To investigate whether structural changes in the amygdala occur during the earliest stages of Alzheimer’s disease (AD).

Neuropsychiatric symptoms are common early manifestations of AD, suggesting that the amygdala may be an early target of AD pathology. While prior studies have investigated amygdala atrophy in AD, little is known about amygdala atrophy during the earliest stages of AD including the preclinical stage.

This retrospective cross-sectional study included subjects from the Alzheimer’s Disease Neuroimaging Initiative with age≥50, 3T 3D T1-weighted magnetic resonance imaging (MRI) scans, and cerebrospinal fluid (CSF) AD biomarkers. Clinical Dementia Rating (CDR) of 0 was defined as cognitively normal. Positive AD pathology was based on previously established CSF criteria. 466 subjects met all inclusion criteria (112 cognitively normal with negative CSF biomarkers (CN), 38 preclinical AD (PAD), 106 early mild cognitive impairment (EMCI), 100 late mild cognitive impairment (LMCI), and 110 AD dementia). Total amygdala volumes were assessed and normalized to intracranial volume (FreeSurfer v7.2). Multiple linear regression analysis adjusting for appropriate covariates was conducted to determine associations between amygdala volume and CSF AD biomarkers or neuropsychiatric measures.

Amygdala volumes were significantly lower with worsening disease severity (CN > PAD > EMCI > LMCI > AD dementia, p <0.001). Amygdala volumes were correlated with CSF amyloid-beta42 (β=0.28653, p <0.001), total tau (β=-0.8881, p <0.001) and phosphorylated tau181 (β=-7.558, p <0.001) levels. Moreover, Neuropsychiatric Inventory (NPI) disinhibition and aberrant motor behavior scores were negatively correlated with the amygdala volume (NPI disinhibition, β=-28.556, p <0.05; NPI aberrant motor, β=-57.427, p <0.05).

Lower amygdala volumes were seen in the early stages of AD that worsened with increasing clinical severity. Furthermore, amygdala volumes were associated with CSF AD biomarkers and neuropsychiatric symptoms. These findings support amygdala atrophy as an early target of AD pathology.