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Cited by 2Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCerebrovascular and genetic disorders

White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults

Open access
Lin, Zixuan, Hong, Yiwen, Hu, Yizhe, Xiao, Qian, Peng, Shin‐Lei, Wu, Dan, Guo, Tengfei, Jiang, Dengrong·2025·Alzheimer's & Dementia
DOI 10.1002/alz.70990PMC PMC12689459
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Abstract

INTRODUCTION: White matter hyperintensities (WMH), a key imaging biomarker of small vessel injury, may play a complex role in Alzheimer's disease (AD). We hypothesize that WMH not only directly contributes to cognitive decline but also moderates the relationship among AD pathology, treatment, and cognitive decline. METHODS: A total of 1169 participants with 240‐week follow‐up in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were analyzed. Linear regression models examined WMH's contribution to cognitive decline, its interaction with Aβ on p‐Tau217 level, and its interaction with anti‐amyloid treatment on cognitive decline. RESULTS: Increase in WMH volume independently contributed to cognitive decline ( p = 0.0028). Baseline WMH significantly moderated the relationship between Aβ change and p ‐Tau217 change ( p = 0.0035). Specifically, Aβ accumulation correlated with p‐Tau217 increase only in participants with low baseline WMH. WMH growth was associated with cognitive decline only in the treatment group ( p < 0.0001). DISCUSSION: WMH modulates the interplay of pathologies, emphasizing the need for comprehensive treatment approaches targeting multiple pathways. Highlights: White matter hyperintensity (WMH) independently contributed to cognitive decline. WMH modulated the longitudinal relationship between Aβ and p‐Tau217. WMH interacted with anti‐amyloid treatment on longitudinal cognitive decline.

AI snapshot

Written from the paper’s full text.

TL;DR

In the A4 trial cohort of asymptomatic amyloid-positive older adults, white matter hyperintensity (WMH) progression independently contributed to cognitive decline and moderated the relationship between amyloid and tau pathology. WMH growth was associated with cognitive decline only in the anti-amyloid treatment group, suggesting WMH burden may influence treatment efficacy.

Key findings

  • Faster WMH growth was independently associated with greater cognitive decline on the PACC (β = −0.11, 95% CI [−0.17, −0.036], p = 0.0028, R² = 0.33, Cohen’s f² = 0.014). Random forest ranked p-Tau217 slope, baseline p-Tau217, and WMH slope as the most important predictors of PACC slope (importance scores = 16.21, 15.75, and 5.08, respectively).
  • Baseline WMH significantly moderated the relationship between Aβ change and p-Tau217 change (interaction β = −154.82, 95% CI [−258.60, −51.04], p = 0.0035). In participants with low baseline WMH, Aβ slope was positively associated with p-Tau217 slope (β = 121.99, 95% CI [53.01, 190.98], corrected p = 0.0011); in those with high baseline WMH, there was no association (β = 3.91, 95% CI [−62.80, 70.61], corrected p > 0.99).
  • A significant treatment × WMH slope interaction on PACC slope was observed (β = −0.16, 95% CI [−0.28, −0.027], p = 0.018). WMH slope was associated with PACC decline in the treatment group (β = −0.22, 95% CI [−0.32, −0.13], corrected p < 0.0001) but not in the placebo group (β = −0.033, 95% CI [−0.13, 0.063], corrected p = 0.99).
  • Anti-amyloid treatment was not significantly related to WMH slope (β = −0.000062, 95% CI [−0.00024, 0.00012], p = 0.50). Higher vascular risk score was weakly positively associated with WMH slope (β = 0.00067, 95% CI [1.87e−05, 0.0013], p = 0.044).

Methods

  • Longitudinal analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study: 1169 randomized participants with preclinical AD, followed to Visit 66 (Week 240). Eligible participants were cognitively unimpaired adults aged 65–85 with evidence of brain amyloid pathology on PET.
  • Cognitive function was measured with the Preclinical Alzheimer Cognitive Composite (PACC). WMH were quantified from T2-FLAIR MRI using HyperMapp3r, corrected for intracranial volume and log-transformed. Aβ was measured with 18F-Florbetapir PET, plasma p-Tau217 with an electrochemiluminescent immunoassay, and gray matter volume from 3D T1-weighted MRI.
  • Linear mixed-effects models estimated personalized slopes for PACC, WMH, Aβ, p-Tau217, and gray matter volume. Linear regression models tested direct and interaction effects; Box-Cox transformation was applied to non-normal slope variables; random forest analysis assessed predictor importance; Bonferroni correction was used for subgroup tests.

