Biochemistry of Alzheimer's disease#Amyloid hypothesis

At a macroscopic level, AD is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.{{cite journal | vauthors = Wenk GL | title = Neuropathologic changes in Alzheimer's disease | journal = The Journal of Clinical Psychiatry | volume = 64 | pages = 7–10 | year = 2003 | issue = Suppl 9 | pmid = 12934968 }}

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.{{cite journal | vauthors = Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J | title = The importance of neuritic plaques and tangles to the development and evolution of AD | journal = Neurology | volume = 62 | issue = 11 | pages = 1984–9 | date = June 2004 | pmid = 15184601 | doi = 10.1212/01.WNL.0000129697.01779.0A | s2cid = 25017332 }} Plaques are dense, mostly insoluble deposits of protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.{{cite journal | vauthors = Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH | title = Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital | journal = Cerebral Cortex | volume = 4 | issue = 2 | pages = 138–50 | year = 1994 | pmid = 8038565 | doi = 10.1093/cercor/4.2.138 }}

Fundamental to the understanding of Alzheimer's disease is the biochemical events that leads to accumulation of the amyloid-beta plaques and tau-protein tangles. A delicate balance of the enzymes secretases regulate the amyloid-beta accumulation. Recently, a link between cholinergic neuronal activity and the activity of alpha-secretase has been highlighted,{{cite journal | vauthors = Baig AM | title = Connecting the Dots: Linking the Biochemical to Morphological Transitions in Alzheimer's Disease | journal = ACS Chemical Neuroscience | volume = 10 | issue = 1 | pages = 21–24 | date = January 2019 | pmid = 30160095 | doi = 10.1021/acschemneuro.8b00409 | doi-access = free }} which can discourage amyloid-beta proteins deposition in brain of patients with Alzheimer's disease.

Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded amyloid-beta proteins in the brains of AD patients. Abnormal amyloid-beta accumulation can first be detected using cerebrospinal fluid analysis and later using positron emission tomography (PET).{{cite journal | vauthors = Palmqvist S, Mattsson N, Hansson O | title = Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography | journal = Brain | volume = 139 | issue = Pt 4 | pages = 1226–36 | date = April 2016 | pmid = 26936941 | pmc = 4806222 | doi = 10.1093/brain/aww015 }}

Although AD shares pathophysiological mechanisms with prion diseases, it is not transmissible in the wild, as prion diseases are.{{cite journal | vauthors = Castellani RJ, Perry G, Smith MA | title = Prion disease and Alzheimer's disease: pathogenic overlap | journal = Acta Neurobiologiae Experimentalis | volume = 64 | issue = 1 | pages = 11–7 | year = 2004 | doi = 10.55782/ane-2004-1487 | pmid = 15190676 | doi-access = free }} Any transmissibility that it may have is limited solely to extremely rare iatrogenic events from donor-derived therapies that are no longer used.{{cite journal |date=2024-01-29 |last1=Banerjee |first1=G |last2=Farmer |first2=SF |last3=Hyare |first3=H |last4=Jaunmuktane |first4=Z |last5=Mead |first5=S |last6=Ryan |first6=NS |last7=Schott |first7=JM |last8=Werring |first8=DJ |last9=Rudge |first9=P |last10=Collinge |first10=J |title=Iatrogenic Alzheimer's disease in recipients of cadaveric pituitary-derived growth hormone |journal=Nature Medicine |volume=30 |issue=2 |pages=394–402 |doi=10.1038/s41591-023-02729-2 |pmid=38287166|doi-access=free |pmc=10878974 }} Amyloid-beta, also written Aβ, is a short peptide that is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of a proteolytic complex involved in APP processing and degradation.

Although amyloid beta monomers are harmless, they undergo a dramatic conformational change at sufficiently high concentration to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils that deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques.

Levels of the neurotransmitter acetylcholine (ACh) are reduced. Levels of other neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Replenishing the ACh by anti-cholinesterases is an approved mode of treatment by FDA. An alternative method of stimulating ACh receptors of M1-M3 types by synthetic agonists that have a slower rate of dissociation from the receptor has been proposed as next generation cholinomimetic in Alzheimer's disease^[15].

While the gross histological features of AD in the brain have been well characterized, several different hypotheses have been advanced regarding the primary cause. Among the oldest hypotheses is the cholinergic hypothesis, which suggests that deficiency in cholinergic signaling initiates the progression of the disease.{{cite journal | vauthors = Francis PT, Palmer AM, Snape M, Wilcock GK | title = The cholinergic hypothesis of Alzheimer's disease: a review of progress | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 66 | issue = 2 | pages = 137–47 | date = February 1999 | pmid = 10071091 | doi = 10.1136/jnnp.66.2.137 | pmc = 1736202 }} Current theories establish that both misfolding tau protein inside the cell and aggregation of amyloid beta outside the cell initiates the cascade leading to AD pathology.{{cite journal | vauthors = Tanzi RE, Bertram L | title = Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective | journal = Cell | volume = 120 | issue = 4 | pages = 545–55 | date = February 2005 | pmid = 15734686 | doi = 10.1016/j.cell.2005.02.008 | s2cid = 206559875 | doi-access = free }}{{cite journal | vauthors = Mohandas E, Rajmohan V, Raghunath B | title = Neurobiology of Alzheimer's disease | journal = Indian Journal of Psychiatry | volume = 51 | issue = 1 | pages = 55–61 | date = January 2009 | pmid = 19742193 | doi = 10.4103/0019-5545.44908 | pmc = 2738403 | doi-access = free }} Newer potential hypotheses propose metabolic factors,{{cite journal | vauthors = Morgen K, Frölich L | title = The metabolism hypothesis of Alzheimer's disease: from the concept of central insulin resistance and associated consequences to insulin therapy | journal = Journal of Neural Transmission | volume = 122 | issue = 4 | pages = 499–504 | date = April 2015 | pmid = 25673434 | doi = 10.1007/s00702-015-1377-5 | s2cid = 21338545 }} vascular disturbance,{{cite journal | vauthors = de la Torre JC, Mussivand T | title = Can disturbed brain microcirculation cause Alzheimer's disease? | journal = Neurological Research | volume = 15 | issue = 3 | pages = 146–53 | date = June 1993 | pmid = 8103579 | doi = 10.1080/01616412.1993.11740127 }} lipid invasion {{Cite journal |last=Rudge |first=Jonathan D’Arcy |date=2023-01-01 |title=The Lipid Invasion Model: Growing Evidence for This New Explanation of Alzheimer's Disease |journal=Journal of Alzheimer's Disease |language=en |volume=94 |issue=2 |pages=457–470 |doi=10.3233/JAD-221175 |issn=1387-2877 |pmc=10357195 |pmid=37302030}} and chronically elevated inflammation in the brain{{cite journal | vauthors = Agostinho P, Cunha RA, Oliveira C | title = Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease | journal = Current Pharmaceutical Design | volume = 16 | issue = 25 | pages = 2766–78 | date = 1 August 2010 | pmid = 20698820 | doi = 10.2174/138161210793176572 }} as contributing factors to AD. The amyloid beta hypothesis of molecular initiation have become dominant among many researchers to date.{{cite journal | vauthors = Makin S | title = The amyloid hypothesis on trial | journal = Nature | volume = 559 | issue = 7715 | pages = S4–S7 | date = July 2018 | pmid = 30046080 | doi = 10.1038/d41586-018-05719-4 | bibcode = 2018Natur.559S...4M | s2cid = 51719878 | doi-access = free }} The amyloid and tau hypothesis are the most widely accepted.

