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The Connection Between Alzheimer's and Small-Vessel Disease

Fitzgerald, Susan

doi: 10.1097/01.NT.0000451832.50347.5d
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Researchers provided new evidence of the association between Alzheimer's disease and vascular pathology, using measures of both amyloid and tau pathology in the CSF.

A new study from the Netherlands supports a theory that the physiological pathways of cerebral small-vessel disease (SVD) and Alzheimer's disease (AD) are interconnected, though it's not clear how the two may interact to cause cognitive decline and dementia.

“Cerebral small-vessel disease could provoke amyloid pathology, while Alzheimer's-associated cerebral amyloid pathology may lead to auxiliary vascular damage,” the study's lead author, Maartje Kester, MD, PhD, from the VU University Medical Center in Amsterdam, told Neurology Today.

The idea that SVD and AD may somehow be interrelated — despite their different presentations in the brain — is not new.

“Postmortem studies show a high prevalence of mixed pathology, especially in elderly populations,” according to background information in the study, which was published online May 12 in JAMA Neurology. “Many studies show cerebral small-vessel disease (SVD) and vascular risk factors increase the risk of developing AD, while in both vascular dementia and SVD, signs of AD pathology have been reported.”

“Our study confirms previous studies that found an association between amyloid pathology on PET scans and vascular damage on MRI,” Dr. Kester told Neurology Today in an e-mail. “Since we measured both amyloid and tau pathology in the CSF, we were able to show that the association between Alzheimer's and vascular pathology is mainly driven by amyloid pathology and not so much by tau pathology.”

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To further explore the connection, the researchers analyzed CSF samples and MRI scans from 914 patients who are part of the Amsterdam Dementia Cohort. Of those, 547 were patients diagnosed with AD, 30 had a diagnosis of vascular dementia, and 337 were control participants with subjective memory complaints.



MRI scans were evaluated for the presence of microbleeds, white matter hyperintensities, and lacunes. CSF samples were analyzed for levels of three AD biomarkers: amyloid-beta-42 (Abeta-42), total tau, and tau phosphorylated at threonine 181 (P-tau 181). Apolipoprotein e4 (APOE-e4) genotyping information was conducted on a subset of 861 patients — 327 controls, 501 AD patients, and 27 patients with vascular dementia — and they were classified as APOE e4 carriers or noncarriers.

Among their findings, the investigators wrote, the presence of both microbleeds (MBs) and white matter hyperintensities was associated with lower CSF levels of Abeta42, indicating a direct relationship between SVD and AD pathology. “Amyloid pathology appears aggravated in patients with vascular damage, which supports pathophysiological synergy. In control participants, tau levels were elevated in the presences of MBs, which could indicate that this increase of tau is a result of neuronal cell death in patients not diagnosed as having AD.”

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The analysis found that the associations between SVD and AD were strongest in patients who were APOE e4 carriers.

“Deposition of amyloid appears aggravated in patients with cerebral small-vessel disease, especially in apolipoprotein E e4 carriers, providing evidence for pathophysiological synergy between these three biological factors,” the researchers wrote.

Dr. Kester offered several possible explanations. “A possible mechanism for this synergy could be that ischemic changes accelerate the rate of amyloid deposition, while vessel wall stiffness, as seen in cerebral small-vessel disease, may impair perivascular drainage of cerebral amyloid, both leading to more deposition,” Dr. Kester said.

“Conversely, vascular amyloid (cerebral amyloid angiopathy), which is commonly seen in Alzheimer's disease and associated with parenchymal amyloid, may lead to ischemic vascular events in the brain, like white matter hyperintensities, microinfarcts, and also microbleeds. It seems that this mechanism of synergy is up-regulated in APOE-e4 carriers,” she said.

The researchers noted that lacunes “seem to reflect a different type of pathology.”

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David S. Knopman, MD, FAAN, a professor of neurology at Mayo Clinic in Rochester, MN, said the study is notable because it includes a large sample of patients with CSF and imaging data, but it would be premature or even wrong to conclude from the findings that a causal link exists between SVD and AD. “I would be very cautious in interpreting these rather complex results,” he told Neurology Today.

Dr. Knopman said the diagnosing of SVD dementia and AD is not always accurate; it's possible that patients with SVD in the study also had AD, blurring distinctions between the two groups. Also, patients with white matter hyperintensities don't necessarily have SVD, he added, noting that neurodegeneration is also linked to the hyperintensities.

“The one thing established in the literature is that when people have both cerebrovascular disease and Alzheimer's, they tend to do worse clinically,” Dr. Knopman said. “The two are additive symptomatically.”

More research is needed to understand the interplay between the two diseases, according to Dr. Knopman. “Whether the interaction occurs at the cellular levels or whether the interaction occurs in worsening symptoms doesn't change the importance of the overlap of the two,” he said.

Anand Viswanathan, MD, PhD, an assistant professor of neurology at Massachusetts General Hospital and Harvard Medical School, said while the new study is “very interesting and adds another piece to the puzzle,” it could be oversimplifying the complexity of what's occurring in the brain.

“It may not be a simple relationship between small-vessel disease and Alzheimer disease,” said Dr. Viswanathan, director of telestroke services at Massachusetts General Hospital and a physician with the Massachusetts Alzheimer's Research Center. “The association of Abeta-42 levels with microbleeds and white matter hyperintensities, known markers of cerebral amyloid angiopathy, may suggest that vascular amyloid deposition is also playing a role in some of these patients.”

He said that although the study did not have immediate clinical relevance, “clinicians may want to keep in mind that different forms of small-vessel disease and AD are not mutually exclusive. They can coexist in patients and that may actually make cognition worse.”

Dr. Kester, who is a resident in neurology, said that her research team is now focusing on microbleeds and white matter hyperintensities and their impact in AD dementia.

“We are examining mortality risk in Alzheimer's disease patients with microbleeds, which seems increased compared to those without microbleeds,” Dr. Kester said.

The Dutch team noted in its conclusions that the connection between SVD and AD should be taken into consideration in clinical trials.

“Treatment trials for vascular risk factors should take amyloid reduction into account, especially in APOE e4 carriers,” they wrote. “Evaluation of effects of amyloid-reducing therapies like immune-directed therapies should be stratified for the presence of microbleeds and white matter hyperintensities, and not only as safety measure, as effects of amyloid reduction could be affected by the presence of SVD pathology.”

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•. Kester MI, Goos JDC, Teunissen CE, et al. Associations between cerebral small-vessel disease and Alzheimer disease pathology as measured by cerebrospinal fluid biomarkers. JAMA Neurology 2014; E-pub 2014 May 12.
    •. Neurology archive on small vessel disease and Alzheimer's:
      © 2014 American Academy of Neurology