Shedding Light on the Effects of Blood Pressure on Cognitive Decline and Dementia Risk by Way of Neurobiological Evidence

Though white matter hyperintensities and infarcts preferentially predict the development of vascular dementia [1], vascular pathology is a prominent feature of Alzheimer’s disease, particularly among the oldest old; it may be found in all neuropathological subtypes of the disease regardless of the distribution of neurofibrillary tangles [2]. Nonetheless, high cognitive function throughout life may lead to less exposure to cerebrovascular risk factors and, therefore, less susceptibility to their effects on cognition [3].

It is currently accepted that, when present throughout life, combinations of cerebrovascular risk factors reduce white matter integrity and increase risk of late life cognitive impairment and dementia [4], while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life, possibly due to enhanced cerebral perfusion overcoming the ineffective cerebral autoregulation [5]. Further evidence has shown that longitudinal decline in late life systolic blood pressure, or even slower increase, may be associated with higher risk of incident dementia [6] and tauopathy measured by cerebrospinal fluid biomarkers [7].

In patients with dementia, blood pressure decreases with time mostly due to degeneration of noradrenergic neurons of the locus coeruleus that may lead to decreased concentrations of norepinephrine in the brain; as a result, rising blood pressure in APOE ɛ4 carriers with Alzheimer’s disease has been shown to improve cognitive and functional test scores [8]. Stratification of samples according to APOE ɛ4 carriership is important [9] due to the fact that endothelial dysfunction and vascular burden are more onerous for APOE ɛ4 carriers [8], while such genetic variants may differentially affect longitudinal outcomes in patients using psychotropic drugs [10]. In addition, higher pulse pressure (a marker of age-related arterial stiffening) has been associated with incident dementia, elevated phospho-tau and reduced Aβ_1–42 in the cerebrospinal fluid of older adults [11]. One study found that high and low pulse pressure and diastolic blood pressure levels were associated with faster cognitive decline in patients with Alzheimer’s disease [12]. Since not all studies have reproduced the same findings [8], controversy remains on what is the best measure of blood pressure to correlate with cognitive decline in dementia, also due to possible reverse causality.

In a recent issue of the Journal of Alzheimer’s Disease, Sible & Nation [13] used the SPRINT (Systolic Blood Pressure Intervention Trial) data to analyze the association of blood pressure variability with changes in plasma total tau and the Aβ_1–42/Aβ_1–40 ratio in 457 participants with high coronary artery disease risk. They found that wider blood pressure variability was associated with increased levels of plasma total tau in the standard blood pressure treatment group, but not in the intensive treatment group. Blood pressure variability was not associated with plasma Aβ_1–42/Aβ_1–40 ratio changes in either group. Mean blood pressure was not associated with Alzheimer’s disease biomarkers in either group. They concluded that, despite strict control of mean blood pressure, blood pressure variability increases risk for pathophysiological change in the Alzheimer’s disease continuum.

It has been known for quite some time that blood pressure variability is associated with structural brain changes and cognitive decline in Alzheimer’s disease [14]. With a properly sized sample [15], the differential aspects of the study by Sible & Nation [13] include the assessment of older adults with high coronary artery disease risk and the availability of neurobiological evidence of neurodegeneration by way of easily collectable biomarkers.

Evidence from SPRINT showed that intensive blood pressure management reduced accrual of white matter hyperintensities compared to standard therapy [16], as well as the incidence of mild cognitive impairment. However, effects of intensive blood pressure management on risk of incident dementia were not appealing possibly due to the fact that the study was underpowered for this aim [17], but also due to dysautonomic regulation of brain perfusion already expected in older adults with higher cerebrovascular risk. In addition, higher coronary artery disease risk has been associated with later onset of Alzheimer’s disease in women [18] and with slower cognitive decline in APOE-ɛ4 carriers with Alzheimer’s disease [19], a possible confounding factor for the analyses of SPRINT data [17]. The study by Sible & Nation [13] shows that blood pressure variability preferentially affects neurodegenerative mechanisms rather than amyloidogenesis, even though the plasma Aβ_1–42/Aβ_1–40 ratio is insufficiently accurate to predict amyloidosis [20]. Moreover, plasma phospho-tau is an indicator of both amyloid-β and tau pathology [21] that might have shed more light on the pathophysiological complexities of Alzheimer’s disease had it been measured. Furthermore, lacking stratification according to APOE ɛ4 carriership is an important limitation of SPRINT, since APOE ɛ4 alleles are genetic risk factors for faster brain atrophy, blood-brain barrier dysfunction, inefficient neural repair, cerebral amyloid-β deposition, tau homeostasis and dissemination of neurofibrillary tangles [9, 22].

Neuroprotective mechanisms have been attributed to several classes of anti-hypertensive drugs, regardless of blood pressure lowering effects [8], though neurobiological evidence seems to stand out with angiotensin modulators when reducing cognitive and functional decline [23]: angiotensin II receptor blockers benefit mostly APOE ɛ4 carriers with Alzheimer’s disease by way of suppression of AT1 receptors while preserving the amyloid-β-degrading properties of the angiotensin-converting enzyme, while angiotensin-converting enzyme inhibitors benefit APOE ɛ4 non-carriers with Alzheimer’s disease due to improved blood pressure control possibly in association with reduced angiotensin II-mediated inhibition of acetylcholine release, increased substance P (which boosts neprilysin activity) and improved insulin sensitivity.

In addition to APOE ɛ4 carriership [24], ACE has been reported as a susceptibility gene for Alzheimer’s disease [25], but not for vascular dementia [26]. The deletion allele of the ACE insertion/deletion polymorphism has been associated with increased serum levels of the angiotensin-converting enzyme and better blood pressure response to angiotensin-converting enzyme inhibitors [27], as well as with increased risk of affective disorders in APOE ɛ4 carriers with Alzheimer’s disease [28]. Incidentally, affective disorders [29] and cognitive function [30] have been associated with cerebrospinal fluid measures of tauopathy and amyloidosis in Alzheimer’s disease.

The implications of the study by Sible & Nation [13] run deep. Precise selection of anti-hypertensive drugs with neurobiological evidence of benefits and considering patients with ideal genetic backgrounds may be the best way to prevent the harmful neurodegenerative mechanisms that result from increased blood pressure variability.