DOI: 10.1002/alz.081888 ISSN: 1552-5260

Behavioral functional networks underlying the effect of Alzheimer’s pathology on cognition

Jacob Ziontz, Theresa M. Harrison, William J. Jagust
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Tau pathology is associated with impaired cognitive function in both aging and Alzheimer’s disease (AD), but the mechanisms by which tau and cognition are linked remain unclear. We hypothesized that the integrity of behaviorally‐defined functional brain networks would help explain the relationship between tau and cognitive performance.


Resting state fMRI, tau PET, and Ab PET were collected in two independent cohorts: 120 cognitively normal older adults from the Berkeley Aging Cohort Study (BACS; 77.6 ± 6.4 yrs), and 174 cognitively normal and MCI individuals from ADNI3 (72.8 ± 8.3 yrs). For each cohort, functional connectivity (FC) for each ROI‐ROI pair of a 246‐region atlas was computed, and LASSO+BIC regression of these values against episodic memory (EM) and executive function (EF) composite measures was used to define a sparse subset of connections positively associated with each cognitive measure. Overall network strength was computed as the sum of FC values for all selected ROI‐ROI pairs.


EM and EF networks were identified within each cohort, with Dice similarity coefficients indicating greater overlap of network regions within cohorts (BACS networks: 0.43; ADNI: 0.33) than within cognitive measures between cohorts (EM networks: 0.25; EF: 0.23; Figure 1). Adjusting for age and sex, lower EM network strength was associated with greater meta‐temporal ROI tau in both BACS (b = ‐4.05, p = .014) and ADNI (b = ‐2.20, p <.001), whereas lower EF network strength was related to meta‐ROI tau in ADNI only (b = ‐1.80, p <.001; Figure 2). In addition, causal mediation analysis revealed that the effect of meta‐ROI tau on EM performance was mediated by EM network strength in both BACS (p = .017) and ADNI (p = .002), but EF network strength was a significant mediator in ADNI only (p <.001; Figure 3).


Greater AD pathology is associated with reduced integrity of EM‐related networks in older adults, a relationship that may also extend to EF‐related networks as individuals progress from cognitively normal to MCI. Given that network strength was observed to mediate the relationship between tau pathology and cognition, behavioral brain networks may be a key mechanism in the effect of neuropathology on cognitive function in aging and AD.

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