Mapping Amyloid-PET Uptake in the White Matter in Alzheimer’s Disease

<title>Abstract</title> <p> Introduction Alzheimer’s disease (AD) is pathologically defined by amyloid-beta plaques and tau neurofibrillary tangles, but white matter (WM) alterations are also a feature whose contribution to the disease process remains poorly understood. Amyloid-PET tracers can show physiological WM uptake, possibly associated to myelin integrity, although its interpretations remain controversial. This study investigated whether WM measures derived from amyloid-PET are associated with AD biomarkers and to determine whether they offer added diagnostic and prognostic value beyond established biomarkers. Methods This study conducted including 320 individuals with available [ ¹⁸ F]flutemetamol amyloid-PET, T1-weighted and T2-FLAIR MRI and mini-mental state examination (MMSE) at baseline. A subset of individuals underwent tau-PET imaging, and cognitive follow-up. WM hyperintensity (WMH) and normal-appearing WM (NAWM) masks, total lesion volume (TLV), and cerebral microbleeds (CMB) were derived from FLAIR; standardized uptake value ratios (SUVR) in WMH and NAWM were regressed out for global amyloid in the gray matter and transformed to z-scores. Linear regression analysis assessed the association between NAWM and WMH SUVR and imaging and blood biomarkers, cognition and cognitive decline. We performed comparison between different linear-mixed models evaluating associations between imaging modalities and cognitive outcomes. Results No significant associations were found between NAWM, WMH SUVR and AD-specific biomarkers. However, WMH SUVR was positively associated with MMSE (P = 0.0001) and NAWM SUVR was negatively associated with TLV (P = 0.005) and with NfL (P = 0.001). Lower NAWM SUVR was associated with higher lobar (P = 0.025) and non-lobar CMB (P = 0.016). When models to predict baseline MMSE were compared, inclusion of NAWM SUVR improved the model (P = 0.003), but when WMH SUVR was included, it led to an additional improvement (P &lt; 0.001). In models predicting annual cognitive decline in the tau subsample adding NAWM SUVR to models including amyloid and tau improved model fit significantly (P = 0.044). Conclusion Results suggest that amyloid-PET uptake in WMH and NAWM reflects myelin integrity and that NAWM SUVR may capture early disease-related changes, while WMH SUVR may suggest damage linked to baseline cognition. Despite their limited value as standalone biomarkers, both WM indices improve models of AD progression, supporting their integration in a multimodal assessment. </p>