09 Aug 2017

Even mild cardiovascular problems in middle age could have drastic consequences on cognition a quarter-century later. This was the main conclusion from a study in the August 7 JAMA Neurology, which used data from the large, ongoing Atherosclerosis Risk in Communities (ARIC) cohort to trace how vascular risk factors recorded in the late 1980s affected dementia risk in the following decades. The researchers, led by Rebecca Gottesman of Johns Hopkins University in Baltimore, reported that diabetes, hypertension, and smoking all boosted dementia risk, while neither high cholesterol nor obesity had a significant effect. Black people had a higher overall risk of dementia, but their risk was less influenced by ApoE4 carriage than it was for whites.

“The bottom line is that most of these risk factors are preventable,” Gottesman told Alzforum. “We may not know how to treat dementia, but we can treat high blood pressure and diabetes, and also quit smoking and live a healthy lifestyle.” 

The study strongly supports mounting evidence that vascular problems in midlife can take their toll on the brain decades down the line (e.g., Swan et al., 1998; Launer et al., 1995; Gottesman et al., 2014; and Aug 2014 news). 

“The findings in this study really nail down the link between midlife risk factors, race, and risk of dementia,” commented Costantino Iadecola of Weill Cornell Medical College in New York (see full comment below).

The goal of making definitive connections between midlife health and late-life cognition is fraught with challenges: people who develop dementia are more likely to be lost to follow-up, studies limited to people seen at memory clinics have selection biases, etc. The ARIC cohort aimed to reduce these problems by tracking down dementia cases in a large population drawn from different communities, (ARIC investigators, 1989). 

Between 1987 and 1989, the ARIC cohort enrolled 15,792 middle-aged participants who hailed from different counties in Maryland, North Carolina, Mississippi, and Minnesota. Nearly a third of the participants were black, a greater proportion than most other studies. At baseline, they were assessed for cardiovascular health and cognitive performance, as well as lifestyle and demographic factors. The current study includes data from up to four follow-up visits, the final one including a more extensive battery of cognitive tests. In addition to the five in-person visits, the researchers conducted annual phone interviews with participants and/or caregivers, and sifted through hospital and death records. Where possible, dementia diagnoses were made following in-person visits, and were supported by tools such as the Clinical Dementia Rating (CDR) scale. When in-person visits were not possible, dementia was diagnosed based on phone interviews and/or hospital records. The underlying cause of the dementia—Alzheimer’s, vascular or frontotemporal dementia, dementia with Lewy bodies—was not determined.

Of the 15,744 participants who identified as either black or white, 6,471 attended the fifth visit. Nearly 10 percent of participants developed dementia over the course of the study.

Age at baseline and ApoE stood out as the strongest risk factors for dementia, with ApoE4 nearly doubling risk among carriers. Low education boosted risk by nearly two-thirds, and race was a strong factor as well, with black people at 30 percent higher risk.

Among vascular risk factors, midlife diabetes had the strongest effect, boosting dementia risk nearly as much as ApoE4. People with prehypertension or hypertension at baseline also had about a third higher chance of developing dementia, while those who identified as current smokers at their first visit had about a 40 percent higher risk. These associations held even when the researchers excluded 1,430 participants with stroke from the analysis.

Iadecola was struck by the finding that prehypertension and hypertension boosted dementia risk by similar amounts. “This finding supports starting treatment of elevated blood pressure earlier than currently done in medical practice,” he commented.

To determine if these factors affected blacks and whites differently, the researchers stratified the data by race. They found that smoking upped dementia risk only in whites, an effect Gottesman speculated could be due to whites smoking more heavily than blacks.

ApoE4 also exerted a stronger effect on dementia risk in whites than blacks, an observation that has been made before (Evans et al., 2003; Tang et al., 1998). The reason for this is unclear, but Gottesman speculated that blacks may have a higher incidence of dementias other than AD. Blacks also have higher rates of hypertension, which could predispose them more to vascular dementia, she added. This would mesh with findings from a recent ARIC substudy, which reported that ApoE4 exerted a similar effect on the risk of a positive amyloid-PET scan between blacks and whites (Apr 2017 news). Iadecola offered another possible explanation for the racial disparity in ApoE4 influence. “One possibility, not yet proven, is that it may reflect the influence of genetic factors on ApoE4 transcription, which could be more efficient in whites, resulting in more ApoE4 protein.”

