Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease

In the paper

“Greater hippocampal activation during encoding tasks is associated with worse task performance [176] in MCI and AD patients [172, 177]”

What the sources say

• Supported

  The Results (Experiment 1; page unavailable) report a negative correlation between right CA3/DG activity and pattern-separation performance, supporting the activation–performance association attributed to this citation. The Discussion cautions that within-group correlations were not statistically reliable. The sentence attaches separate citations to the MCI and AD population claim; this study examined nondemented older adults. (LLM, conf=0.87)

  cites [176] Yassa MA, Lacy JW, Stark SM, Albert MS, Gallagher M, Stark CE. Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults. Hippocampus. 2011;21(9):968–79. source
• Disputed

  The Discussion reports the opposite pattern: greater medial temporal lobe activation was associated with better recognition performance in MCI subjects. In the present study, MCI subjects had greater hippocampal activation and performed similarly to controls, whereas AD patients had less activation and poorer performance. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [172] Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E, Rentz DM, et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology. 2005;65(3):404–11. sourceExperimental — accuracy not yet measured
• Not checked yetcites [177] Miller SL, Fenstermacher E, Bates J, Blacker D, Sperling RA, Dickerson BC. Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline. J Neurol Neurosurg Psychiatry. 2008;79(6):630–5. source

In the paper

“Overall, it has been demonstrated, both in vivo and in vitro, that apoE plays major roles in AD pathogenesis in both an Aβ-dependent and independent manner, and different cellular sources of apoE4 may contribute in distinct ways to AD pathogenesis [4–8, 12–14, 21, 22].”

What the sources say

• Supported

  The ApoE4 section explicitly says that in vitro and in vivo studies have explored apoE4’s Aβ-dependent and independent roles in AD pathogenesis. Its separate subsections address both roles; the copy also describes distinct effects associated with different cellular sources of apoE. (LLM, conf=0.94)

  cites [4] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204–22. source
• Partly supported

  The Abstract and Concluding Remarks identify effects on Aβ aggregation and clearance as apoE’s main proposed contribution to AD pathogenesis. They discuss non-Aβ mechanisms, including effects on tau, synaptic plasticity and neuroinflammation, but say these remain possible or incompletely understood—not that major Aβ-independent roles have been demonstrated. (LLM, conf=0.88)

  cites [5] Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303. sourceExperimental — accuracy not yet measured
• Supported

  The Conclusions state that ApoE4 appears to increase Alzheimer disease risk through both Aβ-dependent and Aβ-independent pathways. The Introduction also describes effects on Aβ aggregation and clearance alongside Aβ-independent functions, supporting the attributed paraphrase. (LLM, conf=0.92)

  cites [6] Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. source
• Supported

  The Summary and Perspective section states that apoE regulates Aβ clearance and aggregation as well as Aβ-independent pathways in AD pathogenesis. It also says apoE4 contributes to AD pathogenesis independently of Aβ. (LLM, conf=0.94)

  cites [7] Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740–54. source
• Supported

  The “Aβ-Dependent Effects of ApoE4 on AD Pathogenesis” section describes apoE’s effects on Aβ metabolism and related neuropathology. The “Aβ-Independent Effects of ApoE4 on AD Pathogenesis” section says in vivo and in vitro studies suggest independent roles that may act alongside the dependent effects. Together, these passages support the attributed claim. (LLM, conf=0.92)

  cites [8] Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. 2014;72:3–12. source
• Supported

  The Introduction explicitly says the review describes Aβ-dependent and Aβ-independent pathways by which apoE isoforms contribute to AD pathogenesis. It also says several such pathways have been identified in vitro and in vivo. No page number is provided in our copy. (LLM, conf=0.94)

  cites [12] Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10(5):333–44. source
• Supported

  The “Mechanisms for apoE4’s involvement in the amyloid pathway” section describes apoE4’s effects on Aβ deposition and clearance. The “ApoE’s direct effects on neuropathology independent of Aβ” section also describes an Aβ-independent pathway, including detrimental effects observed in vitro and in vivo. The paper emphasizes apoE4 within the broader claim about apoE. (LLM, conf=0.91)

  cites [13] Mahley RW. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med. 2016;94(7):739–46. source
• Supported

