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Cited by 1Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchLipoproteins and Cardiovascular Health

Blood PCSK9 Impacts Alzheimer's Disease Risk in an APOE Genotype‐Dependent Manner: A Prospective Cohort Study

Open access
Tao, Qiushan, Ang, Ting Fang Alvin, Huang, Jinghan, Itchapurapu, Indira Swetha, Mez, Jesse, Alosco, Michael, Au, Rhoda, Farrer, Lindsay A. +3 more·2026·Health Science Reports
DOI 10.1002/hsr2.71810PMC PMC12927996
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Abstract

Background and Aims: Apolipoprotein E (APOE) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are both lipid proteins and related to immunity/inflammation. We hypothesized that PCSK9 impacts on Alzheimer's disease (AD) risk in an APOE genotype dependent manner. Methods: We used the Framingham Heart Study (FHS) Offspring cohort (Gen 2), with data on plasma PCSK9 protein concentration, as the baseline exposure for 1,704 study subjects. Using Cox regression models, the outcomes were incidents of AD or all‐cause dementia. Using another FHS dataset with 3,048 individuals with genetic data, we examined the association between PCSK9 genotypes and the incidence of AD/dementia, stratifying the analysis based on APOE ε4 status. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study was used to validate some of the main findings. Results: Higher plasma PCSK9 protein levels were associated with a lower risk of AD (HR [95%CI]: 0.74 [0.58, 0.94]; p = 0.01) in APOE ε4 noncarriers; in contrast, PCSK9 levels were not significantly associated with AD risk in APOE ε4 carriers, after adjusting for common confounders, lipid profile, and lipid treatment. Using the three SNPs (rs502576, rs529787, rs676297) of the PCSK9 gene associated with PCSK9 levels in blood, we consistently found that the genotypes, which determine a low concentration of PCSK9, were associated with AD risk only in APOE ε4 noncarriers. These findings were validated by the ADNI study, which showed that the PCSK9 genotypes were associated with AD risk and with the AD biomarker—a low concentration of Aβ42 in CSF, only in APOE ε4 noncarriers. Conclusions: Our study suggests that high blood PCSK9 levels are protective against AD risk in APOE ε4 noncarriers, potentially through mechanisms related to lipid metabolism. The findings may highlight the importance of considering APOE genotype when prescribing the drugs targeting PCSK9.

AI snapshot

Written from the paper’s full text.

TL;DR

In the Framingham Heart Study Offspring cohort, higher plasma PCSK9 was associated with lower Alzheimer’s disease risk only in APOE ε4 noncarriers, while no significant association was seen in APOE ε4 carriers. PCSK9 genotypes linked to lower blood PCSK9 showed the same APOE ε4–dependent pattern and were validated in ADNI, including lower CSF Aβ42 in noncarriers.

Key findings

  • Among APOE ε4 noncarriers, higher plasma PCSK9 was associated with lower incident AD risk after adjustment (HR [95% CI]: 0.74 [0.58, 0.94]; p = 0.01); in APOE ε4 carriers, the association was not statistically significant.
  • The APOE ε4 × PCSK9 interaction was significant for AD in Model 4 (HR [95% CI]: 1.80 [1.24, 2.62]; p = 0.002) and for all-cause dementia (HR [95% CI]: 1.65 [1.20, 2.28]; p = 0.002).
  • Three PCSK9 SNPs (rs502576, rs529787, rs676297) determining low PCSK9 concentrations were associated with AD risk only in APOE ε4 noncarriers; in ADNI, these genotypes were also associated with lower CSF Aβ42 only in APOE ε4 noncarriers.
  • For all-cause dementia, higher peripheral PCSK9 was associated with reduced hazard in the overall sample in Model 4 (HR [95% CI]: 0.81 [0.66, 0.98]; p = 0.033).

Methods

  • Prospective cohort study using FHS Offspring cohort Exam 5: plasma PCSK9 protein dataset n = 1,704 and PCSK9 genetic dataset n = 3,048; exclusions included missing APOE genotype, APOE ε2/ε4, baseline dementia, and follow-up < 3 years.
  • Cox proportional hazards models estimated incident AD and all-cause dementia over up to 30 years, adjusting for age, sex, education, lipid profile, lipid treatment, CVD, BMI, and APOE ε4; analyses were stratified by APOE ε4 status.
  • Validation used 1,476 ADNI participants with logistic regression for prevalent AD/all-cause dementia and CSF Aβ42 analyses, stratified by APOE ε4 carrier status.