Limitations

  • The paper states that only total WMH volume was investigated, not regional WMH patterns, and that only Aβ PET and plasma p-Tau217 were used as amyloid and tau biomarkers, rather than CSF/plasma Aβ and tau PET.
  • The paper notes that no direct associations were observed between AD pathology and WMH progression, which may be partly attributable to the older age and relatively narrow dynamic range of amyloid and WMH changes in the A4 asymptomatic cohort.
  • Evident from the text: this is a secondary analysis of a completed trial of solanezumab, so treatment findings are specific to that anti-amyloid agent; vascular risk factors were defined from vital/lab measurements because formal medical diagnoses were unavailable in the released A4 datasets.

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

Integrity signals

Registry

Crossref · 10.1002/alz.70990

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 38 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Targeting a single AD-specific pathological process is insufficient to mitigate cognitive decline.

    “While recent clinical trials of anti‐amyloid therapies, such as donanemab and lecanemab, 2 , 3 have shown promising results, the failures of earlier treatments like solanezumab and bapineuzumab indicate that targeting a single AD‐specific pathological process is insufficient to mitigate cognitive decline. 4 , 5 , 6”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [4] Sperling RA, Donohue MC, Raman R, et al. Trial of solanezumab in preclinical Alzheimer's disease. N Engl J Med. 2023; 389(12): 1096‐ 1107. 37458272 PMC10559996 source

      The Conclusions and Discussion report that solanezumab did not slow cognitive decline in people with preclinical Alzheimer’s disease. That supports the cited treatment failure, but not the broader claim that targeting any single Alzheimer’s pathological process is insufficient: the Discussion also reports that substantial amyloid reduction in other trials was associated with slower clinical and cognitive progression. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [5] Salloway S, Sperling R, Fox Nick C, et al. Two phase 3 trials of bapineuzumab in mild‐to‐moderate Alzheimer's disease. N Engl J Med. 2014; 370(4): 322‐ 333. 24450891 PMC4159618 source

      The Discussion reports that bapineuzumab showed no benefit on cognitive or other clinical outcomes in these trials and notes that solanezumab also missed its primary clinical outcomes. But it does not conclude that targeting a single AD pathological process is inherently insufficient: it offers alternative explanations, including limited dosing, insufficient amyloid removal, and treatment starting too late. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [6] Doody Rachelle S, Thomas Ronald G, Farlow M, et al. Phase 3 trials of solanezumab for mild‐to‐moderate Alzheimer's Disease. N Engl J Med. 2014; 370(4): 311‐ 321. 24450890 source
  • Premisecitation

    The presence of WMH serves as a secondary insult necessary for dementia onset in the context of amyloidosis.

    “This aligns with the hypothesis that the presence of WMH serves as a secondary insult necessary for dementia onset in the context of amyloidosis. 34”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Provenzano FA, Muraskin J, Tosto G, et al. White matter hyperintensities and cerebral amyloidosis: necessary and sufficient for clinical expression of Alzheimer disease? JAMA Neurol. 2013; 70(4): 455‐ 461. 23420027 PMC4124641 source
  • Premisecitation

    The A4 trial showed no significant effect of solanezumab compared to placebo.

    “The A4 study was designed to test whether solanezumab could slow cognitive decline by targeting monomeric amyloid in preclinical AD, but the trial showed no significant effect compared to placebo. 4”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Sperling RA, Donohue MC, Raman R, et al. Trial of solanezumab in preclinical Alzheimer's disease. N Engl J Med. 2023; 389(12): 1096‐ 1107. 37458272 PMC10559996 source
  • Findingown data

    Random forest analysis identified p-Tau217 slope, baseline p-Tau217, and WMH slope as the most important predictors for PACC slope.

    “Random forest analyses identified p‐Tau217 slope, baseline p‐Tau217, and WMH slope as the most important predictors for PACC slope (importance score = 16.21, 15.75, and 5.08, respectively; Figure 2B).”
    Quote in the paperSubstantial claim
  • Findingown data

    In participants with high baseline WMH, there was no association between p-Tau217 slope and Aβ slope (β = 3.91, 95% CI [−62.80, 70.61], corrected p > 0.99).

