Alzheimer's Disease & Dementia
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Alzheimer’s Disease—Failure of Drainage of Fluid from the Brain

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Published Online: Feb 16th 2018 US Neurology. 2018;14(1):21–22 DOI:
Authors: Roxana Carare
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Article Information

The annual Alzheimer’s Association International Conference (AAIC) took place in London, UK in July 2017. In an expert interview, Roxana Carare recaps on the topic of her presentation during the ‘Emerging Concepts in Basic Science’ session, clearance of interstitial fluid of the brain and pathogenesis of dementia.1


Alzheimer’s disease, amyloid-beta (Aβ), cerebral
amyloid angiopathy, intramural periarterial
drainage (IPAD), interstitial fluid (ISF)


Q. How is soluble amyloid-beta cleared from the brain in healthy individuals?

Amyloid-beta (Aβ) is produced in all brains, as it is key to the maintenance of brain health. Normally Aβ is broken down by enzymes2 and eliminated across the walls of the blood vessels into the blood,3 or is removed by intramural periarterial drainage (IPAD), described by the Carare group.4 Enzymes and transporters of Aβ5 into the blood fail with increasing age and with other risk factors for Alzheimer’s disease, so the burden of removing Aβ via IPAD from aging brains is increased. IPAD takes place along tiny channels (vascular basement membranes, composed of extracellular matrix) in the walls of arteries that supply blood to the brain.6

Q. How does this process change in Alzheimer's disease?

The direction of IPAD is opposite to that of blood flow and relies on the contraction of smooth muscle cells to function properly.7 With aging, high blood pressure and high cholesterol in midlife, diabetes and obesity, the arteries become stiffer and smooth muscle cells do not contract properly (Figure 1).8–10 This leads to a poor perfusion of the brain with blood, as well as reduced clearance of Aβ from the brain.11 A failure of efficient drainage of Aβ and other proteins from the aging brain results in their deposition in the walls of blood vessels as sticky plaques, giving rise to cerebral amyloid angiopathy, a key feature of Alzheimer’s disease (Figure 2).12

Q. What lifestyle factors might affect protein clearance?

Prevention or early treatment of metabolic diseases such as diabetes, high cholesterol, high blood pressure, low vitamin B and maintaining a healthy heart should also maintain healthy blood vessels in the brain, preventing Alzheimer’s disease.13–15

Q. What therapeutic strategies may help the clearance of Aβ from the brain?

There are already promising experimental studies demonstrating that compounds that increase the activity of the smooth muscle cells of blood vessels are able to reverse the features of Alzheimer’s disease. Such compounds (for example cilostazol, a selective phosphodiesterase type 3 inhibitor in clinical trials in Japan and Edinburgh, UK) are able to slow the progression from mild cognitive impairment to full blown Alzheimer’s disease.16,17

Article Information:

Roxana Carare has nothing to declare in
relation to this article.

Review Process

This is an expert interview and
as such, has not undergone the journal’s standard
peer review process.


The named author meets the International
Committee of Medical Journal Editors (ICMJE) criteria
for authorship of this manuscript, takes responsibility
for the integrity of the work as a whole, and has given
final approval for the version to be published.


Roxana Carare, Faculty of
Medicine, Institute for Life Sciences, University of
Southampton, Southampton General Hospital, South
Academic Block, MP806, Tremona Road, Southampton,
Hampshire, SO16 6YD, UK. E:
Facebook: @unisouthamptonmedicine


No funding was received in
the publication of this article.


This article is published under the Creative
Commons Attribution Noncommercial License, which
permits any noncommercial use, distribution, adaptation,
and reproduction provided the original author(s) and source
are given appropriate credit. © The Author(s) 2018.




  1. Carare RO. EC-01-01 Clearance of interstitial fluid of the brain and pathogenesis of dementia. Alzheimers Dement. 2017;13 Suppl. P180.
  2. Farris W, Schütz SG, Cirrito JR, et al. Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. Am J Pathol. 2007;171:241–51.
  3. Deane R, Wu Z, Sagare A, et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron. 2004;43:333–44.
  4. Carare RO, Bernardes-Silva M, Newman TA, et al. 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;34:131–44.
  5. Tarasoff-Conway JM, Carare RO, Osorio RS, et al. Clearance systems in the brain – implications for Alzheimer disease. Nat Rev Neurol. 2016;12:248.
  6. Morris AW, Sharp MM, Albargothy NJ, et al. Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Acta Neuropathol. 2016;131:725–36.
  7. Diem AK, MacGregor Sharp M, Gatherer M, et al. Arterial pulsations cannot drive intramural periarterial drainage: significance for Ab drainage. Front Neurosci. 2017;11:475.
  8. Hawkes CA, Gatherer M, Sharp MM, et al. Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-b from the mouse brain. Aging Cell. 2013;12:224–36.
  9. Bueche CZ, Hawkes C, Garz C, et al. Hypertension drives parenchymal b-amyloid accumulation in the brain parenchyma. Ann Clin Transl Neurol. 2014;1:124–9.
  10. Hawkes CA, Gentleman SM, Nicoll JA, Carare RO. Prenatal high-fat diet alters the cerebrovasculature and clearance of b-amyloid in adult offspring. J Pathol. 2015;235:619–31.
  11. Weller RO, Hawkes CA, Carare RO, Hardy J. Does the difference between PART and Alzheimer's disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Ab and propagation of tau? Acta Neuropathol. 2015;129:763–6.
  12. Hawkes CA, Jayakody N, Johnston DA, et al. Failure of perivascular drainage of b-amyloid in cerebral amyloid angiopathy. Brain Pathol. 2014;24:396–403.
  13. Hainsworth AH, Yeo NE, Weekman EM, Wilcock DM. Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID). Biochim Biophys Acta. 2016;1862:1008–17.
  14. Mukaetova-Ladinska EB, Purshouse K, Andrade J, et al. Can healthy lifestyle modify risk factors for dementia? Findings from a pilot community-based survey in Chennai (India) and Newcastle (UK). Neuroepidemiology. 2012;39:163–70.
  15. Paillard-Borg S, Fratiglioni L, Xu WL, et al. An active lifestyle postpones dementia onset by more than one year in very old adults. J Alzheimers Dis. 2012;31:835–42.
  16. Maki T, Okamoto Y, Carare RO, et al. Phosphodiesterase III inhibitor promotes drainage of cerebrovascular b-amyloid. Ann Clin Transl Neurol. 2014;1:519–33.
  17. Saito S, Ihara M. New therapeutic approaches for Alzheimer's disease and cerebral amyloid angiopathy. Front Aging Neurosci. 2014;6:290.

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