Limitations

  • The paper states: diet was not accounted for; no experimental validation; no longitudinal PCSK9 measurements, preventing causal inference; limited ethnic diversity in FHS; residual confounding by age because primary analyses did not use age-matched sampling; and no correction for multiple comparisons.
  • The paper also notes that both cohorts lacked data on PCSK9 inhibitor use, and that the nonsignificant findings in APOE ε4 carriers may be due to lack of power.
  • Evident from the text: findings are observational, and the authors note that conclusions on PCSK9 inhibitors and AD risk remain inconclusive.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/hsr2.71810

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 43 cited sources checked · 12 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    C-reactive protein (CRP) and MCP-1 interact with APOE ε4 versus APOE ε2 in an opposite direction to impact Alzheimer's disease risk.

    “our recent studies have shown that several proinflammatory proteins including C‐reactive protein (CRP) and MCP‐1 interact with APOE ε4 versus APOE ε2 in an opposite direction to impact AD risk [3, 4].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [3] Q. Tao, T. F. Alvin Ang, S. C. Akhter‐Khan, et al., “ Impact of C‐Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous Apolipoprotein E Ɛ4 Carriers,” Neurology 97 (2021): 1243– 1252. PMC8480484 34266923 source
    • cites [4] J. Huang, T. D. Stein, Y. Wang, et al., “ Blood Levels of MCP‐1 Modulate the Genetic Risks of Alzheimer's Disease Mediated by HLA‐DRB1 and APOE for Alzheimer's Disease,” Alzheimer's & Dementia 19, no. 5 (2023): 1925– 1937. PMC10182187 36396603 source

      The Results (Characteristics of the FHS population; page not provided) report that MCP-1 interacts with APOE ε4 and APOE ε2 in opposite directions for AD risk. The paper says CRP increases AD risk in APOE ε4 carriers, but does not establish an opposite-direction CRP interaction with APOE ε2. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    PCSK9 is a key regulator of the Alzheimer's disease pathological component Aβ clearance across the blood-brain barrier in an animal model.

    “Basic research has discovered that PCSK9 is a key regulator of the AD pathological component Aβ clearance across the blood‐brain barrier (BBB) in the animal model [9].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] A. D. Mazura, A. Ohler, S. E. Storck, et al., “ PCSK9 Acts as a Key Regulator of Aβ Clearance Across the Blood‐Brain Barrier,” Cellular and Molecular Life Sciences 79, no. 4 (2022): 212. 35344086 PMC8960591 source
  • Interpretationcitation

    ApoE4 carriers may be particularly susceptible to PCSK9-mediated lipid dysregulation.

    “indicating that ApoE4 carriers may be particularly susceptible to PCSK9‐mediated lipid dysregulation [7, 8].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [7] B. Papotti, M. Palumbo, M. P. Adorni, et al., “ Influence of APOE4 Genotype on PCSK9‐lipids Association in Cerebrospinal Fluid and Serum of Patients in the Alzheimer's Disease Continuum,” Journal of Alzheimer's Disease 102, no. 1 (2024): 162– 172. 39497318 source
    • cites [8] G. Testa, S. Giannelli, E. Staurenghi, et al., “ The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer's Disease: A Possible Target for the Disease Treatment,” International Journal of Molecular Sciences 25, no. 24 (2024): 13637. 39769398 PMC11727734 source

      Section 2 links ApoE4 to impaired cholesterol trafficking, and section 3.2 describes ways PCSK9 may disrupt ApoE-related lipid handling. Section 3.5 reports higher PCSK9 levels in ApoE4 carriers with Alzheimer’s disease than in non-carriers. Together these support the proposed link, but the paper does not establish that carriers are more susceptible to PCSK9-mediated lipid dysregulation than non-carriers. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    PCSK9(-/-) mice showed increased levels of BACE1 and Aβ production and accumulation in the brain.

    “PCSK9(‐/‐) mice showed increased levels of BACE1, the key protease in APP processing, and Aβ production and accumulation in the brain [10].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] M. C. Jonas, C. Costantini, and L. Puglielli, “ PCSK9 is Required for the Disposal of Non‐Acetylated Intermediates of the Nascent Membrane Protein BACE1,” EMBO Reports 9, no. 9 (2008): 916– 922. 18660751 PMC2529349 source
  • Premisecitation

    A study using the UK Biobank cohort did not find that PCSK9, either protein or genotypes, is associated with AD risk.

