Vascular Risk in 30s Linked to Brain
Pathology at 70

November 07, 2019

While vascular risk factors in midlife have been implicated in later life cognitive impairment, a new study suggests that vascular risk even earlier in life may actually be more important.

The study showed that vascular risk at both midlife and early adulthood was linked to adverse changes in late-life brain structure and pathology but that the effect was greater for vascular risk in early adulthood.

"Our work suggests that vascular risk influences brain heath from a young age. We should be monitoring people for vascular risk earlier than we do at present and reinforcing the message that what is good for the heart is also good for the head," senior author Jonathan Schott, MD, UCL Queen Square Institute of Neurology, London, United Kingdom, told Medscape Medical News.

The study was published online November 4 in JAMA Neurology.

The findings come from a prospective longitudinal cohort study, known as Insight 46, in which a group of individuals all born in the same week in March 1946 in the United Kingdom are being closely followed throughout their lives.  

They have had vascular risk factors assessed since their 30s, and a subset have had brain multimodal MRI and β-amyloid imaging at ages 69 to 71, with a specific focus on cerebral small-vessel disease, β-amyloid deposition, and brain volumes.

Of the original 502 individuals in the Insight 46 group, the current study included 463 participants with available brain imaging measures and who were cognitively normal. The mean age at brain imaging was 70 years and 18% of individuals were β-amyloid positive.

Office-based Framingham cardiovascular risk scores were derived at ages 36, 53, and 69 years using factors including systolic blood pressure, antihypertensive medication usage, smoking, diabetic status, and body mass index. Analysis models adjusted for age at imaging, sex, APOE genotype, socioeconomic position, and, where appropriate, total intracranial volume.

Results showed that higher vascular risk scores at all ages were associated with smaller whole-brain volume and higher white matter–hyperintensity volume at ages 69 to 71 years, with the strongest association seen with early adulthood vascular risk.

No Link to Amyloid Seen

However, there was no association between vascular risk score at any age and β-amyloid status.

"There has been realization for some time that vascular risk factors influence the risk of dementia, but it is unclear how that happens and what stage of life the impact of vascular risk factors on the brain occurs," Schott said.

"We found those with higher cardiovascular risk scores earlier in life had more white matter hyperintensities representing cerebrovascular issues such as small strokes," he noted. "They also had smaller brain volumes — another index of brain health — but cardiovascular risk factors were not associated with the quantity of amyloid in the brain. These results suggest that vascular risk factors influence brain health in terms of vascular health but not in terms of amyloid disposition."

On the amyloid observation, Schott said: "We can't say definitely from this research that vascular risk factors do not influence the development of Alzheimer's, as there may be other pathways involved in Alzheimer's. All we can say is that in these individuals — who were all cognitively normal — there was no relationship between vascular risk earlier in life and the amount of amyloid in the brain at the age of 70."

In terms of the white matter and brain volume changes, Scott pointed out that vascular risk factors at the age of 36 seemed to have more effect on these than at the age of 53.

"This suggests that poor cardiovascular health in early adulthood influences brain health 3 or 4 decades later, and may be more important than cardiovascular health in midlife — when people are in their 50s." On the mechanism, he postulated that "this may be simply because they will be exposed to risk factors such as raised blood pressure or raised cholesterol for longer."

"Most people don't think very much about their cardiovascular risk when they're in their 30s. Typically they start to think about it in their 50s and beyond. But our results suggest we need to be targeting younger people — those in their 30s — for cardiovascular screening and education," Schott emphasized.  

While there have been several studies showing midlife vascular risk to be associated with later-life brain health he believes this is one of the first reports to show vascular risk in people as young as their mid-30s to be so important.

"Dreaded Clinical Syndrome"

In an accompanying editorial, Sudha Seshadri, MD, from the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health San Antonio, writes, "These data…make a strong case for addressing vascular risk as early as the fourth decade of life; strengthen the case for studying adolescent, early-childhood, and perinatal factors as factors associated with dementia; and warn that effective prevention of dementia in our time will likely require extending thinking well beyond the seductive amyloid hypothesis and the current emphasis on elderly patients as the best target for preventive interventions. Indeed, aging, successful or otherwise, involves many biological pathways and begins at birth."

On the lack of an association with vascular risk factors and amyloid in this study, Seshadri says this remains a controversial area for which further study is urgently required.

She points out that previous studies that did not exclude persons with clinical mild cognitive impairment and dementia have suggested a direct association of greater vascular risk with higher amyloid burden.

Noting that evidence linking vascular risk burden to subsequent risk of cognitive impairment and dementia is "incontrovertible," she says that "it is important to remain open-minded about the relative contributions of various pathways, including vascular, inflammation, tau, and mitochondrial ones and likely other yet-unidentified biological pathways, to the dreaded clinical syndrome of dementia."

This study was principally funded by grants from Alzheimer's Research UK. the Medical Research Council Dementias Platform UK, and the Wolfson Foundation. Schott reports grants from Weston Brain Foundation during the conduct of the study and personal fees from Axon Neuroscience, Roche, Eli Lilly, General Electric Healthcare, Merck Sharp & Dohme, Oxford University Press, Biogen, and EU Horizon 2020 outside the submitted work .

JAMA Neurol. Published online November 4, 2019. Full text, Editorial

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