Angiotensin II blockers

As shown above, epidemiologic data have typically shown an association between use of antihypertensive drugs and lower risk of AD. Drugs that target the renin-angiotensin system and block action of Angiotensin II are one of most effective and widely used means of reducing hypertension and cardiovascular morbidity. These include 2 classes of drugs, angiotensin converting enzyme inhibitors (ACE), (Lisinopril, Enalapril) and Angiotension receptor blockers (ARB), (Candesartan). 

In study by Sink, (81)(Cardiovascular Health study) 2009, followed 1000 persons for 5 years and studied risk of dementia when hypertension treated with ACE inhibitors vs other anti-hypertensive meds. Finding was that centrally acting ACE inhibitors had 65% less decline, while non-centrally acting ACE inhibitors had 20% more risk of decline, Centrally acting ACEs cross the blood-brain-barrier (Lisinopril) while non-centrally acting (enalapril) do not cross BBB and were significantly inferior in prevention AD.

In very large study by Li, 2010,(82) involving 800,000 persons (mostly men) at VA hospital, showed ARBs had HR 0.76 and ACE (Lisinopril, crosses BBB) had HR 0.81 compared to all  other anti-blood pressure meds.

These studies confirmed that reducing effect angiotension II with centrally acting ARB or ACE was most effecting blood pressure meds to reduce risk of AD. 

Only one study was found regarding treatment APOE4 carriers:

"Angiotensin converting enzyme inhibitors and the reduced risk of AD in absence APOE4 allele", Qiu, 2013.(83)

Followed 4800 persons, mean age 76.5 start study for mean 3.4 years with annual exams. Treated with ACEi both peripherally and central acting.

Results: APOE4 NEGATIVE: 0.68, 0.46, Odd ratio for peripheral and central respectfully. Reduced risk to develop AD.

APOE4 carriers: NO BENEFIT; 1.22, 1.04, peripheral and central acting respectfully.

"In conclusion, ACE inhibitors...associated with reduced risk of AD in ABSENCE OF APOE4, but had no such effect on those carrying the APOE4 allele."

My analysis of this result is confirms that AD in APOE4 carriers is a different disease and all results need to be examined specifically as regards APOE4 carriers as was done in this excellent study.

The Qiu study shows in age group of 75 and older, treatment with ACE inhibitors were not of any benefit to reduce risk of AD. This is probably true for all anti-hypertensive meds. 

I would suggest that treatment of hypertension in 75 y/o APOE4 carrier group does not reduce risk of AD because they already have very extensive damage to cerebral microcirculation. I would also suggest that this study does not mean treatment of hypertension in younger age group of APOE4 carriers is not beneficial. I  consider this finding in Qiu study as very important; but specific to this age group and should not be generalized to all age groups.