To examine longitudinal hypothalamic gray matter (GM) density changes by MRI and its association with cerebrospinal fluid (CSF) biomarkers in Alzheimer’s disease (AD).

Weight loss and sleep disturbances commonly precede the cognitive deficits in AD and worsen with disease progression. While these non-cognitive manifestations of AD can be attributed to hypothalamic dysfunction, it remains largely unexplored if progressive atrophy of the hypothalamus occurs in AD.

This retrospective longitudinal study included subjects (n=165) from the Alzheimer’s Disease Neuroimaging Initiative, aged ≥ 50 years with CSF AD biomarkers at baseline and 3 Tesla volumetric T1-weighted MR brain scans at baseline and 24-month follow up. Cognitively normal (CN) and preclinical AD subjects had a Clinical Dementia Rating (CDR) of 0. Based on previously established criteria, CN subjects (n=47) were negative for CSF AD biomarkers, while preclinical AD (n=18), early mild cognitive impairment (EMCI, n=42), late mild cognitive impairment (LMCI, n=44), and AD (n=14) subjects were positive. Average GM densities in the hypothalamus and hippocampus were assessed by voxel-based morphometry (SPM12 with MarsBaR toolbox).

Hypothalamic GM densities decreased after 24 months in all groups; however, GM densities declined with greater magnitude with worse baseline disease severity. Furthermore, after adjusting for age and sex, the decrease in hypothalamic GM densities were significantly associated with baseline CSF levels of amyloid-β₄₂ (β=0.255, p=0.014), tau (β=-0.298, p=0.004), and phosphorylated-tau₁₈₁ (β=-0.362, p<0.0001). These hypothalamic changes were similar in magnitude to those observed in the hippocampi.

Longitudinal hypothalamic atrophy is associated with AD biomarker positivity with increased rates of atrophy seen with worse disease severity. These findings support AD pathology driving hypothalamic atrophy and dysfunction, which may underlie the weight loss, sleep disturbances, and other non-cognitive manifestations in AD.