    “However, there was no association between p‐Tau217 slope and Aβ slope in those with high baseline WMH (β = 3.91, 95% CI [−62.80, 70.61], original p = 0.91, corrected p > 0.99, R 2 = 0.24, Cohen's f 2 < 0.0001, Figure 3B).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 16
  • May combine two claims. 17
  • The quote only partly states this claim. 1

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

    Premisecitation

    Preclinical studies have reported an Aβ-independent relationship between cerebrovascular dysfunction and tau.

    “Several preclinical studies also reported such Aβ‐independent relationship between cerebrovascular dysfunction and tau. 40 , 41”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [40] Qiu L, Ng G, Tan EK, Liao P, Kandiah N, Zeng L. Chronic cerebral hypoperfusion enhances tau hyperphosphorylation and reduces autophagy in Alzheimer's disease mice. Sci Rep. 2016; 6(1): 23964. 27050297 PMC4822118 source
    • cites [41] Raz L, Bhaskar K, Weaver J, et al. Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction. Neurobiol Dis. 2019; 126: 124‐ 136. 30010004 PMC6347559 source

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

    Premisecitation

    WMH are directly related to vascular risk factors such as hypertension, diabetes, and obesity, which impair cerebral blood flow and lead to ischemic injury to small vessels.

    “WMH are directly related to vascular risk factors such as hypertension, diabetes, and obesity, which impair cerebral blood flow and lead to ischemic injury to small vessels. 7 , 8”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [7] Murray AD, Staff RT, Shenkin SD, Deary IJ, Starr JM, Whalley LJ. Brain white matter hyperintensities: relative importance of vascular risk factors in nondemented elderly people. Radiology. 2005; 237(1): 251‐ 257. 16126931 source
    • cites [8] Marcus J, Gardener H, Rundek T, et al. Baseline and longitudinal increases in diastolic blood pressure are associated with greater white matter hyperintensity volume: the northern Manhattan study. Stroke. 2011; 42(9): 2639‐ 2641. 21836088 PMC3189513 source

      The Results and Discussion (page not provided) associate higher diastolic blood pressure and longer hypertension duration with greater WMH volume, supporting the hypertension portion. The paper does not establish the claimed links with diabetes or obesity, nor show that impaired cerebral blood flow causes ischemic small-vessel injury; its Discussion only suggests that peripheral vascular resistance may reflect small-vessel damage. (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

    More severe arteriolosclerosis in the posterior watershed region and higher whole-brain WMH are associated with tau tangle burden but not Aβ.

    “Using autopsy data from 982 cases, Kapasi et al. showed that more severe arteriolosclerosis in the posterior watershed region and higher whole‐brain WMH were associated with tau tangle burden but not Aβ. 39”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Kapasi A, Yu L, Petyuk V, Arfanakis K, Bennett DA, Schneider JA. Association of small vessel disease with tau pathology. Acta Neuropathol. 2022; 143(3): 349‐ 362. 35044500 PMC8858293 source

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

    Premisecitation

    The spatial distribution of WMH is differentially associated with amyloid pathology, vascular risks, and specific cognitive domains.

    “The spatial distribution of WMH was found to be differentially associated with amyloid pathology, vascular risks, and specific cognitive domains. 18 , 19 , 64”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [18] Rizvi B, Lao PJ, Chesebro AG, et al. Association of regional white matter hyperintensities with longitudinal Alzheimer‐like pattern of neurodegeneration in older adults. JAMA Netw Open. 2021; 4(10): e2125166‐ e2125166. 34609497 PMC8493439 source

      The Introduction and Discussion (pages not provided) link parietal WMH and WMH-related cortical changes to memory and executive dysfunction. The paper does not establish differential associations between WMH location and amyloid pathology or vascular risk factors; its Discussion calls for future research on WMH and amyloid biomarkers. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [19] Newton P, Tchounguen J, Pettigrew C, et al. Regional white matter hyperintensities and Alzheimer's disease biomarkers among older adults with normal cognition and mild cognitive impairment. J Alzheimers Dis. 2023; 92(1): 323‐ 339. 36744337 PMC10041440 source

      The Discussion’s “Regional WMH: Distinct etiologies and risk factor associations” section links parietal or posterior WMH with amyloid and frontal WMH with vascular risk factors. The paper does not report associations between WMH distribution and specific cognitive domains; it examines cognitive status (normal cognition versus MCI) instead. Page numbers were not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [64] Garnier‐Crussard A, Bougacha S, Wirth M, et al. White matter hyperintensity topography in Alzheimer's disease and links to cognition. Alzheimers Dement. 2022; 18(3): 422‐ 433. 34322985 PMC9292254 source

  • May combine two claims.