The hypothesis that tau is the primary causative factor has long been grounded in the observation that deposition of amyloid plaques does not correlate well with neuron loss.{{cite journal |display-authors=6 |vauthors=Schmitz C, Rutten BP, Pielen A, Schäfer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch HW, Pradier L, Bayer TA |date=April 2004 |title=Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease |journal=The American Journal of Pathology |volume=164 |issue=4 |pages=1495–502 |doi=10.1016/S0002-9440(10)63235-X |pmc=1615337 |pmid=15039236}} A mechanism for neurotoxicity has been proposed based on the loss of microtubule-stabilizing tau protein that leads to the degradation of the cytoskeleton.{{cite journal |vauthors=Gray EG, Paula-Barbosa M, Roher A |year=1987 |title=Alzheimer's disease: paired helical filaments and cytomembranes |journal=Neuropathology and Applied Neurobiology |volume=13 |issue=2 |pages=91–110 |doi=10.1111/j.1365-2990.1987.tb00174.x |pmid=3614544 |s2cid=41437632}} However, consensus has not been reached on whether tau hyperphosphorylation precedes or is caused by the formation of the abnormal helical filament aggregates. Support for the tau hypothesis also derives from the existence of other diseases known as tauopathies in which the same protein is identifiably misfolded.{{cite journal |vauthors=Williams DR |date=October 2006 |title=Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau |journal=Internal Medicine Journal |volume=36 |issue=10 |pages=652–60 |doi=10.1111/j.1445-5994.2006.01153.x |pmid=16958643 |s2cid=19357113}} However, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.

The amyloid hypothesis was proposed because the gene for the amyloid beta precursor APP is located on chromosome 21, and patients with trisomy 21 – better known as Down syndrome – who have an extra gene copy exhibit AD-like disorders by 40 years of age.{{cite journal |display-authors=6 |vauthors=Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E |date=October 2007 |title=Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain |journal=Neurobiology of Aging |volume=28 |issue=10 |pages=1493–506 |doi=10.1016/j.neurobiolaging.2006.06.023 |pmc=3375834 |pmid=16904243}}{{cite journal |vauthors=Lott IT, Head E |date=March 2005 |title=Alzheimer disease and Down syndrome: factors in pathogenesis |journal=Neurobiology of Aging |volume=26 |issue=3 |pages=383–9 |doi=10.1016/j.neurobiolaging.2004.08.005 |pmid=15639317 |s2cid=27716613}} The amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing apoptosis.{{cite journal |vauthors=Yankner BA, Duffy LK, Kirschner DA |date=October 1990 |title=Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides |journal=Science |volume=250 |issue=4978 |pages=279–82 |bibcode=1990Sci...250..279Y |doi=10.1126/science.2218531 |pmid=2218531}} This hypothesis is supported by the observation that higher levels of a variant of the beta amyloid protein known to form fibrils faster in vitro correlate with earlier onset and greater cognitive impairment in mouse models{{cite journal |vauthors=Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y |date=April 2004 |title=Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=101 |issue=17 |pages=6623–8 |bibcode=2004PNAS..101.6623I |doi=10.1073/pnas.0400895101 |pmc=404095 |pmid=15069204 |doi-access=free}} and with AD diagnosis in humans.{{cite journal |vauthors=Gregory GC, Halliday GM |year=2005 |title=What is the dominant Abeta species in human brain tissue? A review |journal=Neurotoxicity Research |volume=7 |issue=1–2 |pages=29–41 |doi=10.1007/BF03033774 |pmid=15639796 |s2cid=40228398}} However, mechanisms for the induced calcium influx, or proposals for alternative cytotoxic mechanisms, by mature fibrils are not obvious.{{clarify|date=April 2019}}

File:Apomorphine therapeutic scheme.png in Alzheimer's disease.]]

A more recent variation of the amyloid hypothesis identifies the cytotoxic species as an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species, possibly toroidal or star-shaped with a central channel{{cite journal |vauthors=Blanchard BJ, Hiniker AE, Lu CC, Margolin Y, Yu AS, Ingram VM |date=June 2000 |title=Elimination of Amyloid beta Neurotoxicity |journal=Journal of Alzheimer's Disease |volume=2 |issue=2 |pages=137–149 |doi=10.3233/JAD-2000-2214 |pmid=12214104}} that may induce apoptosis by physically piercing the cell membrane.{{cite journal |vauthors=Abramov AY, Canevari L, Duchen MR |date=December 2004 |title=Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |volume=1742 |issue=1–3 |pages=81–7 |doi=10.1016/j.bbamcr.2004.09.006 |pmid=15590058 |doi-access=free}} This ion channel hypothesis postulates that oligomers of soluble, non-fibrillar Aβ form membrane ion channels allowing unregulated calcium influx into neurons.{{cite journal |vauthors=Arispe N, Rojas E, Pollard HB |date=January 1993 |title=Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=90 |issue=2 |pages=567–71 |bibcode=1993PNAS...90..567A |doi=10.1073/pnas.90.2.567 |pmc=45704 |pmid=8380642 |doi-access=free}} A related alternative suggests that a globular oligomer localized to dendritic processes and axons in neurons is the cytotoxic species.{{cite journal |display-authors=6 |vauthors=Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, Bahr M, Schmidt M, Bitner RS, Harlan J, Barlow E, Ebert U, Hillen H |date=November 2005 |title=Globular amyloid beta-peptide oligomer – a homogenous and stable neuropathological protein in Alzheimer's disease |journal=Journal of Neurochemistry |volume=95 |issue=3 |pages=834–47 |doi=10.1111/j.1471-4159.2005.03407.x |pmid=16135089 |doi-access=free}}{{cite journal |vauthors=Kokubo H, Kayed R, Glabe CG, Yamaguchi H |date=January 2005 |title=Soluble Abeta oligomers ultrastructurally localize to cell processes and might be related to synaptic dysfunction in Alzheimer's disease brain |journal=Brain Research |volume=1031 |issue=2 |pages=222–8 |doi=10.1016/j.brainres.2004.10.041 |pmid=15649447 |s2cid=54353507}} The prefibrillar aggregates were shown to be able to disrupt the membrane.{{cite journal |display-authors=6 |vauthors=Flagmeier P, De S, Wirthensohn DC, Lee SF, Vincke C, Muyldermans S, Knowles TP, Gandhi S, Dobson CM, Klenerman D |date=June 2017 |title=Ultrasensitive Measurement of Ca²⁺ Influx into Lipid Vesicles Induced by Protein Aggregates |journal=Angewandte Chemie |volume=56 |issue=27 |pages=7750–7754 |doi=10.1002/anie.201700966 |pmc=5615231 |pmid=28474754}}

