Hypertension interacts with genetic risk to increase the burden of amyloid beta (Aβ) in the brain, a new study suggests.
In Alzheimer’s disease (AD), individuals with the apolipoprotein E (APOE) ε4 gene, indicating higher AD risk, had higher levels of Aβ, researchers report. Even in healthy control patients, the presence of hypertension and APOE ε4-positivity was associated with a greater level of Aβ in the brains of adults older than 70 years.
Despite the strong risk conferred by APOE ε4, age remains the greatest risk factor for AD, suggesting that age-related comorbidities may be important. Among them, “poor vascular health is a significant medical issue in aging populations,” Karen Rodrigue, PhD of the Center for Vital Longevity at the University of Texas at Dallas told delegates here at the 7th Clinical Trials on Alzheimer’s Disease (CTAD).
Previous studies have implicated hypertension in this process. The Honolulu-Asia Aging Study showed a link between midlife diastolic blood pressure, levels of circulating plasma Aβ, and subsequent probable AD in Japanese-American men who were never treated for hypertension. Another study showed that a higher Framingham cardiovascular risk score correlated with a greater amyloid burden.
In the present study, Dr Rodrigue and colleagues investigated the interaction of hypertension and APOE ε4–positivity on the accumulation of Aβ in the brain.
Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), they studied a cognitively diverse group of 1013 adults aged 47 to 89 years and classified them as a control group (comprising individuals having neither risk factor), a genetic risk group (ε4 heterozygous or homozygous patients), a vascular risk group (patients with a diagnosis of hypertension or elevated blood pressure), or a double risk group (patients with both genetic and vascular risks).
Among the participants, 449 (44%) were ε4-positive, and 564 (56%) were ε4-negative; 65% were hypertensive (average blood pressure, 142/77 mm Hg), and 35% were normotensive (123/71 mm Hg). For all participants, complete data on APOE genotype, positron emission tomography 18F-florbetapir scans, diagnostic information for dementia, and hypertension status were available.
18F-florbetapir scan results were expressed as a standardized uptake value ratio (SUVR, normalized to cerebellar gray matter), and scan results were dichotomized according to a cutoff of 1.1, with ratios greater than 1.1 considered positive for Aβ, after adjustment for age and body mass index.
Interaction of Blood Pressure and APOE ε4
“Those individuals with the double risk with the ε4-positivity who carried a hypertension diagnosis showed the highest SUVRs,” Dr Rodrigue reported. Whereas ε4-negative individuals had a mean amyloid SUVR of 1.1 whether hypertensive or not, taken together, ε4-positive patients had an SUVR of about 1.3 if normotensive and almost 1.4 if hypertensive (APOE x hypertension interaction, P < .02).
The synergistic effect of hypertension on ε4-positivity was seen only for the group of individuals with AD (normotensive SUVR = 1.4 vs 1.5 for hypertension, P < .002). Interestingly, for the ε4-negative group of AD patients, those with normal blood pressure had higher SUVR (approximately 1.35) than hypertensive patients (approximately 1.2).
For those with mild cognitive impairment, SUVR was elevated essentially to the same degree (at approximately 1.25 – 1.3) regardless of blood pressure status; for cognitively normal adults, SUVR was approximately 1.1 regardless of blood pressure.
There was a differential effect of hypertension with age. For ε4-positive individuals younger than 70 years, hypertensive patients had a nonsignificantly higher SUVR compared with normotensive patients. But for patients older than 70 years, those with hypertension had significantly more amyloid accumulation (SUVR = 1.2) than did normotensive patients (SUVR = 1.1).
Although ε4-positivity greatly increased the risk of having an elevated brain amyloid burden, hypertension added somewhat to that risk (see table). Blood pressure had no effect for ε4-negative individuals.
Table. Relative Risks Conferred for Amyloid Positivity (SUVR > 1.1)
|APOE ε4–positive (%)||80||70|
|APOE ε4–negative (%)||35||36|
Their odds ratio analyses for Aβ-positivity, using an SUVR cutoff of 1.1, showed a 1.7 times greater risk in the ε4-positive group for hypertensive patients than for normotensive patients to be diagnosed as Aβ-positive, “kind of confirming the synergistic effect of vascular risk and genetic risk on the accumulation of amyloid,” Dr Rodrigue concluded. This synergistic effect was greatest in the AD cohort.
She advised that even though the contribution of hypertension to amyloid accumulation is small compared with the effect of ε4-positivity, blood pressure and other vascular risk factors are modifiable “compared to the immutable genetic risk,” so optimal blood pressure control may help to delay or lessen the burden of AD.
She suggested that further studies were needed to investigate the effects of controlling hypertension and to track outcomes with medication.
Session moderator Paul Aisen, MD, professor of neurosciences at the University of California, San Diego, commented to Medscape Medical News that he “might not have guessed that there would be an effect of hypertension on top of APOE in the risk of developing a positive amyloid signal.”
But in light of the findings of this study, he said, “I think we would need to look further to see whether this is a specific effect of hypertension; what happens when you look at other vascular and other metabolic related risks, like diabetes, obesity, level of exercise? But nonetheless, I think it’s an intriguing observation.”
He said the researchers, by using ADNI data, were limited in how much they could look at specific aspects of hypertension that might increase the risk for amyloid accumulation when combined with APOE status, so the study as presented did not include information on how many of the patients were receiving treatment, how many were complying with treatment, or how extensive was the blood pressure monitoring.