  The introduction says the review considers apoE4’s pathological roles with or without amyloid-β, and the ApoE and AD section describes both amyloid-related and other pathways. The paper also discusses distinct cellular sources of apoE and reports evidence from in vivo and in vitro studies. The supplied passages do not give page numbers. (LLM, conf=0.91)

  cites [14] Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103(15):5644–51. source
• Not checked yetcites [21] Huang Y. Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med. 2010;16(6):287–94. source
• Supported

  In the Introduction section “ApoE Modulation of the Aβ Pathway,” the paper describes apoE’s effects on the Aβ pathway and explicitly says apoE can also affect AD pathogenesis independently of Aβ. This supports the quoted claim; the supplied passages do not provide page numbers. (LLM, conf=0.94)

  cites [22] Mahley RW, Huang Y. Apolipoprotein E sets the stage: response to injury triggers neuropathology. Neuron. 2012;76(5):871–85. source

In the paper

“ApoE assists in Aβ clearance in an isoform-dependent manner wherein apoE2 > apoE3 > apoE4 [29, 30, 59].”

What the sources say

• Not checked yetcites [29] Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J, et al. Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci. 1999;96(26):15233–8. source
• Partly supported

  The Discussion (page unavailable) says human apoE appears to enhance Aβ clearance and proposes that apoE–Aβ interactions regulate it. The Results show more Aβ deposition with apoE4 than apoE3, but the paper does not establish clearance rates for those isoforms or examine apoE2. It therefore does not support the stated apoE2 > apoE3 > apoE4 clearance ranking. (LLM, conf=0.88)

  cites [30] Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2000;97(6):2892–7. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report that apoE3, but not apoE4, restored Aβ clearance by mouse brain capillary pericytes with silenced endogenous apoE. The Conclusions likewise describe isoform-specific clearance, but the paper does not establish the claimed apoE2 > apoE3 > apoE4 ranking: its comparison is limited to apoE3 and apoE4. (LLM, conf=0.89)

  cites [59] Ma Q, Zhao Z, Sagare AP, Wu Y, Wang M, Owens NC, et al. Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism. Mol Neurodegener. 2018;13(1):57. sourceExperimental — accuracy not yet measured

In the paper

“Since perineuronal nets protect these interneurons from oxidative stress and other injuries [161]”

What the sources say

• Partly supported

  The Results section (page not supplied) reports that degrading mature perineuronal nets made parvalbumin-expressing cells more susceptible to oxidative stress. The paper does not establish protection against other kinds of injury; the environmental insults it discusses are linked to oxidative stress. (LLM, conf=0.88)

  cites [161] Cabungcal J, Steullet P, Morishita H, Kraftsik R, Cuenod M, Hensch TK. Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proc Natl Acad Sci. 2013;110(22):9130–5. sourceExperimental — accuracy not yet measured

In the paper

“It has been reported that activated microglia migrate to inhibitory synapses and displace them from excitatory neurons [154]”

What the sources say

• Supported

  The Abstract states that activated microglia migrate to inhibitory synapses and displace them from cortical neurons. The Results section, “Activated microglia displace inhibitory GABAergic synapses” (page not provided), identifies those neurons as cortical projection neurons, consistent with the citing sentence’s description of excitatory neurons. (LLM, conf=0.89)

  cites [154] Chen Z, Jalabi W, Hu W, Park H, Gale JT, Kidd GJ, et al. Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain. Nat Commun. 2014;5:4486. source

In the paper

“A recent study reports that apoE4-expressing neuronal cells have 50% less reserve capacity to generate ATP than apoE3-expressing neuronal cells”

What the sources say

• Supported

  The Results section (“ApoE4 expression alters the bioenergetics profile in neuronal cells,” Fig. 1D; page not provided) reports that total reserve capacity to generate ATP was about 50% lower in apoE4-expressing neuronal cells than in apoE3-expressing cells. This reserve capacity was assessed under maximal stress stimulation, not under basal conditions. (LLM, conf=0.94)

  cites [191] Orr AL, Kim C, Jimenez-morales D, Newton BW, Johnson J, Swaney D, et al. Neuronal apolipoprotein E4 expression results in proteome-wide alterations and compromises bioenergetic capacity by disrupting mitochondrial function. J Alzheimers Dis. 2019;68(3):991–1011. source

In the paper

“Second, healthy elderly apoE4 carriers show increased hippocampal and entorhinal activation during encoding task performance [172, 173].”

