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.
ALZHEIMER DISEASE AND STROKE: MORE ALIKE THAN WE THOUGHT?
Although historically clinicians and researchers have tried to distinguish between Alzheimer disease and vascular dementia, growing evidence indicates that the two disorders overlap significantly and that the pathologies may be synergistic.
Alzheimer disease has been hypothesized as being a vascular disorder.10 It shares many of the risk factors of vascular disease, and preclinical detection of Alzheimer disease is possible from measurements of regional cerebral perfusion. Cerebrovascular and neurodegenerative pathology are parallel in Alzheimer disease and vascular disease.
Pure Alzheimer disease and vascular disease are two ends of a pathologic continuum.11 At one end is “pure” Alzheimer disease, in which patients die only with histologic findings of plaques and neurofibrillary tangles. This form may occur only in patients with the autosomal dominant early-onset form. At the other end of the spectrum are people who have serious vascular disease, multiple strokes, and microvascular ischemia and who die demented but with no evidence of the plaques and tangles of Alzheimer disease.
Between these poles is a spectrum of overlapping pathology that is either Alzheimer disease-dominant or vascular disease-dominant, with varying degrees of amyloid plaque and evidence of microvascular infarcts. Cerebral amyloid angiopathy (the accumulation of beta-amyloid in the wall of arteries in the brain) bridges the syndromes.12 In some drug studies that attempted removing amyloid from the brain, vascular permeability was altered, resulting in brain edema.
Along the same lines as Kalaria’s model,11 Snowden et al13 found at autopsy of aged Catholic nuns that for some the accumulation of Alzheimer pathology alone was insufficient to cause dementia, but dementia was nearly universal in nuns with the same burden of Alzheimer pathology commingled with vascular pathology.
DOES INFLAMMATION PLAY A ROLE?
The inflammatory state is a recognized risk factor for Alzheimer disease, but the clinical data are mixed. Epidemiologic evidence is strong: patients who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids for chronic, systemic inflammatory diseases (eg, arthritis) have a 45% to 60% reduced risk for Alzheimer disease.14,15
However, multiple clinical trials in patients with Alzheimer disease have failed to show a benefit of taking anti-inflammatory drugs. One preliminary report suggested that indomethacin (Indocin) might offer benefit, but because of gastrointestinal side effects its usefulness in an elderly population is limited.
Diabetes and inflammation are also closely linked: hyperinsulinemia is proinflammatory, promoting the formation of reactive oxygen species, inhibiting the degradation of oxidized proteins, and increasing the risk for lipid per-oxidation. Insulin acts synergistically with endotoxins to raise inflammatory markers, eg, proinflammatory cytokines and C-reactive protein.16
It is possible that anti-inflammatory drugs may not work in Alzheimer disease because inflammation in the brain is mediated more by microglial cells than by prostaglandin pathways. In Alzheimer disease, inflammation is mediated by activated microglial cells, which invade plaques with their processes; these are not evident in the diffuse beta-amyloid-rich plaques seen in typical aging. The trigger for their activation is unclear, but the activated microglial cells and the invasion of plaques are seen in transgenic mouse models of Alzheimer disease, and activation is seen when beta-amyloid is injected into the brain of a healthy mouse.17
Activated microglial cells enlarge and their metabolic rate increases, with a surge in the production of proteins and other protein-mediated inflammatory markers such as alpha-antichymotrypsin, alpha-antitrypsin, serum amyloid P, C-reactive protein, nitric oxide, and proinflammatory cytokines. It is unlikely that it is healthy for cells to be exposed to these inflammatory products. Some of the cytokines are now targets of drug development for Alzheimer disease, and agents targeting these pathways have already been developed for connective tissue diseases.
In a controversial pilot study, Tobinick et al18 studied the use of etanercept (Enbrel), an inhibitor of tumor necrosis factor-alpha (an inflammatory cytokine). They injected etanercept weekly into the spinal canal in 15 patients with mild to severe Alzheimer disease, for 6 months. Patients improved in the Mini-Mental State Examination by more than two points during the study. Patent issues surrounding use of this drug in Alzheimer disease may delay further trials.
Thiazolidinediones block microglial cell activation
The reactive microglial phenotype can be prevented in cell culture by peroxisome proliferator-activated receptor (PPAR) gamma agonists. These include the antidiabetic thiazolidinediones such as pioglitazone (Actos), troglitazone (Rezulin), and rosiglitazone (Avandia), and indomethacin and other NSAIDs.
Using a Veterans Administration database of more than 142,000 patients, Miller et al19 retrospectively found that patients who took a thiazolidinedione for diabetes had a 20% lower risk of developing Alzheimer disease compared with users of insulin or metformin (Glucophage).
However, rosiglitazone showed no benefit against Alzheimer disease in a large clinical trial,20 but this may be because it is rapidly cleared from the brain. Pioglitazone is not actively exported from the brain, so it may be a better candidate, but pharmaceutical industry interest in this agent is low because its patent will soon expire.
Fish oil is another PPAR-gamma agonist, and some studies indicate that eating fish may protect against developing Alzheimer disease; it may also be therapeutic if the disease is present. Double-blind controlled studies have not been carried out and likely will not because of patent issues: the costs of such studies are high, and the potential payback is low.
