Abbreviations A??: amyloid-??; AD: Alzheimer’s disease; AICD: amyloid precursor protein intracellular Z-VAD-FMK mw domain; APP: amyloid precursor protein; CAA: cerebral amyloid angiopathy; CTF: carboxy-terminal fragment; FAD: familial Alzheimer’s disease; GSM: ??-secretase modulator; HCHWA-D: hereditary cerebral hemorrhage with amyloidosis Dutch-type; NICD: NOTCH intracellular domain; PSEN: presenilin; TMD: transmembrane domain; WT: wild type. Competing interests DB is a full-time employee of Merck Serono SA. The authors declare that they have no competing interests. Acknowledgements We thank Elisabeth Stein for drawing the figures. SW was supported by grants from the Alzheimer Forschung Initiative and the Competence Network Degenerative Dementias of the German Federal Ministry of Education (grant number 01 GI 1004B).

Resting-state functional magnetic resonance imaging (fMRI), a technique used to image intrinsic functional brain connectivity, is considered a promising biomarker for Alzheimer’s disease (AD) as functional brain changes are thought to precede structural brain changes. Previous work has shown that resting-state functional connectivity is sensitive to functional brain changes related to AD pathology across the clinical spectrum. Resting-state functional connectivity changes within the default mode network, originally identified by Raichle and colleagues [1], have been observed in healthy aging [2,3], mild cognitive impairment, a prodromal stage of AD [4-6], and AD [7-9].

In a review in a previous issue of Alzheimer’s Research & Therapy, Vemuri and colleagues [10] point out that the most consistent finding across previous resting-state fMRI studies of AD is decreased functional connectivity in AD patients versus healthy older controls in a posterior default mode network region composed of the precuneus and posterior cingulate cortex. GSK-3 The review furthermore addresses the recent findings of several additional studies showing increased connectivity in AD patients versus healthy older controls in frontal default mode regions. This increase in functional connectivity could be interpreted as a possible compensatory mechanism (within the default mode network) that is triggered by the functional loss in posterior brain regions. This process is similar to the increased activity that has been observed in frontal brain regions in task-related fMRI studies of U0126 price aging and that has been associated with better performance [11]. Recently, two longitudinal resting-state studies that support this idea of a compensatory mechanism in the progression of AD were published [12,13].