Medical Grand Rounds

Alzheimer disease prevention: Focus on cardiovascular risk, not amyloid?

Author and Disclosure Information



but in other concentrations, it actually facilitates neuronal repair, healing, and connection.


If our current models of drug therapy are not effective against sporadic Alzheimer disease, perhaps focusing on prevention would be more fruitful.

Consider diabetes mellitus as an analogy. Its manifestations include polydipsia, polyuria, fatigue, and elevated glucose and hemoglobin A 1c. Its complications are cardiovascular disease, nephropathy, and retinopathy. Yet diabetes mellitus encompasses two different diseases—type 1 and type 2—with different underlying pathophysiology. We do not treat them the same way. We may be moving toward a similar view of Alzheimer disease.

Links have been hypothesized between vascular risks and dementia. Diabetes, hypertension, dyslipidemia, and obesity might lead to dementia in a process abetted by oxidative stress, endothelial dysfunction, insulin resistance, inflammation, adiposity, and subcortical vascular disease. All of these could be targets of intervention to prevent and treat dementia. 4

Instead of a beta-amyloid trigger, let us hypothesize that metabolic stress is the initiating element of the Alzheimer cascade, which then triggers beta-amyloid overproduction or underclearance, and the immune activation damages neurons. By lessening metabolic stress or by preventing immune activation, it may, in theory, be possible to prevent neurons from entering into the terminal pathway of tangle formation and cell death.


Rates of dementia of all causes are higher in people with diabetes. The strongest effect has been noted in vascular dementia, but Alzheimer disease was also found to be associated with diabetes. 5 The Framingham Heart Study 6 found the association between dementia and diabetes was significant only when other risk factors for Alzheimer disease were minimal: in an otherwise healthy population, diabetes alone appears to trigger the risk for dementia. But in a population with a lot of vascular comorbidities, the association between diabetes and dementia is not as clear. Perhaps the magnitude of the risk is overwhelmed by greater cerebrovascular and cardiovascular morbidity.

A systematic review 7 supported the notion that the risk of dementia is higher in people with diabetes, and even raised the issue of whether we should consider Alzheimer disease “type 3 diabetes.”

Testing of the reverse hypothesis—diabetes is more common in people with Alzheimer disease—also is supportive: diabetes mellitus and even impaired fasting glucose are approximately twice as common in people with Alzheimer disease than in those without. 8 Fasting blood glucose levels increase steadily with age, but after age 65, they are higher in people with Alzheimer disease than in those without.

Glucose has some direct effects on brain metabolism that might explain the higher risk. Chronic hyperglycemia is associated with excessive production of free radicals, which leads to reactive oxygen species. These are toxic to neuronal membranes as well as to mitochondria, where many of the reactive oxygen species are generated. Free radicals also facilitate the inflammatory response.

We also see greater neuronal and mitochondrial calcium influx in the presence of hyperglycemia. The excess calcium interferes with mitochondrial metabolism and may trigger the cascade of apoptosis when it reaches critical levels in neurons.

Chronic hyperglycemia is also associated with increased advanced glycation end-products. These are toxic molecules produced by the persistent exposure of proteins to high sugar levels and may be facilitated by the presence of reactive oxygen species that catalyze the reactions between the sugars and the peptides. Glycation end-products are commonly recognized as the same as those occurring during browning of meat (the Maillard reaction).

Hyperglycemia also potentiates neuronal damage from ischemia. Animal experiments show that brain infarction in the presence of hyperglycemia results in worse damage than the same degree of ischemia in the absence of hyperglycemia. Hyperglycemia may exaggerate other blows to neuronal function such as those from small strokes or microvascular ischemia.


Swerdlow and Khan 9 have proposed an alternative to the amyloid hypothesis as the cause of Alzheimer disease, known as the “mitochondrial cascade hypothesis.” According to this model, as we age we accumulate more wear-and-tear from oxidative mitochondrial damage, especially the accumulation of toxins leading to reduced cell metabolic activity. This triggers the “3-R response”:

Reset. When toxins alter cell metabolism, neurons try to repair themselves by manufacturing beta-amyloid, which is a “repair-and-reset” synaptic signaling molecule that reduces energy production. Under the lower energy state, beta-pleated sheets develop from beta-amyloid, which aggregate and form amyloid plaque.

Remove. Many cells undergo programmed death when faced with oxidative stress. The first step in neuronal loss is reduced synaptic

Next Article: