Alzheimer disease prevention: Focus on cardiovascular risk, not amyloid?
ABSTRACTAutosomal dominant (early-onset) Alzheimer disease and the much more common sporadic Alzheimer disease share a common pathology but not necessarily a common pathophysiology. Common cardiovascular comorbidities are associated with increased risk for Alzheimer disease and offer opportunities for intervention. Class I evidence for prevention is extremely limited. The overall body of evidence suggests the best time to intervene is in midlife, not in old age.
KEY POINTS
- Vascular risk factors clearly increase the risk of Alzheimer disease and can be addressed. However, controlled trials in patients with hypertension or with dyslipidemia have had negative results.
- Risk is lower with a diet high in antioxidants and polyunsaturated fatty acids.
- Estrogen therapy has had mixed results in observational studies, mostly hinting at lower risk. However, a randomized trial of hormone replacement therapy in late life indicated a higher risk of dementia with estrogen.
- Physical activity in midlife and in late life was associated with a lower risk of Alzheimer disease in observational studies. Controlled trials were not so positive, but the benefits of exercise may be slowly cumulative.
ESTROGEN: PROTECTIVE OR NOT?
Whether taking estrogen is a risk factor or is protective has not yet been determined. Estrogen directly affects neurons. It increases the number of dendritic spines, which are associated with improved memory. Meta-analyses suggest that hormone replacement therapy reduces the risk of dementia by about one-third. 21,22 Both positive and negative prospective studies exist, but all are complicated by serious methodologic flaws.23,24
Combined analysis of about 7,500 women from two double-blind, randomized, placebo-controlled trials of the Women’s Health Initiative Memory Study found that the risks of dementia and mild cognitive impairment were increased by hormone replacement therapy. The hazard ratio for dementia was found to be 1.76 (P < .005), amounting to 23 new cases of dementia per 10,000 prescriptions annually.25
Patient selection may account for the conflicting results in different studies. Epidemiologic studies consisted mostly of newly postmenopausal women and those who were being treated for symptoms of vasomotor instability. In contrast, the Women’s Health Initiative enrolled only women older than 65 and excluded women with vasomotor instability. Other studies indicate that the greatest cognitive improvements with hormone therapies are seen in women with vasomotor symptoms.
WHICH RISK FACTORS CAN WE CONTROL?
In summary, some of the risk factors for Alzheimer disease can be modified if we do the following.
Aggressively manage diabetes and cardiovascular disease. Vascular risk factors significantly increase dementia risk, providing good targets for prevention: clinicians should aggressively help their patients control diabetes, hypertension, and hyperlipidemia.26 However, aggressive control of hypertension in a patient with already-existing dementia may exacerbate the condition, so caution is warranted.
Optimize diet. Dietary measures include high intake of antioxidants (which are especially high in brightly colored and tart-flavored fruits and vegetables) and polyunsaturated fats.26 Eating a Mediterranean-type diet that includes a high intake of cold-water ocean fish is recommended. Fish should not be fried: the high temperatures may destroy the omega-3 fatty acids, and the high fat content may inhibit their absorption.
Weigh the risks and benefits of estrogen. Although estrogen replacement therapy for postmenopausal women has had mixed results for controlling dementia, it appears to be clinically indicated to control vasomotor symptoms and likely does not increase the risk of dementia for newly menopausal women. Risks and benefits should be carefully weighed for each patient.
Optimize exercise. People who are physically active in midlife have a lower risk of Alzheimer disease.27 Those who adopt new physical activity late in life may also gain some protective or restorative benefit.28
Many measures, such as taking anti-inflammatory or antihypertensive drugs, probably have a very small incremental benefit over time, so it is difficult to measure significant effects during the course of a typical clinical trial.
Clinicians are already recommending actions to reduce the risk of dementia by focusing on lowering cardiovascular risk. Hopefully, as these actions become more commonly practiced as lifelong habits in those reaching the age of risk for Alzheimer disease, we will see a reduced incidence of that devastating and much-feared illness.
