# Gray matter volume and functional connectivity identify asymptomatic MAPT variant carriers with signs of longitudinal disease progression

## TL;DR

This study finds that brain imaging and connectivity changes in people with a genetic variant linked to neurodegeneration may predict future disease progression before symptoms appear.

## Contribution

The study introduces a novel approach to identify asymptomatic MAPT variant carriers at risk of longitudinal neurodegeneration using baseline GMV and FC changes.

## Key findings

- Asymp-MAPT with lower baseline GMV showed greater longitudinal increases in plasma NfL and cognitive decline.
- Longitudinal decreases in functional connectivity within specific brain networks were linked to greater cortical atrophy and cognitive decline.
- Lower GMV in regions affected during symptomatic phases may signal earlier conversion to symptomatic disease.

## Abstract

Previous studies demonstrate that certain asymptomatic MAPT variant carriers (Asymp‐MAPT) exhibit altered baseline gray matter volume (GMV) and functional connectivity (FC) profiles. It remains unclear whether these imaging measures may herald risk for earlier conversion to the symptomatic phase. To address this, we stratified Asymp‐MAPT based on baseline GMV and longitudinal FC changes to assess whether any Asymp‐MAPT subgroups showed signs of longitudinal neurodegeneration or cognitive decline.

We studied 25 Asymp‐MAPT recruited from the UCSF Memory and Aging Center and ALLFTD Consortia. Using a median split, we divided Asymp‐MAPT into groups with smaller (LowGMV; n = 12) and larger baseline GMV (HighGMV; n = 13) within regions atrophied in symptomatic MAPT carriers (n = 20). Next, we stratified Asymp‐MAPT based on longitudinal FC changes using k‐means clustering on rates of change in FC for four intrinsic connectivity networks associated with common MAPT‐related syndromes: salience (SN), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and default mode (DMN) networks. We compared Asymp‐MAPT subgroups from each stratification on baseline and longitudinal changes in demographics, plasma neurofilament light (NfL) concentration, GMV within 246 Brainnetome regions, and neuropsychological test scores.

Stratification of Asymp‐MAPT based on baseline GMV showed that LowGMV had higher education levels compared to HighGMV, with no other demographic differences. Though LowGMV and HighGMV did not differ in baseline NfL, LowGMV showed greater longitudinal NfL increases. These groups did not differ in baseline or longitudinal GMV changes. LowGMV had lower baseline attention and working memory scores, and greater longitudinal decline in set‐shifting and visuospatial performance. Stratification based on FC changes yielded one group (DecFC; n = 17) exhibiting longitudinal decreases in the SN, PSP, and DMN and another (IncFC; n = 8) showing increases in each network. DecFC and IncFC did not differ in demographics, baseline or longitudinal NfL, or baseline GMV. Longitudinally, DecFC showed greater decline in posterior superior temporal and inferior parietal cortices. DecFC showed lower baseline attention and semantic fluency scores, and greater longitudinal decline in set‐shifting and visuospatial memory performance.

Lower baseline GMV within regions atrophied during the symptomatic phase and longitudinal FC declines within MAPT‐relevant networks may signal earlier symptomatic conversion in Asymp‐MAPT.