To determine whether structural changes to the hypothalamus are an early feature of Alzheimer’s Disease (AD).

Non-cognitive symptoms, such as weight loss and sleep disturbances, commonly precede the cognitive decline in AD and are attributable to hypothalamic dysfunction. However, whether hypothalamic atrophy occurs during early stages of AD has not been established.

This cross-sectional study included subjects (n=470) from the Alzheimer’s Disease Neuroimaging Initiative aged ≥ 50 years with volumetric T1-weighted MR scans at 3 Tesla and cerebrospinal fluid (CSF) AD biomarkers. Normal cognition (cognitively normal, CN, and preclinical AD) was defined as Clinical Dementia Rating (CDR) of 0. Based on previously established criteria, CN subjects (n=112) were negative for CSF AD pathology, while preclinical AD (n=39), early mild cognitive impairment (EMCI, n=108), late mild cognitive impairment (LMCI, n=100), and AD (n=111) subjects were positive for CSF AD pathology. Average grey matter (GM) densities in the hypothalamus, hippocampus, and cerebellar vermis were assessed by voxel-based morphometry (SPM12 with MarsBaR toolbox).

Hypothalamic GM densities decreased with increasing clinical severity to a similar degree as the hippocampus with significant differences beginning with EMCI for both regions. Cerebellar vermis GM densities were similar across all groups. Adjusting for age and sex, hypothalamic GM densities were associated with CSF levels of amyloid-β₄₂ (β=0.257, p<0.001) but not with tau or phosphorylated-tau₁₈₁ (p>0.05). Hippocampal GM densities were associated with all CSF AD biomarkers (p<0.05). Adjusting for age, sex, and education, hypothalamic and hippocampal GM densities were associated with Mini-Mental State Examination (hypothalamus: β=0.360, p<0.001, hippocampus: β=0.512, p<0.001) and CDR Sum of Boxes (hypothalamus: β=-0.441, p<0.001, hippocampus: β=-0.561, p<0.001).

Evidence for hypothalamic atrophy was found in early stages of AD that worsened with clinical severity in a similar fashion to hippocampal atrophy. These findings support hypothalamic atrophy as an early manifestation of AD.