    “A study using the UK Biobank (UKBB) cohort did not find that PCSK9, either protein or genotypes, is associated with AD risk [26].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [26] A. J. Cupido, L. F. Reeskamp, A. D. Hingorani, et al., “ Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease: A Factorial Mendelian Randomization Study,” JAMA Cardiology 7, no. 9 (2022): 955– 964. 35921096 PMC9350849 source

      The Methods (page unavailable) say the UK Biobank analysis investigated Alzheimer disease using genetic scores for predicted PCSK9 concentrations. The Results (page unavailable) report an association for PCSK9 with coronary artery disease after correction for multiple testing, but not with Alzheimer disease. The study did not directly test measured PCSK9 protein concentrations against Alzheimer disease risk, so the protein part of the claim is unsupported. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 32
  • May combine two claims. 24
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The study was designed and reported in accordance with the CONSORT 2010 guidelines.

    “This study was designed and reported in accordance with the CONSORT 2010 guidelines to ensure transparency, reproducibility, and completeness of reporting [13].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] E. von Elm, D. G. Altman, M. Egger, S. J. Pocock, P. C. Gøtzsche, and J. P. Vandenbroucke, “ The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies,” Lancet 370, no. 9596 (2007): 1453– 1457. 18064739 source

      The Introduction identifies CONSORT as a separate guideline and says it was revised in 2001. The Implications and limitations section identifies this paper's guideline as STROBE, for reporting observational studies—not CONSORT 2010. The paper cannot verify how the citing study was designed or reported. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The three common APOE isoforms (APOE2, APOE3, and APOE4) influence both amyloid-β-dependent and independent pathways implicated in Alzheimer's disease pathogenesis.

    “while the three common isoforms (APOE2, APOE3, and APOE4) influence both amyloid‐β–dependent and independent pathways implicated in AD pathogenesis [1, 2].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] L. A. Farrer, “ Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta‐Analysis,” Journal of the American Medical Association 278, no. 16 (1997): 1349– 1356. 9343467

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [2] Y. Yamazaki, N. Zhao, T. R. Caulfield, C. C. Liu, and G. Bu, “ Apolipoprotein E and Alzheimer Disease: Pathobiology and Targeting Strategies,” Nature Reviews Neurology 15, no. 9 (2019): 501– 518. 31367008 PMC7055192 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The APOE ε4 allele is a major genetic risk factor for Alzheimer's disease.

    “Multiple cohort studies have demonstrated that the APOE ε4 allele is a major genetic risk factor for AD”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] L. A. Farrer, “ Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta‐Analysis,” Journal of the American Medical Association 278, no. 16 (1997): 1349– 1356. 9343467

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [2] Y. Yamazaki, N. Zhao, T. R. Caulfield, C. C. Liu, and G. Bu, “ Apolipoprotein E and Alzheimer Disease: Pathobiology and Targeting Strategies,” Nature Reviews Neurology 15, no. 9 (2019): 501– 518. 31367008 PMC7055192 source

  • May combine two claims.

    Premisecitation

    PCSK9 is related to chronic inflammation, leading to the migration of immune cells through endothelia.

    “PCSK9 is also related to chronic inflammation, leading to the migration of immune cells through endothelia [6].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] E. Punch, J. Klein, P. Diaba‐Nuhoho, H. Morawietz, and M. Garelnabi, “ Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis,” Journal of the American Heart Association 11, no. 3 (2022): e023328. 35048716 PMC9238481 source

  • May combine two claims.

    Premisecitation

    Cerebrospinal fluid PCSK9 levels are elevated in Alzheimer's disease patients and correlate with APOE4 presence.

    “Recent studies have shown that cerebrospinal fluid PCSK9 levels are elevated in AD patients and correlate with APOE4 presence”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [7] B. Papotti, M. Palumbo, M. P. Adorni, et al., “ Influence of APOE4 Genotype on PCSK9‐lipids Association in Cerebrospinal Fluid and Serum of Patients in the Alzheimer's Disease Continuum,” Journal of Alzheimer's Disease 102, no. 1 (2024): 162– 172. 39497318 source
    • cites [8] G. Testa, S. Giannelli, E. Staurenghi, et al., “ The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer's Disease: A Possible Target for the Disease Treatment,” International Journal of Molecular Sciences 25, no. 24 (2024): 13637. 39769398 PMC11727734 source

      Section 3.5 reports higher CSF PCSK9 in AD patients than in non-AD subjects and higher levels in AD ApoE4 carriers than in non-carriers. However, it also reports another investigation that found no CSF PCSK9 difference between AD and non-AD individuals, so the unqualified elevation claim overstates the mixed evidence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    PCSK9 acts as a key regulator of Aβ clearance.