What the sources say

• Partly supported

  The Methods describe a face–name encoding task, and the Results report greater entorhinal activation in APOE ε4 carriers across all 29 participants. But that group included people with MCI and AD as well as healthy elderly controls; the Results do not establish the effect specifically in healthy carriers or report a hippocampal genotype effect. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [172] Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E, Rentz DM, et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology. 2005;65(3):404–11. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Search ROI analyses; page unavailable) report greater encoding-related activation in the right hippocampal and parahippocampal cortices of nondemented older APOE ε4 carriers. They do not identify increased entorhinal activation, and they report a lower response in left hippocampal clusters than in ε3 carriers. The claim therefore overgeneralizes the hippocampal finding and adds an unsupported entorhinal finding. (LLM, conf=0.88)

  cites [173] Bondi MW, Houston WS, Eyler LT, Brown GG. fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology. 2005;64(3):501–8. sourceExperimental — accuracy not yet measured

In the paper

“Astrocytes are the primary source of apoE in the brain [23, 24].”

What the sources say

• Not checked yetcites [23] Grehan S, Tse E, Taylor JM. Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain. J Neurosci. 2001;21(3):812–22. source
• Not checked yetcites [24] Pitas RE, Boyles JK, Lee SH, Foss D, Mahley RW. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta (BBA)/Lipids Lipid Metab. 1987;917(1):148–61. source

In the paper

“Cellular origin plays a crucial role in apoE’s biophysical properties and pathological effects.”

What the sources say

• Not checked yetcites [27] Shi Y, Holtzman DM. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol. 2018. https://doi.org/10.1038/s41577-018-0051-1 . source
• Not checked yetcites [28] Huang Y, Weisgraber KH, Mucke L, Mahley RW. Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer’s disease. J Mol Neurosci. 2004;23(3):189–204. source

In the paper

“Importantly, this domain interaction renders apoE4 to be more susceptible to proteolytic cleavage, resulting in the generation of neurotoxic apoE4 fragments [20–22].”

What the sources say

• Not checked yetcites [20] Brecht WJ, Harris FM, Chang S, Tesseur I, Yu G-Q, Xu Q, et al. Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci. 2004;24(10):2527–34. source
• Not checked yetcites [21] Huang Y. Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med. 2010;16(6):287–94. source
• Not checked yetcites [22] Mahley RW, Huang Y. Apolipoprotein E sets the stage: response to injury triggers neuropathology. Neuron. 2012;76(5):871–85. source

In the paper

“Apolipoprotein (apo) E4, an isoform of the APOE gene in humans, is the major genetic risk factor for late-onset familial and sporadic AD [4–8], which account for most AD cases.”

What the sources say

• Not checked yetcites [4] Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204–22. source
• Not checked yetcites [5] Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303. source
• Not checked yetcites [6] Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. source
• Not checked yetcites [7] Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740–54. source
• Not checked yetcites [8] Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. 2014;72:3–12. source

In the paper

“However, under aging and stress conditions, neurons also produce apoE, albeit at lower levels than astrocytes [25, 26].”

What the sources say

• Not checked yetcites [25] Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci. 2006;26(19):4985–94. source
• Not checked yetcites [26] Xu PT, Schmechel D, Rothrock-Christian T, Burkhart DS, Qiu HL, Popko B, et al. Human apolipoprotein E2, E3, and E4 isoform-specific transgenic mice: human-like pattern of glial and neuronal immunoreactivity in central nervous system not observed in wild-type mice. Neurobiol Dis. 1996;3(3):229–45. source

In the paper

“This domain interaction mediated by a salt bridge formation between Arg-61 and Glu-255 is unique to apoE4 (Fig. 1) [15].”

What the sources say

• Not checked yetcites [15] Hatters DM, Peters-Libeu CA, Weisgraber KH. Apolipoprotein E structure: insights into function. Trends Biochem Sci. 2006;31(8):445–54. source

In the paper

“Although apoE interacts with amyloid, it should be noted that plaque load does not correlate well with cognitive impairments, highlighted most obviously by people with substantial plaque burdens and normal cognition [67].”

What the sources say

• Not checked yetcites [67] Giannakopoulos P, Herrmann FR, Bussière T, Bouras C, Kövari E, Perl DP, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003;60(9):1495–500. source

In the paper

“As mentioned above, apoE4 is highly susceptible to neuron-specific proteolysis, which generates neurotoxic fragments [20, 77–79].”

