To evaluate the prevalence and risk factors for anxiety in autopsy-confirmed Alzheimer disease (AD) in early versus late stages and compared to other neuropsychiatric symptoms (NPS). To evaluate the impact of anxiety on progression rate in early stages of autopsy-confirmed AD.

We reviewed retrospective longitudinal evaluations of 212 participants with autopsy-confirmed AD, followed from 1986-2013 at the NYU Alzheimer’s Disease Research Center. Data was analyzed across stages (Global Deterioration Scale) and NPS (BEHAVE-AD). Variables included demographics, ApoE4 status, and secondary neuropathologies.

Anxiety varied uniquely with stage and was the most common NPS in MCI (40% prevalence), and the second most common in mild dementia (49%). Sex differences arose at mild dementia, with females showing higher prevalence (55% vs. 34%, p = 0.02). At MCI and mild dementia, ApoE4 positivity associated with a substantially higher rate of anxiety, reaching nearly 2-fold increased risk at mild dementia (p < 0.05). This was not apparent with other NPS. Secondary neuropathologies did not promote the likelihood of anxiety. Stage progression rate from MCI was nearly 4-fold faster with anxiety (p = 0.02), partially mediated by ApoE4 differences.

Anxiety can arise from AD alone to significantly impact symptom burden and progression at early stages, in a manner suggestive of ApoE4-dependent effects. Such characteristics are unique compared to other NPS and warrant its further study as a critical modifiable factor of the disease experience and course.