    “the basic research study discovered that PCSK9 acts as a key regulator of Aβ clearance [9]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] A. D. Mazura, A. Ohler, S. E. Storck, et al., “ PCSK9 Acts as a Key Regulator of Aβ Clearance Across the Blood‐Brain Barrier,” Cellular and Molecular Life Sciences 79, no. 4 (2022): 212. 35344086 PMC8960591 source

  • May combine two claims.

    Premisecitation

    PCSK9 knockout mice show increased levels of BACE1, leading to increased Aβ production and accumulation in the brain.

    “PCSK9(‐/‐) knockout mice showed increased levels of BACE1, leading to increased Aβ production and accumulation in the brain [10].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] M. C. Jonas, C. Costantini, and L. Puglielli, “ PCSK9 is Required for the Disposal of Non‐Acetylated Intermediates of the Nascent Membrane Protein BACE1,” EMBO Reports 9, no. 9 (2008): 916– 922. 18660751 PMC2529349 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    All statistical analysis and reporting adhered to the Statistical Analyses and Methods in the Published Literature (SAMPL) guidelines.

    “All statistical analysis and reporting adhered to recommended standards for clinical research, following the Statistical Analyses and Methods in the Published Literature (SAMPL) guidelines and standard references [19].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] M. Assel, D. Sjoberg, A. Elders, et al., “ Guidelines for Reporting of Statistics for Clinical Research in Urology,” European Urology 75, no. 3 (2019): 358– 367. 30580902 PMC6391870 source

      The Abstract and Reporting of design and statistical analysis sections provide standards for statistical analysis and reporting in clinical research. The References section identifies SAMPL as a separate work by Lang and Altman; this paper does not establish that the citing authors adhered to SAMPL. No page numbers are available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Increased brain expression of PCSK9 induced atherosclerosis, brain hypoxia, and Aβ deposits in the brain.

    “increased the brain expression of PCSK9 induced atherosclerosis, brain hypoxia and Aβ deposits in the brain [22].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] O. Shabir, B. Pendry, L. Lee, et al., “ Assessment of Neurovascular Coupling and Cortical Spreading Depression in Mixed Mouse Models of Atherosclerosis and Alzheimer's Disease,” eLife 11 (2022): e68242. 35014950 PMC8752088 source

      Materials and methods (Animals; page unavailable) describes atherosclerosis induced by intravenous PCSK9-vector injection together with a Western diet, not by demonstrated increased PCSK9 expression in the brain. Results reports threefold more hippocampal Aβ plaques in the mixed model, while Discussion says the mice could be hypoxic rather than establishing brain hypoxia. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Knockdown of PCSK9 in the brain decreases Aβ level and neuroinflammation and improves behavioral tests in mice.

    “knock‐down the expression of PCSK9 in the brain decreases Aβ level and neuroinflammation, and improve behavioral tests in these mice [23].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] A. Vilella, M. Bodria, B. Papotti, et al., “ PCSK9 Ablation Attenuates Aβ Pathology, Neuroinflammation and Cognitive Dysfunctions in 5XFAD Mice,” Brain, Behavior, and Immunity 115 (2024): 517– 534. 37967665 source

      The Results (p. 1) report that PCSK9 ablation in 5XFAD mice reduced corticohippocampal Aβ burden and neuroinflammatory markers and improved Morris water maze performance. However, the Methods description in the Abstract (p. 1) and the Discussion (p. 11) identify the intervention as genetic ablation or full ablation of PCSK9, not a brain-specific knockdown. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Some proinflammatory proteins in blood impact APOE genotypes differently for AD risk.

    “As some proinflammatory proteins in blood impact APOE genotypes differently for AD risk [4, 20]”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [4] J. Huang, T. D. Stein, Y. Wang, et al., “ Blood Levels of MCP‐1 Modulate the Genetic Risks of Alzheimer's Disease Mediated by HLA‐DRB1 and APOE for Alzheimer's Disease,” Alzheimer's & Dementia 19, no. 5 (2023): 1925– 1937. PMC10182187 36396603 source
    • cites [20] Q. Tao, T. F. A. Ang, C. DeCarli, et al., “ Association of Chronic Low‐Grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers,” JAMA Network Open 1, no. 6 (2018): e183597. 30646251 PMC6324596 source

      The Results report that elevated blood C-reactive protein (CRP) was linked to increased Alzheimer disease risk in ApoE4 carriers, a pattern not observed in ApoE2 or ApoE3 carriers. This supports a genotype-dependent association, but the paper examines CRP rather than multiple proteins and does not establish that it causally impacts risk. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Multiple factors including other genes, diets, and anti-lipid medication use can affect lipid metabolism and AD risk.

