Blood Pressure, Amyloid β and tau, Cerebral Amyloid Angiopathy: A Pathway for Alzheimer's Dementia Management

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Project Summary Maintaining optimal cognitive function is an important component of successful aging. A better understanding of risk factors and the pathophysiological mechanisms of cognitive decline is critical for early diagnosis and treatment of dementia. Alzheimer’s disease (AD) is the leading cause of dementia in older adults. Both high and low systolic blood pressure (SBP) and diastolic blood pressure (DBP) as well as high pulse pressure (PP) in late-life are associated with AD-related dementia. The APOE ε4 allele, a strong genetic risk factor for both early-onset AD and late-onset AD, promotes cerebral amyloid accumulation, aggravates the effect of hypertension on neuronal damage, and promotes cerebral amyloid angiopathy (CAA) formation. CAA, a common asymptomatic feature of older adults and the most frequently seen (about 80-90%) vascular abnormality in AD, is associated with brain atrophy and cognitive decline in older adults leading to AD dementia. Hypertension promotes early endothelial dysfunction leading to accelerated formation of CAA. Considering its significant effect in aging brain outcomes, preventing the formation of CAA through proper monitoring and treatment of BP is essential. The relationship between BP profile and aging brain outcomes can be better understood through a rich longitudinal community-based dataset of older adults like the Adult Changes in Thought (ACT) autopsy data (n=850). Fundamental gaps in knowledge exist regarding the underlying mechanisms of systemic and central vascular risk factors in cognitive decline in AD in relation to APOE ε4 allele status. Thus, we will fill the gaps by examining the following specific aims: 1) To test the hypothesis that late-life elevated BP and PP (≥140/90, PP > 50 mmHg) or low late-life BP (≤90/60mmhg) are associated with higher amyloid β (CERAD) and tau (BRAAK) stages, controlling for age, sex, antihypertensives, APOE ε4 allele. 2) To test the hypothesis that elevated late-life BP or low late-life BP are associated with higher CAA prevalence and severity, controlling for age, sex, antihypertensives, APOE ε4 allele, CERAD and BRAAK stages, and lacunar infarcts. 3) To test the hypothesis that higher CAA prevalence and severity are associated with higher risk for cognitive impairment (CASI) and dementia, controlling for age, sex, APOE ε4 allele, and lacunar infarcts. We will conduct our project with the well-characterized group of individuals from the ACT (U01 AG 06781). Innovations of this study include gold-standard pathological data with longitudinal, prospectively collected community-based research data and assessment of systemic and central vascular risk factors in association with dementia by APOE ε4 allele.