Anxiety Modifies Cortical Amyloid-ß and Incident Mild Cognitive Impairment Association


Those who demonstrated amyloid-ß positivity with clinical anxiety were at a statistically significant increased risk of incident mild cognitive impairment.

Yonas Geda, MD, MSc

Yonas Geda, MD, MSc

Findings from a prospective study of community-dwelling, nondemented older individuals showed that anxiety modified the association between elevated cortical amyloid-beta (Aß) and incident mild cognitive impairment (MCI). Investigators concluded that clinicians should consider anxiety in adults who demonstrate preclinical Alzheimer disease (AD) traits.1

Senior author Yonas Geda, MD, MSc, psychiatrist and behavioral neurologist, Alzheimer’s and Memory Disorders Program, Barrow Neurological Institute, and colleagues followed 1440 cognitive-unimpaired individuals at least 50 years of age for a median of 5.5 years. To measure anxiety and depression, participants completed the Beck Anxiety and Depression inventories (BDI-II and BAI). Investigators performed amyloid PET imaging using the Pittsburgh compound B (PiB) tracer to measure cortical Aß. Those with a standardized uptake value ratio (SUVR) of greater than at least 1.48 were classified as having an abnormal PiB-PET retention (PiB+). In total, 73.7% (n = 1061) persons were PiB-PET–, 26.3% (n = 379) were PiB+ and 14.3% (n = 206) of the total cohort developed incident MCI.

In the efficacy analysis, the reference group was defined as PiB– and no anxiety or depression, respectively. Even in the absence of clinical anxiety (HR, 1.85 [95% CI, 1.38-2.49]; P <.0001) or depression (HR, 2.04 [95% CI, 1.52-2.74]; P <.0001), PiB+ participants were at an increased risk of MCI compared to those in the reference group; however, those PiB+ participants with clinical anxiety showed an elevated risk of incident MCI (HR, 6.77 [95% CI, 3.58-12.79]; P <.0001) than the reference group.

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After adjusting for sex, education, and medical comorbidity, investigators found an additive statistically significant interaction between amyloid positive and clinical anxiety, which showed to increase the risk of incident MCI (P = .0310). A secondary analysis including depression demonstrated no statistically significant interaction between amyloid positivity and clinical depression. These results, while initially adjusted for sex and education as well, remained insignificant when additionally adjusted for medical comorbidity.

"In summary, we expand upon the previous literature by showing that clinical anxiety in community-dwelling individuals during the preclinical phase of AD increases the risk of incident MCI. Therefore, anxiety could be a very early marker of AD,” the study authors wrote. “Thus, assessing anxiety could be an important tool to identify patients at high risk of AD even before cognitive decline occurs. This finding has clinical implications in that the monitoring and possible management of anxiety among CU community-dwelling persons with cortical Aβ deposition may be warranted. Even though there is no effective treatment for AD, it will be crucial to identify high-risk groups at an early preclinical phase to intervene once treatment is available."

Geda et al conducted a similar study in 2014, which estimated the risk of incident MCI in cognitively normal individuals at least 70 years old with or without neuropsychiatric symptoms at baseline. After following patients for a median of 5 years, agitation (HR, 3.06 [95% CI, 1.89-4.93]), apathy (HR, 2.26 [95% CI, 1.49-3.41]), anxiety (HR, 1.87 [95% CI, 1.28-2.73]), irritability (HR, 1.84 [95% CI, 1.31-2.58]), and depression (HR, 1.63 [95% CI, 1.23-2.16]), observed initially, increased risk for later MCI.2

1. Pink A. Krell-Roesch J, Syrjanen JA. A longitudinal investigation of Aß, anxiety, depression, and mild cognitive impairment. Alzheimers Dement. Published online December 8, 2021. Doi:10.1002/alz.12504
2. Geda YE, Roberts RO, Mielke MM, et al. Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: a population-based study. Am J Psychiatry. 2014;171(5):572-81. Doi:10.1176/appi.ajp.2014.12060821
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