Medical Grand Rounds

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

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In the last several years, some have questioned whether the amyloid hypothesis applies to all Alzheimer disease. 1,2 Arguments go back to at least 2002, when Bishop and Robinson in an article entitled “The amyloid hypothesis: Let sleeping dogmas lie?” 3 criticized the hypothesis and suggested that the beta-amyloid peptide appeared to be neuroprotective, not neurotoxic, in most situations. They suggested we await the outcome of antiamyloid therapeutic trials to determine whether the amyloid hypothesis truly explains the disorder.

The antiamyloid trials have now been under way for some time, and we have no definitive answer. Data from the phase II study of the monoclonal antibody agent bapineuzumab suggests there might be some small clinical impact of removing amyloid from the brain through immunotherapy mechanisms, but the benefits thus far are not robust.


A pivotal question might be, “What if sick neurons made amyloid, instead of amyloid making neurons sick?” A corollary question is, “What if the effect were bidirectional?”

It is possible that in certain concentrations amyloid is neurotoxic, 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.”

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