pathology of Alzheimer's disease (AD)
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Pathology
- gross changes
- enlarged ventricles
- diffuse atrophy
- widened sulci
- narrow gyri
- cerebral cortical atrophy occurs slower in elderly >= 80 years of age with preserved episodic memory[12]
- histopathologic changes
- see anatomic predilection of Alzheimer's pathology
- neuronal vulnerability
- projection cells that generate long, unmyelinated or sparsely myelinated axons[8]
- 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
- 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
- an early phase with a slow increase in pathology
- microglial activation & PHF-tau propagate jointly across Braak stages[18]
- interaction between beta-amyloid & activated microglia may facilitate propgation of PHF-tau[18]
- 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]
- neurochemical changes
- deficiency of choline acetyltransferase
- diminished levels of neurotransmitters
- loss of muscarinic M2 receptors in later phases of AD
- 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]
- activation of the complement system
- generation of reactive oxygen species (hypothesis)
- oxysterol toxicity attenuated by peroxisome proliferators[6]
- up-regulation of redox-modulated transcription factors[7]
- sleep disorder possibly linked to higher CSF orexin levels[10]
- 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]
- 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]
- amyloid plaques may form in the hearts of AD patients[11]
- 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]
- suggestion that synpatic dysfunction rather than synaptic or neuronal loss implicated in Alzheimer's disease[14] seems inconsistent with generalized cerebral cortical atrophy
- 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
More general terms
More specific terms
- anatomic predilection of Alzheimer's pathology
- gross pathology of Alzheimer's disease
- histopathology of Alzheimer's disease
- molecular pathology of Alzheimer's disease
Additional terms
References
- ↑ Role of cholinergic therapy in treatment of Alzheimer's disease & other dementias, Farlow, M et al, 2001
- ↑ Jump up to: 2.0 2.1 Tacnet-Delorme P et al, Beta-amyloid fibrils activate the C1 complex of complement under physiological conditions: evidence for a binding site for a beta on the C1q globular regions J Immunol 167(11) 6374, 2001 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11714802
- ↑ Jump up to: 3.0 3.1 Bergamaschini L, Donarini C, Gobbo G, Parnetti L, Gallai V. Activation of complement and contact system in Alzheimer's disease. Mech Ageing Dev. 2001 Nov;122(16):1971-83. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11589915
- ↑ Jump up to: 4.0 4.1 Shen Y, Lue L, Yang L, Roher A, Kuo Y, Strohmeyer R, Goux WJ, Lee V, Johnson GV, Webster SD, Cooper NR, Bradt B, Rogers J. Complement activation by neurofibrillary tangles in Alzheimer's disease. Neurosci Lett. 2001 Jun 15;305(3):165-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11403931
- ↑ Jump up to: 5.0 5.1 McGeer PL, McGeer EG, Yasojima K. Alzheimer disease and neuroinflammation. J Neural Transm Suppl. 2000;59:53-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10961418
- ↑ Jump up to: 6.0 6.1 Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL. Synaptic targeting by Alzheimer's-related amyloid beta oligomers. J Neurosci. 2004 Nov 10;24(45):10191-200. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15537891
- ↑ Jump up to: 7.0 7.1 Lavrovsky Y, Chatterjee B, Clark RA, Roy AK. Role of redox-regulated transcription factors in inflammation, aging and age-related diseases. Exp Gerontol. 2000 Aug;35(5):521-32. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10978675
- ↑ Jump up to: 8.0 8.1 Braak H, Rub U, Schultz C, Del Tredici K. Vulnerability of cortical neurons to Alzheimer's and Parkinson's diseases. J Alzheimers Dis. 2006;9(3 Suppl):35-44. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16914843
- ↑ Jump up to: 9.0 9.1 Bateman RJ et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012 Jul 12 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22784036 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1202753