    “multiple factors including other genes, diets and anti‐lipid medication use can affect lipid metabolism and AD risk [36]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] L. Gutierrez, A. Folch, M. Rojas, et al., “ Effects of Nutrition on Cognitive Function in Adults With or Without Cognitive Impairment: A Systematic Review of Randomized Controlled Clinical Trials,” Nutrients 13, no. 11 (2021): 3728. 34835984 PMC8621754 source

      The Discussion (§4.7, page unavailable) says the Mediterranean diet affects LDL and HDL cholesterol, and the Introduction links dietary patterns to reduced cognitive decline. The paper discusses APOE4 in relation to responses to nutritional interventions (§4.1), but these passages do not establish that other genes or anti-lipid medication use affect lipid metabolism and AD risk. They also address cognitive decline more directly than AD risk. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Peripheral injection of PCSK9 inhibitors into AD mouse models decreases Aβ level and neuroinflammation in the brain and improves behavioral tests.

    “peripheral injection of PCSK9 inhibitors into the AD mouse models are shown to decrease Aβ level and neuroinflammation in the brain, and improve behavioral tests [9, 35].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [9] A. D. Mazura, A. Ohler, S. E. Storck, et al., “ PCSK9 Acts as a Key Regulator of Aβ Clearance Across the Blood‐Brain Barrier,” Cellular and Molecular Life Sciences 79, no. 4 (2022): 212. 35344086 PMC8960591 source

      The Discussion reports that peripheral Alirocumab injections reduced Aβ pathology in 5xFAD mice, and the Results report improved contextual fear-conditioning performance. The paper does not report that the injections reduced brain neuroinflammation; a search for neuroinflammation found it only in a reference title. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [35] S. A. Abuelezz and N. Hendawy, “ HMGB1/RAGE/TLR4 Axis and Glutamate as Novel Targets for PCSK9 Inhibitor in High Fat Cholesterol Diet Induced Cognitive Impairment and Amyloidosis,” Life Sciences 273 (2021): 119310. 33667517 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another study did not show interactive effects with APOE ε4 genotype for cognitive decline and complaints in a large clinical trial.

    “Another study did not show the interactive effects with APOE ɛ4 genotype for cognitive decline and complain in a large clinical trial [33].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] L. E. Korthauer, R. P. Giugliano, J. Guo, et al., “ No Association Between APOE Genotype and Lipid Lowering With Cognitive Function in a Randomized Controlled Trial of Evolocumab,” PLoS One 17, no. 4 (2022): e0266615. 35404972 PMC9000128 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In some trials, PCSK9 inhibitors including evolocumab do not show effects on cognitive decline and complaints.

    “in some trials, PCSK9 inhibitors including evolocumab do not show the effects on cognitive decline and complain in a large clinical trial [33, 34].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [33] L. E. Korthauer, R. P. Giugliano, J. Guo, et al., “ No Association Between APOE Genotype and Lipid Lowering With Cognitive Function in a Randomized Controlled Trial of Evolocumab,” PLoS One 17, no. 4 (2022): e0266615. 35404972 PMC9000128 source
    • cites [34] D. B. Rosoff, A. S. Bell, J. Jung, J. Wagner, L. A. Mavromatis, and F. W. Lohoff, “ Mendelian Randomization Study of PCSK9 and HMG‐CoA Reductase Inhibition and Cognitive Function,” Journal of the American College of Cardiology 80, no. 7 (2022): 653– 662. 35953131 source

  • Classified as probably not a substantial claim. May combine two claims.

    Findingnone given

    The FHS cohort in this study only had <5% of participants taking anti-lipid medications in the 1990s, while the ADNI study was in early and the UKBB study was in late decade of 2000.

    “The FHS cohort in this study only had < 5% of participants taking anti‐lipid medications in the 1990s, while the ADNI study was in early and the UKBB study was in late decade of 2000.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The three PCSK9 genotypes rs502576, rs529787, and rs676297 were significantly associated with plasma PCSK9 protein in the whole sample, especially in APOE ε4 noncarriers.