    Interpretationcitation

    Tau pathology may represent a convergent pathway in AD, with vascular pathology being one of several contributing factors.

    “Therefore, tau pathology may represent a convergent pathway in AD, with vascular pathology being one of several contributing factors. 39”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [39] Kapasi A, Yu L, Petyuk V, Arfanakis K, Bennett DA, Schneider JA. Association of small vessel disease with tau pathology. Acta Neuropathol. 2022; 143(3): 349‐ 362. 35044500 PMC8858293 source

  • May combine two claims.

    Interpretationcitation

    White matter injury disrupts cortical connections responsible for higher-level cognition, and cerebrovascular burden accelerates dementia onset in AD patients.

    “This result supported the model that white matter injury disrupted the cortical connections responsible for higher‐level cognition, 30 reinforcing the role of cerebrovascular burden in accelerating dementia onset in AD patients.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [30] Smith EE, Salat DH, Jeng J, et al. Correlations between MRI white matter lesion location and executive function and episodic memory. Neurology. 2011; 76(17): 1492‐ 1499. 21518999 PMC3087468 source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The A4 study was a multicenter, Phase 3, double-blind, placebo-controlled study in subjects with preclinical AD.

    “The A4 study was a multicenter, Phase 3, double‐blind, placebo‐controlled study in subjects with preclinical AD. 4”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Sperling RA, Donohue MC, Raman R, et al. Trial of solanezumab in preclinical Alzheimer's disease. N Engl J Med. 2023; 389(12): 1096‐ 1107. 37458272 PMC10559996 source

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

    Premisecitation

    Most cross-sectional studies reported an association between WMH and amyloid markers (CSF Aβ42 or Aβ PET) but not tau markers.

    “Most cross‐sectional studies reported an association between WMH and amyloid markers (either CSF Aβ42 or Aβ deposition on PET) but not tau markers. 55 , 56 , 57 , 58 , 59”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [55] Stenset V, Johnsen L, Kocot D, et al. Associations between white matter lesions, cerebrovascular risk factors, and low CSF Abeta42. Neurology. 2006; 67(5): 830‐ 833. 16966546 source

      The Paper I summary reports an association between MRI-rated white matter lesions and low CSF Aβ42 in memory-clinic patients, supporting this study as an example of the amyloid-marker finding. It does not report a comparison between white matter lesions and tau markers, so it does not support the “but not tau markers” part of the claim. This single study also cannot establish what most cross-sectional studies found. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [56] Alban SL, Lynch KM, Ringman JM, et al. The association between white matter hyperintensities and amyloid and tau deposition. Neuroimage Clin. 2023; 38: 103383. 36965457 PMC10060905 source
    • cites [57] Graff‐Radford J, Arenaza‐Urquijo EM, Knopman DS, et al. White matter hyperintensities: relationship to amyloid and tau burden. Brain. 2019; 142(8): 2483‐ 2491. 31199475 PMC6658846 source

  • May combine two claims.

    Interpretationcitation

    In individuals with low baseline WMH, the strong correlation between Aβ accumulation and p-Tau217 change suggests a rapid pathogenetic cross-talk and a temporal sequence of successive amyloid and tau phosphorylation in early pre-clinical stage.

    “Individuals with low baseline WMH exhibited a strong correlation between Aβ accumulation and p‐Tau217 change, consistent with previous findings, 33 , 36 , 37 suggesting a rapid pathogenetic cross‐talk and a temporal sequence of successive amyloid and tau phosphorylation in this early pre‐clinical stage.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [33] Hanseeuw BJ, Betensky RA, Jacobs HIL, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 2019; 76(8): 915‐ 924. 31157827 PMC6547132 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [36] Sanchez JS, Hanseeuw BJ, Lopera F, et al. Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia‐Boston (COLBOS) biomarker study. Alzheimers Res Ther. 2021; 13(1): 27. 33451357 PMC7811244 source

