APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia

In the paper

“We previously identified the APOE3-V236E variant to be protective against AD dementia with a population carrier frequency of 0.3% (10).”

What the sources say

• Partly supported

  The Results and Discussion report that APOE3-V236E is associated with markedly reduced risk of late-onset Alzheimer’s disease. They do not report a 0.3% population carrier frequency: the Discussion gives a 0.12% minor allele frequency in European Americans, while the Results report carriers in a case-control sample. Those figures do not establish the stated population carrier frequency. (LLM, conf=0.85)

  cites [10] Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG, ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 9, 11 (2014). 24607147 PMC3995879 sourceExperimental — accuracy not yet measured

In the paper

“The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for AD and dementia with Lewy bodies (DLB) (1, 5, 6), whereas APOE2, a well-established longevity determinant, affords protection against the disease (7, 8).”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Bertram L, Tanzi RE, Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses. Nature reviews. Neuroscience 9, 768– 778 (2008). 18802446 source
• ?Not checked — no full text of the sourcecites [5] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921– 923 (1993). 8346443 source
• Partly supported

  The Abstract Results report strong associations of APOE ε4 with Alzheimer’s disease and pure dementia with Lewy bodies, and the Conclusions call it a strong risk factor across the Lewy body disease spectrum. The paper does not establish that it is *the major* genetic risk factor for either disease relative to other genetic factors. (LLM, conf=0.83)

  cites [6] Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP, APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70, 223– 228 (2013). 23407718 PMC3580799 sourceExperimental — accuracy not yet measured

In the paper

“To date, this rare APOE3-Jac variant (0.12%) occurs on the APOE3 backbone and confers a reduced risk of AD (OR = 0.10, 0.03 to 0.45) equal to or superior to the APOE2 allele (OR = 0.46, 0.38 to 0.54).”

What the sources say

• Partly supported

  The Introduction reports a 0.12% frequency for p.V236E in European Americans, and the Results place it on the APOE ε3 backbone and report reduced late-onset AD risk (OR 0.10, 0.03–0.45). The Discussion says the resulting ε3b allele reduced risk as much as or more than ε2 in this series. The claim omits those population and study qualifiers, and it pairs the p.V236E estimate from Fisher’s exact test with the ε2 estimate from multivariate regression; the latter analysis gives ε3b a different confidence interval (0.02–0.35). (LLM, conf=0.85)

  cites [10] Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG, ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 9, 11 (2014). 24607147 PMC3995879 sourceExperimental — accuracy not yet measured

In the paper

“Additionally, recent genetic studies have also demonstrated a robust association between the APOE4 allele and risk of DLB (6, 12), the second leading cause of dementia in the elderly.”

What the sources say

• Supported

  The Abstract Results report a strong association between APOE ε4 and pure dementia with Lewy bodies (pDLB), with an adjusted odds ratio of 6.1 (95% CI, 3.5–10.5). The Abstract Conclusions call ε4 a strong risk factor across the Lewy body disease spectrum. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [6] Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP, APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70, 223– 228 (2013). 23407718 PMC3580799 source
• Supported

  The Genetics of DLB section calls APOE ε4 one of the strongest and most replicated genetic risk factors for DLB and says multiple studies associate it with increased DLB risk. It also reports that a recent genome-wide association study confirmed the APOE association. No page number is provided in our copy. (LLM, conf=0.94)

  cites [12] Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D, Donaghy P, Morris C, Taylor JP, Thomas A, Attems J, McKeith I, Dementia with Lewy bodies: an update and outlook. Mol Neurodegener 14, 5 (2019). 30665447 PMC6341685 source

In the paper

“ApoE, critical for brain cholesterol homeostasis and produced primarily by astrocytes, delivers cholesterol and essential lipids to neurons by interacting with members of the low-density lipoprotein receptor (LDLR) family (21).”

What the sources say

• Supported

  The Introduction states that apoE/lipoprotein particles are produced primarily by astrocytes and deliver cholesterol and other essential lipids to neurons via LDLR-family members. The section on brain cholesterol and lipid transport also describes this transport as apoE’s primary function in the brain; no page number is provided in our copy. (LLM, conf=0.95)

  cites [21] Bu G, Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nature reviews. Neuroscience 10, 333– 344 (2009). 19339974 PMC2908393 source

In the paper

“Previous studies showed that apoE is co-deposited in senile plaques and plays a crucial role in fibrillar plaque formation (23, 24).”