The cytotoxic-fibril hypothesis presents a clear target for drug development: inhibit the fibrillization process. Much early development work on lead compounds has focused on this inhibition;{{cite journal |vauthors=Blanchard BJ, Chen A, Rozeboom LM, Stafford KA, Weigele P, Ingram VM |date=October 2004 |title=Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=101 |issue=40 |pages=14326–32 |bibcode=2004PNAS..10114326B |doi=10.1073/pnas.0405941101 |pmc=521943 |pmid=15388848 |doi-access=free}}{{cite journal |vauthors=Porat Y, Abramowitz A, Gazit E |date=January 2006 |title=Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism |journal=Chemical Biology & Drug Design |volume=67 |issue=1 |pages=27–37 |doi=10.1111/j.1747-0285.2005.00318.x |pmid=16492146 |doi-access=free}}{{cite journal |vauthors=Kanapathipillai M, Lentzen G, Sierks M, Park CB |date=August 2005 |title=Ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer's beta-amyloid |journal=FEBS Letters |volume=579 |issue=21 |pages=4775–80 |doi=10.1016/j.febslet.2005.07.057 |pmid=16098972 |doi-access=free|bibcode=2005FEBSL.579.4775K }} most are also reported to reduce neurotoxicity, but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process{{cite journal |display-authors=6 |vauthors=Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, Motomura K, Soejima N, Yamasaki R, Hashimoto T, Tabira T, LaFerla FM, Kira J |date=February 2011 |title=Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation |journal=Annals of Neurology |volume=69 |issue=2 |pages=248–56 |doi=10.1002/ana.22319 |pmid=21387370 |s2cid=242138}}{{cite journal |vauthors=Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJ |date=November 2002 |title=New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease |journal=The Journal of Biological Chemistry |volume=277 |issue=45 |pages=42881–90 |doi=10.1074/jbc.M206593200 |pmid=12167652 |doi-access=free}}

{{cite journal |vauthors=Lee KH, Shin BH, Shin KJ, Kim DJ, Yu J |date=March 2005 |title=A hybrid molecule that prohibits amyloid fibrils and alleviates neuronal toxicity induced by beta-amyloid (1-42) |journal=Biochemical and Biophysical Research Communications |volume=328 |issue=4 |pages=816–23 |doi=10.1016/j.bbrc.2005.01.030 |pmid=15707952}} or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.{{cite journal |display-authors=6 |vauthors=Espeseth AS, Xu M, Huang Q, Coburn CA, Jones KL, Ferrer M, Zuck PD, Strulovici B, Price EA, Wu G, Wolfe AL, Lineberger JE, Sardana M, Tugusheva K, Pietrak BL, Crouthamel MC, Lai MT, Dodson EC, Bazzo R, Shi XP, Simon AJ, Li Y, Hazuda DJ |date=May 2005 |title=Compounds that bind APP and inhibit Abeta processing in vitro suggest a novel approach to Alzheimer disease therapeutics |journal=The Journal of Biological Chemistry |volume=280 |issue=18 |pages=17792–7 |doi=10.1074/jbc.M414331200 |pmid=15737955 |doi-access=free}} For example, apomorphine was seen to significantly improve memory function through the increased successful completion of the Morris Water Maze.

;Soluble intracellular (o)Aβ42

Two papers have shown that oligomeric (o)Aβ42 (a species of Aβ), in soluble intracellular form, acutely inhibits synaptic transmission, a pathophysiology that characterizes AD (in its early stages), by activating casein kinase 2.

{{cite journal |display-authors=6 |vauthors=Moreno H, Yu E, Pigino G, Hernandez AI, Kim N, Moreira JE, Sugimori M, Llinás RR |date=April 2009 |title=Synaptic transmission block by presynaptic injection of oligomeric amyloid beta |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=106 |issue=14 |pages=5901–6 |bibcode=2009PNAS..106.5901M |doi=10.1073/pnas.0900944106 |pmc=2659170 |pmid=19304802 |doi-access=free}}

{{cite journal |display-authors=6 |vauthors=Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S |date=April 2009 |title=Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=106 |issue=14 |pages=5907–12 |bibcode=2009PNAS..106.5907P |doi=10.1073/pnas.0901229106 |pmc=2667037 |pmid=19321417 |doi-access=free}}

Converging evidence suggests that a sustained inflammatory response in the brain is a core modifying feature of AD pathology and may be a key modifying factor in AD pathogenesis.{{cite journal |vauthors=Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT |date=January 2018 |title=Inflammation as a central mechanism in Alzheimer's disease |journal=Alzheimer's & Dementia |volume=4 |issue=1 |pages=575–590 |doi=10.1016/j.trci.2018.06.014 |pmc=6214864 |pmid=30406177}}{{cite journal |vauthors=Griffin WS, Sheng JG, Roberts GW, Mrak RE |date=March 1995 |title=Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution |journal=Journal of Neuropathology and Experimental Neurology |volume=54 |issue=2 |pages=276–81 |doi=10.1097/00005072-199503000-00014 |pmid=7876895 |s2cid=33277264}} The brains of AD patients exhibit several markers of increased inflammatory signaling.{{cite journal |display-authors=6 |vauthors=Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL, Araoz C |date=October 1989 |title=Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=86 |issue=19 |pages=7611–5 |bibcode=1989PNAS...86.7611G |doi=10.1073/pnas.86.19.7611 |pmc=298116 |pmid=2529544 |doi-access=free}}{{cite journal |vauthors=Gomez-Nicola D, Boche D |date=December 2015 |title=Post-mortem analysis of neuroinflammatory changes in human Alzheimer's disease |journal=Alzheimer's Research & Therapy |volume=7 |issue=1 |pages=42 |doi=10.1186/s13195-015-0126-1 |pmc=4405851 |pmid=25904988 |doi-access=free }}{{cite journal |vauthors=Knezevic D, Mizrahi R |date=January 2018 |title=Molecular imaging of neuroinflammation in Alzheimer's disease and mild cognitive impairment |journal=Progress in Neuro-Psychopharmacology & Biological Psychiatry |volume=80 |issue=Pt B |pages=123–131 |doi=10.1016/j.pnpbp.2017.05.007 |pmid=28533150 |s2cid=31181575}} The inflammatory hypothesis proposes that chronically elevated inflammation in the brain is a crucial component to the amyloid cascade{{cite journal |vauthors=McGeer PL, McGeer EG |date=October 2013 |title=The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy |journal=Acta Neuropathologica |volume=126 |issue=4 |pages=479–97 |doi=10.1007/s00401-013-1177-7 |pmid=24052108 |s2cid=32212325}} in the early phases of AD and magnifies disease severity in later stages of AD. Aβ is present in healthy brains and serves a vital physiological function in recovery from neuronal injury, protection from infection, and repair of the blood-brain barrier,{{cite journal |vauthors=Brothers HM, Gosztyla ML, Robinson SR |date=2018-04-25 |title=The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease |journal=Frontiers in Aging Neuroscience |volume=10 |pages=118 |doi=10.3389/fnagi.2018.00118 |pmc=5996906 |pmid=29922148 |doi-access=free}} however it is unknown how Aβ production starts to exceed the clearance capacity of the brain and initiates AD progression. A possible explanation is that Aβ causes microglia, the resident immune cell of the brain, to become activated and secrete pro-inflammatory signaling molecules, called cytokines, which recruit other local microglia.{{cite journal |vauthors=Kreisl WC |date=July 2017 |title=Discerning the relationship between microglial activation and Alzheimer's disease |journal=Brain |volume=140 |issue=7 |pages=1825–1828 |doi=10.1093/brain/awx151 |pmid=29177498 |doi-access=free}} While acute microglial activation, as in response to injury, is beneficial and allows microglia to clear Aβ and other cellular debris via phagocytosis, chronically activated microglia exhibit decreased efficiency in Aβ clearance. Despite this reduced AB clearance capacity, activated microglia continue to secrete pro-inflammatory cytokines like interleukins 1β and 6 (IL-6, IL-1β) and tumor necrosis factor-alpha (TNF-a), as well as reactive oxygen species which disrupt healthy synaptic functioning{{cite journal |vauthors=Agostinho P, Cunha RA, Oliveira C |date=2010-08-01 |title=Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease |journal=Current Pharmaceutical Design |volume=16 |issue=25 |pages=2766–78 |doi=10.2174/138161210793176572 |pmid=20698820}} and eventually cause neuronal death.{{cite journal |vauthors=Wang WY, Tan MS, Yu JT, Tan L |date=June 2015 |title=Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease |journal=Annals of Translational Medicine |volume=3 |issue=10 |pages=136 |doi=10.3978/j.issn.2305-5839.2015.03.49 |pmc=4486922 |pmid=26207229}} The loss of synaptic functioning and later neuronal death is responsible for the cognitive impairments and loss of volume in key brain regions which are associated with AD.{{cite journal |display-authors=6 |vauthors=Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T |date=2000 |title=Inflammation and Alzheimer's disease |journal=Neurobiology of Aging |volume=21 |issue=3 |pages=383–421 |doi=10.1016/s0197-4580(00)00124-x |pmc=3887148 |pmid=10858586}} IL-1B, IL-6, and TNF-a cause further production of Aβ oligomers, as well as tau hyperphosphorylation, leading to continued microglia activation and creating a feed forward mechanism in which Aβ production is increased and Aβ clearance is decreased eventually causing the formation of Aβ plaques.{{cite journal |vauthors=Tuppo EE, Arias HR |date=February 2005 |title=The role of inflammation in Alzheimer's disease |journal=The International Journal of Biochemistry & Cell Biology |volume=37 |issue=2 |pages=289–305 |doi=10.1016/j.biocel.2004.07.009 |pmid=15474976|hdl=11336/94334 |hdl-access=free }}{{cite journal |vauthors=Meraz-Ríos MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernández J, Campos-Peña V |date=2013 |title=Inflammatory process in Alzheimer's Disease |journal=Frontiers in Integrative Neuroscience |volume=7 |pages=59 |doi=10.3389/fnint.2013.00059 |pmc=3741576 |pmid=23964211 |doi-access=free}}

