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Cited by 3,814Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Clinical and biomarker changes in dominantly inherited Alzheimer's disease

Open access
Bateman, Randall J., Xiong, Chengjie, Benzinger, Tammie L.S., Fagan, Anne M., Goate, Alison, Fox, Nick C., Marcus, Daniel S., Cairns, Nigel J. +20 more·2012·New England Journal of Medicine
DOI 10.1056/nejmoa1202753PMC PMC3474597
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Abstract

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Integrity signals

Registry

Crossref · 10.1056/nejmoa1202753

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 10 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In mutation carriers, global cognitive impairment on the MMSE and CDR appeared 5 years before expected symptom onset.

    “Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset”
    • Also stated in: § CLINICAL AND NEUROPSYCHOMETRIC FINDINGS · plain
      “Significant differences in CDR-SOB scores were detected between mutation carriers and noncarriers 5 years before expected symptom onset (Fig. 1A and Table 2).”
    • Also stated in: § CLINICAL AND NEUROPSYCHOMETRIC FINDINGS · plain
      “Significant differences in MMSE scores between mutation carriers and noncarriers were detected at assessments performed 5 years before expected symptom onset”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The estimated years from expected symptom onset normalizes disease stage based on parental age at onset.
    • Rests on an assumption: Mutations in APP, PSEN1, or PSEN2 alter Aβ processing and cause Alzheimer's disease with complete penetrance.
  • Findingown data

    In mutation carriers, bilateral hippocampal atrophy was found 15 years before expected symptom onset.

    “Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset.”
    • Also stated in: § BRAIN ATROPHY · plain
      “Increased atrophy of bilateral hippocampi was detected in mutation carriers 15 years before expected symptom onset (Table 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The estimated years from expected symptom onset normalizes disease stage based on parental age at onset.
    • Rests on an assumption: Mutations in APP, PSEN1, or PSEN2 alter Aβ processing and cause Alzheimer's disease with complete penetrance.
  • Findingown data

    In mutation carriers, CSF Aβ42 levels appeared to decline starting about 25 years before expected symptom onset.

    “Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset.”
    • Also stated in: § COMBINED MODEL · hedged
      “Beginning 25 years before expected symptom onset, Aβ42 concentrations in the CSF in mutation carriers appeared to decline, as compared with those in noncarriers.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The estimated years from expected symptom onset normalizes disease stage based on parental age at onset.
    • Rests on an assumption: Mutations in APP, PSEN1, or PSEN2 alter Aβ processing and cause Alzheimer's disease with complete penetrance.
  • Findingown data

    In autosomal dominant AD, the study found a decades-long sequence of pathophysiological changes involving CSF biomarkers, amyloid deposition, brain metabolism, and worsening cognition.

    “We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The estimated years from expected symptom onset normalizes disease stage based on parental age at onset.
    • Rests on an assumption: Mutations in APP, PSEN1, or PSEN2 alter Aβ processing and cause Alzheimer's disease with complete penetrance.
  • Findingown data

    In mutation carriers, delayed recall on the Logical Memory test was impaired 10 years before expected symptom onset.

    “Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset.”
    • Also stated in: § CLINICAL AND NEUROPSYCHOMETRIC FINDINGS · plain
      “We found significant cognitive impairment in mutation carriers, as compared with noncarriers, in the delayed-recall portion of the Logical Memory test21 10 years before expected symptom onset (Table 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The estimated years from expected symptom onset normalizes disease stage based on parental age at onset.
    • Rests on an assumption: Mutations in APP, PSEN1, or PSEN2 alter Aβ processing and cause Alzheimer's disease with complete penetrance.
  • May combine two claims. 11
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingcitation

    The halving of CSF Aβ42 and the rise in CSF tau in mutation carriers were similar in magnitude to those usually seen in late-onset sporadic AD.

