CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 4, July/August 2014
AFRICA
149
Editorials
Cognitive decline: mechanisms and proposed role of the
renin–angiotensin–aldosterone system
Lionel H Opie
Normal cognitive functioning
Cognition is derived from the Latin ‘cognitio’, meaning the
process of acquiring knowledge, with related meanings such as
study, recognition, social connectivity and discovery. The most
crucial components of cognition are the ability to learn and
remember new information,
1
and to function adequately in daily
intellectual and interactive aspects of life.
Maintenance of normal functional cognitive activity is vitally
important in everyday activities. Conversely, cognitive decline, as
normally occurs during the ageing process, is a handicap. Such
decline varies from moderately inconvenient benign forgetfulness
to the devastating losses associated with Alzheimer’s disease and
brain ischaemia.
2
Cognitive function as part of optimal health
Stroke, often associated with untreated hypertension, is common
in Africa. In the USA, the move is towards stroke prevention,
by paying attention to the blood pressure as one of life’s simple
seven (LS7) health metrics (blood pressure, cholesterol, glucose,
body mass index, smoking, physical activity and diet).
3
Healthy levels of these components are in the higher ranges of
the following scale: inadequate (0–4), average (5–9), or optimum
(10–14) cardiovascular health. In a large USA population
(22 914, 42% black) over 4.9 years of follow up, better
cardiovascular health on the basis of the LS7 score was associated
with lower risk of stroke. Therefore, not surprisingly, higher
LS7 scores were associated with lower incidence of cognitive
impairment.
4
As expected, cognitive function may be related to blood
pressure (BP) control. Starting with a population of Japanese
subjects with mean age 63 years and without cognitive decline,
follow up after nearly eight years showed about one in 10 had
undergone cognitive decline that was associated with an increase
in systolic BP (odds ratio 1.48;
p
=
0.03).
5
Also of interest was the
link between increases in home systolic BP and the significant
association with cognitive decline (odds ratio, 1.48;
p
=
0.03).
5
The benefit of BP reduction was endorsed by links between
systolic BP
≥
140 mmHg or diastolic BP
≥
90 mmHg and faster
decline of cognitive function over two years of follow up in 1 385
persons.
6
Thus far there has been no formal trial on the effects of
BP control on cognitive function but one large trial is planned.
7
Role of the renin–angiotensin–aldosterone
system (Fig. 1)
The brain has an essential evolutionary role in self-protection,
centered on the concept that harmful stimuli must evoke
protective mechanisms. As the renin–angiotensin–aldosterone
system (RAAS) has a pivotal role in cognitive impairment,
8
logically, the use of centrally acting angiotensin converting
enzyme (ACE) inhibitors should and does slow the rate of
decline.
9
These agents act on the RAAS in the hippocampus.
Although statins also benefit mild cognitive impairment,
10
they
do not act centrally on the brain but on the blood–brain barrier.
11
Inhibition of the RAAS to limit cognitive
decline
Inhibition of the RAAS ranks among the best established and
most used cardiovascular therapies by providing protection
against hypertensive damage and heart failure, and the
microvascular complications of diabetes. RAAS inhibitors have
contributed to the longer life expectancy now found in higher-
income populations throughout the world. However, longevity
propels aging persons closer to the inevitable cognitive decline
that is of variable gravity.
Perhaps unexpectedly, it is here that the RAAS inhibitors may
have a special role, especially in the many elderly persons with
hypertension. The two centrally active ACE inhibitors, captopril
Ox stress
Inflammation
Blood-brain-barrier damage
Brain blood flow less
Cognitive function
Ox stress less
Inflammation countered
Blood-brain-barrier better
Brain blood flow increased
AT 1 receptor
Angio 1
Angio 2
Effect on AT 2 receptor
ACEi centrally acting
ACE converting enzyme
Redrawn & revised from Int J HPT, Dec 2012
Fig. 1.
The proposed opposite effects on cognitive function of
stimulation of the angiotensin 1 (AT1) and AT2 recep-
tors. The ARBs have a similar functional effect on the
centrally acting ACE inhibitors in enhancing cognitive
function (see text).