- ↑ Jump up to: 10.0 10.1 Liguori C et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol 2014 Oct 13; PMID: https://www.ncbi.nlm.nih.gov/pubmed/25322206
Ferini-Strambi L. Possible role of orexin in the pathogenesis of Alzheimer disease. JAMA Neurol 2014 Oct 13 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25317720 - ↑ Jump up to: 11.0 11.1 11.2 Troncone L, Luciani M, Coggins M et al Abeta amyloid pathology affects the hearts of patients with Alzheimer's disease: Mind the heart. J Am Coll Cardiol 2016 Dec 6; 68:2395 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27908343 <Internet> http://www.sciencedirect.com/science/article/pii/S0735109716364634
- ↑ Jump up to: 12.0 12.1 Samuelson K Next step in Alzheimer's research: Brain shrinkage rates. SuperAger brains shrink more slowly than peers' brains. Northwestern Now. April 04, 2017 https://news.northwestern.edu/stories/2017/april/alzheimers-research-superagers-brain-shrinkage/
Cook AH, Sridhar J, Ohm D et al Rates of Cortical Atrophy in Adults 80 Years and Older With Superior vs Average Episodic Memory JAMA. 2017;317(13):1373-1375 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28384819 <Internet> http://jamanetwork.com/journals/jama/article-abstract/2614177 - ↑ Jump up to: 13.0 13.1 Mander BA, Winer JR, Jagust WJ, Walker MP. Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease? Trends Neurosci. 2016 Aug;39(8):552-66. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/27325209
- ↑ Jump up to: 14.0 14.1 Poirel O, Mella S, Videau C et al Moderate decline in select synaptic markers in the prefrontal cortex (BA9) of patients with Alzheimer's disease at various cognitive stages. Scientific Reports, 2018; 8 (1) PMID: https://www.ncbi.nlm.nih.gov/pubmed/29343737 Free full text https://www.sciencedaily.com/releases/2018/01/180117085509.htm
- ↑ Sweeney MD, Sagare AP, Zlokovic BV Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nature Reviews Neurology. Jan 29, 2018 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29377008 https://www.nature.com/articles/nrneurol.2017.188
- ↑ Jump up to: 16.0 16.1 Lucey BP, McCullough A, Landsness EC et al Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer's disease. Sci Transl Med. 2019 Jan 9;11(474). PMID: https://www.ncbi.nlm.nih.gov/pubmed/30626715
Holth JK, Fritschi SK, Wang C et al The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. Feb 22, 2019. Vol. 363, Issue 6429, pp. 880-884 PMID: https://www.ncbi.nlm.nih.gov/pubmed/30679382 https://science.sciencemag.org/content/363/6429/880
George J Deep Sleep Linked to Early Alzheimer's Signs - Non-REM slow wave activity tied to tau pathology. MedPage Today Dec 30, 2019 https://www.medpagetoday.com/neurology/alzheimersdisease/84139 - ↑ Jump up to: 17.0 17.1 Brooks M Sleep Apnea Tied to Higher Levels of Alzheimer Protein. Medscape - Mar 05, 2019. https://www.medscape.com/viewarticle/909889
- ↑ Jump up to: 18.0 18.1 18.2 Pascoal TA, Benedet AL, Ashton NJ et al. Microglial activation and tau propagate jointly across Braak stages. Nat Med 2021. August 21 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34446931 https://www.nature.com/articles/s41591-021-01456-w
- ↑ Jump up to: 19.0 19.1 19.2 Stetka B The Cell That Might Trigger Alzheimer's Disease. Medscape. Jan 31, 2022 https://www.medscape.com/viewarticle/967592
- ↑ Jump up to: 20.0 20.1 Phan TX, Malkani RG. Sleep and circadian rhythm disruption and stress intersect in Alzheimer's disease. Neurobiol Stress. 2018;10:100133. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30937343 PMCID: PMC6279965 Free PMC article https://www.sciencedirect.com/science/article/pii/S2352289518300274
- ↑ Jump up to: 21.0 21.1 21.2 Gallego-Rudolf J, Wiesman AI, Pichet Binette A et al Synergistic association of Abeta and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults. Nat Neurosci. 2024 Sep 18 PMID: https://www.ncbi.nlm.nih.gov/pubmed/39294489
- ↑ Jump up to: 22.0 22.1 Gabitto MI, Travaglini KJ, Rachleff VM et al Integrated multimodal cell atlas of Alzheimer's disease Nat Neurosci. 2024 Oct 14. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39402379 https://www.nature.com/articles/s41593-024-01774-5