Covariance-based vs. correlation-based functional connectivity dissociates healthy aging from Alzheimer disease

Prior studies of aging and Alzheimer disease have evaluated resting state functional connectivity (FC) using ei-ther seed-based correlation (SBC) or independent component analysis (ICA), with a focus on particular functional systems. SBC and ICA both are insensitive to differences in signal amplitude. At the same time, accumulating ev-idence indicates that the amplitude of spontaneous BOLD signal fluctuations is physiologically meaningful. We systematically compared covariance-based FC, which is sensitive to amplitude, vs. correlation-based FC, which is not, in affected individuals and controls drawn from two cohorts of participants including autosomal dominant Alzheimer disease (ADAD), late onset Alzheimer disease (LOAD), and age-matched controls. Functional connec-tivity was computed over 222 regions of interest and group differences were evaluated in terms of components projected onto a space of lower dimension. Our principal observations are: (1) Aging is associated with global loss of resting state fMRI signal amplitude that is approximately uniform across resting state networks. (2) Thus, covariance FC measures decrease with age whereas correlation FC is relatively preserved in healthy aging. (3) In contrast, symptomatic ADAD and LOAD both lead to loss of spontaneous activity amplitude as well as severely degraded correlation structure. These results demonstrate a double dissociation between age vs. Alzheimer dis-ease and the amplitude vs. correlation structure of resting state BOLD signals. Modeling results suggest that the AD-associated loss of correlation structure is attributable to a relative increase in the fraction of locally restricted as opposed to widely shared variance.