Deciphering the mechanism underlying late-onset Alzheimer disease

• Published in: Nature reviews. Neurology Vol. 9; no. 1; pp. 25 - 34
• Main Authors: Krstic, Dimitrije, Knuesel, Irene
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2013; Nature Publishing Group
• Subjects: 631/378/371; 631/80/304; 692/699/375/365/1283; Aged; Aging; Alzheimer Disease - diagnosis; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-protein; Animals; Brain; Brain - pathology; Brain - physiopathology; Care and treatment; Cell Death - genetics; Cell Death - physiology; Cognitive ability; Development and progression; Disease Models, Animal; Disease Progression; Etiology; Genetic aspects; Humans; Hypotheses; Immune system; Inflammation; Inflammation Mediators - blood; Medicine; Medicine & Public Health; Mice; Mitochondrial DNA; Mutation; Neurites - pathology; Neurites - physiology; Neurofibrillary Tangles - genetics; Neurofibrillary Tangles - pathology; Neurofibrillary Tangles - physiology; Neurology; Neuropathology; Pathophysiology; Peptides; Physiological aspects; Proteins; Proteostasis Deficiencies - diagnosis; Proteostasis Deficiencies - genetics; Proteostasis Deficiencies - pathology; Proteostasis Deficiencies - physiopathology; review-article; tau Proteins - genetics; Switzerland
• ISSN: 1759-4758; 1759-4766
• DOI: 10.1038/nrneurol.2012.236

Drug development efforts for late-onset Alzheimer disease (AD) have met with disappointing results. Krstic and Knuesel argue for a re-evaluation of pathological mechanisms underlying the disease, with a shift of focus away from amyloid-β as the key therapeutic target. Through integration of their own research with the wider literature, they present a model that places inflammation and impairments in axonal functions and integrity at the heart of AD pathology. Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD. Key Points Despite tremendous investments in basic and clinical research, no cure or preventive treatment for Alzheimer disease (AD) exists A re-evaluation of the current view of the mechanisms underlying late-onset AD pathology is a prerequisite for future translational approaches Inflammatory processes are strongly correlated with AD onset and progression in humans, and could have a pivotal role in disease aetiology Chronic inflammation coupled with neuronal ageing induces cellular stress and concomitant impairments in basic neuronal functions Inflammation-induced hyperphosphorylation and missorting of tau might represent one of the earliest neuropathological changes in late-onset AD Molecular changes underlying late-onset AD involve impairments in cytoskeleton stability and axonal transport, which could trigger axonal degeneration and formation of senile plaques and neurofibrillary tangles, resulting in neuronal death