Alzheimer’s disease (AD) is increasingly understood as a disorder of network-state and plasticity-capacity, in which amyloid-β and tau pathologies disrupt the activity-dependent mechanisms that build and stabilize memory engrams. Here, I review how amyloid-β–driven neuronal hyperactivity contributes to plasticity and memory deficits in AD. I also discuss how various cellular pathologies reinforce one another, leading to a cellular environment that is impermissive to plasticity. I relate these cellular and circuit-level disturbances to failures in memory encoding, consolidation, and recall, emphasizing the role of interference arising from coexisting hyper- and hypoactive neuronal populations. Finally, I discuss the relevance and limitations of amyloid mouse models in understanding the cognitive decline in AD.
AbrahamWC.2008. Metaplasticity: tuning synapses and networks for plasticity. Nat Rev Neurosci. 9(5):387.
2.
AkhterFChenDAkhterAYanSFYanSS. 2021. Age-dependent accumulation of dicarbonyls and advanced glycation endproducts (AGEs) associates with mitochondrial stress. Free Radic Biol Med. 164:429–438.
3.
AlgamalM, et al. 2022. Reduced excitatory neuron activity and interneuron-type-specific deficits in a mouse model of Alzheimer’s disease. Commun Biol. 5(1):1323.
BadimonA, et al. 2020. Negative feedback control of neuronal activity by microglia. Nature. 586(7829):417–423.
6.
BeroAW, et al. 2011. Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat Neurosci. 14(6):750–756.
7.
BezprozvannyIMattsonMP. 2008. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci. 31(9):454–463.
8.
BittnerKCMilsteinADGrienbergerCRomaniSMageeJC. 2017. Behavioral time scale synaptic plasticity underlies CA1 place fields. Science. 357(6355):1033–1036.
9.
BoccardiVMancinettiFMecocciP.2025. Oxidative stress, advanced glycation end products (AGEs), and neurodegeneration in Alzheimer’s disease: a metabolic perspective. Antioxidants (Basel). 14(9):1044.
10.
BordjiKBecerril-OrtegaJNicoleOBuissonA.2010. Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ss production. J Neurosci. 30(47):15927–15942.
11.
BorosBD, et al. 2017. Dendritic spines provide cognitive resilience against Alzheimer’s disease. Ann Neurol. 82(4):602–614.
12.
BraakHAlafuzoffIArzbergerTKretzschmarHDel TrediciK.2006. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 112(4):389–404.
13.
BrintonRD.2008. Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer’s disease. Adv Drug Deliv Rev. 60(13–14):1504–1511.
14.
BrookesPSYoonYRobothamJLAndersMWSheuSS. 2004. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol. 287(4):C817–C833.
15.
BuscheMAKonnerthA.2015. Neuronal hyperactivity—a key defect in Alzheimer’s disease?Bioessays. 37(6):624–632.
16.
BuscheMAKonnerthA.2016. Impairments of neural circuit function in Alzheimer’s disease. Philos Trans R Soc Lond B Biol Sci. 371(1700):20150429.
17.
BuscheMA, et al. 2019. Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimer models in vivo. Nat Neurosci. 22(1):57–64.
18.
Calvo-RodriguezM, et al. 2020. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease. Nat Commun. 11(1):2146.
19.
CarvalhoDZ, et al. 2018. Association of excessive daytime sleepiness with longitudinal beta-amyloid accumulation in elderly persons without dementia. JAMA Neurol. 75(6):672–680.
ClavagueraF, et al. 2009. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 11(7):909–913.
22.
Costa-MattioliM, et al. 2007. EIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell. 129(1):195–206.
23.
CraryJF, et al. 2014. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128(6):755–766.
24.
CrowleyG, et al. 2024. C1q and immunoglobulins mediate activity-dependent synapse loss in the adult brain. bioRxiv. 2024.12.18.629085.
25.
DasU, et al. 2016. Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nat Neurosci. 19(1):55–64.
26.
DewarDChalmersDTGrahamDIMcCullochJ.1991. Glutamate metabotropic and AMPA binding sites are reduced in Alzheimer’s disease: an autoradiographic study of the hippocampus. Brain Res. 553(1):58–64.
27.
DuHYanSS. 2010. Mitochondrial permeability transition pore in Alzheimer’s disease: cyclophilin D and amyloid beta. Biochim Biophys Acta. 1802(1):198–204.