    “The 3 genotypes were significantly associated with plasma PCSK9 protein in the whole sample, especially in APOE ɛ4 noncarriers”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In APOE4 carriers, the interaction between APOE4 and PCSK9 signifies increased risk for all-cause dementia (Model 4 interaction: HR = 1.65 [1.20, 2.28], p = 0.002).

    “in these individuals, the interaction between APOE4 and PCSK9 signifies increased risk (Model 4 interaction: HR = 1.65 [1.20, 2.28], p = 0.002) (Table 1).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Missing data less than 10% were missing at random.

  • May combine two claims.

    Findingown data

    There was a trend of positive association between PCSK9 and AD risk in the presence of APOE4 but it did not reach statistical significance.

    “There was a trend of positive association between PCSK9 and AD risk in the presence of APOE4 (Table 2) but did not reach statistical significance (Tables 2 and 3; Figure 1)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The categorization of PCSK9 genotypes as low, middle, or high based on blood PCSK9 levels in the FHS APOE ε4 noncarrier group is applicable to the ADNI study population and to APOE ε4 carriers.

  • May combine two claims.

    Findingown data

    There was no difference in plasma PCSK9 concentrations between APOE ε4 noncarriers and APOE ε4 carriers or among different APOE genotypes.

    “There was no difference in plasma PCSK9 concentrations between APOE ɛ4 noncarriers and APOE ɛ4 carriers and among different APOE genotypes (Supporting Figure S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among APOE ε4 carriers, neither plasma PCSK9 levels nor PCSK9 genotypes were significantly associated with AD risk.

    “among APOE ε4 carriers, neither plasma PCSK9 levels nor PCSK9 genotypes were significantly associated with AD risk (Table 2)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The categorization of PCSK9 genotypes as low, middle, or high based on blood PCSK9 levels in the FHS APOE ε4 noncarrier group is applicable to the ADNI study population and to APOE ε4 carriers.

  • May combine two claims.

    Findingown data

    In the ADNI study, PCSK9 SNPs were associated with AD dementia in APOE ε4 noncarriers, but not in APOE ε4 carriers.

    “the PCSK9 SNPs were associated with AD dementia in APOE ɛ4 noncarriers, but not in APOE ɛ4 carriers (Supporting Table S4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The categorization of PCSK9 genotypes as low, middle, or high based on blood PCSK9 levels in the FHS APOE ε4 noncarrier group is applicable to the ADNI study population and to APOE ε4 carriers.

  • May combine two claims.

    Findingown data

    Three PCSK9 genotypes were associated with blood PCSK9 concentrations in the absence of APOE ε4, but not in the presence of APOE ε4.

    “While three genotypes were associated with blood PCSK9 concentrations in the absence of APOE ɛ4, the PCSK9 genotypes did not link with PCSK9 protein levels in the presence of APOE ɛ4 (Supporting Figure S5).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The categorization of PCSK9 genotypes as low, middle, or high based on blood PCSK9 levels in the FHS APOE ε4 noncarrier group is applicable to the ADNI study population and to APOE ε4 carriers.

  • May combine two claims.

    Interpretationcitation

    APOE genotypes regulate both lipid metabolism and chronic inflammation differently to mediate Alzheimer's disease risk.

    “These findings suggest that APOE genotypes regulate both lipid metabolism and chronic inflammation differently to mediate AD risk.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PCSK9 is a lipid-protein involved in lipid metabolism via the low density lipoprotein receptor (LDLR), the very low density lipoprotein receptor (VLDLR), and apolipoprotein E receptor 2 (ApoER2).

    “proprotein convertase subtilisin/kexin type 9 (PCSK9), a lipid‐protein involved in lipid metabolism via the low density lipoprotein receptor (LDLR), the very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] S. Poirier, G. Mayer, S. Benjannet, et al., “ The Proprotein Convertase PCSK9 Induces the Degradation of Low Density Lipoprotein Receptor (LDLR) and Its Closest Family Members VLDLR and ApoER2,” Journal of Biological Chemistry 283, no. 4 (2008): 2363– 2372. 18039658 source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The protective effect of high blood PCSK9 in APOE ε4 noncarriers may be through mechanisms related to lipid metabolism.

    “potentially through mechanisms related to lipid metabolism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Plasma PCSK9 impacts Alzheimer's disease dementia differently based on APOE ε4 noncarrier versus carrier status, with similar patterns observed for both Alzheimer's disease dementia and all-cause dementia.

