New research suggests another important reason for keeping blood pressure in check. Scientists report that reducing hypertension may ward off amyloid pathology in people who have the ε4 version of the ApoE gene. As reported in the May 2013 issue of JAMA Neurology, researchers led by Denise Park, University of Texas at Dallas, found that in ApoE4 carriers, large amounts of amyloid deposited in the brain only if these patients had hypertension. Less built up if their diagnosed hypertension was controlled with medication, while those without hypertension had the lowest amount of amyloid compared to non-carriers. The study was cross-sectional.

Although the study begs follow-up and further replication in a larger sample, the implications are significant, wrote Kathleen Hayden, Duke University School of Medicine, Durham, North Carolina, in an e-mail to Alzforum (see full comment below). The study suggests an interaction between a gene and a medical risk factor that can be modified to reduce levels of Alzheimer’s disease (AD) pathology, she suggested.

ApoE4 is the strongest genetic risk factor for AD (see AlzGene). High blood pressure in midlife also confers a higher risk of dementia (see AlzRisk). Previous research has associated both ApoE4 and hypertension with elevated amyloid-β plaque load (see Rebeck et al., 1993; Langbaum et al., 2012). Do these two factors interact? A few studies have hinted that ApoE4 and cardiovascular risk factors work together to accelerate cognitive decline (see Caselli et al., 2011, and Yasuno et al., 2012). Park’s group wanted to explore that relationship further to see if the two have a synergistic effect on amyloid deposition.

First author Karen Rodrigue and colleagues recruited 118 cognitively healthy people between the ages of 47 and 89, all of whom underwent cognitive testing, magnetic resonance imaging, and positron emission tomography with 18F-florbetapir (Amyvid®) as part of the Dallas Lifespan Brain Study. Blood sample genotyping revealed that 23 percent carried at least one ApoE4 allele. The scientists also averaged seven blood pressure measurements taken at separate visits. Forty-nine people had normal, 69 elevated blood pressure; 54 of those were taking antihypertensive medication.

Analyzed separately, ApoE4 carriers and people with a diagnosis of hypertension only trended toward higher levels of amyloid compared to non-carriers and those with normal blood pressure, respectively. However, people with both the risk allele and high blood pressure deposited significantly more Aβ than normotensive ApoE4-negative controls. ApoE-positive people with untreated hypertension had the highest amyloid burden, while those who controlled their blood pressure with drugs had only slightly elevated buildup. In addition, Rodrigue and colleagues looked at pulse pressure—the difference between systolic pressure (when the heart contracts) and diastolic pressure (when the heart relaxes). Pulse pressure correlates with arterial stiffness and is widely believed to be a good predictor of heart disease. This measure, too, positively correlated with Aβ deposition, but only in people who carry an ApoE4 allele. For non-carriers, the severity of hypertension made no difference. The results suggest that ApoE4 carriers can lower their blood pressure—which is relatively easy to do with medication and behavior modification—to mitigate their genetic risk for AD, wrote the authors.

The mechanism that ties ApoE4 to hypertension is unclear. The authors note that hypertension compromises the blood-brain barrier in mice, leading to greater Aβ deposition (see Gentile et al., 2009). If that happens in humans, it might further drive up risk for AD pathology in ApoE4 carriers. Richard Caselli, of the Mayo Clinic in Scottsdale, Arizona, suggested that hypertension causes cerebrovascular damage, which may stress neurons and cause them to produce ApoE. In ε4 carriers, that might lead to greater amyloid deposition, he speculated.

The authors acknowledged caveats to the study. While they adjusted for age in their analyses, people with normal blood pressure were around a decade younger than those in the hypertensive group. Importantly, this aging study cohort is explicitly selected to be in general good health; therefore, the findings may not extrapolate to the general population. The authors plan to follow these participants longitudinally to examine factors that best predict Aβ burden over time.

The conclusions fit with the literature on ApoE4, hypertension, and dementia risk, said Benjamin Wolozin, Boston University School of Medicine, Massachusetts. He and colleagues previously showed that men taking angiotensin receptor blockers, a type of anti-hypertensive drug, had a lower incidence and slower progression of dementia (see ARF related news story on Li et al., 2010). Another report found that this particular class of drugs reduced Aβ pathology in elderly people with hypertension (see ARF related news story). However, Wolozin cautioned that the study is underpowered because the number of ApoE4 subjects with hypertension was small. He raised the possibility that a few people at the highest end of the risk spectrum could be driving a weak statistical correlation. “If they had twice as many people, the data might be definitive,” he told Alzforum.