    “The decrease by half in Aβ42 in the CSF and the increase in tau in the CSF were similar in magnitude to those typically observed in late-onset sporadic Alzheimer’s disease.26”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Fagan AM Roe CM Xiong C Mintun MA Morris JC Holtzman DM Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in non-demented older adults Arch Neurol 2007 64 343 349 17210801 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Noncarriers had stable CDR-SOB scores of 0 across the relative age range, while carriers had increasing scores at higher estimated years from expected symptom onset.

    “Noncarriers had stable CDR-SOB scores of 0 throughout the relative age range, whereas carriers had increasing CDR-SOB scores at higher values of estimated years from expected symptom onset.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The estimated years from expected symptom onset normalizes disease stage based on parental age at onset.
    • Rests on an assumption: Mutations in APP, PSEN1, or PSEN2 alter Aβ processing and cause Alzheimer's disease with complete penetrance.

  • May combine two claims.

    Findingown data

    Noncarriers had no detectable amyloid deposition; all had PIB-PET SUVR below 0.88.

    “There was no detectable amyloid deposition in noncarriers. All noncarriers had PIB-PET SUVR values of less than 0.88.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    After onset, the disease process probably does not depend on chronological age but on when events like Aβ misfolding begin and on other modifiers.

    “Our findings suggest that once initiated, Alzheimer’s disease processes are likely independent of absolute age but rather depend on the start of processes such as Aβ misfolding and other modulating factors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The estimated years from expected symptom onset normalizes disease stage based on parental age at onset.
    • Rests on an assumption: Mutations in APP, PSEN1, or PSEN2 alter Aβ processing and cause Alzheimer's disease with complete penetrance.

  • May combine two claims.

    Interpretationown data

    The findings back a cascade model and raise the possibility that autosomal dominant and sporadic AD share underlying disease mechanisms.

    “Our results support the hypothesis of a pathophysiological cascade and suggest the possibility of a common pathophysiology between autosomal dominant Alzheimer’s disease and the much more common “sporadic” form.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    If autosomal dominant AD resembles late-onset AD, then Alzheimer's dementia will eventually develop in people with positive amyloid scans.

    “If autosomal dominant Alzheimer’s disease is similar to late-onset Alzheimer’s disease, this finding suggests that Alzheimer’s dementia will eventually develop in persons with positive scans for amyloid deposition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    In autosomal dominant AD, the sequence runs from raised Aβ42 to amyloid plaques, tau pathology, atrophy, lower glucose use, cognitive decline, and finally clinical dementia.

    “With the use of estimates of years from expected symptom onset, the order and magnitude of changes indicate that genetic mutations cause increased Aβ42, which is followed by brain amyloidosis, tauopathy, brain atrophy, and decreased glucose metabolism. After these biologic changes, cognitive impairment can be detected, which culminates in clinical impairment and eventually dementia.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The estimated years from expected symptom onset normalizes disease stage based on parental age at onset.
    • Rests on an assumption: Mutations in APP, PSEN1, or PSEN2 alter Aβ processing and cause Alzheimer's disease with complete penetrance.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The statistical model included mutation status and APOE status as covariates.

    “a linear mixed model was used to model each marker as a function of estimated years from expected symptom onset, mutation status (carrier or noncarrier), and apolipoprotein E (APOE) status (positive or negative).”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    MRI quality control and matching between site scanners followed the ADNI protocol.

    “initial and ongoing quality control and matching between site scanners were performed according to the Alzheimer’s Disease Neuroimaging Initiative (ADNI) protocol.19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Mueller SG Weiner MW Thal LJ The Alzheimer’s disease neuroimaging initiative Neuroimaging Clin N Am 2005 15 869 877 16443497 PMC2376747 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 conductnone given

    CSF and blood biomarker values had to meet quality-control standards including a coefficient of variation of 25% or less, kit controls within expected range, and measurement consistency between plates.

    “All values had to meet quality-control standards, including a coefficient of variation of 25% or less, kit “controls” within the expected range as defined by the manufacturer, and measurement consistency between plates of a common sample that was included in each run.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In autosomal dominant AD, onset age tends to be similar across generations and is influenced mainly by the mutation and family genetic background.

