While larger, more definitive clinical trials in both at-risk populations and in AD patients are needed to further assess the effects of ramipril on CSF Aβ levels, our findings indicate that four months of ramipril therapy at 5mg daily has the ability to affect brain CSF ACE activity. Taken together, these results suggests that the AD-related benefits associated with BBB crossing ACE-Is could be attributed, at least in part, to an alternative mechanism such as improved CBF. That the total tau results remained stable in the treatment group but declined in the placebo group should be noted, though neither groups’ levels were suggestive of AD-related pathology (total tau <400 pg/ml [41
]). It is clear from our data that ACE-Is improve BP in mildly hypertensive, middle-aged adults. These improvements were not due to increases in cardiovascular exercise or changes in mood, diet or medications (c.f. study drug). While there were no between-group differences on cognitive task performance in middle-aged, at risk individuals, these results are not surprising considering our young sample was cognitively normal.
There has been conflicting evidence concerning the ability of ACE-I to inhibit ACE activity in the human brain [4
]. Our data indicate that ramipril is able to cross the BBB and inhibit brain ACE activity. This effect may be exacerbated in participants with advanced AD or hypertension, as both have been linked to increased permeability of the BBB [42
]. These data are important due to reports demonstrating increased ACE activity in CSF and postmortem tissue of AD patients [6
]. It is possible that increased ACE activity and subsequent increases in Ang II play a central role in AD neuropathology and decreasing Ang II production via ACE-I therapy could explain reports of AD related benefits by BBB crossing ACE-I, particularly during midlife.
While elevated ACE activity reportedly correlates with AD severity and with parenchymal Aβ load [6
], the exact relationship between ACE activity and Aβ remains unclear and warrants further clinical investigation [45
]. Our data did not reveal a treatment effect of four months of ramipril on Aβ levels. From this pilot clinical trial, we cannot definitively conclude whether ACE-I affect Aβ because CSF Aβ levels declined in both groups. However, prior reports of AD-related benefits such as cognitive performance among AD patients and decreased disease incidence do not appear to be mediated by a direct effect of ACE-I on Aβ from our data.
The lack of a treatment effect in the present study could be due to the short duration of the trial, too few participants, or possibly an effect of dose. Additionally, our middle aged sample demonstrated CSF Aβ levels found in normal control populations (Aβ > 450 pg/ml; [41
]), suggestive of efficient Aβ clearance mechanisms and lower brain Aβ levels compared AD patients. Thus the apparent lack of Aβ neuropathology may lessen the potential treatment effect in our sample more so than an AD sample.
While some basic science studies have reported that Ang II stimulation promotes Aβ production, it is also possible that prior studies reporting AD-related cognitive benefits by ACE-I may be attributed to an alternative mechanism, such as improved CBF [46
]. Recent neuroimaging studies show that patients with MCI and early AD exhibit elevated CSF ACE and hypoperfusion in the parietal cortex [47
]. This region is also co-localized by ACE, Ang I and Ang II receptors and is therefore a potential site for increased vasoconstriction in early AD [48
]. Thus, ACE-I may have the ability to improve CBF via inhibiting ACE activity in regions selectively affected in early AD. While the current study did not employ a measure of CBF, prior research has shown that ACE-I increase CBF in patients with heart failure [50
]. Also, a large randomized trial reported that treatment with perindopril, a BBB crossing ACE-I, prevented development of new white matter hyperintensities (WMH) and delayed the progression of existing WMH in patients with cerebrovascular disease [51
Further evidence for the potential of ACE-I to improve CBF is supported by ACE-I mechanism of action. The ACE-I mechanism of action involves preventing the conversion of Ang I to Ang II, thereby dilating the peripheral arteries and improving vascular function. In the brain, Ang II can exacerbate Aβ production and is known to increase inflammation, vasoconstriction and mitochondrial dysfunction, decrease G-protein signaling and increasing cerebral endothelial dysfunction (For a comprehensive review see [52
]). Thus, if ACE-I have the ability to reduce ACE activity in the CNS, as supported by our data, subsequent reductions in Ang II, a potent vasoconstrictor may improve CBF in the brain as it does in the peripheral vasculature.
Another mechanism by which centrally acting ACE-I may produce favorable AD-related effects is by increasing the release of acetylcholine [52
]. Ang II has been implicated in inhibiting the release of acetylcholine, the neurotransmitter widely recognized in AD [53
]. Thus, ACE-I mediated increases in acetylcholine release via reduction in Ang II may contribute to AD related cognitive benefits [44
A BBB crossing ACE-I was selected over alternative antihypertensive medications based on prior basic science, observational and clinical studies reporting cognitive benefits and reduced AD incidence and progression compared to other medications [12
]. Ramipril is among the most effective agents for lowering BP and the most commonly prescribed ACE-I, comprising 50% of ACE-I prescriptions and 38% of the cost according to the United Kingdom’s NICE guidelines [55
]. The ability of ramipril to cross the BBB is significant, as we were interested in ramipril’s direct action on Aβ levels and ACE activity, and meta-analyses have shown that BBB crossing antihypertensives elicit more pronounced cognitive benefits than non-centrally acting medications [12
The central limitation of the SEAIRA pilot trial is the small sample size. While only 14 well characterized participants were enrolled, this pilot clinical trial has successfully demonstrated the feasibility of conducting randomized clinical trials to investigate the effects of antihypertensive medications on AD biomarkers in humans. While it was not appropriate to control for multiple comparisons in our analyses, it is important to note that post-hoc analyses revealed that the significant effects of ACE activity and BP measures did not survive such analyses, which was likely also due to our small sample size. This is the first randomized, placebo controlled clinical trial examining the effects of a BBB crossing ACE-I on AD biomarkers in a preclinical sample. Initial results from the SEAIRA trial provide support for larger clinical trials which are urgently needed considering the increasing incidence of AD, vascular disease and the number of individuals currently taking antihypertensive medications. Similar clinical trials in AD cohorts are also particularly important, as AD-related cognitive deficits and Aβ neuropathology are more pronounced in patient populations and therefore may be more sensitive to treatment effects.
Further clarification of RAS-acting antihypertensive medications on AD and cognition is crucial. If hypoperfusion and the presence of Aβ lead to neuronal damage in part through deregulation of CNS ACE activity and elevated BP, then modifying CBF and Aβ accumulation through the use of ACE-Is may potentially reduce the risk of developing AD in high-risk individuals. Larger clinical trials with ACE-I and A2RB, particularly those that incorporate CSF Aβ and CBF measures, are highly warranted. Future trial designs would also benefit by including a non RAS-acting treatment arm in order to differentiate between BP mediated effects vs. Ang II related effects in relation to AD pathology.