      The Discussion (page unavailable) reports that Aβ PET changes preceded tau PET changes in PSEN1 mutation carriers, supporting the proposed temporal sequence. It does not examine low baseline WMH or p-Tau217 change. The Results section “Aβ rise precedes rapid neocortical tau increase in ADAD” (page unavailable) instead reports that contemporaneous Aβ and tau PET change rates were not correlated in those carriers, so it does not support the claimed strong correlation or rapid cross-talk. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [37] Gomar JJ, Conejero‐Goldberg C, Davies P, Goldberg TE, the Alzheimer's Disease Neuroimaging I. Anti‐correlated cerebrospinal fluid biomarker trajectories in preclinical Alzheimer's disease. J Alzheimers Dis. 2016; 51: 1085‐ 1097. 26967213 source

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

    Premisecitation

    The longitudinal correlation between WMH and AD pathology is stronger in younger participants, suggesting a potential age-dependent effect of amyloid on WMH.

    “As reported in Luo et al., 35 the longitudinal correlation between WMH and AD pathology was stronger in younger participants, suggesting a potential age‐dependent effect of amyloid on WMH.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [35] Luo J, Ma Y, Agboola FJ, et al. Longitudinal relationships of white matter hyperintensities and Alzheimer disease biomarkers across the adult life span. Neurology. 2023; 101(2): e164‐ e177. 37202169 PMC10351551 source

      The Results say that longitudinal correlations between WMH and PET amyloid biomarkers appeared numerically stronger in younger participants, but the age-group differences were not statistically significant. The Discussion adds that correlations between WMH and amyloid biomarkers were not significant within the younger group; it does not establish an age-dependent effect of amyloid on WMH. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationown data

    At the asymptomatic amyloid-positive stage, vascular and AD pathology independently contribute to cognition, with amyloid effects potentially mediated by tau.

    “These findings suggest that, at this asymptomatic amyloid‐positive stage, vascular and AD pathology independently contribute to cognition, with amyloid effects potentially mediated by tau. 33”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] Hanseeuw BJ, Betensky RA, Jacobs HIL, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 2019; 76(8): 915‐ 924. 31157827 PMC6547132 source

      The Discussion reports a delayed, indirect, tau-mediated association between amyloid and cognition in preclinical AD, including changes shortly after amyloid positivity. It does not report that vascular pathology independently contributes to cognition; the cited paper examines amyloid, tau, and cognition, not that vascular contribution. Page numbers are unavailable in our copy. (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

    Only 15% of the variance in WMH volume is explained by measures of vascular risks, and another 16% by age.

    “A recent large sample study using UK Biobank datasets also reported that only 15% of the variance in WMH volume was explained by measures of vascular risks, and another 16% by age. 49”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] Koohi F, Harshfield EL, Markus HS. Contribution of conventional cardiovascular risk factors to brain white matter hyperintensities. J Am Heart Assoc. 2023; 12(14): e030676. 37421292 PMC10382123 source

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

    Premisecitation

    White matter microstructural changes may be not only a marker of small vessel injury but also directly related to AD pathology.

    “Emerging evidence suggests that white matter microstructural changes may be not only a marker of small vessel injury but also directly related to AD pathology. 53 , 54”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [53] Lee S, Viqar F, Zimmerman ME, et al. White matter hyperintensities are a core feature of Alzheimer's disease: evidence from the dominantly inherited Alzheimer network. Ann Neurol. 2016; 79(6): 929‐ 939. 27016429 PMC4884146 source

      The Discussion describes white matter hyperintensities (WMH) as markers of small-vessel cerebrovascular disease and reports that WMH and beta-amyloid pathology appear related in people with dominantly inherited AD. The claim is broader than the evidence in this paper: it concerns white matter microstructural changes generally, whereas this study examined MRI-visible WMH and says their precise pathological correlates require further research. Our copy provides no page numbers for these passages. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [54] Garnier‐Crussard A, Cotton F, Krolak‐Salmon P, Chételat G. White matter hyperintensities in Alzheimer's disease: beyond vascular contribution. Alzheimers Dement. 2023; 19(8): 3738‐ 3748. 37027506 source

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

    Premisecitation

    Amyloid pathology and vascular risks are associated with distinct patterns of WMH.