The cholinergic hypothesis of AD development was first proposed in 1976 by Peter Davies and A.J.F Maloney.{{cite journal | vauthors = Davies P, Maloney AJ | title = Selective loss of central cholinergic neurons in Alzheimer's disease | journal = Lancet | volume = 2 | issue = 8000 | pages = 1403 | date = December 1976 | pmid = 63862 | doi = 10.1016/S0140-6736(76)91936-X | s2cid = 43250282 }} It claimed that Alzheimer's begins as a deficiency in the production of acetylcholine, a vital neurotransmitter. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by inhibiting acetylcholinesterases (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical.

More recent findings center on the effects of the misfolded and aggregated proteins, amyloid beta and tau: tau protein abnormalities may initiate the disease cascade, then beta amyloid deposits progress the disease.{{cite journal | vauthors = Mudher A, Lovestone S | title = Alzheimer's disease-do tauists and baptists finally shake hands? | journal = Trends in Neurosciences | volume = 25 | issue = 1 | pages = 22–6 | date = January 2002 | pmid = 11801334 | doi = 10.1016/S0166-2236(00)02031-2 | s2cid = 37380445 }}

The human brain is one of the most metabolically active organs in the body and metabolizes a large amount of glucose to produce cellular energy in the form of adenosine triphosphate (ATP).{{cite journal | vauthors = Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S, Castellano A, Pifferi F, Bocti C, Paquet N, Begdouri H, Bentourkia M, Turcotte E, Allard M, Barberger-Gateau P, Fulop T, Rapoport SI | display-authors = 6 | title = Brain fuel metabolism, aging, and Alzheimer's disease | journal = Nutrition | volume = 27 | issue = 1 | pages = 3–20 | date = January 2011 | pmid = 21035308 | pmc = 3478067 | doi = 10.1016/j.nut.2010.07.021 }} Despite its high energy demands, the brain is relatively inflexible in its ability to utilize substrates for energy production and relies almost entirely on circulating glucose for its energy needs.{{cite journal | vauthors = Costantini LC, Barr LJ, Vogel JL, Henderson ST | title = Hypometabolism as a therapeutic target in Alzheimer's disease | journal = BMC Neuroscience | volume = 9 | issue = Suppl 2 | pages = S16 | date = December 2008 | pmid = 19090989 | pmc = 2604900 | doi = 10.1186/1471-2202-9-s2-s16 | doi-access = free }} This dependence on glucose puts the brain at risk if the supply of glucose is interrupted, or if its ability to metabolize glucose becomes defective. If the brain is not able to produce ATP, synapses cannot be maintained and cells cannot function, ultimately leading to impaired cognition.

Imaging studies have shown decreased utilization of glucose in the brains of Alzheimer's disease patients early in the disease, before clinical signs of cognitive impairment occur. This decrease in glucose metabolism worsens as clinical symptoms develop and the disease progresses.{{cite journal | vauthors = Hoyer S | title = Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset cases | journal = Molecular and Chemical Neuropathology | volume = 16 | issue = 3 | pages = 207–24 | date = June 1992 | pmid = 1418218 | doi = 10.1007/bf03159971 }}{{cite journal | vauthors = Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, Lavretsky H, Miller K, Siddarth P, Rasgon NL, Mazziotta JC, Saxena S, Wu HM, Mega MS, Cummings JL, Saunders AM, Pericak-Vance MA, Roses AD, Barrio JR, Phelps ME | display-authors = 6 | title = Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 11 | pages = 6037–42 | date = May 2000 | pmid = 10811879 | pmc = 18554 | doi = 10.1073/pnas.090106797 | bibcode = 2000PNAS...97.6037S | doi-access = free }} Studies have found a 17%-24% decline in cerebral glucose metabolism in patients with Alzheimer's disease, compared with age-matched controls.{{cite journal | vauthors = de Leon MJ, Ferris SH, George AE, Christman DR, Fowler JS, Gentes C, Reisberg B, Gee B, Emmerich M, Yonekura Y, Brodie J, Kricheff II, Wolf AP | display-authors = 6 | title = Positron emission tomographic studies of aging and Alzheimer disease | journal = AJNR. American Journal of Neuroradiology | volume = 4 | issue = 3 | pages = 568–71 | year = 1983 | pmid = 6410799 | pmc = 8334899 }} Numerous imaging studies have since confirmed this observation.