What the sources say

• ?Not checked — no full text of the sourcecites [23] Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins DJ, Piccardo P, Ghetti B, Paul SM, Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet 17, 263– 264 (1997). 9354781 source
• Partly supported

  The ‘ApoE modifies Aβ deposition’ section reports that Apoe deficiency strongly reduced fibrillar amyloid burden, supporting an important role for apoE in fibrillar plaque formation. It also reports that fibrillar plaques remained detectable without apoE, and the passages do not establish that apoE is co-deposited in senile plaques. No page number is available in our copy. (LLM, conf=0.85)

  cites [24] Ulrich JD, Ulland TK, Mahan TE, Nystrom S, Nilsson KP, Song WM, Zhou Y, Reinartz M, Choi S, Jiang H, Stewart FR, Anderson E, Wang Y, Colonna M, Holtzman DM, ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med 215, 1047– 1058 (2018). 29483128 PMC5881464 sourceExperimental — accuracy not yet measured

In the paper

“The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for AD and dementia with Lewy bodies (DLB) (1, 5, 6), whereas APOE2, a well-established longevity determinant, affords protection against the disease (7, 8).”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D, Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 6, 29– 32 (1994). 8136829 source
• Supported

  The Background states that APOE*ε2 decreases Alzheimer’s disease risk compared with APOE*ε3 and explicitly describes its protective effect against AD. The section “APOE*ε2 protects against AD: the pathological evidence” also reports lower amyloid-plaque density in APOE*ε2 carriers. (LLM, conf=0.94)

  cites [8] Li Z, Shue F, Zhao N, Shinohara M, Bu G, APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease. Mol Neurodegener 15, 63 (2020). 33148290 PMC7640652 source

In the paper

“Neurodegenerative diseases, such as AD and DLB, are often characterized as diseases of protein aggregation (30–33).”

What the sources say

• ?Not checked — no full text of the sourcecites [30] Soto C, Unfolding the role of protein misfolding in neurodegenerative diseases. Nature reviews. Neuroscience 4, 49– 60 (2003). 12511861 source
• ?Not checked — no full text of the sourcecites [31] Ross CA, Poirier MA, Protein aggregation and neurodegenerative disease. Nat Med 10 Suppl, S10– 17 (2004). 15272267 source
• Supported

  The Abstract describes Alzheimer’s disease as a mixed proteinopathy involving amyloid and tau. The Background section on Lewy-related pathology describes dementia with Lewy bodies as involving pathological deposition of α-synuclein in Lewy bodies and neurites. Together, these passages support the characterization of both diseases as involving protein aggregation. (LLM, conf=0.91)

  cites [32] DeTure MA, Dickson DW, The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 14, 32 (2019). 31375134 PMC6679484 source
• Supported

  The Background describes AD in terms of insoluble amyloid-β aggregates and tau tangles, and DLB in terms of Lewy bodies containing aggregated α-synuclein. These passages support the sentence’s characterization of both diseases as involving protein aggregation. (LLM, conf=0.92)

  cites [33] Twohig D, Nielsen HM, α-synuclein in the pathophysiology of Alzheimer’s disease. Mol Neurodegener 14, 23 (2019). 31186026 PMC6558879 source

In the paper

“A recent case report found that an individual carrying two copies of the APOE3-Christchurch (R136S) mutation did not develop AD three decades after the expected disease onset (10).”

What the sources say

• ?Could not verify

  The Results discuss a different APOE variant, p.V236E, and report no homozygotes for it in the study sample. Searches for APOE3-Christchurch, R136S, and the claimed three-decade delay found no passage addressing that case report in our copy. (LLM, conf=0.78)

  cites [10] Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG, ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 9, 11 (2014). 24607147 PMC3995879 sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, previous studies showed that the lack of apoE expression impairs plaque-associated microgliosis (24).”

