title: Functional alterations in memory networks in early Alzheimer's disease.
abstract: The hallmark clinical symptom of early Alzheimer's disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD.
authors.affiliation: Department of Neurology, Center for Alzheimer's Research and Treatment, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA. reisa@rics.bwh.harvard.edu
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Dickerson
authors.forename: Maija
authors.initials: M
authors.lastname: Pihlajamaki
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vannini
authors.forename: Peter S
authors.initials: PS
authors.lastname: LaViolette
authors.forename: Ottavio V
authors.initials: OV
authors.lastname: Vitolo
authors.forename: Trey
authors.initials: T
authors.lastname: Hedden
authors.forename: J Alex
authors.initials: JA
authors.lastname: Becker
authors.forename: Dorene M
authors.initials: DM
authors.lastname: Rentz
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.forename: Keith A
authors.initials: KA
authors.lastname: Johnson
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000473:pathology / Q000503:physiopathology*; D009415:Nerve Net / Q000502:physiology / Q000503:physiopathology*; D009483:Neuropsychological Tests