What the sources say

• Not checked yetcites [20] Brecht WJ, Harris FM, Chang S, Tesseur I, Yu G-Q, Xu Q, et al. Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci. 2004;24(10):2527–34. source
• Not checked yetcites [77] Uddin MS, Kabir MT, Al Mamun A, Abdel-Daim MM, Barreto GE, Ashraf GM. APOE and Alzheimer’s disease: evidence mounts that targeting APOE4 may combat Alzheimer’s pathogenesis. Mol Neurobiol. 2018. https://doi.org/10.1007/s12035-018-1237-z . source
• Not checked yetcites [78] Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW. Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci. 2001;98(15):8838–43. source
• Not checked yetcites [79] Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, et al. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci U S A. 2003;100:10966–71. source

In the paper

“In response to injury, or stress such as normal aging, neurons express apoE, likely to facilitate transport of cholesterol and other lipids for membrane repair and/or remodeling [22].”

What the sources say

• Not checked yetcites [22] Mahley RW, Huang Y. Apolipoprotein E sets the stage: response to injury triggers neuropathology. Neuron. 2012;76(5):871–85. source

In the paper

“Loss of GABA, the primary inhibitory neurotransmitter in the brain, is a key component of AD.”

What the sources say

• Not checked yetcites [84] Govindpani K, Calvo-Flores Guzmán B, Vinnakota C, Waldvogel H, Faull R, Kwakowsky A, et al. Towards a better understanding of GABAergic remodeling in Alzheimer’s disease. Int J Mol Sci. 2017;18(8):1813. source
• Not checked yetcites [85] Lanctôt KL, Herrmann N, Mazzotta P, Khan LR, Ingber N. GABAergic function in Alzheimer’s disease: evidence for dysfunction and potential as a therapeutic target for the treatment of Behavioural and psychological symptoms of dementia. Can J Psychiatr. 2016;49(7):439–53. source

In the paper

“Substantial evidence shows that loss of GABAergic tone leads to seizures [97].”

What the sources say

• Not checked yetcites [97] Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia. 2001;42(SUPPL. 3):8–12. source

In the paper

“In particular, GABAergic interneurons in the dentate gyrus (DG) are particularly vulnerable to apoE4 fragment-mediated neurotoxicity, and in apoE4 fragment transgenic mice, knocking out tau rescues GABAergic interneuron loss as well as learning and memory deficits, demonstrating the tau-dependent nature of apoE4-induced cognitive impairment [71].”

What the sources say

• Not checked yetcites [71] Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, et al. Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010;30(41):13707–17. source

In the paper

“Additionally, AD patients have a specific loss of somatostatin-positive interneurons in the cortex [94] and hippocampus [95].”

What the sources say

• Not checked yetcites [94] Davies P, Katzman R, Terry RD. Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementa. Nature. 1980;288(5788):279–80. source
• Not checked yetcites [95] Chan-Palay V. Somatostatin immunoreactive neurons in the human hippocampus and cortex shown by immunogold/silver intensification on vibratome sections: coexistence with neuropeptide Y neurons, and effects in Alzheimer-type dementia. J Comp Neurol. 1987;260(2):201–23. source

In the paper

“For example, both apoE4 transgenic and apoE4-KI mice show age- and sex-dependent learning and memory deficits in the absence of Aβ accumulation, as compared to apoE3 transgenic and apoE3-KI mice [68–71].”

What the sources say

• Not checked yetcites [68] Raber J, Wong D, Buttini M, Orth M, Bellosta S, Pitas RE, et al. Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc Natl Acad Sci U S A. 1998;95(18):10914–9. source
• Not checked yetcites [69] Raber J, Wong D, Yu G-Q, Buttini M, Mahley R, Pitas R, et al. Apolipoprotein E and cognitive performance. Nature. 2000;404(6776):352–4. source
• Not checked yetcites [70] Leung L, Andrews-Zwilling Y, Yoon SY, Jain S, Ring K, Dai J, et al. Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice. PLoS One. 2012;7(12):e53569. source
• Not checked yetcites [71] Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, et al. Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010;30(41):13707–17. source

In the paper

“Inhibitory interneurons regulate network oscillations, which synchronize neuronal activity to rhythms that are crucial to learning and memory [112–116].”

