Age, sex, and cerebral microbleeds in EFAD Alzheimer disease mice.

• Microbleeds of EFAD are detected by 2 months; most are "naked" with no plaque contact. • Microbleeds and cerebral amyloid angiopathy are distributed in different cortical layers. • The ratio of microbleeds:plaques decreases after 2 months, with female bias. • Microbleed size does not increase with age, suggesting single event of extravasation. • MBs may seed amyloid aggregation in plaque formation. Cerebral microbleeds (MBs) increase at later ages in association with increased cognitive decline and Alzheimer Disease (AD). MB prevalence is also increased by APOE4 and hypertension. In EFAD mice (5XFAD+/−/human APOE+/+), cerebral cortex MBs are most prevalent in E4 females at 6 months, paralleling plaque amyloid. We evaluated MBs at 2, 4, and 6 months in relation to amyloid in plaques and cerebral amyloid angiopathy (CAA) by age, sex, APOE allele, and blood pressure. At 2 mo, MBs were 50% more numerous than plaques, followed by decreased ratio of MBs:Aβ plaques with female excess to 6 mo. The stable size of MBs suggests MBs arise as single events of extravasation, which may "seed" plaque formation. Blood pressure was normal from 2 to 6 months, minimizing a role of hypertension. Memory, assessed by fear conditioning, decreased with age in correlation with MBs and amyloid. Cortical layer analysis showed prevalent MBs and plaque in layers 4 and 5. Contrarily, CAA was prevalent in layers 1 and 2, discounting its contribution to MBs. [ABSTRACT FROM AUTHOR]