    “The data suggested that plasma PCSK9 impact AD dementia differently based on APOE ɛ4 noncarriers versus carriers, with similar patterns observed for both AD dementia and all‐cause dementia.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Dementia diagnoses were made according to DSM-IV criteria.

    “Dementia diagnoses were made according to DSM‐IV criteria, based on longitudinal cognitive assessments, caregiver interviews, medical records, neuroimaging, and autopsy data when available.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Q. Tao, T. F. Alvin Ang, S. C. Akhter‐Khan, et al., “ Impact of C‐Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous Apolipoprotein E Ɛ4 Carriers,” Neurology 97 (2021): 1243– 1252. PMC8480484 34266923 source
    • cites [18] S. Seshadri, A. Beiser, J. Selhub, et al., “ Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease,” New England Journal of Medicine 346, no. 7 (2002): 476– 483. 11844848 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    APOE4 protein may suppress the expression of PCSK9 to inhibit PCSK9 regulating the pathways of immune responses and lipid metabolism.

    “APOE4 protein may suppress the expression of PCSK9 to inhibit PCSK9 regulating the pathways of immune responses and lipid metabolism.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The mechanism of peripheral PCSK9 for the brain is unclear.

    “the mechanism of peripheral PCSK9 for the brain is unclear.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Diagnoses of Alzheimer's disease dementia were determined using NINCDS-ADRDA criteria, distinguishing Alzheimer's disease dementia from preclinical Alzheimer's disease or mild cognitive impairment.

    “Importantly, diagnoses of Alzheimer's disease dementia (ADD) were determined using NINCDS‐ADRDA criteria, thereby distinguishing ADD from preclinical AD or mild cognitive impairment (MCI).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Adjusted analyses were conducted to control for potential confounders including age, sex, education, lipid profile, and lipid treatments.

    “Adjusted analyses were conducted to control for potential confounders including age, sex, education, lipid profile and lipid treatments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Diet components and taking drugs targeting peripheral lipid metabolism could influence the associations between PCSK9 and AD.

    “Thus, diet components and taking the drugs targeting peripheral lipid metabolism could influence the associations between PCSK9 and AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Noncarriers with higher PCSK9 may have substantially reduced AD risk, whereas APOE ε4 carriers do not appear to benefit.

    “Clinically, these findings suggest that noncarriers with higher PCSK9 may have substantially reduced AD risk, whereas ε4 carriers do not appear to benefit.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Sensitivity analyses were performed to evaluate the robustness of the findings.

    “Sensitivity analyses were performed to evaluate the robustness of our findings.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The rate of cardiovascular disease, average BMI, lipid profiles, and lipid treatment were similar between the two FHS datasets.

    “In addition, the rate of CVD, the average BMI, lipid profiles and lipid treatment were similar between two datasets.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    PCSK9 plays a role in neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, AD, alcohol use disorder, and stroke.

    “PCSK9 plays a role in neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, AD, alcohol use disorder, and stroke [24]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] A. S. Bell, J. Wagner, D. B. Rosoff, and F. W. Lohoff, “ Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in the Central Nervous System,” Neuroscience & Biobehavioral Reviews 149 (2023): 105155. 37019248 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Cross-validation was performed using logistic regression in 1,476 ADNI participants to validate the association between PCSK9 genotypes and Alzheimer's disease or all-cause dementia, stratified by APOE genotype.

    “Cross‐validation was performed using logistic regression model (the results were reported as odds ratio (OR) with its 95% CI) of the association between PCSK9 genotypes and prevlent of AD or all‐cause dementia among 1476 ADNI participants to validate the association between AD/Dementia and the selected SNPs of PCSK, stratified by APOE genotype.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Both cohorts used did not have data on PCSK9 inhibitor use.

    “both cohorts we used did not have the data on PCSK9 inhibitor use.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The lack of ethnic diversity of the FHS cohort may restrict the generalizability of our findings to more diverse populations.

    “the lack of ethnic diversity of the FHS cohort may restrict the generalizability of our findings to more diverse populations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Another limitation was the absence of experimental validation.

    “Another limitation was the absence of experimental validation”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PCSK9 inhibitors may be harmful for AD in the minor frequencies of some PCSK9 genotypes.