28.
DunwiddieTLynchG.1978. Long-term potentiation and depression of synaptic responses in the rat hippocampus: localization and frequency dependency. J Physiol. 276:353–367.
29.
EyoUBPengJSwiatkowskiPMukherjeeABispoAWuLJ. 2014. Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J Neurosci. 34(32):10528–10540.
30.
GiorgioJAdamsJNMaassAJagustWJBreakspearM.2024. Amyloid induced hyperexcitability in default mode network drives medial temporal hyperactivity and early tau accumulation. Neuron. 112(4):676–686.e4.
31.
GreenamyreJT.1991. Neuronal bioenergetic defects, excitotoxicity and Alzheimer’s disease: “use it and lose it.”Neurobiol Aging. 12(4):334–336; discussion 352–355.
HanX, et al. 2013. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell. 12(3):342–353.
34.
HardinghamGEFukunagaYBadingH.2002. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 5(5):405–414.
35.
HebbDO.1949. The organization of behavior: a neuropsychological theory. Wiley.
36.
HendersonBW, et al. 2019. Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against beta-amyloid. Sci Signal. 12(587):eaaw9318.
37.
HetzCMollereauB.2014. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci. 15(4):233–249.
38.
HollerSKostingerGMartinKACSchuhknechtGFPStratfordKJ. 2021. Structure and function of a neocortical synapse. Nature. 591(7848):111–116.
39.
HooperCKillickRLovestoneS.2008. The GSK3 hypothesis of Alzheimer’s disease. J Neurochem. 104(6):1433–1439.
40.
IliffJJ, et al. 2012. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 4(147):147ra111.
41.
InoueK.2002. Microglial activation by purines and pyrimidines. Glia. 40(2):156–163.
42.
ItoM. 1972. Neural design of the cerebellar motor control system. Brain Res. 40(1):81–84.
43.
IwataNHiguchiMSaidoTC. 2005. Metabolism of amyloid-beta peptide and Alzheimer’s disease. Pharmacol Ther. 108(2):129–148.
44.
JansenWJ, et al. 2015. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 313(19):1924–1938.
45.
JosselynSATonegawaS.2020. Memory engrams: recalling the past and imagining the future. Science. 367(6473):eaaw4325.
46.
KatzmanR, et al. 1988. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 23(2):138–144.
47.
KellarDCraftS.2020. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 19(9):758–766.
48.
KellyL, et al. 2021. Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer’s patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability. Neuropathol Appl Neurobiol. 47(4):488–505.
49.
LauterbornJC, et al. 2021. Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease. Nat Commun. 12(1):2603.
50.
LeeAKWilsonMA. 2002. Memory of sequential experience in the hippocampus during slow wave sleep. Neuron. 36(6):1183–1194.
51.
LeeHKMinSSGallagherMKirkwoodA.2005. NMDA receptor-independent long-term depression correlates with successful aging in rats. Nat Neurosci. 8(12):1657–1659.
52.
LeeWJ, et al. 2022. Regional Abeta-tau interactions promote onset and acceleration of Alzheimer’s disease tau spreading. Neuron. 110(12):1932–1943.e5.
53.
LiSJinMKoeglspergerTShepardsonNEShankarGMSelkoeDJ. 2011. Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci. 31(18):6627–6638.
54.
LimDTapellaLDematteisGGenazzaniAACorazzariMVerkhratskyA.2023. The endoplasmic reticulum stress and unfolded protein response in Alzheimer’s disease: a calcium dyshomeostasis perspective. Ageing Res Rev. 87:101914.
55.
LinMMLiuNQinZHWangY.2022. Mitochondrial-derived damage-associated molecular patterns amplify neuroinflammation in neurodegenerative diseases. Acta Pharmacol Sin. 43(10):2439–2447.
56.
LinX, et al. 2022. Spatial coding defects of hippocampal neural ensemble calcium activities in the triple-transgenic Alzheimer’s disease mouse model. Neurobiol Dis. 162:105562.
57.
LuscherCHuberKM. 2010. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron. 65(4):445–459.
58.
MageeJCGrienbergerC.2020. Synaptic plasticity forms and functions. Annu Rev Neurosci. 43:95–117.
59.
MagistrettiPJAllamanI.2015. A cellular perspective on brain energy metabolism and functional imaging. Neuron. 86(4):883–901.
60.