Abnormally low rates of cerebral glucose metabolism are found in a characteristic pattern in the Alzheimer's disease brain, particularly in the posterior cingulate, parietal, temporal, and prefrontal cortices. These brain regions are believed to control multiple aspects of memory and cognition. This metabolic pattern is reproducible and has even been proposed as a diagnostic tool for Alzheimer's disease. Moreover, diminished cerebral glucose metabolism (DCGM) correlates with plaque density and cognitive deficits in patients with more advanced disease.{{cite journal | vauthors = Meier-Ruge W, Bertoni-Freddari C, Iwangoff P | title = Changes in brain glucose metabolism as a key to the pathogenesis of Alzheimer's disease | journal = Gerontology | volume = 40 | issue = 5 | pages = 246–52 | year = 1994 | pmid = 7959080 | doi = 10.1159/000213592 }}

Diminished cerebral glucose metabolism (DCGM) may not be solely an artifact of brain cell loss since it occurs in asymptomatic patients at risk for Alzheimer's disease, such as patients homozygous for the epsilon 4 variant of the apolipoprotein E gene (APOE4, a genetic risk factor for Alzheimer's disease), as well as in inherited forms of Alzheimer's disease.{{cite journal | vauthors = Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J | display-authors = 6 | title = Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 1 | pages = 284–9 | date = January 2004 | pmid = 14688411 | pmc = 314177 | doi = 10.1073/pnas.2635903100 | doi-access = free | bibcode = 2004PNAS..101..284R }} Given that DCGM occurs before other clinical and pathological changes occur, it is unlikely to be due to the gross cell loss observed in Alzheimer's disease.

In imaging studies involving young adult APOE4 carriers, where there were no signs of cognitive impairment, diminished cerebral glucose metabolism (DCGM) was detected in the same areas of the brain as older subjects with Alzheimer's disease. However, DCGM is not exclusive to APOE4 carriers. By the time Alzheimer's has been diagnosed, DCGM occurs in genotypes APOE3/E4, APOE3/E3, and APOE4/E4.{{cite journal | vauthors = Corder EH, Jelic V, Basun H, Lannfelt L, Valind S, Winblad B, Nordberg A | title = No difference in cerebral glucose metabolism in patients with Alzheimer disease and differing apolipoprotein E genotypes | journal = Archives of Neurology | volume = 54 | issue = 3 | pages = 273–7 | date = March 1997 | pmid = 9074396 | doi = 10.1001/archneur.1997.00550150035013 }} Thus, DCGM is a metabolic biomarker for the disease state.{{cite news|title=Diminished cerebral glucose metabolism: A key pathology in Alzheimer's disease|url=http://www.about-axona.com/assets/files/us-en/hcp/pdf/KAXO1056_DCGM_Adv_NR_MV01a.pdf|access-date=9 October 2013|archive-date=15 October 2013|archive-url=https://web.archive.org/web/20131015222052/http://www.about-axona.com/assets/files/us-en/hcp/pdf/KAXO1056_DCGM_Adv_NR_MV01a.pdf|url-status=dead}}

A connection has been established between Alzheimer's disease and diabetes during the past decade, as insulin resistance, which is a characteristic hallmark of diabetes, has also been observed in brains of subjects with Alzheimer's disease.{{cite journal | vauthors = De Felice FG | title = Alzheimer's disease and insulin resistance: translating basic science into clinical applications | journal = The Journal of Clinical Investigation | volume = 123 | issue = 2 | pages = 531–9 | date = February 2013 | pmid = 23485579 | pmc = 3561831 | doi = 10.1172/JCI64595 }} Neurotoxic oligomeric amyloid-β species decrease the expression of insulin receptors on the neuronal cell surface{{cite journal | vauthors = De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL | display-authors = 6 | title = Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 6 | pages = 1971–6 | date = February 2009 | pmid = 19188609 | pmc = 2634809 | doi = 10.1073/pnas.0809158106 | bibcode = 2009PNAS..106.1971D | doi-access = free }} and abolish neuronal insulin signaling. It has been suggested that neuronal gangliosides, which take part in the formation of membrane lipid microdomains, facilitate amyloid-β-induced removal of the insulin receptors from the neuronal surface.{{cite journal | vauthors = Herzer S, Meldner S, Rehder K, Gröne HJ, Nordström V | title = Lipid microdomain modification sustains neuronal viability in models of Alzheimer's disease | journal = Acta Neuropathologica Communications | volume = 4 | issue = 1 | pages = 103 | date = September 2016 | pmid = 27639375 | pmc = 5027102 | doi = 10.1186/s40478-016-0354-z | doi-access = free }} In Alzheimer's disease, oligomeric amyloid-β species trigger TNF-α signaling. c-Jun N-terminal kinase activation by TNF-α in turn activates stress-related kinases and results in IRS-1 serine phosphorylation, which subsequently blocks downstream insulin signaling.{{cite journal | vauthors = Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT | display-authors = 6 | title = Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin | journal = Nature | volume = 388 | issue = 6643 | pages = 686–90 | date = August 1997 | pmid = 9262404 | doi = 10.1038/41792 | bibcode = 1997Natur.388..686W | s2cid = 4383461 | doi-access = free }}{{cite journal | vauthors = Saraiva LM, Seixas da Silva GS, Galina A, da-Silva WS, Klein WL, Ferreira ST, De Felice FG | title = Amyloid-β triggers the release of neuronal hexokinase 1 from mitochondria | journal = PLOS ONE | volume = 5 | issue = 12 | pages = e15230 | date = December 2010 | pmid = 21179577 | pmc = 3002973 | doi = 10.1371/journal.pone.0015230 | bibcode = 2010PLoSO...515230S | doi-access = free }} The resulting insulin resistance contributes to cognitive impairment. Consequently, increasing neuronal insulin sensitivity and signaling may constitute a novel therapeutic approach to treat Alzheimer's disease.{{cite journal | vauthors = Craft S | title = Alzheimer disease: Insulin resistance and AD--extending the translational path | journal = Nature Reviews. Neurology | volume = 8 | issue = 7 | pages = 360–2 | date = June 2012 | pmid = 22710630 | doi = 10.1038/nrneurol.2012.112 | s2cid = 31213610 | url = https://zenodo.org/record/1233572 }}{{cite journal | vauthors = de la Monte SM | title = Brain insulin resistance and deficiency as therapeutic targets in Alzheimer's disease | journal = Current Alzheimer Research | volume = 9 | issue = 1 | pages = 35–66 | date = January 2012 | pmid = 22329651 | pmc = 3349985 | doi = 10.2174/156720512799015037 }}

