Already in Mid-30s, Poor Vascular Health Means Small Brain at 70

Updated November 14, 2019

Thirty-somethings take heed. A new study suggests it’s time to take care of your vascular health. Using data from the longest continuously running birth cohort in the world, researchers led by Jonathan Schott of University College London report that poor vascular health at age 36 forecasted smaller brains, with more white matter damage, at age 70. In fact, associations between vascular health and late-life brain atrophy were stronger at 36 than they were later in mid-life. Importantly, at no age did a person’s vascular health correlate with his or her late-life Aβ burden. Published November 4 in JAMA Neurology, the findings suggest that the contribution of overall vascular health to brain damage starts earlier than one might expect, and works in ways other than Aβ deposition.

  • Health of British cohort has been tracked since their birth in 1946.
  • Their vascular risk scores at age 36 correlated with brain disease 30 years later.
  • At no age did vascular risk correlate with late-life amyloid plaques.

The members of the British birth cohort were born within a week of each other in 1946. Concerned about Britain’s population in the wake of the Second World War, U.K. government scientists first interviewed the mother of every child—13,687 of them—born across England, Scotland, and Wales from March 3–9. They then tracked more than 5,000 of the children, first for educational attainment, socioeconomic status, diet, and exercise, and then later for a more extensive bevy of health factors. In 1982, when the cohort was 36 years old, researchers started monitoring vascular risk factors.

In 2014, egged on by members of the cohort themselves, UCL’s Nick Fox and colleagues secured funding to begin Insight 46, a study to image a subset of the participants’ brains every two years for the rest of their lives. So far, around 500 participants have received MRI and amyloid PET scans once, and more than half have had their second round of imaging, said Schott, who attended a 70th birthday party for the cohort in 2016. “When you have 500 people in the same room who were all born in the same week, the differences between biological and chronological age become very apparent,” he said. While some participants had already passed away and others sat in wheelchairs, a few had recently run marathons.

The first analysis from Insight 46 found that mid-life hypertension associated with a smaller brain and more extensive white-matter hyperintensities—a proxy for cerebral small vessel disease—at age 69–71 (see Aug 2018 news and Aug 2019 news on Lane et al., 2019). That study also found that increasing blood pressure between the ages of 36 and 43 correlated with these later-life brain pathologies, but not with Aβ.

In the current study, first author Christopher Lane and colleagues extended their analysis to a wider range of vascular risk factors. They took stock of associations between Framingham Heart Study-Cardiovascular risk scores (FHS-CVS) at ages 36, 53, and 69. The FHS-CVS calculates a 10-year risk of cardiovascular events, based on a weighted sum of age, sex, systolic blood pressure, antihypertensive medication usage, diabetes, current smoking, and body mass index. The study included 463 people who were free of dementia at the time of brain imaging. Notably, only three participants were excluded due to a dementia diagnosis.

As with hypertension, higher CVS at 36, 53, and 69 associated with more white-matter hyperintensities, and smaller whole brain volume, at age 69–71. The associations were strongest at 36, and weakened as the cohort aged. High vascular risk scores at age 36 also correlated with smaller hippocampal volume, though CVS scores at later ages did not.

Why was the association between vascular risk and late-life brain pathology strongest at 36? One possibility is that earlier vascular health problems are a proxy for longer exposure to those risk factors, Schott said. The longer a person lives with hypertension, for example, the more time it has to wreak havoc on the brain.

The findings meshed with those from the Framingham Heart Study, which found that associations between vascular risk at younger ages most strongly associated with late-life brain atrophy (Pase et al., 2018). For that study, measurements went back to age 45.

Jaime Grutzendler of Yale School of Medicine in New Haven, Connecticut, noted that the association between vascular risk and subsequent white-matter damage meshes with his group’s finding that axon myelination, which gives white matter its color and conductivity, is a lifelong process (Hill et al., 2018). “Microvascular pathology and brain hypoperfusion could have a detrimental effect on the brain’s capacity to form new myelin internodes, even in the absence of ischemia,” he wrote.

Though the earliest cardiovascular risk scores from this cohort were measured 37 years ago, they have striking implications for people in their 30s and 40s today, said Costantino Iadecola of Weill Cornell Medical College in New York. He pointed out that while rates of some risk factors, such as smoking, have plummeted since the 1980s, others, including obesity and diabetes, have increased and affect younger populations than ever before.

Rebecca Gottesman of Johns Hopkins School of Medicine in Baltimore agreed, adding that associations between vascular risk and late-life brain pathology may well exist at even younger ages than measured by the British birth cohort. “Although these risk factors are less common in younger populations, they are not absent, and as the population develops diseases of adulthood at exceedingly earlier stages (such as Type 2 diabetes), it is likely that risk status even in adolescence or soon after plays an important role in subsequent brain health,” she wrote to Alzforum.

Lane and colleagues also looked for associations between vascular health throughout life and Aβ plaque status at 69–71. Eighty-three participants had a positive amyloid scan, defined by 18-F Florbetapir standardized uptake value ratios in the upper range of a Gaussian distribution (see below). However, vascular risk scores at no age correlated with Aβ status. On the other hand, people who carried at least one copy of the ApoE4 risk allele were five times more likely to test positive for Aβ deposition than noncarriers. Neither ApoE4 nor Aβ status correlated with any of the other brain imaging measures.

Gottesman noted that the ongoing Atherosclerosis Risk in Communities (ARIC) study drew similar associations between mid-life vascular risk and late-life brain health measures. However, unlike Insight 46, ARIC did tie mid-life vascular risk to late-life Aβ burden (Apr 2017 news). Gottesman suggested this difference could come down to the characteristics of the cohorts—ARIC participants were older and in poorer vascular health than the British birth cohort—as well as differences in the way Aβ status was determined.

