Association between blood pressure and Alzheimer disease measured up to 27 years prior to diagnosis: the HUNT Study

Blood pressure (BP) level is a commonly investigated vascular risk factor. Results reported to date in the epidemiological literature on BP and dementia are conflicting and unclear because researchers have faced challenges when examining individuals with declining cognition over time that impact findings [1]. Cross-sectional studies have shown both positive and negative correlations between hypertension and cognition. Longitudinal studies of the association of midlife BP and later AD have found that elevated BP predicts the development of Alzheimer disease (AD) [2‐4]. Other longitudinal studies have suggested a J-shaped relationship whereby only a very high BP increases the risk of AD, and some studies have demonstrated a nonlinear association whereby both high and low BP are associated with cognitive decline or dementia [5‐9]. Systolic blood pressure (SBP) variability has been associated with dementia, and greater variability was a predictor of faster disease progression in AD [10]. There have been studies in which researchers have found BP decline in patients with prevalent dementia, and few prospective studies have demonstrated that this decline is present prior to dementia onset [11, 12]. However, previous prospective studies on BP and dementia reported limitations due to small sample sizes, short durations of study follow-up, and limited data evaluating an age- and sex-dependent association [13, 14]. The aim of the present study was therefore to prospectively examine the relationship between BP measured up to 27 years prior to dementia diagnosis on the development of all-cause dementia, AD, vascular dementia (VaD), and a mixture of these in a population-based sample.

The study population consisted of 24,059 subjects without dementia (52.9% female) and 579 with dementia (66.4% female). Descriptive statistics are shown in Table 1. Persons diagnosed with dementia were older, had a lower education status, and higher percentages were women. The BP averages of SBP, DBP, MAP, and PP in persons with dementia were consistently higher in persons diagnosed with dementia during both HUNT 1 and HUNT 2.

Multiple logistic regression analyses were performed for the total sample and separately for the groups less than and greater than or equal to 60 years of age at the time of HUNT 1 (1984–1986). The results for SBP in the total sample are shown in the upper part of Table 2. Results for DBP, PP, and MAP are presented in Additional file 2. There was a trend for protective effects of high SBP, and this trend tended to be stronger for HUNT 1 than for HUNT 2. In fully adjusted models for age and all other covariates, there was a protective effect of SBP on AD, and a similar, nonsignificant trend was observed for mixed AD/VaD and all-cause dementia. Age, sex, and education (model 2), as well as further blockwise adjustments with the clinical variables (model 3) and general health status (model 4), did not change the estimated effect of SBP much. There was no effect of the quadratic SBP term in fully adjusted models.

We tested for an interaction effect between sex and SBP and between age and SBP. The age × SBP effect was significant (p < 0.01). To further examine this interaction effect, the effect of SBP was examined in different age strata. Splitting the sample into subjects younger than 60 years old at HUNT 1 and 60+ years old at HUNT 1 showed that all the apparent protective effects of high SBP occurred in the oldest group. There was a significant sex × BP interaction effect among subjects younger than 60 years old; however, no sex × BP interaction effect was observed among subjects ≥60 years. The results are shown in the lower part of Table 2. PP had a similar inverse association with the risk of AD (OR 0.99/10-mmHg increase in PP, 95% CI 0.98–0.99), but there were no significant effects of DBP and MAP. These results are shown in Additional file 2: Tables S1, S2, and S3.

To examine whether antihypertensive medication moderated the effect of SBP, samples were split according to antihypertensive use, and results from logistic regression analyses are shown in Table 3. There was an adverse association with AD, PP, and SBP in HUNT 2 in participants <60 years old who reported taking BP medication. Antihypertensive use in participants ≥60 years old did not influence the protective effects of high SBP, because a similar inverse trend was observed among both samples. However, the effect of SBP reached significance only among the participants ≥60 years old who never reported using antihypertensive medication. The BP means in both measurements were highest among participants with a history of taking antihypertensive medication (Table 4).

