve cardiac output in subclinical congestive heart failure and/or coronary artery disease, thus improving brain perfusion and conceivably improving cognitive function.
Diuretic use was associated with more rapid functional decline by 1.0 CDR-Sum units annually (59% increase). This is opposite in effect to reported data from the CCSMHA that diuretics are associated with lower incidence of AD.13
This difference in effect may be attributable to the stage-specific effect of risk factors, to a greater burden of medical illness, or to higher-order interactions between medication use and illness that cannot be addressed by a sample of this size.
The major limitation of the study is that the limited number of participants and follow-ups results in in-sufficient power to examine the interaction of medication treatments with vascular risk factors (and other potential interactions) over time. When the follow-up visits are completed, even with the high rate of attrition due to death in this very elderly cohort, this dataset should be adequately powered to address these crucial issues. Other limitations of the study include: 1) limited duration of follow-up, which limits the power of the study to detect change; 2) lack of laboratory studies to assess changes in lipid levels associated with LLA use, for example; 3) no objective assessment of medication adherence; 4) since participants were enrolled in DPS with incident AD, most of the subjects had mild dementia severity limiting the generalizability to more advanced disease stages.
Strengths of the study include 1) population-based sample which is more likely to reflect the natural variability and course of AD than clinical populations which include referral bias; 2) in most cases, participants have been followed prior to onset of dementia in the Cache County Study on Memory, Health, and Aging and thus incident dementia cases are identified close to onset of dementia as evidenced by the short duration of dementia (<2 years) at baseline; 3) systematic diagnosis of AD by a geriatric multispecialty team in a consensus conference; 4) data analysis using prospective design; 5) systematic assessment of medication use combining visual inspection of medicine cabinet with interview of proxy informants.
These results add to the data suggesting the protective effect of statins on AD progression and suggest an additional protective effect of beta-blockers, while casting doubt on the previously reported protective effect of diuretics. If replicated in epidemiologic and clinical studies, these findings could have substantial impact on our ability to slow the progressive functional decline of AD and thus diminish the tremendous burden of disability on AD patients and caregivers.