Can Arterial Health Predict Amyloid Deposition?

In case you needed it, here’s another incentive to take good care of your cardiovascular system. In the March 31 JAMA Neurology, researchers led by Timothy Hughes at Wake Forest School of Medicine, Winston-Salem, North Carolina, reported that hardening of the arteries correlates with amyloid load in the brain. In a small longitudinal study of cognitively healthy people over 80, those with the stiffest arteries had the most brain Aβ at baseline and also deposited the most amyloid over the next two years. Further research will be needed to elucidate this relationship. One possibility is that disrupted blood flow in the brain slows the clearance of Aβ. “This data tells us that we need to look more closely at vascular factors and how they might relate to amyloid deposition and clearance,” Hughes told Alzforum.

Other researchers agreed the new data represent a significant finding. “We’re building a case that there is a profound pathogenic interaction between the health of brain blood vessels and the accumulation of Aβ,” said Costantino Iadecola at Weill Medical College of Cornell University, New York City. “The next step is to determine the basis for this and to develop approaches to counteract it.”

Many epidemiological studies have linked heart disease with Alzheimer’s risk (see Qiu et al., 2010; Whalley 2012). For example, hypertension in midlife heightens the odds of developing AD, although this association disappears in older people (see AlzRisk analysis; Jun 2011 news story). The advent of amyloid imaging now allows researchers to correlate cardiovascular and amyloid changes in living people in an attempt to move beyond epidemiology and tease out the timing and contribution of different vascular factors.

One such factor is elasticity in blood vessels. Arterial hardening worsens with age. The large arteries near the heart are affected first. As they lose their ability to expand and smooth out variations in blood pressure, small peripheral arteries receive a more intense pounding with each beat of the heart. Over time, these forces can damage small vessels and lead to ischemia in surrounding tissue. The brain, with its high blood flow, may be particularly vulnerable (see O’Rourke and Safar, 2005). Intriguingly, high arterial stiffness associates with cognitive decline in several epidemiological studies (see Watson et al., 2011; Benetos et al., 2012; Zeki et al., 2013), suggesting that it might be a risk factor for AD.  

Hughes and colleagues wondered if arterial stiffness might correlate with Alzheimer’s pathology as well. Previously, the authors had looked at baseline arterial stiffness and amyloid load in a group of 81 nondemented people who were 83 or older and had participated in the Ginkgo Evaluation of Memory (GEM) study. To determine the degree of stiffening, the researchers measured how quickly a pressure wave traveled from one artery to another at a distant site in the body. The harder the arteries, the higher the pulse wave velocity. Brain amyloid levels were assessed using PiB-PET. The authors found that people with a high degree of arterial stiffness, as measured between the arm and ankle, were twofold likelier to have brain amyloid than those with more elastic vessels (see Hughes et al., 2013). 

For the current study, the same group of participants underwent a second amyloid scan two years after the first. The association between arterial stiffness and brain amyloid strengthened. Those with the greatest arm-to-ankle stiffness were threefold likelier to have brain amyloid at follow-up. In addition, participants who had the stiffest arteries in the torso accumulated the most additional Aβ over the two years of the study. Many of those with central stiffness started out negative for Aβ, but most became positive. While the findings do not prove that arterial hardening causes amyloid build-up, they do establish that stiffening can precede Aβ deposition, Hughes noted.

It is unclear why central rigidity predicted future accumulation, while systemic stiffness better reflected the current amyloid load. The data may indicate that central hardening drives the disease, which would fit with the known role of these arteries in determining pressure throughout the vasculature and particularly in the brain, Hughes said. Alternatively, the difference may represent a statistical anomaly in this small cohort. Systemic stiffness trended close to significance for amyloid progression, and when the authors analyzed the data using a more rigorous cutoff for Aβ positivity, central stiffness correlated with amyloid load.

In future work, Hughes will attempt to replicate the finding in independent cohorts at different age ranges. He is particularly interested in whether people in their 50s who have arterial stiffening deposit more Aβ in the brain than those with more elastic vessels. If so, arterial stiffness might be a useful biomarker. So far, it demonstrates a more consistent relationship with Alzheimer’s disease than does hypertension. Since vascular hardening and blood pressure are closely related, this divergence is puzzling, noted Kevin King at the University of Texas Southwestern Medical Center, Dallas, in an accompanying JAMA Neurology editorial. The explanation might be that in older people, blood pressure measured at the arm poorly reflects elevated central pressure, whereas pulse wave velocities capture the deterioration in these vessels, King suggested.

How might vascular hardening and Aβ relate to each other? Disruptions in brain blood flow may prevent the clearance of Aβ through the perivascular space, which has been shown to be an important elimination route (see Carare et al., 2008; Aug 2012 news story). “Our group has demonstrated that interstitial fluid and solutes are cleared from the brain by bulk flow along the basement membranes of capillary and artery walls. … The work by Timothy Hughes and colleagues provides substantive evidence to our experimental results,” Roxana Carare and Roy Weller at the University of Southampton, U.K., wrote to Alzforum (see full comment below). To take a closer look at the vascular dynamics, Hughes will measure brain blood flow using MRI and transcranial Doppler in future studies.

