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Alzheimer's and Cerebral Small Vessel Disease Processes Worsen Cognition Independently Prior to Dementia

Article In Brief

A new paper finds that the deleterious effect of amyloid-beta on cognition worsened when white matter hyperintensities were also present. The findings underscore an associated but synergistically independent interaction between cerebral small-vessel disease and Alzheimer's disease.

Alzheimer's disease(AD) and cerebral small vessel disease appear to affect cognition independently and perhaps synergistically in the pre-dementia stage, according to an observational study published in the October 12 online edition of Neurology.

The study, involving 186 patients at a memory clinic, found that those with cognitive impairment but no dementia (CIND) displayed a significant interaction between the volume of white matter hyperintensities (WMHs) and a measure of global brain amyloid-beta (Abeta) in regard to their performance on the Mini-Mental State Examination (MMSE). That is, the deleterious effect of Abeta on cognition worsened when WMHs were also present.

Predictably, the study also found that an increase in that measure of Abeta, the [11C]-PiB-PET global standardized uptake value ratio (SUVR), was associated with a lower score on the MMSE in both CIND and frank Alzheimer's disease.

Only during CIND, however, did the research team observe significant interaction between global Abeta levels and the volume of WMHs in relation to patients' performance on the MMSE (p for interaction: 0.009). The harmful effect size of Abeta nearly doubled when calculated as interacting with WMHs (β=-6.03(1.50), p<0.001) compared with the model without the interaction (β =-2.57(0.80), p =0.002).

“We propose that the negative effect of brain Aβ on MMSE when co-occurring with severe WMH might be caused by damage to the functional and/or structural connectivity network in the subcortical white matter,” the research team concluded.

The senior author of the study, Christopher Chen, MD, director of the Memory & Cognition Centre at the Yong Loo Lim School of Medicine at National University of Singapore, told Neurology Today that previous studies evaluating the relationship of Abeta and cerebral small vessel disease (CSVD) on cognition have shown conflicting results. Most studies have failed to find a relationship between brain Abeta and WMH, while a few have “reported that higher brain Abeta was correlated with higher WMH, which we have confirmed and extended,” he said.

“Only one study showed an interaction between brain Abeta and WMH on cognition in individuals with small vessel disease and mild cognitive impairment (MCI), which we have now also shown in CIND, which includes subjects with MCI.”

Neurologists and others who have published related studies said they look forward to seeing larger, multicenter trials designed to further explore the relationships observed by Dr. Chen and colleagues.

“This study finds a statistical interaction between cerebral small-vessel disease and Alzheimer's disease,” said James Meschia, MD, FAAN, professor and chair of neurology at the Mayo Clinic in Jacksonville, FL. “But the statistical interaction does not prove that cerebral small vessel disease and Alzheimer's disease are tightly, mechanistically linked. We would need evidence beyond observational studies to prove a mechanistic link.”

Even so, the first author of a recent paper in Nature on cognitive decline in patients with APOE4 said he found the new results compelling.

“They show that amyloid and the vascular pathways are independent,” said Axel Montagne, PhD, associate professor of research physiology and neuroscience and assistant director of the Functional Biological Imaging Core at the Keck School of Medicine at the University of Southern California.

“Some people have believed that amyloid is driving the vascular disease,” Dr. Montagne said. “The authors of the current study show that there are two different processes. It is helping us enter a new era, where we see that amyloid is not the only factor, that the vascular component is important too.”


“Only one study showed an interaction between brain Abeta and WMH on cognition in individuals with small vessel disease MCI, which we have now also shown in CIND, which includes subjects with MCI.”—DR. CHRISTOPHER CHEN

Study Details

The current study sought to address limitations of the current literature, which tends to under-represent participants with mixed pathology in favor of those with either pure brain Abeta or purely vascular disease.

“This categorization into pure groups might result in masking of possible interaction effects between Aβ and CSVD,” the paper noted. “Moreover, pure groups are not representative of the actual population of individuals with cognitive impairment, since it has been shown that up to 47 percent of demented individuals have mixed pathologies rather than pure disease.”

Therefore, Dr. Chen said, “In this study, we used a memory clinic population with mixed pathology and a wide spectrum of cognitive impairment.”

Using a case-control design involving 186 individuals from an ongoing memory clinic study at the National University Hospital in Singapore, the study sought to evaluate the association between brain Abeta as identified by PET imaging and individual markers of CSVD (including WMH, lacunes and cerebral microbleeds), and their joint effect on cognition.

The 29 controls had no evidence of neuropsychological deficits or any functional loss. Cases were categorized as either CIND (n= 101), Alzheimer's dementia (n=36), or vascular dementia (n= 20).