    “Biesbroek et al. reported that amyloid pathology and vascular risks were associated with distinct patterns of WMH. 48”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Biesbroek JM, Coenen M, DeCarli C, et al. Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: a multicenter study in 3132 memory clinic patients. Alzheimers Dement. 2024; 20(4): 2980‐ 2989. 38477469 PMC11032573 source

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

    Premisecitation

    Only a few studies reported faster longitudinal WMH growth in individuals with higher baseline Aβ deposition.

    “Only a few studies reported faster longitudinal WMH growth in individuals with higher baseline Aβ deposition. 35 , 61 , 62 , 63”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [35] Luo J, Ma Y, Agboola FJ, et al. Longitudinal relationships of white matter hyperintensities and Alzheimer disease biomarkers across the adult life span. Neurology. 2023; 101(2): e164‐ e177. 37202169 PMC10351551 source

      The Results and the ‘Longitudinal Correlations Between WMH Volume and AD Biomarkers’ section report that faster WMH growth was associated with faster increases in PET amyloid uptake. They do not show that higher *baseline* Aβ deposition predicted faster subsequent WMH growth. The Discussion says earlier longitudinal WMH studies had focused on structural changes and cognition, not this amyloid relationship; page numbers were not available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [61] Cha WJ, Yi D, Ahn H, et al. Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities. Alzheimers Res Ther. 2024; 16(1): 50. 38454444 PMC10918927 source
    • cites [62] Dadar M, Camicioli R, Duchesne S, Collins DL. The temporal relationships between white matter hyperintensities, neurodegeneration, amyloid beta, and cognition. Alzheimers Dement (Amst). 2020; 12(1): e12091. 33083512 PMC7552231 source

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

    Premisecitation

    Potential molecular mechanisms linking vascular pathology to tau include activation of Cdk5, calpain-mediated cleavage of p35, and activation of GSK-3β.

    “Potential molecular mechanisms include activation of cyclin‐dependent kinase‐5 (Cdk5), calpain‐mediated cleavage of the Cdk5 regulatory subunit p35, and activation of glycogen synthase kinase‐3β. 45”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Tarawneh R. Microvascular contributions to Alzheimer Disease pathogenesis: is Alzheimer disease primarily an endotheliopathy?. Biomolecules. 2023; 13(5): 830. 37238700 PMC10216678 source

  • The quote only partly states this claim.

    Findingown data

    In the anti-amyloid treatment group, WMH slope was significantly associated with PACC slope (β = −0.22, 95% CI [−0.32, −0.13], corrected p < 0.0001).

    “WMH growth was associated with cognitive decline only in the treatment group (p < 0.0001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Baseline WMH was not directly correlated with either p-Tau217 slope or Aβ slope.

    “In addition, we examined whether baseline WMH was directly correlated with either p‐Tau217 slope or Aβ slope but found no significant associations (p > 0.05).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the solanezumab treatment group, WMH growth was significantly associated with cognitive decline, whereas no such association was observed in the placebo group.

    “WMH growth was significantly associated with cognitive decline only in the treatment group.”
    • Also stated in: § DISCUSSION · plain
      “in the treatment group, WMH growth was highly associated with cognition decline, whereas no such relationship was observed in the placebo group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WMH progression directly contributed to cognitive decline, with a higher importance than baseline and changes in Aβ.

    “Our findings indicated that WMH progression directly contributed to cognitive decline, with a higher importance than baseline and changes in Aβ.”
    • Also stated in: § DISCUSSION · plain
      “our study showed that faster WMH accrual was associated with worse cognitive deterioration.”
    • Also stated in: § DISCUSSION · plain
      “both linear regression and random forest analysis identified WMH as a stronger predictor of cognitive decline than Aβ, ranking only slightly lower than p‐Tau217.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    WMH not only directly contributes to cognitive decline but also moderates the relationship between AD pathologies, treatment, and cognitive decline.

    “WMH modulates the interplay of pathologies, emphasizing the need for comprehensive treatment approaches targeting multiple pathways.”
    • Also stated in: § PET imaging for Aβ quantification · hedged
      “These findings suggest that WMH not only directly contributes to cognitive decline but also moderates the relationship between AD pathologies, treatment, and cognitive decline, emphasizing the need for comprehensive treatment approaches targeting multiple pathways.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Bonferroni correction was performed for statistical tests in high- and low-WMH subgroups and in treatment and placebo subgroups.