What the sources say

• Supported

  The Introduction reports significantly reduced plaque-associated microgliosis in Apoe-deficient mice. The Results section, “Decreased plaque-associated microgliosis,” specifies that fewer microglia clustered near amyloid plaques in two Apoe-deficient APP/PS1 mouse models. (LLM, conf=0.94)

  cites [24] Ulrich JD, Ulland TK, Mahan TE, Nystrom S, Nilsson KP, Song WM, Zhou Y, Reinartz M, Choi S, Jiang H, Stewart FR, Anderson E, Wang Y, Colonna M, Holtzman DM, ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med 215, 1047– 1058 (2018). 29483128 PMC5881464 source

In the paper

“Brain is highly enriched in lipid contents; the deficits of lipids have been implicated in the pathophysiology of AD (37, 38).”

What the sources say

• Supported

  The section on inositol lipids and synaptic dysfunction reports reduced phosphoinositide levels in AD brain tissue and describes how depletion of PtdIns(4,5)P2 contributes to Aβ-related synaptic impairment. This supports the claim that lipid deficits have been implicated in AD pathophysiology, though the evidence concerns specific lipids rather than a general loss of all lipids. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [37] Di Paolo G, Kim TW, Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12, 284– 296 (2011). 21448224 PMC3321383 source
• Partly supported

  Section 9 (Phosphatidylserine and cognitive function; page unavailable) reports reduced DHA content in phosphatidylserine in brain tissue from patients with Alzheimer’s disease. That supports a specific lipid change, but the authors say its contribution to pathogenesis is unknown and the proposed link remains open to question; the broader claim about lipid deficits in AD pathophysiology goes beyond the passage. (LLM, conf=0.84)

  cites [38] Kim HY, Huang BX, Spector AA, Phosphatidylserine in the brain: metabolism and function. Prog Lipid Res 56, 1– 18 (2014). 24992464 PMC4258547 sourceExperimental — accuracy not yet measured

In the paper

“Importantly, apoE4 was shown to have greater tendency to aggregate and existed primarily as tetramers (28, 29), whereas apoE4-Jac variant consisted mostly dimers even when a high concentration of apoE (30 μM) was used (Fig. S10A).”

What the sources say

• Partly supported

  The Discussion (Differences between the isoforms; page unavailable) reports that ApoE4 is predominantly tetrameric above 2.5 μM, supporting the tetramer portion of the cited clause. It finds only small differences in self-association among the isoforms and does not establish a greater tendency for ApoE4 to aggregate relative to ApoE4-Jac. The dimer finding for ApoE4-Jac is attributed to the citing paper’s own Fig. S10A, not to this source. (LLM, conf=0.84)

  cites [28] Garai K, Frieden C, The association-dissociation behavior of the ApoE proteins: kinetic and equilibrium studies. Biochemistry 49, 9533– 9541 (2010). 20923231 PMC3038193 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (‘Size distribution of full-length apoE3 and apoE4 proteins’; page unavailable) reports greater aggregation of apoE4 than apoE3. It describes several apoE4 species, however, and does not establish that full-length apoE4 existed primarily as tetramers. The apoE4-Jac dimer finding is attributed to the citing paper’s Fig. S10A, not to this source. (LLM, conf=0.86)

  cites [29] Chou CY, Lin YL, Huang YC, Sheu SY, Lin TH, Tsay HJ, Chang GG, Shiao MS, Structural variation in human apolipoprotein E3 and E4: secondary structure, tertiary structure, and size distribution. Biophys J 88, 455– 466 (2005). 15475580 PMC1305022 sourceExperimental — accuracy not yet measured

In the paper

“In addition, several studies have demonstrated that increasing apoE lipidation, either through genetic or pharmacological approaches, promotes Aβ clearance and improves cognitive performance in mice (27, 44, 45).”

What the sources say

• Partly supported

  The Aβ metabolism and aggregation section says LXR or RXR stimulation facilitates Aβ clearance, probably by increasing ApoE levels and lipidation. The Regulation of ApoE expression section reports improved cognition or memory after receptor-agonist treatment in amyloid mouse models. The paper does not establish that increased lipidation caused both benefits, and its genetic evidence concerns ABCA1 deficiency worsening clearance and memory deficits in ApoE4 mice, not a genetic approach that increases lipidation and improves performance. (LLM, conf=0.85)

  cites [27] Liu CC, Kanekiyo T, Xu H, Bu G, Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9, 106– 118 (2013). 23296339 PMC3726719 sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that genetic overexpression of ABCA1 increased apoE lipidation and reduced Aβ deposition in PDAPP mice. It describes increased Aβ clearance as a possibility for future testing, not an established result; it also proposes cognitive-performance studies rather than reporting improvement. The cited study does not establish the pharmacological part of the claim. (LLM, conf=0.89)

  cites [44] Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM, Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118, 671– 682 (2008). 18202749 PMC2200302 sourceExperimental — accuracy not yet measured
• Supported