Neither microbleeds nor lacunes interacted with Abeta at any stage, the study authors reported, perhaps because the median count of lacunes was zero for all patient groups except those with diagnosed vascular dementia, while the median count of microbleeds was zero for controls and those with CIND, and just one for those with either type of dementia.

“The discrepancy between our results [on microbleeds] and previous literature,” the paper stated, “may be due to a very strict selection in previous literature of either brain Aβ negative individuals with subcortical vascular cognitive impairment or healthy controls.”

Why did WMHs increase the adverse effect of Abeta on cognition only during the CIND stage, and not when the disease process has reached frank dementia? Dr. Chen said: “The interaction may not be present in dementia as either amyloid (in AD) or WMH (in vascular dementia) becomes the predominant driver of cognitive impairment.”

In any case, Dr. Chen said, “patients with WMH are at higher risk and targeting such high-risk subjects may be beneficial. I advise my patients with WMH that they are at higher risk of stroke and dementia, hence they should control their vascular risk factors.”

Expert Commentary

Steven M. Greenberg, MD, PhD, FAAN, the John J. Conway chair of neurology at Harvard Medical School and director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital, said: “The results from the study are consistent with the now well supported idea that the combination of cerebral small vessel disease (as measured by white matter hyperintensity volume) and amyloid pathology (measured by amyloid PET) cause greater symptoms than either alone, possibly to a greater than additive extent.”

Dr. Greenberg added: “This idea underscores the importance of treating vascular risk factors to improve brain health and reduce age-related cognitive decline. It remains unclear if other markers of cerebral small vessel disease beyond white matter hyperintensity volume might capture the small vessel contribution to brain dysfunction even more accurately.”

Dr. Meschia said it was important to not overstate the clinical implications of the observational findings. “Using PiB, the investigators found that overall Abeta deposition seemed to result in worse cognition in those with white matter hyperintensities in the CIND group. They jump from that to saying therefore, in the preclinical phases of Alzheimer's disease, that white matter should be targeted for preventing cognitive dysfunction. They interpret this interaction as being mechanistic.”

In Dr. Meschia's view, “The clinical thing that matters is not so much whether there is a statistical interaction between cerebral small-vessel disease and Abeta deposition but whether you can stave off dementia by altering these processes.”

“From the SPRINT MIND study, we know that tight blood-pressure control can significantly reduce the rate of white matter disease progression,” he added. “More importantly, tight blood pressure control can significantly reduce the rate of cognitive decline as well. There also appears to be evidence from clinical trials that statin treatment can reduce the accrual of covert ischemic lesions on neuroimaging. So, two techniques, lowering blood pressure and statin therapy, seem to help slow down the cerebrovascular journey to dementia.”


“The clinical thing that matters is not so much whether there is a statistical interaction between cerebral small-vessel disease and beta-amyloid deposition but whether you can stave off dementia by altering these processes.”—DR. JAMES MESCHIA

Dr. Montagne said the findings of the Neurology paper were consistent with those reported in his April 29 study in Nature. He found that APOE4, which puts people at increased risk of developing Alzheimer's disease, is associated with a breakdown in the blood-brain barrier (BBB).

“We found that even in cognitively normal people carrying one APOE4 allele, they have vascular dysfunction that predicts future cognitive decline,” Dr. Montagne said.

He said he hoped future studies by Dr. Chen's group will look at APOE4 as a covariate, as well as at tau levels and CSF biomarkers of cognitive decline. He also expressed interest in measures of Abeta in regions of interest in the brain rather than only globally.

Regarding the reported significance of WMH, Dr. Montagne said, “We have similar findings, where we really associate WMH with a change in the BBB, causing permeability to increase.”

Dr. Montagne's studies have led him to conclude that a leaky BBB is an early covert cause of both vascular and Alzheimer's dementia.

“Leakiness predicts future amyloid buildup and future cognitive decline,” Dr. Montagne said. “Twenty years ago people were laughing at this hypothesis. Now so many papers in major journals have shown that there are different types of dementia, but they are all driven by early vascular problems including a leaky BBB.”

Link Up for More Information

• Saridin FN, Hilal S, Villaraza SG, et al. Brain amyloid β, cerebral small vessel disease and cognition: A memory clinic study Neurology 2020; Epub 2020 Oct 12.
• Vipin A, Loke YM, Liu S, et al. Cerebrovascular disease influences functional and structural network connectivity in patients with amnestic mild cognitive impairment an Alzheimer's disease Alzheimers Res Ther 2018;10:82.
• Montagne A, Nation DA, Sagare AP, et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline Nature 2020;581(7806):71–76.
• Hasan T., Barrett K., Brott T., et al. Severity of white matter hyperintensities and effects on all-cause mortality in the Mayo Clinic Florida Familial Cerebrovascular Diseases Registry Mayo Clin Proc 2019; 94: 408–416.