    “The age at clinical onset of autosomal dominant Alzheimer’s disease is similar between generations14 and is affected mostly by the mutation type and background family genetics.15”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Lopera F Ardilla A Martínez A Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation JAMA 1997 277 793 799 9052708 source

      Not checked in the free run.

    • cites [15] Wijsman EM Daw EW Yu X APOE and other loci affect age-at-onset in Alzheimer’s disease families with PS2 mutation Am J Med Genet B Neuropsychiatr Genet 2005 132B 14 20 15389756 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Statistical analyses adjusted for correlation among family members.

    “after adjustment for the correlation among family members.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    There were no significant differences in APOE ε4 allele presence or sex between asymptomatic mutation carriers and noncarriers.

    “There were no significant differences in the presence of an APOE ε4 allele or sex between asymptomatic mutation carriers and noncarriers.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Clinicians who performed clinical assessments were unaware of participants' mutation status.

    “Clinicians who performed the assessments were not aware of the mutation status of participants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Vascular and other confounders were uncommon (under 15%) and balanced between carriers and noncarriers.

    “Owing to the younger age of the cohort, the prevalence of confounders such as vascular risk factors was low (<15%) in this cohort and not significantly different between carriers and noncarriers.”
    Quote in the paperSubstantial claim
15 of 15

  • The paper relies on this without support.

    The estimated years from expected symptom onset normalizes disease stage based on parental age at onset.

    “The estimated year from expected symptom onset normalizes the stage of disease on the basis of the parental age of onset.”

  • The paper relies on this without support.

    Mutations in APP, PSEN1, or PSEN2 alter Aβ processing and cause Alzheimer's disease with complete penetrance.

    “Mutations in one of three genes (APP, PSEN1, and PSEN2) have been identified that cause alterations in Aβ processing and lead to Alzheimer’s disease with complete penetrance.”
2 of 2

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?

  • Changes in brain chemistry begin to occur 20 years or more prior to the onset of noticeable cognitive symptoms in AD.

    “Efforts continue to be placed on the early detection of AD as changes in brain chemistry begin to occur 20 years or more prior to the onset of noticeable cognitive symptoms [137,138,139,140].”

    From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [138]

    The Results (Combined Model) report that CSF Aβ42 began declining about 25 years before expected symptom onset in mutation carriers, supporting the timing of early biochemical change. The study concerns dominantly inherited Alzheimer’s disease; the Discussion suggests, but does not establish, that the same timeline applies to the more common sporadic form. The claim’s unqualified reference to AD therefore extends beyond the studied population. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Progression of biomarker measures in Alzheimer's disease is a continuous process that begins before symptoms.

    “and that progression of biomarker measures is also a continuous process that begins before symptoms [9–14]”

    From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [9]

    The Results (Combined Model and Biochemical Measures; page unavailable) show biomarker changes beginning years before expected symptom onset, including CSF Aβ42 declining as a function of estimated time to onset. But these are cross-sectional estimates in people with dominantly inherited Alzheimer’s disease; they do not establish continuous progression in individuals or across Alzheimer’s disease generally. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • A widely held view is that amyloid biomarkers represent the earliest evidence of AD neuropathologic change currently detectable in living persons.

    “Consequently, a widely held view is that amyloid biomarkers represent the earliest evidence of AD neuropathologic change currently detectable in living persons [9,11,72,103,104].”

    From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [9]

    The Results (Combined Model; page unavailable) place the CSF amyloid-β42 change about 25 years before expected symptom onset in mutation carriers, earlier than the other changes measured. The Discussion suggests a possible shared pathophysiology with sporadic Alzheimer’s disease, but the paper does not establish that amyloid biomarkers are the earliest detectable evidence across Alzheimer’s disease generally. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Abundant human and animal data implicate A and T in the primary pathogenesis of AD.

    “Abundant human and animal data implicate A and T in the primary pathogenesis of AD [9,100], including the observation that the age-related exponential increase in prevalence of A (by biomarkers and neuropathology) anticipates the age-related exponential increase in prevalence of clinically defined possible/probable “AD” by around 15 years [53,212].”