  The paper supplies the pharmacological example in this multi-citation sentence. Its treatment results (section labeled Abstract; page unavailable) report that bexarotene increased lipidated apoE and reduced Aβ in mouse models, while behavioral results report improved memory and cognition. (LLM, conf=0.91)

  cites [45] Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE, ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335, 1503– 1506 (2012). 22323736 PMC3651582 source

In the paper

“Brain lipids transported by apoE/lipoprotein particles have been shown to play critical roles in neuronal membrane homeostasis and synaptic functions (21).”

What the sources say

• Supported

  In “ApoE and apoE receptors in brain cholesterol and lipid transport” (page not provided), the paper says apoE transports cholesterol from astrocytes to neurons, that cholesterol is essential to membranes and synaptic integrity, and that cholesterol carried by apoE/lipoprotein particles is essential for mature synapse formation in vitro. This supports the citing sentence’s paraphrase. (LLM, conf=0.93)

  cites [21] Bu G, Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nature reviews. Neuroscience 10, 333– 344 (2009). 19339974 PMC2908393 source

In the paper

“As stated, APOE4 is the strongest genetic risk factor for late-onset AD (5, 27).”

What the sources say

• ?Not checked — no full text of the sourcecites [5] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921– 923 (1993). 8346443 source
• Supported

  The Introduction explicitly calls the APOE ε4 allele the strongest genetic risk factor for late-onset AD. The section “APOE ε4 as a strong risk factor for AD” also reports that genome-wide association studies identify it as the strongest genetic risk factor for AD. (LLM, conf=0.95)

  cites [27] Liu CC, Kanekiyo T, Xu H, Bu G, Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9, 106– 118 (2013). 23296339 PMC3726719 source

In the paper

“Biochemical analysis showed a vastly reduced affinity of this apoE variant to heparin which has been implicated in multiple Aβ- and tau-related pathogenic pathways (34, 35).”

What the sources say

• Supported

  The citation is attached to the clause about heparin’s involvement in pathogenic pathways, not the preceding biochemical measurement of apoE-variant affinity. The Discussion (page unavailable) reports that heparin blocks tau aggregate binding, uptake, and propagation, supporting the tau-related part for which this paper is cited. (LLM, conf=0.87)

  cites [34] Holmes BB, DeVos SL, Kfoury N, Li M, Jacks R, Yanamandra K, Ouidja MO, Brodsky FM, Marasa J, Bagchi DP, Kotzbauer PT, Miller TM, Papy-Garcia D, Diamond MI, Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A 110, E3138– 3147 (2013). 23898162 PMC3746848 source
• ?Could not verify

  The Discussion says apoE binds heparan sulfate proteoglycans, but it does not discuss the APOE3-Christchurch variant or report a biochemical comparison of its affinity for heparin. Searches for the variant and heparin-binding affinity found no passage addressing that result. The cited paper addresses the heparan-sulfate context of the sentence, not the stated affinity finding. (LLM, conf=0.76)

  cites [35] Liu CC, Zhao N, Yamaguchi Y, Cirrito JR, Kanekiyo T, Holtzman DM, Bu G, Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-beta clearance and aggregation in Alzheimer’s disease. Sci Transl Med 8, 332ra344 (2016). PMC5512541 27030596 sourceExperimental — accuracy not yet measured

In the paper

“In addition, lipid-poor apoE has been suggested to have greater susceptibility to aggregation, which may impair Aβ clearance and promote Aβ deposition (22).”

What the sources say

• Partly supported

  The Discussion links possible apoE4 aggregation and poor lipidation to reduced Aβ clearance or increased Aβ deposition. It does not establish that lipid-poor apoE is more susceptible to self-aggregation; it suggests instead that apoE4 aggregation may impair lipidation. The Results discuss lipid-poor apoE promoting Aβ aggregation, which is a different point. (LLM, conf=0.84)

  cites [22] Hu J, Liu CC, Chen XF, Zhang YW, Xu H, Bu G, Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Abeta metabolism in apoE4-targeted replacement mice. Mol Neurodegener 10, 6 (2015). 25871773 PMC4356137 sourceExperimental — accuracy not yet measured

In the paper

“Decreases of major lipid species (i.e., PA, PC, PE, PS and sulfatide) were previously observed in AD APOE4 carriers (43).”