Alternatively, there may be no direct causal relationship, and instead some third factor, for example a hormone, affects both arterial stiffness and brain amyloid. Intriguingly, while arterial stiffness can cause lesions around blood vessels, this form of brain damage was unrelated to Aβ deposits in the current study. This agrees with other research that showed no correlation between vascular damage and amyloid (see Feb 2013 news story). 

Although the mechanism remains to be determined, the data suggest that improving vessel elasticity could slow Aβ accumulation. No approved medications directly target elasticity, although some classes of antihypertensive drugs, such as angiotensin receptor blockers (ARBs) and calcium channel blockers, have been shown to relax arteries (see Dudenbostel and Glasser, 2012). Intriguingly, ARBs have been found to reduce amyloid deposition (see Sep 2012 news story), and a calcium channel blocker has been found to slow cognitive decline (see Jul 2011 news story). Ideally, more specific drugs for improving elasticity should be developed and tested in clinical trials along with existing antihypertensive drugs, said Simon Rabkin at the University of British Columbia, Vancouver. 

In the meantime, the best way to improve vascular tone is through exercise and other lifestyle interventions. Blood vessels are sensitive to insulin, and diabetics tend to have stiffer arteries, Hughes noted. Studies suggest exercise reduces whereas diabetes increases Alzheimer’s risk. Lowering vascular risk factors has been shown to slow amyloid deposition and ward off cognitive decline (see Deschaintre et al., 2009; Jul 2011 news story; May 2013 news story), and has been credited with a drop in dementia incidence in recent years (see May 2013 news story; Jul 2013 news story).—Madolyn Bowman Rogers

Comments

  1. Our group has demonstrated that interstitial fluid and solutes are cleared from the brain by bulk flow along the basement membranes of capillary and artery walls, analogous to the lymphatics of other organs (1). In aging, fibrils of amyloid accumulate in the basement membranes of cerebral arteries as cerebral amyloid angiopathy (CAA), suggesting that with increasing age there is a failure of elimination of solutes such as Aβ from the central nervous system (2, 3). The work by Timothy Hughes and colleagues provides substantive evidence to our experimental results, demonstrating that arterial stiffness measured by pulse wave velocity correlates with the accumulation of Aβ in the brain, increasing with age. Our mathematical models suggest that pulsations together with biochemical interactions provide the biophysical force necessary for the clearance of Aβ along the cerebrovascular basement membranes (4, and Keith Sharp et al., submitted). Despite the relatively small numbers of patients assessed in the study by Hughes and colleagues, it provides the rationale for assessing markers of peripheral arterial elasticity or stiffness as early biomarkers for the onset and progression of dementia.

    References:

    Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, Weller RO. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008 Apr;34(2):131-44. Epub 2008 Jan 16 PubMed.

    Hawkes CA, Gatherer M, Sharp MM, Dorr A, Yuen HM, Kalaria R, Weller RO, Carare RO. Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Aging Cell. 2013 Apr;12(2):224-36. PubMed.

    Carare RO, Hawkes CA, Jeffrey M, Kalaria RN, Weller RO. Cerebral amyloid angiopathy, Prion angiopathy, CADASIL and the spectrum of Protein Elimination-Failure Angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol Appl Neurobiol. 2013 Mar 13; PubMed.

    Schley D, Carare-Nnadi R, Please CP, Perry VH, Weller RO. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol. 2006 Feb 21;238(4):962-74. PubMed.

    View all comments by Roy Weller

  2. The study by Hughes and colleagues highlights the utility of longitudinal amyloid imaging and pulse wave velocity (PWD) to measure arterial stiffness. By capitalizing on the relatively consistent age-related upward trajectory of PWD, the authors demonstrate that arterial stiffness is dynamically associated with increasing amyloid aggregation. Simply put, this article suggests that arterial stiffness is not just related to the amount of Aβ in the brain, but also the rate of Aβ aggregation. Many participants had significant Aβ deposition prior to measurement of PWD; therefore determining the initiating variable, Aβ or arterial stiffness, cannot be done. Nonetheless these findings are exciting because they take us a step further in explaining how specific components of the vascular system, i.e. central and peripheral measures of arterial stiffness, may be associated with Aβ deposition.

    View all comments by Natalie Marchant
    • User Profile Image Ivan Maksimovich
      Clinic of Cardiovascular Diseases named after Most Holy John Tobolsky
    • Posted:

    This extremely interesting research points out the existence of a close correlation between capillary and microcirculatory blood flow in the brain and the process of amyloid accumulation in the cerebral tissue. The authors say that the deterioration of capillary blood flow enhances the deposition of amyloid in the cerebral tissue. These studies confirm our earlier work [1, 2, 3] that showed the presence of dyscirculatory angiopathy of Alzheimer's type (DAAT) in patients with AD, which leads to serious disorders of capillary blood flow in the brain and not only promotes the accumulation of Aβ in the cerebral tissue but also reduces its excretion, which was noted by Professor B. Zlokovic as well [4]. 

