Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains

Douglas M. Zeppenfeld, Matthew Simon, J. Douglas Haswell, Daryl D'Abreo, Charles Murchison, Joseph F. Quinn, Marjorie R. Grafe, Randall L. Woltjer, Jeffrey Kaye, Jeffrey J. Iliff

Research output: Contribution to journalArticlepeer-review

275 Scopus citations


IMPORTANCE Cognitive impairment and dementia, including Alzheimer disease (AD), are common within the aging population, yet the factors that render the aging brain vulnerable to these processes are unknown. Perivascular localization of aquaporin-4 (AQP4) facilitates the clearance of interstitial solutes, including amyloid-β, through the brainwide network of perivascular pathways termed the glymphatic system, which may be compromised in the aging brain. OBJECTIVES To determine whether alterations in AQP4 expression or loss of perivascular AQP4 localization are features of the aging human brain and to define their association with AD pathology. DESIGN, SETTING, AND PARTICIPANTS Expression of AQP4was analyzed in postmortem frontal cortex of cognitively healthy and histopathologically confirmed individuals with AD by Western blot or immunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidic protein. Postmortem tissue and clinical data were provided by the Oregon Health and Science University Layton Aging and Alzheimer Disease Center and Oregon Brain Bank. Postmortem tissue from 79 individuals was evaluated, including cognitively intact "young" individuals aged younger than 60 years (range, 33-57 years), cognitively intact "aged" individuals aged older than 60 years (range, 61-96 years) with no known neurological disease, and individuals older than 60 years (range, 61-105 years) of age with a clinical history of AD confirmed by histopathological evaluation. Forty-eight patient samples (10 young, 20 aged, and 18 with AD) underwent histological analysis. Sixty patient samples underwentWestern blot analysis (15 young, 24 aged, and 21 with AD). MAIN OUTCOMES AND MEASURES Expression of AQP4 protein, AQP4 immunoreactivity, and perivascular AQP4 localization in the frontal cortex were evaluated. RESULTS Expression of AQP4 was associated with advancing age among all individuals (R2 = 0.17; P = .003). Perivascular AQP4 localization was significantly associated with AD status independent of age (OR, 11.7 per 10% increase in localization; z = -2.89; P = .004) and was preserved among eldest individuals older than 85 years of age who remained cognitively intact. When controlling for age, loss of perivascular AQP4 localization was associated with increased amyloid-β burden (R2 = 0.15; P = .003) and increasing Braak stage (R2 = 0.14; P = .006). CONCLUSIONS AND RELEVANCE In this study, altered AQP4 expression was associated with aging brains. Loss of perivascular AQP4 localization may be a factor that renders the aging brain vulnerable to the misaggregation of proteins, such as amyloid-β, in neurodegenerative conditions such as AD.

Original languageEnglish (US)
Pages (from-to)91-99
Number of pages9
JournalJAMA Neurology
Issue number1
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Clinical Neurology


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