What the sources say

• Supported

  The Results section reports that PA, PC, PE and ST were significantly lower in APOEε4-carrier AD brain samples than in at least one comparison genotype group. It also reports significantly diminished PS in APOEε4-carrier samples. The paper reports these as differences in postmortem inferior parietal lobule samples, rather than decreases measured over time. (LLM, conf=0.91)

  cites [43] Lefterov I, Wolfe CM, Fitz NF, Nam KN, Letronne F, Biedrzycki RJ, Kofler J, Han X, Wang J, Schug J, Koldamova R, APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain. Alzheimers Res Ther 11, 113 (2019). 31888770 PMC6937981 source

In the paper

“Recent transcriptomics studies identified sub-clusters of disease-associated microglia (DAM) across AD mouse models and human brains with APOE being one of the highly regulated genes (25).”

What the sources say

• Partly supported

  The Results describe single-cell RNA sequencing in the 5XFAD mouse model and identify distinct disease-associated microglia groups; the Introduction reports Apoe upregulation during DAM activation. The paper also finds DAM markers in human AD brain tissue, but through staining rather than transcriptomic identification of human DAM sub-clusters. The claim therefore extends the transcriptomics finding beyond the population studied. (LLM, conf=0.88)

  cites [25] Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell 169, 1276– 1290 e1217 (2017). 28602351 sourceExperimental — accuracy not yet measured

In the paper

“Herein, we resolve the functional mechanism in which apoE3-Jac reduces apoE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays.”

In the paper

“Importantly, the V236E substitution was not observed in any of the DLB patients but was observed in three control subjects (3/975; carrier frequency 0.3%; P=0.11) (Table 1), which although not statistically significant, further supports a protective effect.”

In the paper

“Importantly, mice expressing apoE3-Jac have a reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy.”

In the paper

“Interestingly, brain tissues from APOE3-Jac carriers exhibited vastly reduced insoluble apoE, as well as increased ratios of soluble/insoluble apoE (Fig. 1D, E), suggesting that this apoE variant reduces its propensity for aggregation.”

In the paper

“In addition, soluble Aβ42 levels and both insoluble Aβ40 and Aβ42 levels were lower in the brains of APOE3-Jac carriers (Fig. 1F, G; Fig. S1A).”

In the paper

“Significantly, we identified an additional APOE3-Jac carrier in each series giving an overall carrier frequency of 2.0% in our exceptional-aging subjects compared to our control series and previous studies (Table 1).”

In the paper

“The APOE3-Jac variant is localized adjacent to the lipid-binding region and within a region implicated in apoE oligomerization (Fig. 2A).”

In the paper

“Interestingly, we observed a positive correlation between the levels of apoE and Aβ40, as well as between the levels of apoE and Aβ42 in the detergent-insoluble fraction (Fig. S5B), suggesting that the aggregated apoE contributes to Aβ pathology.”

In the paper

“The expression level of apoE3-Jac variant was similar to that of apoE3 in the brain although a decreasing trend of apoE3-Jac in the detergent-insoluble fractions was observed (Fig. S5A).”

In the paper

“Importantly, our in vivo results support an association between amyloid plaque-associated apoE, plaque load, and related toxicity, whereas the presence of apoE3-Jac significantly ameliorated these effects.”

In the paper

“Furthermore, immunohistochemical evaluation identified typical cored Aβ plaques in the brains of APOE3 individuals, whereas brains with APOE3-Jac variant had either a few diffused, amorphous Aβ deposits or were absent for any plaque pathology (Fig. 1H; Fig. S1B).”

In the paper

“We identify an apolipoprotein E3 variant (APOE3-V236E), named apoE3-Jacksonville (apoE3-Jac), that is associated with healthy brain aging and reduced risk for Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB).”

In the paper

“Cross-linking analysis further demonstrated that apoE4 existed primarily as aggregates, while apoE4-Jac was mostly monomeric (Fig. 4B–C).”

In the paper

“In addition, apoE4-Jac exhibited a lower affinity to heparin and showed reduced aggregation upon cross-linking (Fig. 4D–F).”