What the sources say

• Not checked yetcites [112] Mongillo G, Rumpel S, Loewenstein Y. Inhibitory connectivity defines the realm of excitatory plasticity. Nat Neurosci. 2018;21(10):1463–70. source
• Not checked yetcites [113] Cobb SR, Buhl EH, Halasy K, Paulsen O, Somogyi P. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature. 1995;378(6552):75–8. source
• Not checked yetcites [114] Somogyi P, Klausberger T. Defined types of cortical interneurone structure space and spike timing in the hippocampus. J Physiol. 2005;562(Pt 1):9–26. source
• Not checked yetcites [115] Xu X, An L, Mi X, Zhang T. Impairment of cognitive function and synaptic plasticity associated with alteration of information flow in Theta and gamma oscillations in melamine-treated rats. PLoS One. 2013;8(10):e77796. source
• Not checked yetcites [116] Cardin JA. Inhibitory interneurons regulate temporal precision and correlations in cortical circuits. Trends Neurosci. 2018;41(10):689–700. source

In the paper

“Strikingly, much of AD pathology seen in vivo was successfully recapitulated in this hiPSC-derived neuronal model in vitro.”

What the sources say

• Not checked yetcites [128] Wang C, Najm R, Xu Q, Jeong D, Walker D, Balestra ME, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a Small-molecule structure corrector. Nat Med. 2018;24(5):647–57. source

In the paper

“Strikingly, the majority of neurons surrounded by perineuronal nets are parvalbumin-expressing GABAergic interneurons [159]”

What the sources say

• Not checked yetcites [159] Härtig W, Brauer K. G B. Wisteria floribunda agglutinin-labelled nets surround parvalbumin- containing neurons. Neuroreport. 1992;3(10):869–72. source

In the paper

“apoE signaling in microglia following phagocytosis of apoptotic neurons or in response to Aβ accumulation leads to a transcriptional switch from promoting homeostasis to promoting inflammation and neurodegeneration [150, 151].”

What the sources say

• Not checked yetcites [150] Frigerio CS, Wolfs L, Fattorelli N, Perry VH, Fiers M, De SB, et al. The Major risk factors for Alzheimer’s disease: age, sex, and genes modulate the microglia response to Aβ plaques. Cell Rep. 2019;27(4):1293–306. source
• Not checked yetcites [151] Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47(3):566–81 e9. source

In the paper

“For example, apoE4/4 neurons produced significantly more Aβ and phosphorylated tau than apoE3/3 neurons.”

What the sources say

• Not checked yetcites [128] Wang C, Najm R, Xu Q, Jeong D, Walker D, Balestra ME, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a Small-molecule structure corrector. Nat Med. 2018;24(5):647–57. source

In the paper

“ApoE is upregulated in primed/activated microglia [149, 150]”

What the sources say

• Not checked yetcites [149] Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions : a co-expression meta-analysis. Acta Neuropathol. 2015;3(31):1–18.
• Not checked yetcites [150] Frigerio CS, Wolfs L, Fattorelli N, Perry VH, Fiers M, De SB, et al. The Major risk factors for Alzheimer’s disease: age, sex, and genes modulate the microglia response to Aβ plaques. Cell Rep. 2019;27(4):1293–306. source

In the paper

“For example, apoE4-KI mice display an age- and tau-dependent decrease in hilar GABAergic somatostatin-positive interneurons in the hippocampus [71].”

What the sources say

• Not checked yetcites [71] Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, et al. Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci. 2010;30(41):13707–17. source

In the paper

“Loss of phasic inhibition manifests as reduced hippocampal rhythms [130].”

What the sources say

• Not checked yetcites [130] Lee V, Maguire J. The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front Neural Circuits. 2014;8:3. source

In the paper

“and an increase in CX3CR1 expression in activated microglia suppresses GABAA receptor signaling in excitatory neurons [155]”

What the sources say

• Not checked yetcites [155] Roseti C, Fucile S, Lauro C, Martinello K, Bertollini C, Esposito V, et al. Fractalkine/CX3CL1 modulates GABA(a) currents in human temporal lobe epilepsy. Epilepsia. 2013;5(10):1834–44. source

In the paper

“Furthermore, reducing hippocampal GABA levels impairs learning and memory [120, 121], and silencing inhibitory interneurons in the dentate gyrus prevents both encoding of new memories and recall of old memories [122].”

What the sources say

• Not checked yetcites [120] Hu J-H, Ma Y-H, Jiang J, Yang N, Duan S, Jiang Z-H, et al. Cognitive impairment in mice over-expressing gamma-aminobutyric acid transporter 1 (GAT1). Neuroreport. 2004;15(1):9–12. source
• Not checked yetcites [121] Prut L, Prenosil G, Willadt S, Vogt K, Fritschy J-M, Crestani F. A reduction in hippocampal GABA a receptor α5 subunits disrupts the memory for location of objects in mice. Genes. Brain Behav. 2010;9(5):478–88.