Oxidative stress is emerging as a key factor in the pathogenesis of AD.{{cite journal | vauthors = Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L | title = Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications | journal = Oxidative Medicine and Cellular Longevity | volume = 2017 | pages = 2525967 | date = 2017 | pmid = 28785371 | pmc = 5529664 | doi = 10.1155/2017/2525967 | doi-access = free }} Reactive oxygen species (ROS) over-production is thought to play a critical role in the accumulation and deposition of amyloid beta in AD.{{cite journal | vauthors = Bonda DJ, Wang X, Lee HG, Smith MA, Perry G, Zhu X | title = Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass | journal = Neuroscience Bulletin | volume = 30 | issue = 2 | pages = 243–52 | date = April 2014 | pmid = 24733654 | pmc = 4097013 | doi = 10.1007/s12264-013-1424-x }} Brains of AD patients have elevated levels of oxidative DNA damage in both nuclear and mitochondrial DNA, but the mitochondrial DNA has approximately 10-fold higher levels than nuclear DNA.{{cite journal | vauthors = Wang J, Xiong S, Xie C, Markesbery WR, Lovell MA | title = Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease | journal = Journal of Neurochemistry | volume = 93 | issue = 4 | pages = 953–62 | date = May 2005 | pmid = 15857398 | doi = 10.1111/j.1471-4159.2005.03053.x | doi-access = free }} Aged mitochondria may be the critical factor in the origin of neurodegeneration in AD. Even individuals with mild cognitive impairment, the phase between normal aging and early dementia, have increased oxidative damage in their nuclear and mitochondrial brain DNA{{cite journal | vauthors = Wang J, Markesbery WR, Lovell MA | title = Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment | journal = Journal of Neurochemistry | volume = 96 | issue = 3 | pages = 825–32 | date = February 2006 | pmid = 16405502 | doi = 10.1111/j.1471-4159.2005.03615.x | doi-access = free }} (see Aging brain). Naturally occurring DNA double-strand breaks (DSBs) arise in human cells largely from single-strand breaks induced by various processes including the activity of reactive oxygen species, topoisomerases, and hydrolysis due to thermal fluctuations.{{cite journal |vauthors=Vilenchik MM, Knudson AG |date=October 2003 |title=Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=100 |issue=22 |pages=12871–6 |bibcode=2003PNAS..10012871V |doi=10.1073/pnas.2135498100 |pmc=240711 |pmid=14566050 |doi-access=free}} In neurons DSBs are induced by a type II topoisomerase as part of the physiologic process of memory formation.{{cite journal |display-authors=6 |vauthors=Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao PC, Stott RT, Gjoneska E, Nott A, Cho S, Kellis M, Tsai LH |date=June 2015 |title=Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes |journal=Cell |volume=161 |issue=7 |pages=1592–605 |doi=10.1016/j.cell.2015.05.032 |pmc=4886855 |pmid=26052046}} DSBs are present in both neurons and astrocytes in the postmortem human hippocampus of AD patients at a higher level than in non-AD individuals.{{cite journal |vauthors=Thadathil N, Delotterie DF, Xiao J, Hori R, McDonald MP, Khan MM |date=January 2021 |title=DNA Double-Strand Break Accumulation in Alzheimer's Disease: Evidence from Experimental Models and Postmortem Human Brains |journal=Molecular Neurobiology |volume=58 |issue=1 |pages=118–131 |doi=10.1007/s12035-020-02109-8 |pmid=32895786 |s2cid=221541995}} AD is associated with an accumulation of DSBs in neurons and astrocytes in the hippocampus and frontal cortex from early stages onward.{{cite journal |display-authors=6 |vauthors=Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, Rissman RA, Masliah E, Mucke L |date=May 2019 |title=Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease |journal=Acta Neuropathologica Communications |volume=7 |issue=1 |pages=77 |doi=10.1186/s40478-019-0723-5 |pmc=6524256 |pmid=31101070 |doi-access=free }} DSBs are increased in the vicinity of amyloid plaques in the hippocampus, indicating a potential role for Aβ in DSB accumulation or vice versa. The predominant mechanism for repairing DNA double-strand breaks is non-homologous end joining (NHEJ), a mechanism that utilizes the DNA-dependent protein kinase (DNA-PK) complex. The end joining activity and protein levels of DNA-PK catalytic subunit are significantly lower in AD brains than in normal brains.{{cite journal |vauthors=Shackelford DA |date=April 2006 |title=DNA end joining activity is reduced in Alzheimer's disease |journal=Neurobiology of Aging |volume=27 |issue=4 |pages=596–605 |doi=10.1016/j.neurobiolaging.2005.03.009 |pmid=15908050 |s2cid=7327609}}

The cholesterol hypothesis is a combination of the amyloid hypothesis, tau hypothesis, and potentially the inflammatory hypothesis. Cholesterol was shown to be upstream of both amyloid and tau production.{{cite journal |last1=Wang |first1=H |last2=Kulas |first2=JA |last3=Wang |first3=C |last4=Holtzman |first4=DM |last5=Ferris |first5=HA |last6=Hansen |first6=SB |date=17 August 2021 |title=Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol. |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=118 |issue=33 |bibcode=2021PNAS..11802191W |doi=10.1073/pnas.2102191118 |pmc=8379952 |pmid=34385305 |doi-access=free}} The cholesterol is produced in the astrocytes and shipped to neurons where it activates amyloid production through a process called substrate presentation. The process required apoE. Cholesterol's regulation of Tau production is less well understood, but knocking out the cholesterol synthesis enzyme SREBP2 decreased Tau phosphorylation. {{cite journal |last1=Wang |first1=H |last2=Kulas |first2=JA |last3=Wang |first3=C |last4=Holtzman |first4=DM |last5=Ferris |first5=HA |last6=Hansen |first6=SB |date=17 August 2021 |title=Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol. |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=118 |issue=33 |bibcode=2021PNAS..11802191W |doi=10.1073/pnas.2102191118 |pmc=8379952 |pmid=34385305 |doi-access=free}} Innate immunity triggers cholesterol synthesis and cells take up the cholesterol.{{cite journal |last1=Tall |first1=Alan R. |last2=Yvan-Charvet |first2=Laurent |date=February 2015 |title=Cholesterol, inflammation and innate immunity |journal=Nature Reviews Immunology |volume=15 |issue=2 |pages=104–116 |doi=10.1038/nri3793 |pmc=4669071 |pmid=25614320}} Presumably a cell in the brain dies with old age and this triggers innate immunity. More studies are needed to directly tie the inflammatory hypothesis to cholesterol synthesis in the brain.

