Bad Synergy—Together, Vascular Problems and Aβ Hasten Memory Slippage

People at risk for future cardiovascular events also face greater odds of developing memory problems, according to a May 23 study in JAMA Neurology. Using a bevy of health factors such as age, sex, body mass index, and blood pressure, researchers led by Jasmeer Chhatwal at Massachusetts General Hospital in Charlestown calculated vascular risk scores in a cohort of cognitively normal people. They reported that these scores correlated with future cognitive decline independently of Aβ burden or other brain imaging markers. People with both—high vascular risk and Aβ accumulation— were more likely to decline than those with just one of these factors, suggesting a synergistic effect between two harbingers of neurodegeneration.

  • In cognitively normal people, high vascular risk scores at baseline meant future decline.
  • Aβ burden and vascular risk scores synergized in their correlation with future memory problems.
  • Vascular risk scores associated with cognitive decline independently of white-matter hyperintensities.

Costantino Iadecola of Weill Cornell Medical College in New York said that the study adds further evidence to the importance of vascular health in the brain. The synergism between Aβ and vascular problems could reflect the erosion of compensation mechanisms in the brain as people age, he told Alzforum. “As we age and more pathology builds up in the brain, a little bit does a lot of damage,” he said.

Myriad studies have implicated vascular problems with cognitive decline, so researchers now use MRI to look for cerebrovascular pathologies, such as white-matter hyperintensities and cerebral infarcts, which can help gauge dementia risk. The scans indicate that vascular disease exerts its toll on cognition independently of Aβ (Feb 2013 news; Park et al., 2014; Vemuri et al., 2015). Another recent study suggested that cerebrovascular damage as seen on MRI evokes tau pathology independently of Aβ (May 2018 news). 

Chhatwal and colleagues set out to determine if a broader measure of vascular risk might correlate with cognitive decline, and if it would do so on its own or with Aβ. The researchers calculated baseline cardiovascular disease risk scores for 223 cognitively normal participants, averaging 73 years old, in the Harvard Aging Brain Study (HABS). First author Jennifer Rabin used the Framingham Heart Study Cardiovascular Disease (FHS-CVD) risk score, which takes several health factors into account to estimate the odds of future cardiovascular events such as heart attack or stroke. The HABS volunteers also had PiB PET scans to measure Aβ burden, FDG-PET to assess glucose metabolism, and further MRIs to record hippocampal volume and white-matter hyperintensities (WMH). The researchers then tracked the volunteers’ cognition annually using the Preclinical Alzheimer Cognitive Composite (PACC), a test originally designed to pick up early memory problems caused by Aβ accumulation. Volunteers thus far have been tracked for an average of 3.7 years.

At baseline, vascular risk scores ranged from 4 percent to 88 percent likelihood of a cardiovascular event. They correlated modestly with WMH and lower brain-glucose metabolism, but not at all with hippocampal volume or Aβ burden. Vascular scores correlated marginally with lower baseline cognition, but Aβ burden did not.

Associations popped up when the researchers looked at the longitudinal cognitive data. They found that both Aβ burden and vascular risk scores correlated strongly with the annual rate of slippage on the PACC. While vascular scores associated with cognitive decline in both the Aβ-positive and Aβ-negative groups, the association was stronger in the Aβ-positive group, suggesting a synergistic effect. People burdened with both high vascular scores and Aβ accumulation had the highest risk of developing memory problems during the study, while people with low vascular risk scores and no Aβ accumulation had the lowest risk. Finally, the researchers reported that the association between vascular risk and cognitive decline held up independently of other imaging biomarkers, including hippocampal volume, FDG-PET, and even WMH.

The researchers concluded that vascular abnormalities that fly below the radar of MRI scans could effectively shorten the preclinical phase of AD. This could make vascular scores useful biomarkers of progression, especially in the context of clinical trials that enroll Aβ-positive, cognitively normal participants, Chhatwal told Alzforum. He added that other vascular risk scales, including those that take into account family history of vascular disease or markers of systemic inflammation, could make the biomarker even more informative.

Prashanthi Vemuri of the Mayo Clinic in Rochester, Minnesota, agreed that the vascular risk score could provide useful information in the context of clinical trials, given that the vascular problems are likely to influence the rate of cognitive decline and treatment efficacy. She added that trials could be designed with the goal of evenly distributing people in different vascular risk categories among treatment groups. Vemuri’s previous studies relied on imaging biomarkers, such as WMH and microinfarcts, to gauge cerebrovascular pathology, and she still believes those imaging markers are important, especially in populations that already have cognitive decline or more advanced vascular disease than those in the HABS cohort.

Iadecola thinks that irrespective of whether vascular dysfunction and Aβ have additive or synergistic effects on cognitive decline, maintaining healthy blood vessels in the brain is crucial. “We don’t know how to cure AD, but we do know how to improve cardiovascular health, and that is what we should be helping everyone achieve,” he said.—Jessica Shugart

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References

News Citations

  1. Vascular Dementia or Alzheimer’s: Is the Delineation Emerging?
  2. Cerebrovascular Disease: Does Tau Mediate Cognitive Decline?

Paper Citations

  1. Park JH, Seo SW, Kim C, Kim SH, Kim GH, Kim ST, Jeon S, Lee JM, Oh SJ, Kim JS, Choe YS, Lee KH, Shin JS, Kim CH, Noh Y, Cho H, Yoon CW, Kim HJ, Ye BS, Ewers M, Weiner MW, Lee JH, Werring DJ, Na DL. Effects of cerebrovascular disease and amyloid beta burden on cognition in subjects with subcortical vascular cognitive impairment. Neurobiol Aging. 2014 Jan;35(1):254-60. Epub 2013 Aug 7 PubMed.
  2. Vemuri P, Lesnick TG, Przybelski SA, Knopman DS, Preboske GM, Kantarci K, Raman MR, Machulda MM, Mielke MM, Lowe VJ, Senjem ML, Gunter JL, Rocca WA, Roberts RO, Petersen RC, Jack CR Jr. Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain. 2015 Mar;138(Pt 3):761-71. Epub 2015 Jan 15 PubMed.

Further Reading

Papers

  1. Kim HJ, Yang JJ, Kwon H, Kim C, Lee JM, Chun P, Kim YJ, Jung NY, Chin J, Kim S, Woo SY, Choe YS, Lee KH, Kim ST, Kim JS, Lee JH, Weiner MW, Na DL, Seo SW. Relative impact of amyloid-β, lacunes, and downstream imaging markers on cognitive trajectories. Brain. 2016 Sep;139(Pt 9):2516-27. Epub 2016 Jun 21 PubMed.

Primary Papers

  1. Rabin JS, Schultz AP, Hedden T, Viswanathan A, Marshall GA, Kilpatrick E, Klein H, Buckley RF, Yang HS, Properzi M, Rao V, Kirn DR, Papp KV, Rentz DM, Johnson KA, Sperling RA, Chhatwal JP. Interactive Associations of Vascular Risk and β-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals: Findings From the Harvard Aging Brain Study. JAMA Neurol. 2018 Sep 1;75(9):1124-1131. PubMed.

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