In the paper

“epilepsy patients with at least one APOE4 allele are six times more likely to exhibit treatment resistance [141].”

What the sources say

• Not checked yetcites [141] Sporis D, Sertic J, Henigsberg N, Mahovic D, Bogdanovic N, Babic T. Association of refractory complex partial seizures with a polymorphism of ApoE genotype. J Cell Mol Med. 2005;9(3):698–703. source

In the paper

“AD patients have reduced perineuronal net density [158].”

What the sources say

• Not checked yetcites [158] Baig S, Wilcock GK, Love S. Loss of perineuronal net N -acetylgalactosamine in Alzheimer’s disease. Acta Neuropathol. 2005;110(4):393–401. source

In the paper

“and evidence suggests disrupted GABA signaling in the olfactory bulb may mediate this olfactory loss [147].”

What the sources say

• Not checked yetcites [147] Hu B, Geng C, Hou X-Y. Oligomeric amyloid-β peptide disrupts olfactory information output by impairment of local inhibitory circuits in rat olfactory bulb. Neurobiol Aging. 2017;51:113–21. source

In the paper

“These studies together suggest that apoE4-mediated odor memory impairment, a potential early biomarker of cognitive dysfunction, may be due to apoE4-induced hyperactivity.”

In the paper

“First, cognitively normal apoE4 carriers show reduced task-induced deactivation of the default mode network (DMN) [162–164].”

What the sources say

• Not checked yetcites [162] Persson J, Lind J, Larsson A, Ingvar M, Sleegers K, Van Broeckhoven C, et al. Altered deactivation in individuals with genetic risk for Alzheimer’s disease. Neuropsychologia. 2008;46(6):1679–87. source
• Not checked yetcites [163] Fleisher AS, Sherzai A, Taylor C, Langbaum JBS, Chen K, Buxton RB. Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer’s disease risk groups. Neuroimage. 2009;47(4):1678–90. source
• Not checked yetcites [164] Pihlajamäki M, Sperling RA. Functional MRI assessment of task-induced deactivation of the default mode network in Alzheimer’s disease and at-risk older individuals. Behav Neurol. 2009;21(1):77–91. source

In the paper

“Younger mice recorded before the onset of significant interneuron loss do not show significant slow gamma power loss”

What the sources say

• Not checked yetcites [182] Gillespie AK, Jones EA, Lin Y-H, Karlsson MP, Kay K, Yoon SY, et al. Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples. Neuron. 2016;90(4):740–51. source

In the paper

“In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex.”

In the paper

“and even predicts future cognitive decline in cognitively healthy elderly [178].”

What the sources say

• Not checked yetcites [178] Leal SL, Landau SM, Bell RK, Jagust WJ. Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline. Elife. 2017;6:e22978. source

In the paper

“This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.”

In the paper

“Healthy young and middle-aged adult apoE4 carriers show increased DMN activation at rest [179]”

What the sources say

• Not checked yetcites [179] Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, et al. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proc Natl Acad Sci U S A. 2009;106(17):7209–14. source

In the paper

“as well as widespread changes in mitochondrial protein production and translocation”

What the sources say

• Not checked yetcites [191] Orr AL, Kim C, Jimenez-morales D, Newton BW, Johnson J, Swaney D, et al. Neuronal apolipoprotein E4 expression results in proteome-wide alterations and compromises bioenergetic capacity by disrupting mitochondrial function. J Alzheimers Dis. 2019;68(3):991–1011. source

In the paper

“The network dysfunction and hyperexcitability themselves contribute to learning and memory deficits”

In the paper

“suggesting that this DMN hyperactivity could be the result of inhibitory deficits.”

In the paper

“working model: Aging and/or stress induces neuronal expression of apoE.”