Perhaps the prospect of fending off AD will further motivate people to treat their hypertension, Caselli suggested. While he generally agrees with the conclusions of the current study, he echoed Wolozin’s concerns and cautioned that people in the highest risk group also had the lowest average MMSE score. “In a small study like this one, the findings could be driven by one or two people with early-stage disease.”—Gwyneth Dickey Zakaib

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  1. Rodrigue et al. report exciting findings that suggest an interaction between hypertension and ApoE4. Individuals with hypertension and one or more ApoE4 alleles had a greater amyloid burden than those with no hypertension and no ApoE4 alleles. Further, breaking the sample down into controlled and uncontrolled hypertensives, they demonstrated the greatest risk of Aβ deposition in uncontrolled hypertensives with one or more ApoE4 alleles. Although the study begs follow-up and further replication in a larger sample, the implications are significant. These investigators have shed light not only on the association of a modifiable risk factor and AD pathology, but also a gene-by-environment interaction. Importantly, they have shown suggestive evidence that treatment of that modifiable factor is associated with reduced levels of AD pathology.

  2. The determinants of amyloid deposition in the brain for most older individuals are not well understood. At least three hypotheses should be considered: 1) there are unique, important risk factors, such as hypertension, brain vascular disease, and inflammation; 2) genetic factors, including ApoE4, are the major determinants of amyloid deposition; and 3) amyloid deposition in the brain is primarily a function of normal aging.

    <p>It is very unlikely that genetic factors alone account for deposition of amyloid except in very rare genetic disorders. If aging is the primary factor, then prevention and possibly treatments should focus on aging and not necessarily on specific amyloid deposition in the brain. If risk factors such as hypertension increase amyloid deposition, then there is a great opportunity to decrease or postpone amyloid deposition and dementia. It is very unlikely that major advances in preventing and/or treating Alzheimer's disease, i.e., amyloid deposition, will occur until we have a better understanding of etiology (causes) in humans. The paper by Rodrigue et al. adds to a growing literature that brain vascular disease secondary to elevated blood pressure contributes to Alzheimer's disease and dementia. The unanswered question is whether prevention or treatment of hypertension will prevent dementia. It is also possible that specific antihypertensive drug(s) will be more effective in preventing dementia. The association with ApoE4 only in the current paper may just relate to small sample size or indicate that a genetic marker, ApoE4, interacts with a risk factor, elevated BP, to increase amyloid deposition.

References

News Citations

  1. In Veterans, Blood Pressure Meds Delay Dementia
  2. Can Blood Pressure Drug Put the Squeeze on Brain Amyloid?

Paper Citations

  1. . Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron. 1993 Oct;11(4):575-80. PubMed.
  2. . Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons. Neurobiol Aging. 2012 Apr;33(4):827.e11-9. PubMed.
  3. . Cerebrovascular risk factors and preclinical memory decline in healthy APOE ε4 homozygotes. Neurology. 2011 Mar 22;76(12):1078-84. PubMed.
  4. . Effect of plasma lipids, hypertension and APOE genotype on cognitive decline. Neurobiol Aging. 2012 Jan 26; PubMed.
  5. . Beta-amyloid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiol Aging. 2009 Feb;30(2):222-8. PubMed.
  6. . Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465. PubMed.

External Citations

  1. AlzGene
  2. AlzRisk
  3. Dallas Lifespan Brain Study

Further Reading

Papers

  1. . Vascular Risk Factors and Neurodegeneration in Ageing related Dementias: Alzheimer's Disease and Vascular Dementia. Curr Alzheimer Res. 2013 Apr 29; PubMed.
  2. . High blood pressure effects on the blood to cerebrospinal fluid barrier and cerebrospinal fluid protein composition: a two-dimensional electrophoresis study in spontaneously hypertensive rats. Int J Hypertens. 2013;2013:164653. PubMed.
  3. . Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia. Cardiovasc Psychiatry Neurol. 2012;2012:367516. PubMed.
  4. . Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons. Neurobiol Aging. 2012 Apr;33(4):827.e11-9. PubMed.

Primary Papers

  1. . Risk Factors for β-Amyloid Deposition in Healthy Aging: Vascular and Genetic Effects. JAMA Neurol. 2013 May 1;70(5):600-6. PubMed.