Midlife Blood Pressure, Plasma β-Amyloid, and the Risk for Alzheimer Disease

Abstract

Beta-amyloid (Aβ), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer’s disease (AD) and possibly vascular dementia (VaD). We investigated the joint association of mid-life BP and Aβ peptide levels with the risk for late-life AD and VaD. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965 – 2000). Mid-life BP was measured starting in 1971 participants mean age 58 years, Aβ was measured in specimens collected1980/82, and assessment of dementia and autopsy collection started in 1991/93. The outcome measures were prevalent (present in 1991/3) and incident AD (n= 53, including 38 with no contributing cardiovascular disease), and VaD (n=24). Cerebral amyloid angiopathy (CAA), β-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in post-mortem tissue. The risk for AD significantly increased with lower levels of plasma Aβ (Aβ1-40 hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.4 – 3.1; Aβ1-42 HR 1.6, 95% CI 1.1 – 2.3). Evidence of interaction between diastolic BP and plasma Aβ (1-40 pinteraction <0.05; 1-42 pinteraction <0.07) levels, indicated the Aβ-related risk for AD was higher when BP was higher. Low plasma Aβ was associated with the presence of CAA (ptrend<0.05), but not the other neuropathologies. Aβ plasma levels start decreasing at least 15 years before AD is diagnosed, and the association of Aβ to AD is modulated by mid-life diastolic BP. Elevated BP may compromise vascular integrity leading to CAA and impaired Aβ clearance from the brain.

Association of arterial stiffness with progression of subclinical brain and cognitive disease

“…In addition, prior evidence has suggested that arterial stiffness, blood pressure, and vascular disease strongly influence amyloid deposition in the brain and clinical manifestations of Alzheimer disease. [37][38][39] We also noted effect modification by age in our cohort, whereby larger effect sizes of the associations between abnormal arterial hemodynamics and neurocognitive dysfunction were seen in older individuals.…”

The neuropathology and cerebrovascular mechanisms of dementia

“…The authors observed that A -related risk for AD positively correlated with blood pressure, suggesting that chronic hypertension may compromise vascular integrity and is a major contributor to CAA as well as impaired A clearance. 85 In support of these observations, animal studies using the spontaneously hypertensive stroke-prone rats, an animal model of chronic arterial hypertension and cerebral small-vessel disease, have demonstrated an age-dependent parenchymal A accumulation similar to that observed in AD models. 86 Additional studies in the spontaneously hypertensive stroke-prone rats rat reveal an age-specific increase in A deposition at 12 weeks of life, followed by APP overexpression at 20 weeks and p-tau by 26 weeks in the cortex and hippocampus.…”

Antihypertensive medication use and risk of cognitive impairment

“…14 In prior HAAS analyses, lower plasma b-amyloid was associated with an increased risk of Alzheimer disease and cerebral amyloid angiopathy at autopsy, particularly among those with elevated midlife blood pressure, suggesting that hypertension may lead to microvascular injury, promoting amyloid angiopathy and impaired b-amyloid clearance from the brain. 32 It has also been suggested that, among the elderly, aortic stiffness may increase pulsatile energy in the cerebral vasculature, with subsequent microvascular damage and thereby worsening of cognitive function. 33 We hypothesize that, among individuals with hypertension, BB use may provide neuroprotection through alterations in cerebral blood perfusion, improvement of microvascular integrity, and possibly reduction of subsequent neuropathology, including cerebral angiopathy, amyloid deposition, widening of periarteriolar spaces, microinfarcts, and atrophy.…”