What the sources say

• Not checked yetcites [25] Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci. 2006;26(19):4985–94. source
• Not checked yetcites [26] Xu PT, Schmechel D, Rothrock-Christian T, Burkhart DS, Qiu HL, Popko B, et al. Human apolipoprotein E2, E3, and E4 isoform-specific transgenic mice: human-like pattern of glial and neuronal immunoreactivity in central nervous system not observed in wild-type mice. Neurobiol Dis. 1996;3(3):229–45. source

In the paper

“Reduced ability to deactivate the DMN during memory encoding is found in AD patients [168–170]”

What the sources say

• Not checked yetcites [168] Buckner RL, Andrews-Hanna JR, Schacter DL. The Brain’s default network:anatomy, function and relevance to disease. Ann N Y Acad Sci. 2008;1124:1–38. source
• Not checked yetcites [169] Mevel K, Chételat G, Eustache F, Desgranges B. The default mode network in healthy aging and Alzheimer’s disease. Int J Alzheimers Dis. 2011;2011:535816. source
• Not checked yetcites [170] Lustig C, Snyder AZ, Bhakta M, O’Brien KC, McAvoy M, Raichle ME, et al. Functional deactivations: change with age and dementia of the Alzheimer type. Proc Natl Acad Sci U S A. 2003;100(24):14504–9. source

In the paper

“suggesting that apoE4-induced network hyperactivity occurs before significant Aβ accumulation in human brains.”

In the paper

“This activation is dysfunctional hyperactivity rather than task-related, as levetiracetam treatment of amnestic MCI patients both reduces hippocampal over-activation and improves cognitive performance during a recognition memory task [109, 175].”

In the paper

“A recent study found that aged apoE4-KI mice had increased field potential synchrony and pyramidal cell firing in the entorhinal cortex [174].”

What the sources say

• Not checked yetcites [174] Nuriel T, Angulo SL, Khan U, Ashok A, Chen Q, Figueroa HY, et al. Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology. Nat Commun. 2017;8(1):1464. source

In the paper

“and through a tau-dependent mechanism, results in GABAergic interneuron dysfunction and death.”

In the paper

“treating apoE4-KI mice with pentobarbital early in life prevents learning and memory deficits late in life [126].”

What the sources say

• Not checked yetcites [126] Tong LM, Yoon SY, Andrews-Zwilling Y, Yang A, Lin V, Lei H, et al. Enhancing GABA signaling during middle adulthood prevents age-dependent GABAergic interneuron decline and learning and memory deficits in ApoE4 mice. J Neurosci. 2016;36(7):2316–22. source

In the paper

“and is correlated with worse task performance [171]”

What the sources say

• Not checked yetcites [171] Broyd SJ, Demanuele C, Debener S, Helps SK, James CJ, Sonuga-Barke EJS. Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci Biobehav Rev. 2009;33(3):279–96. source

In the paper

“Susceptibility of GABAergic interneurons to apoE4 and subsequent loss of inhibitory function can also lead to reduced coordination of hippocampal network activity involved in memory.”

In the paper

“the local field potential of hippocampal replay events which are critical for consolidating spatial memory [182, 183]”

What the sources say

• Not checked yetcites [182] Gillespie AK, Jones EA, Lin Y-H, Karlsson MP, Kay K, Yoon SY, et al. Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples. Neuron. 2016;90(4):740–51. source
• Not checked yetcites [183] Buzsáki G. Hippocampal sharp wave-ripple: a cognitive biomarker for episodic memory and planning. Hippocampus. 2015;25(10):1073–188. source

In the paper

“indicating that these phenotypes are caused by intraneuronal apoE4 expressed in GABAergic interneurons.”

In the paper

“Notably, removing apoE4 from inhibitory interneurons specifically rescues slow gamma power and learning and memory deficits”

What the sources say

• Not checked yetcites [182] Gillespie AK, Jones EA, Lin Y-H, Karlsson MP, Kay K, Yoon SY, et al. Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples. Neuron. 2016;90(4):740–51. source

In the paper

“the use of a structure corrector has been shown in vitro to ameliorate apoE4-mediated AD pathologies in hiPSC-derived neurons, including GABAergic neuron deficits [128].”

What the sources say

• Not checked yetcites [128] Wang C, Najm R, Xu Q, Jeong D, Walker D, Balestra ME, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a Small-molecule structure corrector. Nat Med. 2018;24(5):647–57. source

In the paper

“The loss of hippocampal GABAergic interneurons leads to network dysfunction and hyperexcitability.”

In the paper

“ApoE4-KI mice show reduced abundance of sharp-wave ripples, the local field potential of hippocampal replay events which are critical for consolidating spatial memory [182, 183].”

