Anxiety Modifies Relationship Between Aβ Deposition and Cognitive Impairment

Study data published in Alzheimer’s & Dementia suggest that anxiety may mediate the relationship between cortical amyloid beta (Aβ) deposition and risk for mild cognitive impairment (MCI). In a longitudinal study of older adults, anxiety appeared to exacerbate the progression of MCI in amyloid-positive patients.

Elevated Aβ deposition has been associated with cognitive decline in older adults and can be an early sign of Alzheimer disease (AD). Additional studies have also identified anxiety and depressive symptoms as independent risk factors for cognitive impairment. However, the intersecting associations between anxiety, depression, Aβ deposition, and MCI are relatively unexplored. To inform this gap, investigators conducted a population-based study of community-dwelling adults aged ≥50 years.

Patients were followed up for a median of 5.5 years, during which they underwent regular neuropsychiatric screenings. Baseline cortical Aβ was measured using Pittsburgh compound B positron emission tomography (PiB-PET). Elevated deposition (PiB+) was defined by a standardized uptake ratio ≥1.48. Cox proportional hazards models were used to estimate the effect of anxiety and depression on the relationship between Aβ deposition and MCI. Clinical anxiety was defined by a Beck Anxiety Inventory score ≥10; clinical depression was defined by a Beck Depression Inventory score ≥13.

A total of 1,440 cognitively unimpaired adults were enrolled. Median age was 70.9 (IQR, 63.0-77.7) years and 52.8% were men. At baseline, 379 (26.3%) patients had elevated deposition (PiB+) and 1061 (73.7%) patients were PiB-. A total of 206 participants (14.3%) developed incident MCI over follow-up.

Compared with patients who were PiB-, patients who were PiB+ were significantly more likely to develop MCI, even in the absence of anxiety (hazard ratio [HR], 1.85; 95% CI, 1.38-2.49; P <.0001). Patients with PiB+ and anxiety had further elevated risk for MCI compared with the PiB- reference group (HR, 6.77; 95% CI, 3.58-12.79; P <.0001). The interaction between amyloid positivity and depression symptoms did not appear to significantly affect the risk for MCI.

Per these data, clinical anxiety may have an additive effect with amyloid positivity on the risk for MCI in cognitively normal older adults. As study limitations, investigators noted the small number of patients with co-occurring depression and PiB+, which limited statistical power for these comparisons. Further research is necessary to assess whether treatments designed to mitigate anxiety may improve cognitive outcomes in patients with cortical Aβ deposition.

“[A]ssessing anxiety could be an important tool to identify patients at high risk of AD even before cognitive decline occurs,” investigators wrote.

“This finding has clinical implications in that the monitoring and possible management of anxiety among [cognitively unimpaired] community-dwelling persons with cortical deposition may be warranted.”

Disclosure: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Pink A, Krell-Roesch J, Syrjanen JA, et al. A longitudinal investigation of Aβ, anxiety, depression, and mild cognitive impairment. Alzheimers Dement. Published online December 8, 2021. doi: 10.1002/alz.12504