Impact of Cerebral Microbleeds on Tau-Associated Cognitive and Structural Decline

Cognitive impairment in older adults is influenced by coexisting β-amyloid (Aβ), tau, and cerebral small vessel disease (CSVD). Cerebral microbleeds (CMBs) are associated with Aβ and CSVD, but their role on tau-related neurodegeneration remains unclear. We investigated whether the CMBs modify tau-related disease progression.

A longitudinal, prospective cohort study was conducted involving participants with mild cognitive impairment, Alzheimer disease dementia from the memory disorder clinic of the single tertiary center, or cognitively unimpaired from the community. All participants underwent cognitive assessment, MRI, ¹⁸F-flutemetamol PET for Aβ, and ¹⁸F-MK-6240 PET for tau at baseline. Cognitive tests were performed annually and MRI at 2 years. Cognitive decline was defined by score changes over this period and cortical atrophy as annual cortical thickness change. Linear regression analyses were conducted after stratifying by total or lobar CMB presence.

Among the 201 participants (mean age 71.3 ± 7.0 years, 66.7% female), 95 had CMBs and 106 did not. Baseline Aβ or tau burden did not significantly differ between the 2 groups while white matter hyperintensity volume and lacunes were greater in the CMB group. Cross-sectionally, greater tau burden correlated with worse cognition, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) or Mini-Mental State Examination (MMSE) in both groups. Longitudinally, baseline tau burden was associated with CDR-SOB progression in the non-CMB group (β = 1.558, SE = 0.249, p < 0.001), but not in the CMB group (β = -0.031, SE = 0.405, p = 0.940; p-for-interaction = 0.001). Similar group differences were found for MMSE changes (non-CMB: β = -2.365, SE = 0.566, p < 0.001; CMB: β = -0.816, SE = 0.653, p = 0.217; p-for-interaction = 0.073). Stratification by lobar CMBs confirmed significant interaction effects for both CDR-SOB (p-for-interaction = 0.007) and MMSE (p-for-interaction = 0.045) scores. Imaging analysis showed more extensive cortical atrophy in the CMB group, but tau-related cortical atrophy was widespread only in the non-CMB group and minimal in the CMB group.

In the non-CMB group, tau burden was strongly associated with cognitive decline and cortical atrophy. By contrast, the CMB group exhibited greater CSVD burden and pronounced neurodegeneration not explained by tau, suggesting that additional mechanisms such as CSVD related to cerebral amyloid angiopathy or neuroinflammation may contribute to disease progression in this group.