    “PCSK9 inhibitors may be harmful for AD in the minor frequencies of some PCSK9 genotypes [21, 24].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] X. B. Zhu, Y. Y. Xu, L. C. Li, et al., “ Function of Proprotein Convertase Subtilisin/Kexin Type 9 and Its Role in Central Nervous System Diseases: An Update on Clinical Evidence,” Drug Development Research 85 (2023): e22131. 37943623 source
    • cites [24] A. S. Bell, J. Wagner, D. B. Rosoff, and F. W. Lohoff, “ Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in the Central Nervous System,” Neuroscience & Biobehavioral Reviews 149 (2023): 105155. 37019248 source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The analyses were hypothesis-driven and focused on predefined outcomes.

    “the analyses were hypothesis‐driven and focused on predefined outcomes”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Residual confounding by age remains a potential limitation because primary analyses did not use age-matched sampling.

    “residual confounding by age remains a potential limitation, as our primary analyses did not use age‐matched sampling.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PCSK9 inhibitors are effective drugs to reduce cholesterol levels and atherosclerosis to decrease the risk of cardiovascular diseases.

    “PCSK9 inhibitors are the effective drugs to reduce the cholesterol levels and atherosclerosis to decrease the risk of cardiovascular diseases [5]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] S. Poirier, G. Mayer, S. Benjannet, et al., “ The Proprotein Convertase PCSK9 Induces the Degradation of Low Density Lipoprotein Receptor (LDLR) and Its Closest Family Members VLDLR and ApoER2,” Journal of Biological Chemistry 283, no. 4 (2008): 2363– 2372. 18039658 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Corrections for multiple comparisons were not applied, which may increase the risk of type I error.

    “corrections for multiple comparisons were not applied, which may increase the risk of type I error.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Our study did not account for diet as a potential confounding factor.

    “our study did not account for diet as a potential confounding factor.”
    Quote in the paperNot a substantial claim
47 of 47

  • The authors state this as an assumption.

    Missing data less than 10% were missing at random.

    “In case of missing data less than 10%, we assumed the data were missing at random and still employed complete case analysis in the multivariate analysis.”

  • The paper relies on this without support.

    The categorization of PCSK9 genotypes as low, middle, or high based on blood PCSK9 levels in the FHS APOE ε4 noncarrier group is applicable to the ADNI study population and to APOE ε4 carriers.

    “The label “Low”, “Middle”, and “High” of each genotypes were based on the PCSK protein levels in the APOE ε4 non‐carriers group as shown in the Supporting Figure 5, respectively.”
    “Three SNPs in the PCSK9 gene were analyzed, with genotypes labeled as “Low”, “Middle”, and “High” based on corresponding blood PCSK9 protein levels in the APOE ε4 non‐carriers groups as shown in Supporting Figure S5, respectively.”

  • The paper relies on this without support.

    CSF Aβ42 is a valid biomarker indicating AD diagnosis.

    “a biomarker indicating AD diagnosis”

  • The paper relies on this without support.

    The ADNI dataset is suitable for validating the FHS findings.

    “We used the ADNI dataset and logistic model to validate the findings in FHS.”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • rs529787 high-PCSK9 genotype is mislabeled in the table note

    Minor

    The Table 3 note calls GG both the low and high genotype for rs529787. The table itself identifies CC, not GG, as the high genotype.

  • Claimed CONSORT citation identifies STROBE instead

    Minor

    The methods say citation [13] supports use of CONSORT 2010 guidelines, but reference 13 is the STROBE statement.

2 of 2

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Tao, Q., Ang, T. F. A., Huang, J., Itchapurapu, I. S., Mez, J., Alosco, M., Au, R., Farrer, L. A., Zhang, X., Qiu, W. Q., & Initiative, F. T. A. D. N.
Affiliations
Boston University (US)
Corresponding author
Qiu, Wei Qiao
ORCID
Venue
Health Science Reports
Publisher
Wiley
Published
2026-02
Volume
9
Issue
2
Pages
e71810-e71810
ISSN
2398-8835 (ISSN-L)
DOI
10.1002/hsr2.71810
PMC
PMC12927996
OpenAlex
W7131126299
Semantic Scholar
89d774c75202b228365593e15713ef18e00f2033
Cited by
1
References
33
Citations by year
2026: 1
FWCI
3.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Health Science Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
National Institute on Aging (AG‐09899 (Qiu W.Q.), K24AG050842 (Qiu W.Q.), U19‐AG068753 (Farrer L.A., and Au R.))
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
PCSK9, Alzheimer's disease, APOE ε4, plasma PCSK9 levels, dementia risk, lipid metabolism, amyloid-beta 42

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-19.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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