For instance, patients with LOAD often branch into distinct groups including (i) slow versus rapid cognitive decliners ( 7), (ii) amnestic versus nonamnestic AD ( 8), (iii) executive versus cortical visual defect versus dysphasia-predominant AD ( 9), (iv) psychosis and depression-associated AD ( 10– 12), and (v) metabolic dysfunction–associated AD modulated by abnormalities in insulin resistance, hormonal deficiencies, or homocysteinemia ( 13). There is growing evidence that disease progression and responses to interventions differ substantially within LOAD. Concurrent with the neuronal loss in AD, there is an additional coordinated breakdown across other brain cell types such as gliosis, demyelination, and inflammation that exacerbates cognitive dysfunction ( 3).įurthermore, it is very challenging to predict the progression of AD, suggesting high heterogeneity in disease progression among patients with AD. Both Aβ and NFT accumulation typically progress to targeted neuronal and synaptic loss, mainly in regions of the cerebral cortex and the hippocampus. It is traditionally understood that these include the accumulation of amyloid-beta (Aβ) peptide as extracellular plaques and hyperphosphorylated tau as intracellular neurofibrillary tangles (NFTs), typically identified on postmortem biopsy and used for definitive AD diagnosis. The neuropathological manifestations of AD start long before apparent cognitive symptoms, however. AD is primarily characterized by progressive neurological decline, especially selectively targeted memory loss and cognitive dysfunction ( 2). Therefore, subtyping patients with AD is a critical step toward precision medicine for this devastating disease.Īlzheimer’s disease (AD) is the most common form of dementia in the elderly, estimated to affect more than 5.8 million individuals in the United States and more than 50 million worldwide, with almost half of individuals aged over 75 years ( 1). We further demonstrate that variations between existing AD mouse models recapitulate a certain degree of subtype heterogeneity, which may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalized human trials across all AD subtypes.
Advances before 0 ad drivers#
Multiscale network analysis reveals subtype-specific drivers such as GABRB2, LRP10, MSN, PLP1, and ATP6V1A.
We identify three major molecular subtypes of AD corresponding to different combinations of multiple dysregulated pathways, such as susceptibility to tau-mediated neurodegeneration, amyloid-β neuroinflammation, synaptic signaling, immune activity, mitochondria organization, and myelination. In this study, we interrogate the molecular heterogeneity of AD by analyzing 1543 transcriptomes across five brain regions in two AD cohorts using an integrative network approach. Brennand, Vahram Haroutunian, and Bin Zhang Show FewerĪlzheimer’s disease (AD), the most common form of dementia, is recognized as a heterogeneous disease with diverse pathophysiologic mechanisms. Ehrlich, Pavel Katsel, Eric Schadt, Dongming Cai, Kristen J. Castranio, Julia TCW, Lap Ho, Alison Goate, Valentina Fossati, Scott Noggle, Sam Gandy, Michelle E.
Neff, Minghui Wang, Sezen Vatansever, Lei Guo, Chen Ming, Qian Wang, Erming Wang, … Show All …, Emrin Horgusluoglu-Moloch, Won-min Song, Aiqun Li, Emilie L.