In the paper

“Intriguingly, mice expressing apoE3-Jac variant exhibited a significant reduction in microglial clustering around Aβ plaques (Fig. 3E) and Thio S-positive fibrillar plaques (Fig. S5E) compared with those expressing apoE3.”

In the paper

“The ratios of insoluble to soluble apoE were highest in patients homozygous for APOE4 and lowest in APOE4 non-carriers (Fig. S9B, C).”

In the paper

“Behavioral analysis demonstrated that FAD/apoE3-Jac mice had a trend of improved cognitive function compared to FAD/apoE3 mice without influencing anxiety-related behaviors (Fig. S8).”

In the paper

“Importantly, we showed that apoE levels were increased in detergent-insoluble formic acid (FA) fractions but decreased in TBS-soluble fractions, in an APOE4 gene dose-dependent manner (Fig. S9A).”

In the paper

“In contrast to apoE4, which existed primarily as oligomers, a major monomeric peak and a minor oligomeric shoulder were detected for apoE4-Jac (Fig. 4A).”

In the paper

“Though the protective APOE3-Jac variant was found to reside in the APOE3 backbone in the carriers, our study demonstrated that V236E substitution is also sufficient to reduce apoE4 aggregation and increase cholesterol efflux.”

In the paper

“Furthermore, regression analysis showed that plaque-associated apoE positively correlated with amyloid plaque burden and the numbers of microglia surrounding plaques (Fig. 3F, G).”

In the paper

“These results are consistent with the notion that apoE self-aggregation might facilitate Aβ aggregation and deposition, signifying that reduced apoE aggregation in APOE3-Jac carriers might be a critical mechanism for its protective role against the development of AD.”

In the paper

“Our findings have vital implications for the role of apoE aggregation in the pathogenesis of AD and DLB, and provide insights into the development of a therapeutic strategy targeting apoE aggregation in dementia.”

In the paper

“By performing human genetic and pathological analyses, and functional assays in cellular and animal models, we demonstrate that the apoE3-Jac promotes healthy brain aging and decreases amyloid deposition by reducing apoE self-association and increasing lipidation.”

In the paper

“Because the amyloid plaque level was undetectable in the other two APOE3-Jac human brains, we could not perform quantitative analysis.”

In the paper

“This result suggests that the plaque-associated apoE3, but not apoE3-Jac variant, facilitates amyloid deposition and associated neurotoxicity.”

In the paper

“Thus, learning from nature, compounds targeting apoE self-aggregation might reproduce the protective effects of the APOE-Jac variant.”

In the paper

“In summary, apoE3-Jac represents one of the critical apoE variants that gain a functional advantage over the common isoforms, conferring protection against AD and DLB, by promoting dementia-free prosperous brain aging.”

In the paper

“The introduced mutations were confirmed by DNA sequencing.”

In the paper

“In summary, our study uncovers a potential pathogenic mechanism of aggregated apoE as well as the plaque-associated microglial responses and neurotoxicity, supporting that pharmacological targeting of apoE aggregation should be explored as a therapeutic strategy for AD and related dementias.”

In the paper

“This large population-based study further supports the protective nature of APOE3-Jac against general dementia and promotion of healthy aging.”

In the paper

“Our in vivo study demonstrates that expression of apoE3-Jac in an amyloid mouse model decreases the association of apoE with amyloid plaques, which may in turn reduce amyloid deposition as well as plaque-associated microgliosis and resultant neuronal toxicity.”

In the paper

“Increased plaque-associated neuritic dystrophy, induced by deposits of fibrillar Aβ, has been shown to contribute to cognitive decline over the clinical course of AD (26).”

What the sources say

• ?Not checked — no full text of the sourcecites [26] Serrano-Pozo A, Betensky RA, Frosch MP, Hyman BT, Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease. Am J Pathol 186, 375– 384 (2016). 26687817 PMC4729270 source

In the paper

“Our study demonstrates that apoE3-Jac protects against AD and related dementia, and promotes healthy brain aging by reducing its self-aggregation, leading to decreased amyloid plaques and related toxicity, as well as enhanced lipidation.”

In the paper

“The identification of protective factors that occur normally in the population provides direct insight into the pathophysiology of the disease and can nominate novel therapeutic avenues.”

In the paper

“Average age of the subjects was 90.13 ± 2.8 years and was not significantly different between the two groups (p = 0.90).”