In all people, hypertension is the main risk factor for stroke. In APOE4 carriers, untreated hypertension also increases risk of amyloid accumulation in brain, cognitive decline and risk of of AD in APOE4 carriers. 

Rodrigue, "Risk factor for B-Amyloid Deposition in Healthy Aging" (64) was excellent study to demonstrate great importance of hypertension in pathogenesis of neurodegeneration and AD as regards APOE4 carriers. They included 147 participants, (aged 30-89, mean age 54) who underwent PET scan for amyloid in brain. They were divided into two groups, APOE4 positive and APOE4 negative.The amount of amyloid was correlated with normotensive, hypertensive treated and hypertensive untreated. Amyloid increased with age.

The normotensive E4+ and E4- groups were the same for amyloid.

The hypertensive treated groups both showed slight increase in amyloid.

The E4 negative group with untreated hypertension had minimal increase in amyloid.

The group E4 positive plus untreated hypertension had dramatic increase in brain beta-amyloid.

In E4 positive group there was direct relationship between pulse pressure and amount of amyloid.

The study showed that untreated hypertension greatly increases amyloid burden in APOE4 carriers.

The  Guo(65) paper, "Apolipoprotein E genotypes and the incidence of AD among persons aged 75 and Older", examined treatment of hypertension in elderly Swedish subjects, 75 and older for 3 years. They found use of anti-hypertensive med (80% used diuretics) very beneficial to reduce risk of AD in all groups. As regards APOE4 vs APOE3 risk was 1.7 for AD. All subjects using anti-hypertensive medication at baseline had decreased risk of AD (RR= 0.5). 

For APOE4 carriers, those not treated for hypertension had RR of 2.3 for AD and those using anti-hypertension medications had RR of 1.1 for AD. They concluded, "The effect of antihypertensive medication was more pronounced among E4 carriers."

The de Frias study (66)  followed a group of 563 non-demented adults, ages 32 to 74 years, for 21 years, measuring 7 tests of cognitive performance. The study looked at effect APOE4 and hypertension over time. This was a Seattle Longitudinal study begun in 1984. 

 "APOE e4 carriers had a performance advantage at baseline  on reasoning ability, relative to non-E4 carrriers".

"The additive effect of hypertension on level of cognitive flexibility (i.e., lower performance for hypertensives) was qualified by a significant APOE x Hypertension interaction on the slope. Hypertension moderated the effects of APOE e4 on the rate of change of cognitive flexibility, such that the presence of the APOE e4 allele and hypertension was associated with steeper cognitive decline over a 21-year period."

The cognitive decline over time of APOE4 carriers was exacerbated  by hypertension.

This study followed the effect of untreated mid-life hypertension on risk of late-age dementia. "Midlife blood pressure and dementia, Honolulu Heart Program", Launer, 2000. (67). The study followed 3700 men from 1965-1971 and then evaluated men for dementia @20 years later in 1991.

                   Diastolic BP          Odds Ratio

                       80-89                         1.0

                       90-94                         3.8

                       >94                            4.3

                  Systolic BP

                       110-139                    1.0

                       >160                          4.8

Blood pressure associated with risk of dementia and AD in untreated men in contrast to treated men. They conclude: "This study suggests elevated levels of blood pressure in middle age can increase the risk for late age dementia in men never treated with anti-hypertensive medication."  [not specific for APOE status]

The Cache County study, Khachatarian, 2006,(68) looked at relationship between elderly persons (aged 65 years and older) and AD. They looked at treatment for hypertension over 3 year period. The results were use of any anti-hypertensive medication at baseline was associated with adjusted hazard ration of 0.64.  [Note: In Qiu study (83) treatment of hypertension in elderly [mean age 76] with angiotensin II blockers was of benefit only to non-E4 carriers; but not of benefit to APOE4 carriers.]

These studies show great importance to treat hypertension, especially in middle-aged, in APOE4 carriers to prevent accumulation of amyloid in brain, to prevent cognitive decline and to decrease risk of AD.