    References:

    Maksimovich IV. Dyscirculatory Angiopathy of Alzheimer's Type. J Behav Brain Sci 2011;1(2):57-68.

    Maksimovich IV. Vascular factors in Alzheimer’s disease. Health. 2012 Sep; 4(9A):735-42.

    Maksimovich IV. Disorders of cerebrovascular angioarchitectonics and microcirculation in the etiology and pathogenesis of Alzheimer’s disease. Adv Alzheimer Dis. 2013 Dec;(2)4:171-181.

    Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011 Dec;12(12):723-38. PubMed.

    View all comments by Ivan Maksimovich

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References

News Citations

  1. AlzRisk Adds Fifth Factor to Database: Meta-Analysis of Hypertension
  2. Brain Drain—“Glymphatic” Pathway Clears Aβ, Requires Water Channel
  3. Vascular Dementia or Alzheimer’s: Is the Delineation Emerging?
  4. Can Blood Pressure Drug Put the Squeeze on Brain Amyloid?
  5. Search for AD Drugs Turns to a Hypertension Medicine
  6. Exercise and the Brain: More Support for Protective Effects
  7. Controlling Blood Pressure May Lower Amyloid in ApoE4 Carriers
  8. Dementia Incidence Said to Drop as Public Health Improves
  9. Dementia Prevalence Falls in England

Paper Citations

  1. Qiu C, Xu W, Fratiglioni L. Vascular and psychosocial factors in Alzheimer's disease: epidemiological evidence toward intervention. J Alzheimers Dis. 2010;20(3):689-97. PubMed.
  2. Whalley LJ. Spatial distribution and secular trends in the epidemiology of Alzheimer's disease. Neuroimaging Clin N Am. 2012 Feb;22(1):1-10, vii. PubMed.
  3. O'Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension. 2005 Jul;46(1):200-4. Epub 2005 May 23 PubMed.
  4. Watson NL, Sutton-Tyrrell K, Rosano C, Boudreau RM, Hardy SE, Simonsick EM, Najjar SS, Launer LJ, Yaffe K, Atkinson HH, Satterfield S, Newman AB. Arterial stiffness and cognitive decline in well-functioning older adults. J Gerontol A Biol Sci Med Sci. 2011 Dec;66(12):1336-42. Epub 2011 Jul 18 PubMed.
  5. Benetos A, Watfa G, Hanon O, Salvi P, Fantin F, Toulza O, Manckoundia P, Agnoletti D, Labat C, Gautier S, PARTAGE Study Investigators. Pulse wave velocity is associated with 1-year cognitive decline in the elderly older than 80 years: the PARTAGE study. J Am Med Dir Assoc. 2012 Mar;13(3):239-43. Epub 2010 Oct 20 PubMed.
  6. Zeki Al Hazzouri A, Newman AB, Simonsick E, Sink KM, Sutton Tyrrell K, Watson N, Satterfield S, Harris T, Yaffe K, Health ABC Study. Pulse wave velocity and cognitive decline in elders: the Health, Aging, and Body Composition study. Stroke. 2013 Feb;44(2):388-93. Epub 2013 Jan 15 PubMed.
  7. Hughes TM, Kuller LH, Barinas-Mitchell EJ, Mackey RH, McDade EM, Klunk WE, Aizenstein HJ, Cohen AD, Snitz BE, Mathis CA, Dekosky ST, Lopez OL. Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults. Neurology. 2013 Nov 5;81(19):1711-8. Epub 2013 Oct 16 PubMed.
  8. Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, Weller RO. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008 Apr;34(2):131-44. Epub 2008 Jan 16 PubMed.
  9. Dudenbostel T, Glasser SP. Effects of antihypertensive drugs on arterial stiffness. Cardiol Rev. 2012 Sep-Oct;20(5):259-63. PubMed.
  10. Deschaintre Y, Richard F, Leys D, Pasquier F. Treatment of vascular risk factors is associated with slower decline in Alzheimer disease. Neurology. 2009 Sep 1;73(9):674-80. PubMed.

External Citations

  1. AlzRisk analysis
  2. exercise
  3. diabetes

Further Reading

Primary Papers

  1. Hughes TM, Kuller LH, Barinas-Mitchell EJ, McDade EM, Klunk WE, Cohen AD, Mathis CA, Dekosky ST, Price JC, Lopez OL. Arterial stiffness and β-amyloid progression in nondemented elderly adults. JAMA Neurol. 2014 May;71(5):562-8. PubMed.
  2. King KS. Arterial stiffness as a potential determinant of β-amyloid deposition. JAMA Neurol. 2014 May;71(5):541-2. PubMed.

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