The Lipid Invasion Model (LIM) is a hypothesis {{cite journal |vauthors=Rudge JD |date=2023 |title=The Lipid Invasion Model: Growing Evidence for This New Explanation of Alzheimer's Disease |journal=Journal of Alzheimer's Disease |publisher=IOS Press |volume=94 |issue=2 |pages=457–470 |doi=10.3233/JAD-221175|pmc=10357195 }}{{cite journal |vauthors=Rudge JD |date=2022 |title=A New Hypothesis for Alzheimer's Disease: The Lipid Invasion Model |journal=Journal of Alzheimer's Disease Reports |publisher=IOS Press |volume=6 |issue=1 |pages=129–161 |doi=10.3233/ADR-210299|pmid=35530118 |pmc=9028744 }} for AD published in 2022, which argues that AD is a result of external lipid invasion to the brain, following damage to the blood-brain barrier (BBB). The LIM provides a comprehensive explanation of the observed neuropathologies associated with the disease, including the lipid irregularities first described by Alois Alzheimer himself, and accounts for the wide range of risk factors now identified with AD (including old age, ApoE4, Aβ, brain trauma, high blood pressure, smoking, type 2 diabetes, obesity, alcohol, stress and sleep deprivation), most of which are also associated with damage to the BBB. {{cite journal |vauthors=Rhea EM , Salameh TS , Logsdon AF , Hanson AJ , Erickson MA , Banks WA |date=2017 |title=Blood-brain barriers in obesity |journal=AAPS J |publisher=Epub |volume=19 |issue=4 |pages=921–930 |doi=10.1208/s12248-017-0079-3|pmid=28397097 |pmc=5972029 }}{{cite journal |vauthors=Mazzone P, Tierney W, Hossain M, Puvenna V, Janigro D, Cucullo L |date=2010 |title=Pathophysiological impact of cigarette smoke exposure on the cerebrovascular system with a focus on the blood-brain barrier: Expanding the awareness of smoking toxicity in an underappreciated area |journal=Int J Environ Res Public Health |publisher=MDPI |volume=7 |issue=12 |pages=4111–4126 |doi=10.3390/ijerph7124111|doi-access=free |pmid=21317997 |pmc=3037043 }}{{cite journal |vauthors=Alluri H , Wiggins-Dohlvik K , Davis ML , Huang JH , Tharakan B |date=2015 |title=Blood-brain barrier dysfunction following traumatic brain injury |journal=Metab Brain Dis |publisher=Epub |volume=30 |issue=5 |pages=1093–1104 |doi=10.1007/s11011-015-9651-7|pmid=25624154 }}{{cite journal |vauthors=Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, Pachicano M, Joe E, Nelson AR, D'Orazio LM, Buennagel DP, Harrington MG, Benzinger TL, Fagan AM, Ringman JM, Schneider LS, Morris JC, Reiman EM, Caselli RJ, Chui HC, TCW J, Chen Y, Pa J, Conti PS, Law M, Toga AW, Zlokovic BV |date=2020 |title=APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline |journal=Nature |publisher=Nature Portfolio |volume=581 |issue=7806 |pages=71–76 |doi=10.1038/s41586-020-2247-3|pmid=32376954 |pmc=7250000 }}{{cite journal |vauthors=Hurtado-Alvarado G , Domínguez-Salazar E , Pavon L , Velázquez-Moctezuma J , Gómez-González B |date=2016 |title=Blood-brain barrier disruption induced by chronic sleep loss:Low-grade inflammation may be the link |journal=Journal of Immunology Research |publisher=Hindawi Publishing Corporation |volume=2016 |pages=e4576012 |doi=10.1155/2016/4576012|doi-access=free }}{{cite journal |vauthors=Dudek KA , Dion-Albert L , Lebel M , LeClair K , Labrecque S , Tuck E , Perez CF , Golden SA , Tamminga C , Turecki G , Mechawar N , Russo SJ , Menard C |date=2020 |title=Molecular adaptations of the blood– brain barrier promote stress resilience vs. depression |journal=Proc Natl Acad Sci U S A |publisher=PNAS |volume=117 |issue=6 |pages=3326–3336 |doi=10.1073/pnas.1914655117|doi-access=free |pmid=31974313 |pmc=7022213 }}{{cite journal |vauthors=Welcome MO , Mastorakis NE |date=2020 |title=Stress-induced blood brain barrier disruption: Molecular mechanisms and signaling pathways |journal=Pharmacological Research |publisher=Elsevier |volume=157 |pages=104769 |doi=10.1016/j.phrs.2020.104769|pmid=32275963 }}{{cite journal |vauthors=Gosselet F , Saint-Pol J , Candela P , Fenart L |date=2013 |title=Amyloid-β peptides, Alzheimer's disease and the blood-brain barrier |journal=Current Alzheimer Research |publisher=Bentham Science |volume=10 |issue=10 |pages=1015–1033 |doi=10.2174/15672050113106660174}}

The LIM can be viewed as a development of the cholesterol hypothesis, and incorporates and extends the amyloid hypothesis, the current dominant explanation of the disease. It goes back a step to argue that the cause of the amyloid plaques, neurofibrillary/tau tangles and many other features of the disease is the invasion of Low-density lipoprotein (LDL) and other forms of 'bad cholesterol' along with free fatty acids (FFAs) into the brain, following breakdown of the BBB. Such lipids would normally be excluded from the brain by the BBB. {{cite journal |vauthors=Ladu MJ , Reardon C , Eldik LV , Fagan AM , Bu G , Holtzman D , Getz GS |date=2000 |title=Lipoproteins in the central nervous system |journal=Ann N Y Acad Sci |publisher=Wiley |volume=903 |issue=1 |pages=167–175 |doi=10.1111/j.1749-6632.2000.tb06365.x|pmid=10818504 }}{{cite journal |vauthors=Hamilton J , Brunaldi K |date=2007 |title=A model for fatty acid transport into the brain |journal=Journal of Molecular Neuroscience |publisher=Springer Nature |volume=33 |pages=12–17 |doi=10.1007/s12031-007-0050-3|pmid=17901540 }}

The LIM argues that the influx of 'bad cholesterol' is the primary cause of the excess Aβ, plaque formation and neurofibrillary/tau tangles in Late Onset AD (LOAD), due to changes in lipid raft composition and endosomal-lysosomal trafficking. This concurs with a large body of evidence showing an association of excess cholesterol with increased Aβ production, amyloid plaques {{cite journal |vauthors=Wang H , Kulas JA , Wang C , Holtzman DM , Ferris HA , Hansen SB |date=2021 |title=Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol |journal=Proc Natl Acad Sci U S A |publisher=PNAS |volume=118 |issue=33 |pages=e2102191118 |doi=10.1073/pnas.2102191118|doi-access=free |pmc=8379952 }}{{cite journal |vauthors=Xiong H , Callaghan D , Jones A , Walker DG , Lue LF , Beach TG , Sue LI , Woulfe J , Xu H , Stanimirovic DB , Zhang W |date=2008 |title=Cholesterol retention in Alzheimer's brain is responsible for high β- and γ-secretase activities and Aβ production |journal=Neurobiol Dis |publisher=Elsevier |volume=29 |issue=3 |pages=422–437 |doi=10.1016/j.nbd.2007.10.005|pmid=18086530 |pmc=2720683 }} and neurofibrillary/tau tangles. {{cite journal |vauthors=Distl R, Meske V, Ohm TG |date=2001 |title=Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons |journal=Acta Neuropathologica |publisher=Springer Nature |volume=101 |issue=6 |pages=547–554 |doi=10.1007/s004010000314|pmid=11515782 }}{{Cite journal |last1=Distl |first1=Roland |last2=Treiber-Held |first2=Stephanie |last3=Albert |first3=Frank |last4=Meske |first4=Volker |last5=Harzer |first5=Klaus |last6=Ohm |first6=Thomas G |date=2003 |title=Cholesterol storage and tau pathology in Niemann–Pick type C disease in the brain |url=https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.1320 |journal=The Journal of Pathology |language=en |volume=200 |issue=1 |pages=104–111 |doi=10.1002/path.1320 |issn=1096-9896}}

Plaques and tangles are thought to contribute to memory loss in AD. However, not all AD brains display plaques or tangles, and plaques and tangles do not always lead to AD. Therefore, the LIM proposes that it is the FFAs, rather than cholesterol-driven Aβ, that could be the primary drivers of AD. FFAs can account for all the common features of AD, including amnesia, synaptic disruption, neuroinflammation, brain shrinkage, body clock disruption, changes in brain energy production from glucose to ketone bodies, mitochondrial toxicity and oxidative stress within neurons. The LIM argues that the impact of the FFAs could cause most of the memory loss in AD, in addition to the spatial confusion, sleep disruption and sometimes paranoia also associated with the disease.

