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Cited by 575Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype

Open access
Vermunt, Lisa, Sikkes, Sietske A.M., van den Hout, Ardo, Handels, Ron, Bos, Isabelle, van der Flier, Wiesje M., Kern, Silke, Ousset, Pierre‐Jean +17 more·2019·Alzheimer's & Dementia
DOI 10.1016/j.jalz.2019.04.001PMC PMC6646097
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Abstract

Introduction: We estimated the age‐specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration. Methods: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration. Results: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage. Discussion: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.

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Crossref · 10.1016/j.jalz.2019.04.001

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Claims the paper makes

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  • Findingown data

    The study did not reveal significant sex differences in the duration of preclinical and prodromal Alzheimer's disease stages.

    “The study did not reveal significant sex differences in the duration of preclinical and prodromal AD stages.”
    Quote in the paperSubstantial claim
  • Findingown data

    For individuals with preclinical Alzheimer's disease, predicted overall disease duration decreased with older age, from 24 years at age 60 to 15 years at age 80.

    “Figure 2A shows for those with preclinical AD a lower predicted overall disease duration at older age, which ranged from 24 years (95% CI, 22-25) at age 60 to 15 years (95% CI, 11-17) at age 80.”
    Quote in the paperSubstantial claim
  • Findingown data

    Baseline abnormal cerebrospinal fluid total tau was not associated with the duration of the Alzheimer's disease dementia stages.

    “There was no association of baseline abnormal t-tau with the duration of the dementia stages.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Total predicted Alzheimer's disease duration ranged from 12 to 25 years depending on APOE ε4 genotype, age, and setting.

    “Figure 2C shows how the total predicted disease duration ranged from 12 to 25 years depending on APOE ε4 genotype, age and setting.”
    Quote in the paperSubstantial claim
  • Findingown data

    In females, the moderate Alzheimer's disease dementia stage duration was longer than in males, for example 2.1 years at age 70 in a clinical setting.

    “In females the moderate AD dementia stage duration was longer than in males (e.g. 2.1 years (95% CI, 1.1-3.2, p<0.0001 at age 70 in a clinical setting; Figure 2B, suppl. table B.3).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    Abnormal cerebrospinal fluid total tau was associated with shortening of the estimated preclinical Alzheimer's disease stage by about 3 years and the prodromal stage by about 2.5 years.

    “The estimated preclinical AD stage was shortened by around 3 years and the prodromal AD stage by around 2.5 years (Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In prodromal Alzheimer's disease, abnormal tau was associated with a decreased reversion rate to preclinical Alzheimer's disease (HR 0.41) and an increased progression rate to mild Alzheimer's disease dementia (HR 1.91).

    “In prodromal AD, abnormal tau associated with a decreased reversion rate to preclinical AD stage (HR=0.41 [95% CI, 0.23-0.71]) and increased progression rate to the mild AD dementia stage (HR=1.91 [95% CI, 1.48-2.48]).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Clinical setting was associated with a higher rate of progression from preclinical to prodromal Alzheimer's disease (HR 4.40) and a higher reversion rate (HR 1.98) than research setting.

    “Compared to data collected in a research setting, data from clinical settings was associated with a higher progression rate (HR=4.40 [95% CI, 2.80-6.94]) and reversion rate (HR=1.98 [95% CI, 1.15-3.39]) between preclinical and prodromal AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Clinical setting was associated with higher progression rates from prodromal to mild Alzheimer's disease dementia (HR 1.48) and from mild to moderate Alzheimer's disease dementia (HR 1.41).

    “Additionally, in the clinical setting the progression rates from the prodromal AD to the mild AD dementia stage (HR=1.48 [95% CI, 1.34-1.92]) and from the mild AD to the moderate AD dementia stage (HR=1.41 [95% CI,1.16-1.72]) were higher.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Females had a higher progression rate from mild to moderate Alzheimer's disease dementia (HR 1.24) and a lower mortality risk in moderate Alzheimer's disease dementia (HR 0.60) than males.

    “Females had a higher progression rate from mild AD to moderate AD dementia, compared to males (HR=1.24 [95% CI, 1.04-1.47]), while their mortality risk in moderate AD dementia was lower (HR=0.60 [95% CI, 0.46-0.80]).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For a person with preclinical Alzheimer's disease at age 70, the predicted total disease duration was 20 years, comprising 10 years preclinical, 4 years prodromal, 3 years mild dementia, and 3 years moderate dementia.

