Frequency of Microvascular Pathology and Hippocampal Atrophy on Magnetic Resonance Imaging in a Community Study of Alzheimer's Disease with Blood-Based Biomarkers.

OBJECTIVE

Blood-based biomarkers for Alzheimer's disease (AD), representing antemortem indicators of AD pathophysiology, have greatly improved the accuracy of diagnosis. However, these biomarkers may not capture a frequent coincident pathology, such as cerebrovascular disease.

METHODS

We measured plasma amyloid-β40, amyloid-β42, total tau, tau phosphorylated at threonine 181, tau phosphorylated at threonine 217, glial fibrillary acidic protein, and neurofilament light chain in 685 multiancestral individuals who had clinical assessments and brain magnetic resonance imaging. The cohort was represented by individuals of European, African American, and Caribbean Hispanic ancestry. Participants were then classified as biomarker-positive or -negative for AD based on previously established cutoffs: 2.65 pg/mL for, tau phosphorylated at threonine 181 and 0.39 pg/mL for tau phosphorylated at threonine 217. We used magnetic resonance images to compare white matter hyperintensity volume (WMH), silent brain infarcts, microhemorrhages, and hippocampus volume across groups by their clinical diagnosis and biomarker status.

RESULTS

In the P-tau181 group (n = 685), 70 individuals (10.2%) had dementia or amnestic mild cognitive impairment. A total of 40 (57%) were biomarker-positive for AD, and 30 were classified as other dementia. Among 615 without dementia, 265 (40.3%) were preclinical AD, and 348 (50.8%) were biomarker-negative controls. In the tau phosphorylated at threonine 217 group (n = 535), 54 (10.1%) had dementia or amnestic mild cognitive impairment, including 33 biomarker-positive for AD and 21 with other dementia, whereas 183 (38.0%) were preclinical AD and 298 (61.9%) were biomarker-negative controls. Across both classifications, biomarker-positive for AD and other dementia individuals showed greater WMH volumes, more infarcts, and smaller hippocampus. However, P-tau217 positivity was more sensitive to WMH volume differences, whereas tau phosphorylated at threonine 181 better captured hippocampal atrophy and silent brain infarcts. Interestingly, ethnic differences may also influence detection of changes in WMH volumes, hippocampal volume, and infarcts in relation to specific biomarkers.

INTERPRETATION: The results indicate that cerebrovascular disease is consistently involved in dementia either directly or as a coincident pathology in AD. These results underscore the need to incorporate both blood-based biomarkers and structural imaging in the evaluation of patients with dementia. ANN NEUROL 2025;98:1027-1043.