What the sources say

• Not checked yetcites [182] Gillespie AK, Jones EA, Lin Y-H, Karlsson MP, Kay K, Yoon SY, et al. Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples. Neuron. 2016;90(4):740–51. source
• Not checked yetcites [183] Buzsáki G. Hippocampal sharp wave-ripple: a cognitive biomarker for episodic memory and planning. Hippocampus. 2015;25(10):1073–188. source

In the paper

“leading to increased levels of neurotoxic fragment generation”

In the paper

“Higher resting state GABA levels in the DMN are associated with enhanced task-induced deactivation of this network [165–167]”

What the sources say

• Not checked yetcites [165] Hu Y, Chen X, Gu H, Yang Y. Resting-state glutamate and GABA concentrations predict task-induced deactivation in the default mode network. J Neurosci. 2013;33(47):18566–73. source
• Not checked yetcites [166] Kapogiannis D, Reiter DA, Willette AA, Mattson MP. Posteromedial cortex glutamate and GABA predict intrinsic functional connectivity of the default mode network. Neuroimage. 2013;64:112–9. source
• Not checked yetcites [167] Chen X, Fan X, Hu Y, Zuo C, Whitfield-Gabrieli S, Holt D, et al. Regional GABA concentrations modulate inter-network resting-state functional connectivity. Cereb Cortex. 2018. https://doi.org/10.1093/cercor/bhy059 . source

In the paper

“further implicating inhibitory interneurons in apoE4-induced hippocampal gamma loss [182].”

In the paper

“Based on both in vivo and in vitro studies, GABAergic interneurons appear to be selectively vulnerable to apoE4 induced neurotoxicity, although the underlying molecular and cellular mechanisms are still unclear.”

In the paper

“which makes apoE4-expressing neuronal cells more vulnerable to metabolic stress [191].”

In the paper

“and increased hippocampal activation during encoding task performance [179–181]”

What the sources say

• Not checked yetcites [179] Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, et al. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proc Natl Acad Sci U S A. 2009;106(17):7209–14. source
• Not checked yetcites [180] Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, Pericak-Vance MA, Mazziotta JC, et al. Patterns of brain activation in people at risk for Alzheimer’s disease. N Engl J Med. 2000;343(7):450–6. source
• Not checked yetcites [181] Dennis NA, Browndyke JN, Stokes J, Need A, Burke JR, Welsh-Bohmer KA, et al. Temporal lobe functional activity and connectivity in young adult APOE ɛ4 carriers. Alzheimers Dement. 2010;6(4):303–11. source

In the paper

“suggesting reduced accuracy of these replay events [182, 184].”

In the paper

“This process culminates in further GABAergic interneuron loss and eventual cognitive decline (Fig. 2).”

In the paper

“However, across several clinical trials, these agents have produced behavioral, but not cognitive, improvements [85].”

What the sources say

• Not checked yetcites [85] Lanctôt KL, Herrmann N, Mazzotta P, Khan LR, Ingber N. GABAergic function in Alzheimer’s disease: evidence for dysfunction and potential as a therapeutic target for the treatment of Behavioural and psychological symptoms of dementia. Can J Psychiatr. 2016;49(7):439–53. source

In the paper

“theta burst stimulation via transcranial magnetic stimulation has been used successfully to increase GABA within the DMN [200].”

What the sources say

• Not checked yetcites [200] Vidal-Piñeiro D, Martín-Trias P, Falcón C, Bargalló N, Clemente IC, Valls-Solé J, et al. Neurochemical modulation in posteromedial default-mode network cortex induced by transcranial magnetic stimulation. Brain Stimul. 2015;8(5):937–44. source

In the paper

“transplantation of mouse MGE-derived GABAergic progenitors into aged apoE4-KI mice without or with Aβ accumulation rescues learning and memory deficits [127].”

What the sources say

• Not checked yetcites [127] Tong LM, Djukic B, Arnold C, Gillespie AK, Yoon SY, Wang MM, et al. Inhibitory interneuron progenitor transplantation restores Normal learning and memory in ApoE4 Knock-in mice without or with Aβ accumulation. J Neurosci. 2014;34(29):9506–15. source

In the paper

“exogenous neuregulin 1 increases excitability of parvalbumin-positive interneurons [206]”

What the sources say

• Not checked yetcites [206] Li K-X, Lu Y-M, Xu Z-H, Zhang J, Zhu J-M, Zhang J-M, et al. Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy. Nat Neurosci. 2011;15(2):267–73. source