    “The predicted total disease duration, based on the model with age, for an individual with preclinical AD at age 70 was 20 years (95% CI, 17-21), consisting of a preclinical stage of 10 years (95% CI, 8-11), followed by a prodromal stage of 4 years (95% CI, 3-5), mild AD dementia for 3 years (95% CI, 2-3), and moderate AD dementia for 3 years (95% CI, 2-3, Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the clinical setting, prodromal Alzheimer's disease duration was shorter, dementia stage duration was equal between settings, and more time was spent in the moderate dementia stage.

    “In the clinical setting, for individuals with prodromal AD, the stage duration of prodromal AD was also shorter, and while the dementia stage duration for these individuals was equal between settings, more time was spent in the moderate AD stage (Suppl. table B.7a and b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Depending on age, sex, APOE genotype, baseline cerebrospinal fluid total tau, and setting, total Alzheimer's disease duration varied between 12 and 25 years; preclinical stage between 2 and 15 years, prodromal stage between 3 and 7 years, mild dementia between 2 and 6 years, and moderate dementia between 1 and 7 years.

    “Depending on age, sex, APOE genotype, baseline CSF t-tau and setting, the total disease duration varied between 12 and 25 years, the preclinical stage between 2 and 15, the prodromal stage between 3 to 7, mild AD dementia stage between 2 and 6 and moderate AD dementia stage between 1 and 7 years.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared with a non-carrier, an APOE ε4 carrier aged 70 in a clinical setting had 1.6 years shorter preclinical Alzheimer's disease, 1.1 years shorter prodromal Alzheimer's disease, and 1.0 year longer mild dementia stage.

    “When compared to a non-carrier, an APOE ε4 carrier aged 70 in the clinical setting had a 1.6 years (95% CI, 0.4-3.3; p=0.0295) shorter estimated preclinical AD stage duration, and 1.1 years (95% CI, 0.3-2.1; p=0.0110) shorter prodromal AD stage duration, but 1.0 year (95% CI, 0.3-1.8; p=0.0050) longer mild dementia stage duration (suppl. table B.4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Estimated total duration starting from preclinical Alzheimer's disease ranged from 19 years at age 60 to 11 years at age 80 in the clinical setting, and from 26 years at age 60 to 15 years at age 80 in the research setting.

    “The estimated total duration with starting stage preclinical AD ranged in the clinical setting 19 years (95% CI, 17-20) at age 60 to 11 years (95% CI, 10-12) at age 80 and in the research setting from 26 years (95% CI, 23-28) at age 60 to 15 years (95% CI, 12-17) at age 80.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    APOE ε4 carriers had increased progression rates from preclinical to prodromal Alzheimer's disease (HR 1.63) and from prodromal to mild Alzheimer's disease dementia (HR 1.50), and a trend toward slower decline from mild to moderate dementia (HR 0.77).

    “APOE ε4 carriers had, compared to non-carriers, an increased rate of progression from the preclinical AD to prodromal AD stage (HR=1.63 [95% CI, 1.11-2.41]) and from the prodromal AD to mild AD dementia stage (HR=1.50 [95% CI, 1.18-1.90]), and a trend for slower decline from the mild to the moderate AD dementia stage (HR 0.77 [95% CI, 0.60-1.00]).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Unlike previous studies, no effect of tau on mortality and duration of the Alzheimer's disease dementia stage was found, which may be explained by dichotomization of cerebrospinal fluid total tau in this analysis.

    “Unlike previous studies, no effect of tau on mortality and duration of the AD dementia stage were found, which may be explained by dichotomization of CSF t-tau in our analysis [16, 17].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Rhodius-Meester HFM,, Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease. Alzheimers Res Ther, 2018 10(1): p. 23. 29458426 PMC5819199

      Not checked in the free run.

    • cites [17] Degerman Gunnarsson M,, High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease. Alzheimers Res Ther, 2016 8(1): p. 22. 27263933 PMC4893835

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Residual life expectancy at age 80 was reported as 8-10 years in the USA and Australia (2010-2012), while in this study it ranged from 4 years for moderate Alzheimer's disease to 15 years for preclinical Alzheimer's disease.