The present study investigated associations between BP measured an average of 17.6 (range 0.6–26.8) years prior to symptom presentation of dementia, AD, and VaD. One of the findings was that high BP did not seem to be a risk factor for dementia when adjusted for age, sex, education, and other covariates in the total sample. Upon further examination, we found that age interactions were apparent in the total sample that required further stratified analyses. Interestingly, in persons 60 years or older, SBP was inversely associated with all-cause dementia, mixed AD/VaD, and AD, but not with VaD. Conversely, among middle-aged subjects (<60 years old), elevated SBP and PP were associated with eventual AD in participants who reported using antihypertensive medication.

The inverse association of SBP with all-cause dementia, mixed AD/VaD, and AD might seem paradoxical because hypertension is generally acknowledged as a risk factor for cognitive decline and dementia [2‐4]. However, recent findings suggest that the association between BP and brain health is complex and dependent on factors such as age, chronic hypertension, and antihypertensive medication use [21]. Indeed, inverse associations of BP have been reported in prior studies [11, 12, 22‐25].

Our findings raise a question whether high SBP actually has a protective effect against developing AD in a targeted population over 60 years of age. There is evidence to support this because a recent Mendelian randomization study of AD using single-nucleotide polymorphism revealed that higher SBP was associated with lower AD risk [26]. In addition, in studies examining centenarians, researchers have reported that higher BP is associated with higher cognition and functionality [27, 28]. Iadecola et al. summarized the existing evidence that BP in midlife is associated with altered cognitive function in both midlife and late life. However, the association of BP in late life and oldest old age with cognition is less clear, with evidence of both harmful and beneficial effects of high BP on cognition [18, 29]. Although it is known that BP declines in patients with manifest dementia, it is unclear when this decline occurs along the disease trajectory [22]. The Kungsholmen Project indicated that the drop in SBP was evident in subjects over 70 years of age with dementia 3 years prior to onset [4, 30]. The East Boston Cohort also found an inverse association between AD and SBP among participants ≥65 years of age approximately 4 years prior to dementia onset; however, there was no association with BP measured 13 years prior to diagnosis [12]. The East Boston Cohort publication refutes our findings with respect to time lapse prior to disease onset. In our study, the time of onset of dementia was registered on the basis of retrospective data in hospital records and interviews with the closest relatives of nursing home residents; therefore, inaccurate information may have been recorded both because of recall bias and because neurodegenerative disorders are known to begin many years before the patients get symptoms that are very vague in the beginning. However, because measurements in the present study were taken an average of 17.6 (SD 4.6) years prior to diagnosis, we think that it is unlikely that BP decline caused by neurodegeneration can explain these findings. This is in line with a review by Walker et al., who showed limited evidence that mildly elevated BP in late life may be protective against cognitive decline, especially for individuals with a history of long-standing hypertension [21].

In line with previous published studies, our data indicate that higher BP in midlife was associated with greater dementia risk in those who were treated with antihypertensive medication. Midlife BP data have previously been examined in a number of studies providing substantial evidence that there is a longitudinal association between midlife BP and worse cognitive function in later life [31‐34]. PP was also found to be associated with greater dementia risk in midlife among participants using antihypertensive medication. PP is a measure of arterial stiffness that increases with age and chronic hypertension, and previous studies showed that elevated PP was associated with cognitive decline and cognitive impairment [35‐37]. Collectively, these findings align with well-known midlife studies in which researchers reported adverse associations in hypertensive individuals with a higher prevalence of cardiovascular disease and therefore at increased risk for developing AD [5, 29, 38]. Additional analyses in our study showed that higher initial BP was found among those treated with antihypertensive medication. It is therefore likely that BP in those taking antihypertensive medication was confounded by indication, reflecting that they had higher overall exposure to elevated BP (Table 4).