MalenkaRCBearMF. 2004. LTP and LTD: an embarrassment of riches. Neuron. 44(1):5–21.
61.
Melgosa-EcenarroLDoostdarNRadulescuCIJacksonJSBarnesSJ. 2023. Pinpointing the locus of GABAergic vulnerability in Alzheimer’s disease. Semin Cell Dev Biol. 139:35–54.
62.
MorminoECPappKV. 2018. Amyloid accumulation and cognitive decline in clinically normal older individuals: implications for aging and early Alzheimer’s disease. J Alzheimers Dis. 64(s1):S633–S646.
63.
MosconiL, et al. 2021. Menopause impacts human brain structure, connectivity, energy metabolism, and amyloid-beta deposition. Sci Rep. 11(1):10867.
64.
MosconiLPupiADe LeonMJ. 2008. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci. 1147:180–195.
65.
NahmMGreysonBKellyEWHaraldssonE.2012. Terminal lucidity: a review and a case collection. Arch Gerontol Geriatr. 55(1):138–142.
66.
NemethDPQuanN.2021. Modulation of neural networks by interleukin-1. Brain Plast. 7(1):17–32.
67.
NiraulaS, et al. 2023. Excitation-inhibition imbalance disrupts visual familiarity in amyloid and non-pathology conditions. Cell Rep. 42(1):111946.
68.
NiswenderCMConnPJ. 2010. Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol. 50:295–322.
69.
NixonRARubinszteinDC. 2024. Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases. Nat Rev Mol Cell Biol. 25(11):926–946.
NotoNMSpethRCRobisonLS. 2025. Cerebral amyloid angiopathy: a narrative review. Front Aging Neurosci. 17:1632252.
72.
O’BrienJL, et al. 2010. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology. 74(24):1969–1976.
73.
O’ConnorT, et al. 2008. Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron. 60(6):988–1009.
74.
PalopJJChinJMuckeL.2006. A network dysfunction perspective on neurodegenerative diseases. Nature. 443(7113):768–773.
75.
PalopJJMuckeL.2010a. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci. 13(7):812–818.
76.
PalopJJMuckeL.2010b. Synaptic depression and aberrant excitatory network activity in Alzheimer’s disease: two faces of the same coin?Neuromolecular Med. 12(1):48–55.
77.
PalopJJMuckeL.2016. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 17(12):777–792.
78.
PandeyUB, et al. 2007. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 447(7146):859–863.
79.
ParhizkarSHoltzmanDM. 2025. The night’s watch: exploring how sleep protects against neurodegeneration. Neuron. 113(6):817–837.
80.
ParkS, et al. 2008. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron. 59(1):70–83.
81.
Perez OrtizJMSwerdlowRH. 2019. Mitochondrial dysfunction in Alzheimer’s disease: role in pathogenesis and novel therapeutic opportunities. Br J Pharmacol. 176(18):3489–3507.
82.
PhielCJWilsonCALeeVMKleinPS. 2003. GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature. 423(6938):435–439.
83.
PollS, et al. 2020. Memory trace interference impairs recall in a mouse model of Alzheimer’s disease. Nat Neurosci. 23(8):952–958.
84.
PoolerAM, et al. 2015. Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease. Acta Neuropathol Commun. 3:14.
85.
RavasengaTRubenMRegioVPolenghiAPetriniEMBarberisA.2022. Spatial regulation of coordinated excitatory and inhibitory synaptic plasticity at dendritic synapses. Cell Rep. 38(6):110347.
86.
RizzutoRSimpsonAWBriniMPozzanT.1992. Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature. 358(6384):325–327.
87.
RobersonED, et al. 2007. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science. 316(5825):750–754.
88.
Roemer-CassianoSN, et al. 2025. Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer’s disease. Sci Transl Med. 17(782):eadp2564.
89.
RollsETTrevesA.1998. Neural networks and brain function. Oxford University Press.
90.
RoyDSAronsAMitchellTIPignatelliMRyanTJTonegawaS.2016. Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature. 531(7595):508–512.
91.
Rueda-CarrascoJ, et al. 2023. Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer’s disease models. EMBO J. 42(19):e113246.
92.
RuggieroAKatsenelsonMSlutskyI.2021. Mitochondria: new players in homeostatic regulation of firing rate set points. Trends Neurosci. 44(8):605–618.
93.
SantelloMBezziPVolterraA.2011. TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron. 69(5):988–1001.