    “For example, the residual life expectancy at age 80 was reported to be 8-10 years in the USA and Australia (data from 2010-2012), while in our study this ranged from 4 years for those with moderate AD to 15 years for individuals with preclinical AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] www.lifetable.de (2010-2012 USA).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Amyloid accumulation in the brain is thought to be the earliest sign of Alzheimer's disease and may begin up to 20 years before a clinical dementia diagnosis.

    “Accumulation of amyloid in the brain is believed to be the first sign of the disease and can precede a clinical diagnosis of dementia by up to 20 years [1, 4, 5].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Winblad B,, Defeating Alzheimer's disease and other dementias: a priority for European science and society. Lancet Neurol, 2016 15(5): p. 455– 532. 26987701 source

      Not checked in the free run.

    • cites [4] Jansen WJ,, Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA, 2015 313(19): p. 1924– 38. 25988462 PMC4486209 source

      Not checked in the free run.

    • cites [5] Jack CR Jr.,, Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol, 2013 12(2): p. 207– 16. 23332364 PMC3622225 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Age had the strongest effect on the duration of the preclinical and dementia stages, which could be explained by higher progression and mortality rates.

    “Age had the strongest effect on the duration of the preclinical and dementia stages, which could be explained by higher progression and mortality rates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The dementia stage duration was longer in women, driven by lower mortality in this group.

    “The dementia stage duration was longer in women, which was driven by lower mortality in this group.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Varying the mortality assumptions for unknown mortality dates did not change the results.

    “Varying the mortality assumptions for unknown mortality dates of those who died, did not change the results.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    The effects of setting on disease progression are consistent with other Alzheimer's disease studies.

    “The effects of setting on disease progression are consistent with other AD studies [40, 41].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Qian J,, APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts. PLoS Med, 2017 14(3): p. e1002254. 28323826 PMC5360223

      Not checked in the free run.

    • cites [41] Snitz BE,, Risk of progression from subjective cognitive decline to mild cognitive impairment: The role of study setting. Alzheimers Dement, 2018 14(6): p. 734– 742. 29352855 PMC5994356

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    While the prodromal stage was shorter in APOE ε4 carriers, the dementia stage was longer, implying that total symptomatic disease duration is similar but divided differently across stages.

    “While the prodromal stage was shorter in APOE ε4 carriers, the dementia stage was longer which would imply that the total symptomatic disease duration is similar, but differently divided over the stages.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Patients with prodromal Alzheimer's disease and elevated cerebrospinal fluid total tau tend to convert to Alzheimer's disease dementia sooner.

    “The patients with prodromal AD and increased CSF t-tau levels tended to convert sooner to AD dementia [19, 20].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] van Rossum IA,, Injury markers predict time to dementia in subjects with MCI and amyloid pathology. Neurology, 2012 79(17): p. 1809– 16. 23019259 PMC3475623 source

      Not checked in the free run.

    • cites [20] Buchhave P,, Cerebrospinal fluid levels of beta-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry, 2012 69(1): p. 98– 106. 22213792 source

      Not checked in the free run.

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

    Premisecitation

    Earlier studies reported that the Alzheimer's disease dementia stage lasts between 3 and 10 years.

    “Previous studies on the length of the AD dementia stage reported a duration of 3 to 10 years [14, 15].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Brodaty H, Seeher K, and Gibson L, Dementia time to death: a systematic literature review on survival time and years of life lost in people with dementia. Int Psychogeriatr, 2012 24(7): p. 1034– 45. 22325331 source

      Not checked in the free run.

    • cites [15] Wattmo C, Londos E, and Minthon L, Risk factors that affect life expectancy in Alzheimer's disease: a 15-year follow-up. Dement Geriatr Cogn Disord, 2014 38(5-6): p. 286– 99. 24992891

      Not checked in the free run.

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

    Premisecitation

    Younger age, female sex, and lower cerebrospinal fluid total tau are associated with a longer Alzheimer's disease dementia stage, while the effect of APOE genotype is uncertain.

