Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer’s disease

Abstract

Although previous studies have emphasized the vulnerability of the default mode network (DMN) in Alzheimer's disease (AD), little is known about the involvement of other functional networks and their relationship to clinical phenotype. To test whether clinicoanatomic heterogeneity in AD is driven by the involvement of specific networks, network connectivity was assessed in healthy subjects by seeding regions commonly and specifically atrophied in three clinical AD variants: early-onset AD (age at onset, <65 y; memory and executive deficits), logopenic variant primary progressive aphasia (language deficits), and posterior cortical atrophy (visuospatial deficits). Four-millimeter seed regions of interest were used to obtain intrinsic connectivity maps in 131 healthy controls (age, 65.5 ± 3.5 y). Atrophy patterns in independent cohorts of AD variant patients and their correspondence to connectivity networks in controls were also assessed. The connectivity maps of commonly atrophied regions of interest support posterior DMN and precuneus network involvement across AD variants, whereas seeding regions specifically atrophied in each AD variant revealed distinct, syndrome-specific connectivity patterns. Goodness-of-fit analysis of each connectivity map with network templates showed the highest correspondence between the early-onset AD seed connectivity map and anterior salience and right executive-control networks, the logopenic aphasia seed connectivity map and the language network, and the posterior cortical atrophy seed connectivity map and the higher visual network. Connectivity maps derived from controls matched regions commonly and specifically atrophied in the patients. Our findings indicate that the posterior DMN and precuneus network are commonly affected in AD variants, whereas syndrome-specific neurodegenerative patterns are driven by the involvement of specific networks outside the DMN. A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular accumulation of amyloid plaques, intracellular neurofibrillary tangles, and neuronal loss (1). Although most patients present with memory deficits, a significant minority of patients with AD present with nonamnestic syndromes (2, 3). Patients with nonfamilial early-onset AD (EOAD, defined as onset <65 y in most studies) often show heterogeneous cognitive deficits, including impairment in attention and executive functions (4, 5). Focal syndromes such as posterior cortical atrophy (PCA, characterized by predominant visuospatial and visuoperceptual deficits; ref. 6) and the logopenic variant of primary progressive aphasia [lvPPA, a progressive disorder of language (7,8)] are also most commonly caused by AD pathology. It has been suggested that up to 15% of patients with AD seen in dementia centers have nonamnestic presentations (2), and the importance of these syndromes is reflected in their inclusion in new diagnostic guidelines for AD (9, 10). The factors driving the clinicoanatomical heterogeneity in AD are not well understoo...

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