94.
ScadutoP, et al. 2023. Functional excitatory to inhibitory synaptic imbalance and loss of cognitive performance in people with Alzheimer’s disease neuropathologic change. Acta Neuropathol. 145(3):303–324.
95.
ScimemiAMeabonJSWoltjerRLSullivanJMDiamondJSCookDG. 2013. Amyloid-beta1-42 slows clearance of synaptically released glutamate by mislocalizing astrocytic GLT-1. J Neurosci. 33(12):5312–5318.
SiskovaZ, et al. 2014. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer’s disease. Neuron. 84(5):1023–1033.
98.
Spires-JonesTLHymanBT. 2014. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron. 82(4):756–771.
99.
StargardtASwaabDFBossersK.2015. Storm before the quiet: neuronal hyperactivity and Abeta in the presymptomatic stages of Alzheimer’s disease. Neurobiol Aging. 36(1):1–11.
100.
StellwagenDMalenkaRC. 2006. Synaptic scaling mediated by glial TNF-alpha. Nature. 440(7087):1054–1059.
101.
SternY.2012. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 11(11):1006–1012.
102.
SunEMotolaniACamposLLuT.2022. The pivotal role of NF-kB in the pathogenesis and therapeutics of Alzheimer’s disease. Int J Mol Sci. 23(16):8972.
103.
TalantovaM, et al. 2013. Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A. 110(27):E2518–E2527.
104.
Targa Dias AnastacioHMatosinNOoiL. 2022. Neuronal hyperexcitability in Alzheimer’s disease: what are the drivers behind this aberrant phenotype?Transl Psychiatry. 12(1):257.
105.
TerryRD, et al. 1991. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 30(4):572–580.
106.
TeylanM, et al. 2020. Cognitive trajectory in mild cognitive impairment due to primary age-related tauopathy. Brain. 143(2):611–621.
107.
ThalDRRubUOrantesMBraakH.2002. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 58(12):1791–800.
108.
TurrigianoG.2012. Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harb Perspect Biol. 4(1):a005736.
109.
TyagarajanSKFritschyJM. 2014. Gephyrin: a master regulator of neuronal function?Nat Rev Neurosci. 15(3):141–156.
110.
ValdiviaG, et al. 2023. MGluR-dependent plasticity in rodent models of Alzheimer’s disease. Front Synaptic Neurosci. 15:1123294.
111.
VerretL, et al. 2012. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell. 149(3):708–721.
112.
VicenteMAddo-OsafoKVosselK.2024. Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy bodies. Front Neurol. 15:1277613.
113.
VosselKA, et al. 2016. Incidence and impact of subclinical epileptiform activity in Alzheimer’s disease. Ann Neurol. 80(6):858–870.
114.
WalkerCKHerskowitzJH. 2021. Dendritic spines: mediators of cognitive resilience in aging and alzheimer’s disease. Neuroscientist. 27(5):487–505.
115.
WalkerCK, et al. 2024. Dendritic spine head diameter predicts episodic memory performance in older adults. Sci Adv. 10(32):eadn5181.
116.
WangCHoltzmanDM. 2020. Bidirectional relationship between sleep and Alzheimer’s disease: role of amyloid, tau, and other factors. Neuropsychopharmacology. 45(1):104–120.
117.
WangL, et al. 2025. Amyloid beta peptides inhibit glucose transport at the blood-brain barrier by disrupting the insulin-AKT pathway. J Cereb Blood Flow Metab. 45(10):1961–1979.
118.
WangXWangWLiLPerryGLeeHGZhuX.2014. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta. 1842(8):1240–1247.
119.
WattsJCPrusinerSB. 2018. β-Amyloid prions and the pathobiology of Alzheimer’s disease. Cold Spring Harb Perspect Med. 8(5):a023507.
120.
WhitehousePJPriceDLStrubleRGClarkAWCoyleJTDelonMR. 1982. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science. 215(4537):1237–1239.
121.
WhitlockJRHeynenAJShulerMGBearMF. 2006. Learning induces long-term potentiation in the hippocampus. Science. 313(5790):1093–1097.
122.
WuJW, et al. 2016. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 19(8):1085–1092.
123.
XuJ, et al. 2009. Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J Neurosci. 29(29):9330–9343.
124.
ZhaoWQTownsendM.2009. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta. 1792(5):482–496.