    “Younger age, female sex and lower CSF total tau (t-tau) were found to be associated with a longer duration of the AD dementia stage, while the effect of APOE genotype was equivocal [14-17].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [14] Brodaty H, Seeher K, and Gibson L, Dementia time to death: a systematic literature review on survival time and years of life lost in people with dementia. Int Psychogeriatr, 2012 24(7): p. 1034– 45. 22325331 source

      Not checked in the free run.

    • cites [15] Wattmo C, Londos E, and Minthon L, Risk factors that affect life expectancy in Alzheimer's disease: a 15-year follow-up. Dement Geriatr Cogn Disord, 2014 38(5-6): p. 286– 99. 24992891

      Not checked in the free run.

    • cites [16] Rhodius-Meester HFM,, Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease. Alzheimers Res Ther, 2018 10(1): p. 23. 29458426 PMC5819199

      Not checked in the free run.

    • cites [17] Degerman Gunnarsson M,, High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease. Alzheimers Res Ther, 2016 8(1): p. 22. 27263933 PMC4893835

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Excluding ε4 carriers during a trial may affect the rate of progression and possibly the power of the study.

    “For example, exclusion of ε4 carriers during a trial, what happened in the high-dose group of the BAN2401 trial, may affect rate of progression and possibly the power of the study [45].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] https://www.alzforum.org/news/conference-coverage/ban2401-removes-brain-amyloid-possibly-slows-cognitive-decline 20 2 2019].

      Not checked in the free run.

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

    Premisecitation

    In a pooled memory clinic cohort, the median prodromal Alzheimer's disease duration was three years, with no age-specific estimates and no adjustment for mortality.

    “The median duration of prodromal AD was three years in a pooled memory clinic cohort study, but no age-specific estimates were provided and mortality was not taken into account [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Vos SJ,, Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage. Brain, 2015 138(Pt 5): p. 1327– 38. 25693589 PMC5013930 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The shorter age-specific duration of the preclinical stage in APOE ε4 carriers is consistent with earlier onset of Alzheimer's disease dementia in epidemiological studies and faster cognitive decline in APOE ε4 carriers with preclinical Alzheimer's disease in research studies.

    “The shorter age-specific duration of the preclinical stage in APOE ε4 carriers is consistent with the observed earlier onset of dementia due to AD in epidemiological studies and the faster cognitive decline of APOE ε4 carriers with preclinical AD in research studies [11, 42-44].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Lim YY,, Association of beta-Amyloid and Apolipoprotein E epsilon4 With Memory Decline in Preclinical Alzheimer Disease. JAMA Neurol, 2018 75(4): p. 488– 494. 29356823 PMC5933393

      Not checked in the free run.

    • cites [42] Roberts RO,, Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting. JAMA Neurol, 2018. PMC6142936 29710225 source

      Not checked in the free run.

    • cites [43] van der Lee SJ,, The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study. Lancet Neurol, 2018 17(5): p. 434– 444. 29555425

      Not checked in the free run.

    • cites [44] Mormino EC,, Amyloid and APOE epsilon4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology, 2014 82(20): p. 1760– 7. 24748674 PMC4035706

      Not checked in the free run.

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

    Premisecitation

    The combined preclinical and prodromal Alzheimer's disease stage has been estimated to last 17 years based on extrapolating positron emission tomography amyloid load over time.

    “The duration of the preclinical AD stage has been estimated in combination with the prodromal AD stage, which was 17 years, based on extrapolations of change in positron emission tomography (PET) amyloid load over time [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Villemagne VL,, Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol, 2013 12. 23477989 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Increased cerebrospinal fluid total tau was associated with a shorter pre-dementia disease duration, confirming that increased tau is associated with faster disease progression.

    “The presence of increased CSF t-tau was associated with a shorter pre-dementia disease duration, which confirms that increased tau is associated with faster disease progression.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    When all variables were combined in one model, most estimates remained unchanged.

    “When all variables were combined in one model, most estimates remained unchanged.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    In the subset of individuals with all covariates (n=1518), the effects were similar.

    “In the additional analysis of the same models in the subset of individuals with all covariates (n=1518, see Suppl. Table B.8), the effects were similar.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Premisecitation

    Studies estimating Alzheimer's disease duration should be age-specific and should account for APOE genotype, sex, and cerebrospinal fluid tau levels.

