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β-Amyloid (Aβ), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer disease (AD) and possibly vascular dementia. We investigated the joint association of midlife BP and Aβ peptide levels with the risk for late-life AD and vascular dementia. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965-2000). Midlife BP was measured starting in 1971 in participants with a mean age of 58 years; Aβ was measured in specimens collected in 1980-1982, and assessment of dementia and autopsy collection started in 1991-1993. The outcome measures were prevalent (present in 1991-1993) and incident AD (n=53, including 38 with no contributing cardiovascular disease) and vascular dementia (n=24). Cerebral amyloid angiopathy, β-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in postmortem tissue. The risk for AD significantly increased with lower levels of plasma Aβ (Aβ1-40 hazard ratio: 2.1 [95% CI: 1.4 to 3.1]; Aβ1-42 hazard ratio: 1.6 [95% CI: 1.1 to 2.3]). Evidence of interaction between diastolic BP and plasma Aβ (1-40 P(interaction)<0.05; 1-42 P(interaction)<0.07) levels indicated that the Aβ-related risk for AD was higher when BP was higher. Low plasma Aβ was associated with the presence of cerebral amyloid angiopathy (P(trend)<0.05) but not the other neuropathologies. Aβ plasma levels start decreasing ≥15 years before AD is diagnosed, and the association of Aβ to AD is modulated by midlife diastolic BP. Elevated BP may compromise vascular integrity leading to cerebral amyloid angiopathy and impaired Aβ clearance from the brain. [ABSTRACT FROM AUTHOR]