The findings highlight the need for clinicians to consider race when seeking to thwart dementia risk factors, Gottesman said. For example, it is unclear why black people have higher rates of hypertension, and whether this risk factor may be exacerbated by lack of access to medications, or whether anti-hypersensitive medications are not equally effective across ethnic groups.

In future studies, it would be helpful to know more about why blacks are at higher dementia risk, commented Charles DeCarli at the University of California, Davis. “Whether this is entirely due to elevated incidence of hypertension and diabetes, or to other variables, would be helpful to know for prevention efforts,” he said. Still, he praised the study for including a much higher proportion of nonwhite participants than most, adding that inclusion of even more diverse communities will be important for future research.—Jessica Shugart 

Comments

1. • Costantino Iadecola
     Weill College Medicine
   • Posted: 09 Aug 2017

   The findings in this study really nail down the link between midlife risk factor, race, and risk of dementia. I find particularly interesting the racial disparity data on dementia risk.

   Also very interesting is the link between prehypertension—that is, blood pressure of >120 systolic but <140 mmHg—and dementia. Prehypertension is linked to a 31 percent increase in dementia risk, while full-blown hypertension to a 39 percent greater risk, not a large difference between the two.

   Although the study was not designed to test treatments, this finding supports starting treatment of elevated blood pressure earlier than currently done in medical practice. 

   That ApoE4 is more relevant in white than black people has been described previously. One possibility, not yet proven, is that it may reflect the influence of genetic factors on ApoE4 transcription, which could be more efficient in whites resulting in more ApoE4 protein.

   One caveat is that the relationship between ApoE4 in whites and dementia is not driven by stroke, but the role of white-matter disease was not examined. 

   As for the previous ARIC study suggesting equal amyloid deposition in whites and blacks, that result seems in conflict with the effect of ApoE (which seems to be involved in amyloid deposition) being more relevant in whites. While the possibility of increased ApoE4 transcription in whites could contribute, a confounder may be that amyloid deposition as assessed by PET tracers is also present in normal individuals. Therefore, the comparison between the two studies is complex. 

   The take-home message is that healthy vessels are key to keeping a healthy mind, and this new study suggests that this has to be a lifelong effort since the harmful impact of vascular risk factors starts decades earlier.

   View all comments by Costantino Iadecola

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References

News Citations

1. Treating Midlife Hypertension Helps Preserve Cognition in Old Age 8 Aug 2014
2. Vascular Disease in 50s Begets Brain Amyloid in 70s 14 Apr 2017

Paper Citations

1. Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Jack LM, Carmelli D. Association of midlife blood pressure to late-life cognitive decline and brain morphology. Neurology. 1998 Oct;51(4):986-93. PubMed.
2. Launer LJ, Masaki K, Petrovitch H, Foley D, Havlik RJ. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA. 1995 Dec 20;274(23):1846-51. PubMed.
3. Gottesman RF, Schneider AL, Albert M, Alonso A, Bandeen-Roche K, Coker L, Coresh J, Knopman D, Power MC, Rawlings A, Sharrett AR, Wruck LM, Mosley TH. Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol. 2014 Oct;71(10):1218-27. PubMed.
4. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am J Epidemiol. 1989 Apr;129(4):687-702. PubMed.
5. Evans DA, Bennett DA, Wilson RS, Bienias JL, Morris MC, Scherr PA, Hebert LE, Aggarwal N, Beckett LA, Joglekar R, Berry-Kravis E, Schneider J. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003 Feb;60(2):185-9. PubMed.
6. Tang MX, Stern Y, Marder K, Bell K, Gurland B, Lantigua R, Andrews H, Feng L, Tycko B, Mayeux R. The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA. 1998 Mar 11;279(10):751-5. PubMed.

Further Reading

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