Striatal functional connectivity alterations in mild cognitive impairment subtypes defined by CSF A/T biomarkers

Mild cognitive impairment (MCI) is the prodromal stage of Alzheimer's disease (AD), the primary cause of dementia. In addition to supporting motor and higher-order cognitive activities, the basal ganglia, particularly the caudate nucleus and putamen, may exhibit early AD-related network changes. This study investigated differences in striatal functional connectivity (FC) across MCI subtypes marked by cerebrospinal fluid (CSF) amyloid-β (Aβ42) and phosphorylated tau (p-tau) (A/T) biomarkers (A+/A- and T+/T-), along with associations among altered FC, AD pathology, and cognitive performance.

From the ADNI database, 212 individuals with MCI were stratified into three groups: A-T- (n = 54), A+T- (n = 28), and A+T+ (n = 52). Group differences in putamen and caudate connectivity were investigated using seed-based FC analyses. Changes in FC, CSF biomarkers, and cognitive function were evaluated using partial correlation analyses. The discriminative value of FC changes was assessed using univariate and multivariate logistic regression analyses.

Compared with the A-T- and A+T- groups, the A+T+ group was older and showed lower episodic memory (EM) scores. The left caudate and bilateral cerebellar anterior lobes, between the right caudate and bilateral medial frontal gyrus (MFG), and between the left putamen and left MFG all had higher FC in the A+T+ group. In the A+T+ group, right caudate-MFG connectivity was positively correlated with CSF p-tau levels (r = 0.424, p = 0.012) and negatively correlated with EM scores (r = -0.38, p = 0.018). Compared with single-region models, multivariate logistic regression demonstrated superior classification performance.

Patients with MCI and coexisting CSF Aβ and tau pathologies (A+T+) exhibit increased FC in striatal-cortical circuits, which is strongly associated with tau pathology and episodic memory impairment. These findings provide neuroimaging evidence that striatal network alterations are linked to tau-related pathology in prodromal AD. Changes in striatal FC may serve as an early neurobiological indicator of AD-related MCI.