Simon Cox of the University of Edinburgh commented that the absence of a relationship between mid-life vascular health and late-life Aβ could stem from the bifurcation of the cohort into approximately high/low Aβ groups in the British cohort study. “[This] does not allow the possibility to examine the (perhaps more likely) subtler relationship between vascular risk and this brain hallmark of Alzheimer’s disease,” he wrote.

Grutzendler took a different view. “This suggests that vascular factors act through a direct pathway rather than by exacerbating AD pathology, as is frequently proposed,” he wrote.

Schott agreed, noting that the findings jibe with mounting evidence that about a third of dementia risk is preventable, likely though vascular health and lifestyle (Aug 2017 news; Aug 2019 news). Vascular disease is likely to influence the brain’s blood vessels, sensitizing the brain to all manner of neurodegenerative insults, he said. Though vascular health may not drive amyloid deposition, it could make people who have plaques more susceptible to neurodegenerative and cognitive consequences of amyloid. The two-thirds unpreventable dementia risk could reflect a strong genetic component that drives AD-related dementia in particular, he said.

On November 14, 2019, the Alzheimer’s Association announced a five-year, $7 million grant to University College London to help Schott and colleagues expand their research into genetic and lifestyle risk factors for dementia in the British 1946 birth cohort.—Jessica Shugart

Comments

  1. There are larger and more detailed studies that have previously explored vascular risk with brain volumes and white-matter damage across mid- to later life in greater depth, and the results of this study are in line with the direction previously reported (more vascular risk, less healthy brain). Beyond this, the study offers some valuable and welcome insights.

    Showing links between vascular risk measured at age 36 and some—but not other—aspects of brain health measured decades later is important. It adds further weight to the argument (informed by many studies) that we should not wait until later life to address our cardiovascular health if we want to age healthily. The study also used PET imaging to see if people with greater vascular risk showed greater prevalence of Alzheimer’s related plaques in the brain; they did not.

    The authors themselves caution that their brain measures were not fine-grained: They chose to divide people into approximately high/low plaque groups, which does not allow the possibility to examine the (perhaps more likely) subtler relationship between vascular risk and this brain hallmark of Alzheimer’s disease. In addition, they did not conduct any work to look at whether some risk factors were more important than others, and whether this depended upon the time of life at which they were measured, which could have been highly informative.

    View all comments by Simon R. Cox

  2. This is an interesting article that provides further evidence that vascular risk factors are independently associated with brain volume loss (a likely correlate of neurodegenerative processes). Interesting aspects of this paper include the finding that vascular factors were not associated with plaque accumulation (as assessed by PET scan). This suggests that vascular factors act through a direct pathway rather than by exacerbating AD pathology, as is frequently proposed.

    Other interesting aspects include the finding that the longer people are exposed to vascular risk factors the greater likelihood of brain atrophy and white-matter hyperintensities. It appears that atrophy included both gray- and white-matter areas, showing that all cell types beyond oligodendrocytes are susceptible to chronic hypoperfusion. However, we have recently shown in mice that that myelination of axons is a lifelong process (Hill et al., 2017). Microvascular pathology and brain hypoperfusion could have a detrimental effect on the brain’s capacity to form new myelin internodes even in the absence of ischemia.

    References:

    Hill RA, Li AM, Grutzendler J. Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nat Neurosci. 2018 May;21(5):683-695. Epub 2018 Mar 19 PubMed.

    View all comments by Jaime Grutzendler

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References

News Citations

  1. Brain Damage from Cardiovascular Disease Starts Earlier Than You Think
  2. Blood Pressure: How Low to Prevent Dementia—and When?
  3. Vascular Disease in 50s Begets Brain Amyloid in 70s
  4. Lancet Commission Claims a Third of Dementia Cases Are Preventable
  5. Healthy Lifestyle Hedges Dementia Risk, but Not if Genetic Risk Runs High

Paper Citations

  1. Lane CA, Barnes J, Nicholas JM, Sudre CH, Cash DM, Parker TD, Malone IB, Lu K, James SN, Keshavan A, Murray-Smith H, Wong A, Buchanan SM, Keuss SE, Gordon E, Coath W, Barnes A, Dickson J, Modat M, Thomas D, Crutch SJ, Hardy R, Richards M, Fox NC, Schott JM. Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): an epidemiological study. Lancet Neurol. 2019 Oct;18(10):942-952. Epub 2019 Aug 20 PubMed.
  2. Pase MP, Davis-Plourde K, Himali JJ, Satizabal CL, Aparicio H, Seshadri S, Beiser AS, DeCarli C. Vascular risk at younger ages most strongly associates with current and future brain volume. Neurology. 2018 Oct 16;91(16):e1479-e1486. Epub 2018 Sep 19 PubMed.
  3. Hill RA, Li AM, Grutzendler J. Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nat Neurosci. 2018 May;21(5):683-695. Epub 2018 Mar 19 PubMed.

Further Reading

Primary Papers

  1. Lane CA, Barnes J, Nicholas JM, Sudre CH, Cash DM, Malone IB, Parker TD, Keshavan A, Buchanan SM, Keuss SE, James SN, Lu K, Murray-Smith H, Wong A, Gordon E, Coath W, Modat M, Thomas D, Richards M, Fox NC, Schott JM. Associations Between Vascular Risk Across Adulthood and Brain Pathology in Late Life: Evidence From a British Birth Cohort. JAMA Neurol. 2019 Nov 4;:1-9. PubMed.

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