The HTT gene influences plasma neurofilament light chain and brain metabolism in prodromal Alzheimer’s disease

Objective: HTT, encoding a protein involved in axonal trafficking, contains a key region of CAG repeats. When expanded beyond 39 repeats, this region leads to Huntington's disease (HD). However, several studies have suggested that increasing the number of CAG repeats below the pathological threshold may confer functional advantages by enhancing HTT activity. In the present study, we aim to investigate the association between CAG repeat length below the pathological threshold and neurodegeneration biomarkers in prodromal Alzheimer's disease (AD). Methods: Ninety-five patients (36 with SCD and 59 with MCI) underwent blood collection for NfL measurement and HTT genetic analysis. Cerebrospinal fluid was collected for the measurement of Aβ₄₂, Aβ₄₀, total tau, and phosphorylated tau, and/or amyloid PET imaging was performed. Thirty-nine patients who were positive for both Aβ and phosphorylated tau biomarkers were classified as "A+/T+", while 56 patients who were either negative for both markers or positive for only one were classified as "isolated Aβ/non-AD." Results: In the A+/T+ group, quadratic models described the association between CAG repeat length with NfL concentrations and 18F-FDG uptake. In particular, a concave curve was observed in the medial and middle frontal gyri, while a convex curve was found in the parahippocampal and fusiform gyri. Interpretation: Among individuals with SCD and MCI who show evidence of AD pathology, CAG repeat length in the HTT gene below the HD pathological threshold is associated with biomarkers of neurodegeneration in a region-specific and U-shaped manner. These findings suggest a modulatory role of HTT in prodromal AD.