    “Bonferroni correction was performed when conducting statistical tests in high‐ and low‐WMH subgroups or in treatment and placebo subgroups.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The current study only investigated total WMH volume but not regional WMH patterns.

    “First of all, the current study only investigated the total WMH volume but not regional WMH patterns.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Individuals with low WMH burden may represent a 'pure' AD phenotype, whereas those with high WMH likely represent a vascular or 'mixed' subtype that may show attenuated responses to Aβ-targeted therapies.

    “Individuals with low WMH burden may represent a “pure” AD phenotype, whereas those with high WMH likely represent a vascular or “mixed” subtype that may show attenuated responses to Aβ‐targeted therapies.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Extensive studies have reported a direct effect of WMH on cognitive deficits, both cross-sectionally and longitudinally.

    “Extensive studies have reported the direct effect of WMH on cognitive deficits, both cross‐sectionally and longitudinally. 23 , 29”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Roseborough AD, Saad L, Goodman M, Cipriano LE, Hachinski VC, Whitehead SN. White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: a meta‐analysis, systematic review, and recommendations for future study harmonization. Alzheimers Dement. 2023; 19(1): 194‐ 207. 35319162 source
    • cites [29] Kloppenborg RP, Nederkoorn PJ, Geerlings MI, van den Berg E. Presence and progression of white matter hyperintensities and cognition: a meta‐analysis. Neurology. 2014; 82(23): 2127‐ 2138. 24814849 source

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

    Interpretationcitation

    The weak association between WMH growth and VRS may be explained by amyloid pathology and vascular risks being associated with distinct patterns of WMH, whereas the current study evaluated total WMH volume.

    “This may explain the weak association found in the current study, which evaluated total WMH volume.”
    Quote in the paperNot a substantial claim
26 of 26

  • The paper relies on this without support.

    The potential interactions between WMH and AD pathologies remain unknown.

    “While previous studies have primarily focused on the direct impact of WMH on cognition, its potential interactions with AD pathologies remain unknown.”
    “However, its potential interactions with AD pathologies remain unknown.”

  • The paper relies on this without support.

    WMH is a key imaging biomarker of small vessel injury in both normal aging and dementia.

    “White matter hyperintensities (WMH), characterized by hyperintense signals on T2‐weighted or fluid‐attenuated inversion recovery (FLAIR) MRI images, are a key imaging biomarker of small vessel injury in both normal aging and dementia.”

  • The paper relies on this without support.

    Most prior studies on WMH and cognition did not account for AD pathology in statistical analysis.

    “However, most of these studies did not account for AD pathology in statistical analysis.”

  • The paper relies on this without support.

    The A4 study's asymptomatic cohort has a relatively narrow dynamic range of amyloid and WMH changes.

    “Therefore, the insignificant associations we observed between WMH and either Aβ or tau may be partially attributable to the older age and the relatively narrow dynamic range of amyloid and WMH changes in the A4 study's asymptomatic cohort.”

  • The paper relies on this without support.

    The A4 study's cohort is older.

    “Therefore, the insignificant associations we observed between WMH and either Aβ or tau may be partially attributable to the older age and the relatively narrow dynamic range of amyloid and WMH changes in the A4 study's asymptomatic cohort.”
5 of 5

Cites

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Authors
Lin, Z., Hong, Y., Hu, Y., Xiao, Q., Peng, S., Wu, D., Guo, T., & Jiang, D.
Affiliations
  • Zhejiang University (CN)
  • Shanghai Jiao Tong University (CN)
  • China Medical University (TW)
  • Shenzhen Bay Laboratory (CN)
Corresponding author
Jiang, Dengrong
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2025-12
Volume
21
Issue
12
Pages
e70990-e70990
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.70990
PMC
PMC12689459
OpenAlex
W4417180954
Semantic Scholar
1e81baa3415429ea8ebde10cb28fb364c33cf49c
Cited by
2
References
63
Citations by year
2026: 2
FWCI
1.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Eli Lilly and Company
  • Alzheimer's Association
  • GHR Foundation
  • National Natural Science Foundation of China (82302144, 62401363)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
Keywords
white matter hyperintensities, amyloid-beta
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Cognition, Female, Humans, Magnetic Resonance Imaging, Male, Amyloid beta-Peptides, tau Proteins, Treatment Outcome, Cognitive Dysfunction, White Matter

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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