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Hypertension and late-life dementia - Editorial
  A real link?

David S. Knopman, MD

From the Department of Neurology, Mayo Clinic, Rochester, MN.

Address correspondence and reprint requests to Dr Knopman, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905

In this issue of Neurology®, two articles discuss the role of hypertension in late-life dementia. One, a clinical-neuropathologic study,1 reports that persons who were treated for hypertension in midlife were less demented clinically and had less Alzheimer disease (AD) pathology than either hypertensive patients who were not treated or nonhypertensive patients. The second article2 was from an epidemiologic study that found that antihypertensive use was associated with a reduction in dementia risk, more so in persons <75 years old. Taken together with the very large body of literature on the relationship of midlife and late-life hypertension to late-life dementia, the findings offer some encouragement for prevention of dementia. Although the two current studies are observational, they complement results from primary prevention trials.

While the results are not uniform,3 some large-scale randomized controlled trials of antihypertensive medications have shown reductions in incident dementia or improvements in cognition.4-7 The concordance of observational studies and at least a few clinical trials in antihypertensive treatment is a rare bright spot in the otherwise dismal track record of other putative interventions for dementia such as hormone replacement in women, statins, nonsteroidal antiinflammatory drugs, vitamin B12, and vitamin E therapies. Congratulations are not yet in order, however. There are many complexities and nuances to the story.

There has been a persistent question as to whether the type of antihypertensive medication makes a difference on cognitive outcomes. While there are reasons why one drug might be superior to others based on mechanisms of action, the evidence is not consistent. In neither of the current studies1,2 was there a consistent signal favoring one class of antihypertensive drug. Other studies have made various claims4,6,8,9 for specific drug classes. The choice of an antihypertensive that is optimal for prevention of dementia is not going to be resolved by the two current studies, but the suggestion is that the specific drug or drug class does not make a difference.

The age at onset of hypertension appears to have a substantial impact on the association between hypertension and dementia. Hypertension in midlife is clearly a major risk factor for later life cardiovascular and cerebrovascular disease as well as dementia. In contrast, in late life, blood pressure appears to have a J-shaped relationship to dementia because low blood pressure in late life emerges as a risk factor.10,11 In fact, there is an increasing prevalence of hypotension with advancing age.12 As a consequence, not all studies find hypertension to be a risk factor for dementia in late life.13 To make matters more complicated, hypotension in the elderly could either cause brain injury through ischemia and hypoperfusion, or itself could be a consequence of the brain disease that either directly affects the central control of blood pressure or indirectly leads to poor oral intake and weight loss. So, in order to demonstrate the effects of hypertension on dementia, it is probably in midlife and early elderly years where therapy needs to be directed. Later, among more elderly persons (roughly, over age 75 years), treatment of hypertension may have less value, as shown by one of the current studies.2 At some point in the aging process, somewhere but not exactly at age 75 years, the balance among blood pressure, cerebral autoregulation, and brain metabolism must change. Perhaps the higher existing disease burden of either AD or cerebrovascular pathology together with aging changes in the conduit and microvessels in the very elderly preclude benefits from treating hypertension. The rising prevalence of hypotension12 with advancing age due to central or peripheral nervous system disease might also interact with attempts to treat hypertension. Another possibility to account for the alteration in association of hypertension and dementia with advancing age is that some of the age-related differences in response to hypertension and its treatment could reflect survival biases, in which premature cardiovascular death in hypertensive patients culled out persons without other protective mechanisms.

Finally, it is not clear whether the consequences of hypertension or the target of the antihypertensive drugs are on AD pathology or cerebrovascular pathology. The obvious pathogenetic mechanism for hypertension would be endothelial dysfunction, leading to microinfarction and more widespread cerebral ischemia.14-16 But pivotal studies from the Honolulu Asia Aging Study17 as well as the current neuropathologic study1 suggest that at least some of hypertension's impact is on AD pathology. Microvascular mechanisms for ß-amyloid clearance could conceivably be altered by endothelial changes from hypertension.18 Some antihypertensive drugs such as calcium channel blockers19 or angiotensin-converting enzyme inhibitors20 could interact with ß-amyloid trafficking. Regardless of the pathophysiologic target or mechanism, the evidence that hypertension earlier in life plays an important role in late-life dementia is consistent. It may not be a major determinant, but greater attention to the role of hypertension's impact on the brain is warranted. Because hypertension is so common, its treatment would impact a large segment of the population at risk for late-life dementia.

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