This two-sample MR study, in which we used genetic variants as proxies associated with BP in a very large cohort of well-characterized research participants, provided suggestive evidence for associations between genetically exposure to BP-lowering through AHMs and a reduced risk of AD, and further identified CCB as a promising strategy for AD prevention. However, these results should be interpreted with great caution.
Hypertension has been implicated as a risk factor for AD . However, uncertainties remain over the nature of the association, which perhaps is complicated by misclassification of different forms of dementia, or the age of study participants [2, 27]. Several studies suggested that high BP in midlife was associated with a higher risk of AD, whereas other studies indicated that high BP in late life might be protective against AD [2, 27, 28]. Large-scale biobank datasets can provide an unparalleled opportunity to undertake hypothesis-free causal inference. Using a MR approach, the current study failed to identify a causal relationship between SBP level and AD risk. Previous observational studies have produced a consistent finding of no association between high blood pressure and AD in late-life . There are two earlier studies using MR to evaluate the association of SBP with AD cases-control status. Østergaard and colleagues observed that higher SBP was associated with a reduced risk of AD . However, Larsson and colleagues exploited more SNPs, finding no significant association between SBP level and AD . Andrews and colleagues also found a null association between PRS for increased SBP and AD risk .
The association of DBP level with clinically diagnosed AD has not been extensively studied, though several studies have conducted phenome-wide scans. Using data from the UK Biobank, Richardson and colleagues found that a higher AD PRS was associated with lower DBP . Similarly, a second study by Korologou-Linden and colleagues evaluated the association of an AD PRS composed of 18 SNPs, inclusive of APOE, finding that a higher AD PRS was associated with lower DBP . This present result was also suggestive of an association between high DBP level and a lower risk of AD. High BP in late life might be protective against AD. Consistent with this, one study also showed a greater effect of decreased DBP on white matter hyperintensity volume (WMHV) burden, particularly among those who previously had a greater increase in SBP . Hypotension in late life might aggravate cerebral small vessel disease and decrease brain volume in cognitively normal individuals, potentially via shifts in the auto-regulatory curve and resultant cerebral hypoperfusion [32, 33]. Alternatively, this finding might be mediated by increased arterial stiffness, which is associated with decreased DBP, although we did not find a direct association between PP, a proxy marker of arterial stiffness, and AD risk. One recent MR analysis observed association between high BP and vascular brain injury (VBI), which suggests that while reducing BP in late life may have limited utility in the prevention of AD, it may reduce the risk of vascular dementia by reducing the risk of VBI, but not specifically affect the risk of AD .
There is also a wealth of evidence in the literature from observational studies indicating that antihypertensive therapy may protect against AD or delay its onset [4, 5]. A recent high-quality meta-analysis found that among people with high BP, the use of AHMs might reduce the risk of AD . A British cohort study of dementia-free individuals concluded that BP monitoring and interventions need to start around 40 years of age to preserve cognition in older age . However, the well-known SPRINT MIND study didn’t found any significant difference in the risk of dementia between intensive and standard BP control . The study may have been underpowered for this end point due to early study termination and fewer than expected cases of dementia. Using MR, the current study extends previous evidence using genetic variants in a very large cohort of well-characterized research participants, and then selected gene targets of AHMs, showing that genetically determined lowering BP through AHMs was associated with a lower risk of AD, and CCB was identified as a promising strategy for AD prevention (we depicted a schematic diagram of mechanism here, see Figure 4). One RCT found beneficial cerebrovascular effects of calcium antagonists on AD . However, one recent MR analysis have showed that lowering SBP via AHMs is unlikely to affect the risk of developing AD, and if specific AHM classes do reduce the risk of AD, the mechanism may not be via SBP pathway . Actually, studies have pointed out that some drugs, acting through calcium channel blocking mechanisms, have protective effects on AD, independently of BP lowering . For example, the intracellular buildup of calcium in neurons can be neurotoxic and thus CCB might result in neuroprotection . Although, the underlying mechanism mediating the protective effects of AHMs on AD remains unclear and warrants further research, MR analyses surely hold huge promise in the era of large-scale genetic epidemiology to identify risk or protective factors. Associations detected between AHMs (including CCB) and AD risk undertaken by large-scale analyses should prove powerful for future studies that wish to unravel causal relationships between complex traits .
The results of this study should be interpreted in conjunction with some limitations. First, we used genetic variants derived from a study with a relatively large sample size which were strongly associated with BP to avoid weak instrument problems, but our finding may still be affected by weak instrument bias . Second, we were limited by the fact that MR explores the effect of lifelong exposure, whereas drugs typically have much shorter periods of exposure and BP may have age-dependent effects. The effect sizes that we have estimated will not represent the associations between critical periods of exposure and the outcome . This can also be particularly problematic if the protein target of a drug is beneficial at one point during the life course and harmful at another. Thus, further work, especially RCTs, is recommended to investigate the pathways from BP/AHMs to AD and to explore how the effect varies with age. Third, as drug target models only focus on-target effects of the specific therapeutics, our genetic results for drug targets cannot reflect the pharmacokinetics of drug use. Thus, the associations between the drugs and the outcome can’t be fully reflected by the present analysis. Fourth, though we chose a liberal LD clumping threshold (R2<0.4) when selecting the variants associated with AHMs according to previously published approaches, this threshold introduced several dependent variants. We further employed more stringent thresholds (R2<0.1 and R2<0.001); these results inferred the possibility that a single locus with multiple SNPs might partly drive the association. Therefore, the positive associations of AHMs, including CCB with reduced AD risk should be interpreted with great caution. Fifth, we failed to explore the protective effects of other AHM classes, including ACEI, ARB, BB and thiazide diuretics. These null results didn’t mean that there were no protective effects of these medications, given that the limited number of included SNPs failed to offer sufficient statistical power to perform meaningful analyses. Future studies encompassing larger GWAS datasets for BP might identify more variants and offer deeper insights into the effects of different classes of BP lowering agents on AD. Sixth, the estimated effect of BP level on AD risk, which is associated with a high risk of mortality, may be susceptible to survival bias. Last, since all of participants are of European ancestry, the results of this study are not necessarily valid for other ethnic groups.