    “Attempts to quantify the duration of AD should be age-specific, because age imposes the greatest risk for both dementia and mortality, and take into account APOE genotype, sex, and cerebrospinal fluid (CSF) tau levels [4, 6, 10-12].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [4] Jansen WJ,, Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA, 2015 313(19): p. 1924– 38. 25988462 PMC4486209 source

      Not checked in the free run.

    • cites [6] Jack CR Jr.,, NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement, 2018 14(4): p. 535– 562. 29653606 PMC5958625 source

      Not checked in the free run.

    • cites [10] Neu SC,, Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol, 2017 74(10): p. 1178– 1189. 28846757 PMC5759346 source

      Not checked in the free run.

    • cites [11] Lim YY,, Association of beta-Amyloid and Apolipoprotein E epsilon4 With Memory Decline in Preclinical Alzheimer Disease. JAMA Neurol, 2018 75(4): p. 488– 494. 29356823 PMC5933393

      Not checked in the free run.

    • cites [12] Vos SJ,, Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol, 2013 12(10): p. 957– 65. 24012374 PMC3904678 source

      Not checked in the free run.

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

    Premisecitation

    Progression from mild cognitive impairment to dementia takes longer in research settings than in clinical settings.

    “Setting is also important, as progression from MCI to dementia was longer in research settings than in clinical settings [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Farias ST,, Progression of mild cognitive impairment to dementia in clinic- vs community-based cohorts. Arch Neurol, 2009 66(9): p. 1151– 7. 19752306 PMC2863139

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Male sex, clinical setting, APOE ε4 genotype, and abnormal cerebrospinal fluid tau were associated with shorter Alzheimer's disease duration, and these effects depended on disease stage.

    “Male sex, clinical setting, APOE ε4 genotype and abnormal CSF tau were associated with a shorter duration and these effects depended on disease stage.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    A strength of the study is the large sample of participants with amyloid accumulation.

    “A strength of the study is the large sample of participants with amyloid accumulation.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The sample is not representative of the general population, but may be representative of patients physicians need to inform and volunteers that participate in clinical trials.

    “Finally, our sample is not representative of the general population, but may be representative of the patients who physicians need to inform, and volunteers that participate in clinical trials.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The study used old criteria for the preclinical Alzheimer's disease definition, while recent research criteria also require tau positivity.

    “Additionally, we used the old criteria for the preclinical AD definition, while the recent research criteria also require tau positivity [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Sperling RA,, Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement, 2011 7. PMC3220946 21514248 source

      Not checked in the free run.

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

    Study design and conductreasoning

    The sample consisted of over 3000 individuals, but not all effects were estimable.

    “As such, the sample consisted of over 3000 individuals, still not all the effects were estimable.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The multi-state model approach is a strength because it enabled incorporation of multiple clinical stages, including fluctuations between stages, and mortality risk in a data-driven manner.

    “The multi-state model approach is another strength, because it enabled the incorporation of multiple clinical stages, including fluctuations between stage, and the mortality risk in a data driven manner.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Amyloid status and APOE genotype were unknown for AD-type dementia patients of the ICTUS study, but sensitivity analysis without ICTUS yielded very similar results.

    “Another limitation was that amyloid status and APOE genotype were unknown for AD-type dementia patients of the ICTUS study, but the sensitivity analysis without the ICTUS, yielded very similar results.”
    Quote in the paperNot a substantial claim
38 of 38

  • The paper relies on this without support.

    It is unclear how long individuals with amyloid pathology spend in each Alzheimer's disease stage.

    “but it is unclear how long individuals with amyloid pathology spend in each stage.”

  • The authors state this as an assumption.

    Progression risk is independent of the time already spent in a stage.

    “underlying assumption that progression risk is independent on the previous time spend in a stage”

  • The paper relies on this without support.

    A better understanding of the stage-specific duration of Alzheimer's disease is needed to inform patients, caregivers, and clinicians.

    “A better understanding of the stage-specific duration of AD is needed to inform patients, caregivers, and clinicians.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • AD has a preclinical phase that precedes clinical symptoms by at least 10-20 years.

    “Longitudinal studies of cognitive function and CSF and neuroimaging biomarker changes in ADAD and LOAD have identified a significant preclinical phase of disease preceding onset of clinical symptoms by at least 10-20 years”

    From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Vermunt et al., 2019

  • Alzheimer disease pathology accumulates 15-20 years before clinical symptoms appear.

