Background: Alzheimer's disease (AD) pathology impacts the response to treatment in patients with idiopathic normal pressure hydrocephalus (iNPH), possibly through changes in resting-state functional connectivity (rs-FC).

Objective: To explore the relationship between cerebrospinal fluid biomarkers of AD and the default mode network (DMN)/hippocampal rs-FC in iNPH patients, based on their outcome after cerebrospinal fluid tap test (CSFTT), and in patients with AD.

Methods: Twenty-six iNPH patients (mean age: 79.9±5.9 years; 12 females) underwent MRI and clinical assessment before and after CSFTT and were classified as responders (Resp) or not (NResp), based on the improvement at the timed up and go test and walking speed. Eleven AD patients (mean age: 70.91±5.2 years; 5 females), matched to iNPH for cognitive status, were also included. DMN and hippocampal rs-FC was related to amyloid-β42 and phosphorylated tau (pTau) levels.

Results: Lower amyloid-β42 levels were associated with reduced inter- and intra-network rs-FC in NResp, and the interaction between amyloid-β42 and rs-FC was a predictor of outcome after CSFTT. The rs-FC between DMN and salience networks positively correlated to amyloid-β42 levels in both NResp and AD patients. The increase in the inter-network rs-FC after CSFTT was associated with higher pTau and lower amyloid-β42 levels in NResp, and to lower pTau levels in Resp.

Conclusion: Amyloid-β42 and pTau impact on rs-FC and its changes after CSFTT in iNPH patients. The interaction between AD biomarkers and rs-FC might explain the responder status in iNPH.