The Lipid Invasion Model is the only model of AD that explains both the plaques and neurofibrillary/tau tangles commonly seen in LOAD (which accounts for 95% of AD cases), as well as all the other standard features of AD. It also explains why AD so disproportionally affects older people, and the high instance in contact sports players. By arguing that the root cause of AD is primarily damage to the BBB and the subsequent invasion of harmful lipids, the model offers new insights into the fundamental causes of AD, and potential new pathways for remedies for the disease. The LIM may also provide insights into other dementias and neurological diseases, such as Parkinson’s and ALS/Motor Neurone Disease.

A 1994 study {{cite journal |vauthors=Edlund C, Söderberg M, Kristensson K |date=July 1994 |title=Isoprenoids in aging and neurodegeneration |journal=Neurochemistry International |volume=25 |issue=1 |pages=35–8 |doi=10.1016/0197-0186(94)90050-7 |pmid=7950967 |s2cid=34009482}} showed that the isoprenoid changes in Alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of premature aging. During aging the human brain shows a progressive increase in levels of dolichol, a reduction in levels of ubiquinone, but relatively unchanged concentrations of cholesterol and dolichyl phosphate. In Alzheimer's disease, the situation is reversed with decreased levels of dolichol and increased levels of ubiquinone. The concentrations of dolichyl phosphate are also increased, while cholesterol remains unchanged. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of glycosylation in the diseased brain and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from oxidative stress, for instance induced by lipid peroxidation. Ropren, identified previously in Russia, is neuroprotective in a rat model of Alzheimer's disease.{{cite journal |display-authors=6 |vauthors=Sviderskii VL, Khovanskikh AE, Rozengart EV, Moralev SN, Yagodina OV, Gorelkin VS, Basova IN, Kormilitsyn BN, Nikitina TV, Roshchin VI, Sultanov VS |year=2006 |title=A comparative study of the effect of the polyprenol preparation ropren from coniferous plants on the key enzymes of the cholinergic and monoaminergic types of nervous transmission |journal=Doklady. Biochemistry and Biophysics |language=ru |volume=408 |pages=148–51 |doi=10.1134/S1607672906030112 |pmid=16913416 |s2cid=12431221}}{{cite journal |vauthors=Fedotova J, Soultanov V, Nikitina T, Roschin V, Ordayn N |date=March 2012 |title=Ropren(®) is a polyprenol preparation from coniferous plants that ameliorates cognitive deficiency in a rat model of beta-amyloid peptide-(25-35)-induced amnesia |journal=Phytomedicine |volume=19 |issue=5 |pages=451–6 |doi=10.1016/j.phymed.2011.09.073 |pmid=22305275}}

A relatively recent hypothesis based mainly on rodent experiments links the onset of Alzheimer's disease to the hypofunction of the large extracellular protein reelin. A decrease of reelin in the human entorhinal cortex where the disease typically initiates is evident {{cite journal |vauthors=Chin J, Massaro CM, Palop J, Thwin MT, Yu GQ, Bien-Ly N, Bender A, Mucke L |date=2007 |title=Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease. |journal=Journal of Neuroscience |volume=27 |issue=11 |pages=2727–2733 |doi=10.1523/JNEUROSCI.3758-06.2007 |pmc=6672562 |pmid=17360894}} while compensatory increase of reelin levels in other brain structures of the patients is also reported.{{cite journal |vauthors=Cuchillo-Ibañez I, Mata-Balaguer T, Balmaceda V, Arranz JJ, Nimpf J, Sáez-Valero J |date=2016 |title=The β-amyloid peptide compromises Reelin signaling in Alzheimer's disease. |journal=Scientific Reports |volume=6 |pages=31646 |bibcode=2016NatSR...631646C |doi=10.1038/srep31646 |pmc=4987719 |pmid=27531658}} Of key importance, overexpression of reelin rescues the cognitive capacities of Alzheimer's disease model mice {{cite journal |vauthors=Pujadas L, Rossi D, Andres R, Teixeira C, Serra-Vidal B, Parcerisas A, Maldonado R, Giralt E, Carulla N, Soriano E |date=2014 |title=Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer's disease. |journal=Nature Communications |volume=5 |pages=3443 |bibcode=2014NatCo...5.3443P |doi=10.1038/ncomms4443 |pmid=24599114 |doi-access=free}} and τ-protein overexpressing mice.{{cite journal |vauthors=Rossi D, Gruart A, Contreras-Murillo G, Muhaisen A, Ávila J, Delgado-García JM, Pujadas L, Soriano E |date=2020 |title=Reelin reverts biochemical, physiological and cognitive alterations in mouse models of Tauopathy. |journal=Progress in Neurobiology |volume=186 |pages=101743 |doi=10.1016/j.pneurobio.2019.101743 |pmid=31870804 |s2cid=209430879 |hdl-access=free |hdl=10261/238425}} A recent circuit level model proposed a mechanism of how reelin depletion leads to the early deterioration of episodic memory thereby laying the theoretical foundation of the reelin hypothesis.{{cite journal |vauthors=Kovács KA |date=December 2021 |title=Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer's Disease |journal=International Journal of Molecular Sciences |volume=23 |issue=1 |pages=462 |doi=10.3390/ijms23010462 |pmc=8745479 |pmid=35008886 |doi-access=free}}

A bioinformatics analysis in 2017{{cite journal | vauthors = Soheili-Nezhad S |year=2017 |title= Alzheimer's disease: the large gene instability hypothesis |journal= bioRxiv |doi= 10.1101/189712 |doi-access= free }} revealed that extremely large human genes are significantly over-expressed in brain and take part in the postsynaptic architecture. These genes are also highly enriched in cell adhesion Gene Ontology (GO) terms and often map to chromosomal fragile sites.{{cite journal | vauthors = Smith DI, Zhu Y, McAvoy S, Kuhn R | title = Common fragile sites, extremely large genes, neural development and cancer | journal = Cancer Letters | volume = 232 | issue = 1 | pages = 48–57 | date = January 2006 | pmid = 16221525 | doi = 10.1016/j.canlet.2005.06.049 }} The majority of known Alzheimer's disease risk gene products including the amyloid precursor protein (APP) and gamma-secretase, as well as the APOE receptors and GWAS risk loci take part in similar cell adhesion mechanisms. It was concluded that dysfunction of cell and synaptic adhesion is central to Alzheimer's disease pathogenesis, and mutational instability of large synaptic adhesion genes may be the etiological trigger of neurotransmission disruption and synaptic loss in brain aging. As a typical example, this hypothesis explains the APOE risk locus of AD in context of signaling of its giant lipoprotein receptor, LRP1b which is a large tumor-suppressor gene with brain-specific expression and also maps to an unstable chromosomal fragile site. The large gene instability hypothesis puts the DNA damage mechanism at the center of Alzheimer's disease pathophysiology.

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{{DEFAULTSORT:Biochemistry Of Alzheimer's Disease}}

Category:Alzheimer's disease

Category:Neurology

Category:Unsolved problems in neuroscience

Category:Pathology