    “Though this represents an intermediate phase of clinical disease, this is actually an advanced stage of the biological disease when considering that pathology accumulates in the AD brain 15-20 years prior to onset of clinical symptoms (Vermunt et al., 2019).”

    From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Vermunt et al., 2019

  • Aberrant Aβ deposition begins over a decade before the onset of clinical symptoms and spreads diffusely throughout the cerebral cortex.

    “Aberrant Aβ deposition begins over a decade before the onset of clinical symptoms and spreads diffusely throughout the cerebral cortex [16, 17].”

    From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [17]

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.

  • Stated overall duration range excludes reported estimates

    Minor

    The discussion gives a total-duration range of 12-25 years, but the results report estimates of 11 and 26 years for people starting in preclinical AD.

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Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. TFagan GStrobelhttps://www.alzforum.org/news/conference‐coverage/ban2401‐removes‐brain‐amyloid‐possibly‐slows‐cognitive‐declineAccessed February 20 2019.

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Authors
Vermunt, L., Sikkes, S. A. M., van den Hout, A., Handels, R., Bos, I., van der Flier, W. M., Kern, S., Ousset, P., Maruff, P., Skoog, I., Verhey, F. R. J., Freund‐Levi, Y., Tsolaki, M., Wallin, Å. K., Olde Rikkert, M., Soininen, H., Spiru, L., Zetterberg, H., Blennow, K., Scheltens, P., Muniz‐Terrera, G., Visser, P. J., Initiative, F. T. A. D. N., AIBL Research Group, & groups, I. S.
Affiliations
  • Amsterdam Neuroscience (NL)
  • Harvard University (US)
  • Department of Statistical Science University College London London UK
  • Maastricht University (NL)
  • Department of Neurology Alzheimer Center Amsterdam Amsterdam Neuroscience Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands
  • University of Gothenburg (SE)
  • Inserm (FR)
  • The University of Melbourne (AU)
  • Karolinska University Hospital (SE)
  • Aristotle University of Thessaloniki (GR)
  • Lund University (SE)
  • Department of Geriatric Medicine Radboudumc Alzheimer Centre Radboud University Medical Center Nijmegen The Netherlands
  • University of Eastern Finland (FI)
  • Carol Davila University of Medicine and Pharmacy (RO)
  • Sahlgrenska University Hospital (SE)
  • Centre for Dementia Prevention University of Edinburgh Edinburgh UK
Corresponding author
Vermunt, Lisa
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2019-06
Volume
15
Issue
7
Pages
888-898
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1016/j.jalz.2019.04.001
PMC
PMC6646097
OpenAlex
W2947634966
Semantic Scholar
a7cc914d460367dcba0fdb7e9290bc681d8a3b4a
Cited by
570
References
48
Citations by year
2026: 70 · 2025: 100 · 2024: 115 · 2023: 81 · 2022: 94 · 2021: 68 · 2020: 37 · 2019: 2
FWCI
39.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (acceptedVersion, other-oa)
  • Archive ouverte UNIGE (University of Geneva) (acceptedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • VU Research Portal (submittedVersion, other-oa)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Interreg (SFC, 2016-202)
  • National Institutes of Health (P01AG043362, U01 AG024904)
  • Seventh Framework Programme (FP7/2007-2013)
  • U.S. Department of Defense (W81XWH-12-2-0012)
  • Vetenskapsrådet (2015-02830, 2013-8717)
  • Forskningsrådet om Hälsa, Arbetsliv och Välfärd (2013-2496, 2013-2300, 2010-0870, 2012-1138)
  • Sahlgrenska Universitetssjukhuset (ALF 716681)
  • Alzheimer's Association (ZEN-01-3151, IIRG-00-2159)
  • European Commission (QLK6-CT-2002-02645)
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 › Amyotrophic Lateral Sclerosis Research
Keywords
Alzheimer's disease, disease duration
MeSH terms
Aged, Alleles, Alzheimer Disease, Amyloid, Female, Genotype, Humans, Longitudinal Studies, Male, Sex Factors, Time Factors, Biomarkers, tau Proteins, Disease Progression, Positron-Emission Tomography, Apolipoprotein E4, Cognitive Dysfunction, Prodromal Symptoms

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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