    From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [9]

    The Results (Combined Model; page unavailable) show that amyloid deposition and increased CSF tau preceded expected symptoms in people with dominantly inherited Alzheimer’s disease. The Discussion links early amyloid changes to a possible pathogenic role, but the paper does not present animal data or establish that both amyloid and tau have primary causal roles in AD. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Neuroimaging and biomarker studies show consistencies in the sequential onset of amyloid deposition, tau, FDG-PET hypometabolism, grey matter atrophy, and clinical presentation between late-onset and autosomal-dominant Alzheimer's disease.

    “Nevertheless, neuroimaging and biomarker studies show consistencies in the sequential onset of amyloid deposition, tau, FDG-PET hypometabolism, grey matter atrophy, and clinical presentation between late-onset and autosomal-dominant Alzheimer’s disease (Bateman et al., 2012; Benzinger et al., 2013; Young et al., 2014; Gordon et al., 2018; Oxtoby et al., 2018), suggesting substantial commonalities”

    From White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease (2018) · cites this paper as Bateman et al., 2012

    The Results (Combined Model) describe the sequence of amyloid deposition, CSF tau increase, brain atrophy, cerebral hypometabolism, and clinical impairment in autosomal-dominant Alzheimer’s disease. The Discussion says these results suggest only the possibility of common pathophysiology with sporadic late-onset disease; this paper does not establish that the full sequence is consistent between the two forms. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Bateman, R. J., Xiong, C., Benzinger, T. L. S., Fagan, A. M., Goate, A., Fox, N. C., Marcus, D. S., Cairns, N. J., Xie, X., Blazey, T. M., Holtzman, D. M., Santacruz, A., Buckles, V., Oliver, A., Moulder, K., Aisen, P. S., Ghetti, B., Klunk, W. E., McDade, E., Martins, R. N., Masters, C. L., Mayeux, R., Ringman, J. M., Rossor, M. N., Schofield, P. R., Sperling, R. A., Salloway, S., & Morris, J. C.
Affiliations
  • Washington University in St. Louis (US)
  • University of Pittsburgh (US)
  • Edith Cowan University (AU)
  • Mental Health Research Institute (AU)
  • Columbia University Irving Medical Center (US)
  • University of California, Los Angeles (US)
  • UNSW Sydney (AU)
  • Brigham and Women's Hospital (US)
  • Brown University (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2012-08-30
Volume
367
Issue
9
Pages
795-804
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1202753
PMC
PMC3474597
OpenAlex
W2171250577
Semantic Scholar
f9e95e5b9f5f5f7439a49c2f9832d72c680590a1
Cited by
3,814
References
34
Citations by year
2026: 227 · 2025: 276 · 2024: 297 · 2023: 300 · 2022: 290 · 2021: 340 · 2020: 345 · 2019: 267 · 2018: 266 · 2017: 225 · 2016: 232 · 2015: 240 · 2014: 238 · 2013: 223 · 2012: 40
FWCI
168.71
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion)
  • Australasian Journal of Paramedicine (submittedVersion)
  • Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • National Institute for Health and Care Research (NF-SI-0508-10123)
  • National Institutes of Health (UL1TR000124, UL1TR000448)
  • National Institute on Aging (UF1AG032438, U19AG032438, U19AG010483)
  • National Institute of Neurological Disorders and Stroke (P30NS048056)
  • National Center for Advancing Translational Sciences
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
autosomal dominant Alzheimer's disease, preclinical Alzheimer's disease, amyloid-beta, tau protein, cerebrospinal fluid biomarkers, amyloid deposition, Pittsburgh compound B PET, brain atrophy, brain hypometabolism, episodic memory impairment, cognitive impairment, age of symptom onset, disease progression, DIAN
MeSH terms
Alzheimer Disease, Brain, Cerebrospinal Fluid, Cross-Sectional Studies, Female, Genes, Dominant, Glucose, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Neuropsychological Tests, Biomarkers, Amyloid beta-Peptides, Age of Onset

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