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White Matter Hyperintensities and Alzheimer's Pathology Are Associated with Risk for Cognitive Impairment

Article In Brief

White matter hyperintensities (WMH) primarily affect the risk of progression to mild cognitive impairment (MCI) when cerebrospinal fluid (CSF) measures of neurodegeneration or neuronal injury are low. But CSF biomarkers of amyloid, phosphorylated-tau, and WMH appear to have an independent effect on the risk of progression to MCI.

Recent studies have supported the idea that a heavy burden of white matter hyperintensity (WMH) can contribute to an increased risk for dementia due to Alzheimer's disease (AD) or a faster progression once the disease has taken hold.

In a current analysis of longitudinal data from hundreds of older adults, however, investigators at Johns Hopkins University were not able to show a link between AD biomarkers and WMH and the risk of progression from normal cognition to mild cognitive impairment (MCI).

“We were interested in whether WMHs, a marker for small vessel cerebrovascular disease, were directly influencing cerebrospinal fluid (CSF) measures of amyloid and phosphorylated tau (p-tau), which are biomarkers of Alzheimer's disease,” said the lead study author Anja Soldan, PhD, assistant professor of neurology at the Johns Hopkins University School of Medicine.

“We thought we could use the longitudinal data from the BIOCARD study [which was launched by the National Institute of Mental Health (NIMH) in the 1990s] to see if people with more WMH were at greater risk for MCI and whether WMH load was linked to the levels of AD biomarkers we identified.”

Rather, the study, published in the December 30 online edition of Neurology, found that WMH primarily affects the risk of progression when CSF measures of neurodegeneration or neuronal injury are low. But CSF biomarkers of amyloid and p-tau and WMH appear to “have largely independent and non-synergistic effects on the risk of progression to MCI,” Dr. Soldan and her study coauthors wrote.


“If WMH plays a role in the progression of MCI, this association is independent of Abeta and p-tau pathology, and not synergistic.”—DR. ANJA SOLDAN

Study Design, Findings

The scientists set out to look at the relationship between whole brain WMH volume based on MRI images and biomarkers of AD pathology—amyloid beta (Abeta) and p-tau measured in CSF.

Seventy-five percent of participants—all considered cognitively fit at baseline—had a first-degree relative with AD. Following the baseline measures, NIMH scientists conducted annual cognitive testing of the study participants and collected their CSF, blood, and MRIs every two years. Recruitment began in 1995 and the study ran for a decade.

In 2009, scientists at Hopkins reinstated the study and began contacting study participants to see if they would be interested in continuing in the longitudinal study. At that time, 274 of the 317 study participants who had had CSF testing at baseline agreed to continue. The scientists had access to all of the original data and had both CSF and MRI data on 204 of the volunteers. In 2015, they added bi-annual PET amyloid and PET tau imaging two years later.

For the current study, the scientists used the longitudinal data to assess whether the volume of WMH and the CSF AD biomarkers for Abeta and p-tau had any relationship to the time-to-onset of MCI symptoms in 60 of the study volunteers. (The clinical assessments to determine MCI or dementia status were done annually at NIMH and Johns Hopkins. The mean time from baseline scan to symptom onset was 6.4 years.)

They looked at the baseline WMH load and its relationship to CSF Abeta or p-tau as well as total tau (t-tau) levels over several time points. T-tau is considered a biomarker for neurodegeneration or neuronal injury and is not specific to AD. They found that CSF Abeta or p-tau at baseline were associated with risk of symptom onset of MCI, independent of WMH load, which did not further increase the risk of symptom onset.

They also found that WMH load only predicted symptom onset of MCI when t-tau levels were low. When t-tau was high, WMH load was not associated with symptom onset. The changes in the CSF biomarkers over time were not associated with rates of change in the volume of the WMH, suggesting that WMH and AD pathology do not directly influence each other.

“If WMH plays a role in the progression of MCI, this association is independent of Abeta and p-tau pathology, and not synergistic,” Dr. Soldan said.

The scientists reported that participants who progressed to MCI were “older, had greater WMH volumes, lower CSF Abeta1–42 levels, higher CSF t-tau and p-tau levels at baseline, compared to those who remained cognitively normal.” They were also more likely to have high cholesterol and “showed a greater tendency for hypertension even though the overall rates of vascular risks were low.”