Researchers in a number of studies have examined whether BP variability over time plays a significant role in the onset and progression of dementia [10, 39, 40]. In particular, SBP variability was found to be associated with significant cognitive deterioration in patients with mild to moderate AD, adding evidence to support the hypothesis that vascular and degenerative processes may interact through an additive or synergistic effect [39, 41]. Although in our present study we did not examine BP variability, the mechanism by which fluctuations in BP and impairment in cerebral blood perfusion may share similar pathologic alterations in cerebral hemodynamics.

It is well known that vascular factors contribute to dementia. The dementia spectrum has previously been described on one end with pure dementia of vascular type, on the other end among those with pure AD, and in between among the largest group with pathologies from both AD and vascular damage [42‐45]. On the basis of our data, we found that the association between SBP and VaD was different from the association with AD and may reflect different pathogenesis, as might be expected. Because BP is a known risk factor for stroke, hypertension is often considered a risk factor for VaD [21, 46]. The ICD classification for VaD used in the present study is quite restrictive, and patients who were classified with VaD mostly had a history of stroke or cerebral infarcts that were detected on computed tomographic or magnetic resonance imaging scans, which likely explains our difference in findings.

Our study has a number of strengths, including the very large sample size and the longitudinal design with a long period of follow-up. The dementia diagnoses were validated by experts in the field among a unique, large, population-based sample, and we examined a large set of variables that permitted adjustments and stratification into subgroups. Missing data are hard to avoid when examining longitudinal data, and data analyses were performed using complete-case data. Imputation analyses were not performed, as the data were assumed to be missing at random. Selection bias was probably moderate because the HUNT-HMS study is a prospective, population-based study with a high response rate that provides information about BP measured prospectively up to 27 years prior to onset of dementia. The dementia diagnoses were set by experienced clinicians by using the standardized ICD criteria. However, ascertaining the subtypes of dementia diagnoses was retrospective and based on access to comprehensive medical records from both panels, which were therefore sufficient to subclassify according to the ICD criteria. Furthermore, cognition assessments were not initiated in the county hospitals until 1995, leaving a questionable period during startup in 1995–2000, when scarce numbers of dementia cases were ascertained. A larger fraction of dementia cases were diagnosed during the period 2000–2009, and most cases were identified in 2009–2011. Cognition was not evaluated during HUNT 1 or HUNT 2, but participants were required to complete several questionnaires and underwent extensive screening that intuitively required intact cognition among participants [47]. Although efforts were made to identify participants diagnosed with dementia in the region during 1995–2011 by performing hospital record searches and examining nursing home residents, we had no access to data from individuals with dementia who were under the care of their general practitioner, and these will appear as false-negatives in the data set. However, the proportion of false-negatives to true-negatives in the noncase group is quite low because the prevalence of dementia is, after all, low. Thus, the contamination of the noncase group will not be substantial, and the extent to which the false-negatives affect the observed difference in exposure between the case and noncase groups, and, in turn, the effect estimates, will be little more than inconsequential. Another limitation is an unavoidable characteristic of elderly cohort studies, whereby competing risk from mortality can have affected the results. Finally, the prescription register was established in 2004 in Norway and provides statistics on sales and use from 1990; therefore, data were based on self-reported history, and type of BP-lowering agents was unavailable for analyses [48].

We conclude that elevated BP does not seem to be a risk factor for dementia when adjusted for age, sex, education, and other covariates. In fact, in persons over 60 years of age, SBP was inversely associated with a prospective dementia diagnosis, whereas in the middle-aged subjects (<60 years old), elevated SBP and PP were associated with eventual AD in participants who reported using BP-lowering medication. These findings are consistent with previously published studies and appear to be dependent on factors such as age, hypertension chronicity, and antihypertensive medication use. Future population-based prospective studies with repeated BP measurements examining BP variability, as well as more detailed data on BP-lowering agents, are needed because the nature of the association between BP and dementia remains unclear.