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pathology of Alzheimer's disease (AD)

Pathology: 1) gross changes a) enlarged ventricles b) diffuse atrophy - widened sulci - narrow gyri - cerebral cortical atrophy occurs slower in elderly >= 80 years of age with preserved episodic memory [12] 2) histopathologic changes a) see anatomic predilection of Alzheimer's pathology b) neuronal vulnerability - projection cells that generate long, unmyelinated or sparsely myelinated axons [8] c) abnormal morphologic structures - neurofibrillary tangles formed from paired helical filaments of hyperphosphorylated microtubule-associated protein tau (PHF-tau) - neuritic plaques resulting from deposition of Abeta42 - granulovacuolar degeneration - Hirano bodies d) progression of AD in the middle temporal gyrus occurs in 2 phases - an early phase with a slow increase in pathology - presence of inflammatory microglia & reactive astrocytes - a loss of somatostatin-positive inhibitory neurons - a remyelination response by oligodendrocyte precursors - a later phase - exponential increase in pathology - loss of excitatory neurons - loss of Pvalb-positive & VIP-positive inhibitory neurons [22] e) microglial activation & PHF-tau propagate jointly across Braak stages [18] - interaction between beta-amyloid & activated microglia may facilitate propgation of PHF-tau [18] f) CD33 may be a microglial on-off switch, activating microglia as part of an inflammatory pathway sensing brain injury as an infection [19] - microglia may mistake early Alzheimer's disease as an infection [19] 3) neurochemical changes a) deficiency of choline acetyltransferase b) diminished levels of neurotransmitters - acetylcholine - norepinephrine - serotonin - substance P - GABA c) loss of muscarinic M2 receptors in later phases of AD d) activation of inflammatory mediators - activation of the complement system - interaction of A4-beta peptide with C1q [2] - activation of C4 by A4-beta peptide [3] - complement activation by tau [4] - upregulation of C-reactive protein in CSF [5] e) generation of reactive oxygen species (hypothesis) - oxysterol toxicity attenuated by peroxisome proliferators [6] - up-regulation of redox-modulated transcription factors [7] f) sleep disorder possibly linked to higher CSF orexin levels [10] 4) pathology begins > 20 years before clinical symptoms develop [9] - amyloid-beta interacts synergistically with tau to modulate cortical neurophysiology & cognitive decline in asymptomatic adults [21] - early amyloid-beta deposits increase neurophysiological activity with subsequent tau deposition suppressing activity as behavioral deficits manifest [21] 5) systemic effects - amyloid plaques may form in the hearts of AD patients [11] - diastolic dysfunction & increased ventricular wall thickness may be noted in oldest AD patients [11] 6) sleep, especially glymphatic clearance may play a role in AD [13] - diminished slow wave sleep associated with tau pathology [16] - obstructive sleep apnea may play a role in tau accumulation [17] - interaction between stress & sleep & circadian rhythm disruption & Alzheimer's disease (AD) bidirectionally & synergistically exacerbates AD pathology & cognitive impairment leading to a cycle that perpetuates & amplifies AD [20] 7) suggestion that synpatic dysfunction rather than synaptic or neuronal loss implicated in Alzheimer's disease [14] seems inconsistent with generalized cerebral cortical atrophy 8) breakdown of the blood brain barrier occurs in Alzheimer disease, as well as other neurodegenerative disorders * Selective vulnerability of neurons in Alzheimer's disease contrasts with that of frontotemporal dementia

Related

Braak staging of Alzheimer's disease pathologic mechanisms in Alzheimer's disease

Specific

anatomic predilection of Alzheimer's pathology gross pathology of Alzheimer's disease histopathology of Alzheimer's disease molecular pathology of Alzheimer's disease

General

neuropathology

Figures/Diagrams

hypothetical AD pathology events

References

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