In the 60 study participants who progressed to MCI or dementia, 24 were thought to have vascular disease as a contributing cause of their MCI diagnosis. But even when they restricted the analysis to only these patients, they did not find that WMH volume was associated with the time-to-symptom onset, Dr. Soldan said. However, they did find an association between WMH burden and risk of progression to MCI proximal to symptom onset (within six years, although that was only in cases where t-tau levels were low).

“These findings suggest that small vessel cerebrovascular disease, as reflected in WMH volumes, increases the risk of progression to MCI when levels of neurodegeneration/neuronal injury are low (as reflected by t-tau levels),” the scientists wrote in the Neurology paper. “These findings are consistent with evidence demonstrating that vascular risks, such as hypertension, increase the likelihood of subsequent cognitive decline when present in mid-life, but not at older ages when levels of neurodegeneration/injury are likely to be higher.”

Dr. Soldan and her colleagues believe that both cerebral small vessel disease and AD pathology work independently to increase the risk for cognitive impairment.

Expert Commentary

By the 1990s scientists began to appreciate the relationships between the presence and severity of WMH and cognitive function, said Adam M. Brickman, PhD, professor of neuropsychology at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and in the department of neurology at the College of Physicians and Surgeons at Columbia University. Studies linking WMH with vascular risk factors, such as hypertension, and clinico-pathological studies suggested strongly that WMHs were ischemic in nature.

“The thinking is that in the context of aging WMH generally reflect the burden of small vessel ischemic disease,” Dr. Brickman said.

Scientists began asking whether WMH predict severity and progression of cognitive impairment and dementia. Dr. Brickman's work shed light on this complex relationship. “It would be hard to argue today that there is not a relationship between WMH severity and risk of dementia or cognitive impairment but the question of whether they are involved in AD specifically is still argued.”

In the DIAN study, which includes individuals with autosomal dominant forms of AD, Dr. Brickman and colleagues found increased WMH volume in posterior regions up to 20 years prior to the expected onset of clinical symptoms. Similarly, Dr. Brickman's laboratory has found increased WMH volume, particularly in posterior regions, among individuals with Down syndrome diagnosed clinically with dementia, which is notable because most adults with Down syndrome have AD pathology by their 40s and clinical symptoms of dementia by their 60s.

Dr. Brickman noted that WMHs are common in aging and “certainly [are] not diagnostic for AD but their examination points us to a more complete understanding of what the neurobiology of AD might be.”

“The scientific community generally agrees that WMHs have an overall negative effect on cognition but the level of risk imposed and mechanisms of increase risk remains debated,” said Julie A. Schneider, MD, an endowed professor of pathology and neurological sciences and associate director of the Rush Alzheimer's Disease Center at Rush University Medical Center.


“It would be hard to argue today that there is not a relationship between WMH severity and risk of dementia or cognitive impairment but the question of whether they are involved in AD specifically is still argued.”—DR. ADAM M. BRICKMAN

“In this study while persons who progressed to MCI/dementia tended to have higher WMH, it turned out that this was only true for those with low total CSF tau, which suggests low neurodegeneration.”

Dr. Schneider said that while the study was “nicely done with excellent statistical methodologies, good length of follow-up, and MRI and CSF markers, there are multiple caveats including the relatively small number [of participants], a wide age range (since effects may vary with age), low vascular risk levels not reflective of the general population, and high AD genetic risk, and that may also influence their findings.

“Also, it is important to note that WMHs are not specific for vascular tissue injury and the CSF markers are not equivalent to the actual amount of brain pathology,” she said, adding that “multiple other pathologies associated with AD could also be influencing results.”


Drs. Soldan, Brickman, and Schneider reported no competing interests.

Link Up for More Information

• Soldan A, Pettigrew C, Zhu Y, et al. White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease Neurology 2019; Epub 2019 Dec 30.
    • Roseborough A, Ramirez J, Black SE, Edwards JD. Associations between amyloid β and white matter hyperintensities: A systematic review Alzheimer's Dement 2017;13(10):1154–1167.
    • Marnane M, Al-Jawadi OO, Mortazavi S, et al. Periventricular hyperintensities are associated with elevated cerebral amyloid Neurology 2016;86(6):535–543.
    • Lee S, Viqar F, Zimmerman ME, et al; for the Dominantly Inherited Alzheimer Network. White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network Ann Neurol 2016;79(6):929–939.