Lowering risk of Alzheimer’s disease

Cardiovascular risk factors

The risk of developing AD or vascular dementia appears to be increased by conditions that damage the heart or blood vessels. Recent evidence suggests that successfully managing cardiovascular risk factors may decrease the likelihood of dementia in later life.

Hypertension is associated with a higher risk of AD and all-cause dementia. Curiously, some studies have shown that low blood pressure also increases dementia risk, suggesting a U-shaped relationship between blood pressure and cognitive decline. Systolic hypertension in midlife may be associated with dementia 20 years later.

One might assume that antihypertensive therapy would help prevent dementia, but the data are conflicting. The Systolic Hypertension in Europe (SYST-EUR) study¹ showed a 53% reduction in vascular dementia or mixed dementia among patients receiving antihypertensive medication and a 60% reduction in AD. Similarly, the PROGRESS² clinical trial of prevention of recurrent stroke by antihypertensive treatment reported a 34% reduction in a composite measure of cognitive impairment and dementia. On the other hand, cognitive function neither improved nor worsened in the Hypertension in the Very Elderly Trial (HYVET-COG),³ whether patients received blood pressure treatment or placebo.

Hyperlipidemia. Lipid metabolism likely is an important pathway in amyloid beta-protein deposition, tau phosphorylation, and disruption of synaptic plasticity and neurodegenerative endpoints. Cognitive decline and incident dementia have been associated with higher dietary intake of saturated fats, partially hydrogenated unsaturated fatty acids (trans fats), and cholesterol. Not all studies have found this association, however. This could be because serum cholesterol levels may decrease in early dementia, limiting the ability to detect an effect of hypercholesterolemia on dementia risk when measurements are made later in life.

Using statins (3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors) to treat hypercholesterolemia has been hypothesized to impede large vessel atherosclerosis and its consequences and to trigger metabolic effects in the brain related to AD pathogenesis. Mechanisms by which statins might help prevent dementia include:

• a direct association between amyloid processing and cholesterol in the brain
• an indirect effect by decreasing the risk of stroke, as even small cerebral infarcts worsen AD severity.

Nonrandomized epidemiologic studies such as the Cardiovascular Health Study⁴ and MRC/BHF Heart Protection Study⁵ suggested that statin treatment might reduce the incidence of dementia, the degree of age-related cognitive decline, and AD’s neuropathologic burden. Large, randomized, controlled trials have not supported these observations, however. Statins failed to reduce the incidence of dementia in:

• the Heart Protection Study, testing simvastatin for 5 years in 20,536 subjects age 40 to 80⁵
• the 3-year Preventive Study of Pravastatin in the Elderly at Risk (PROSPER) of 5,800 subjects.⁶

Similarly, patients receiving adjunctive atorvastatin or placebo showed no significant differences in cognition assessments after 72 weeks in the Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study. This trial enrolled 640 subjects age 50 to 90 with mild-to-moderate dementia who were treated with donepezil.⁷ A recent Cochrane review concluded that high serum cholesterol may contribute to the development of AD and vascular dementia, but lowering cholesterol levels with statins does not prevent these problems.⁸

Diabetes mellitus. Diabetes and cognitive decline are closely associated. Diabetes is associated with a 50% to 100% increase in risk of AD and dementia overall and a 100% to 150% increased risk of vascular dementia. The mechanism by which diabetes increases dementia risk is uncertain but does not appear to be mediated entirely through vascular disease. High and low insulin levels may increase the risk of dementia, independent of diabetes and blood glucose. Increased peripheral insulin levels are associated with reduced brain atrophy and cognitive impairment in patients with early AD, suggesting a role for insulin signaling in AD pathophysiology. A possible relationship between insulin and beta amyloid metabolism is being studied.

Elevated postprandial plasma glucose has been associated with accelerated declines in cognitive performance.⁹ An inverse correlation has been noted between some cognitive measures and hemoglobin A1C levels.¹⁰ It is not clear that treating diabetes reduces the risk of dementia. In addition, in the prospective, population-based Rotterdam study, elderly patients with type 2 diabetes treated with insulin had the highest incidence of dementia.¹¹

Tobacco smoke directly affects neuronal function, integrity, and survival. Chronic smoking has been linked to decreased global cerebral blood flow, accelerated cerebral atrophy, and ventricular enlargement.

Some studies suggest an increased risk of dementia in middle-aged and elderly smokers, possibly through a cerebrovascular mechanism such as stroke. Other studies found no association between smoking and dementia risk, and 1 suggested that nicotine may protect against AD by reducing senile plaque formation. Any protective effect of smoking would be offset by increased risks of lung cancer, chronic obstructive pulmonary disease, and vascular dementia.