CoChat
Sign Up
Cited by 528Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCognitive Abilities and Testing

Longitudinal Modeling of Age-Related Memory Decline and the APOE ε4 Effect

Open access
Caselli, Richard J., Dueck, Amylou C., Osborne, David, Sabbagh, Marwan N., Connor, Donald J., Ahern, Geoffrey L., Baxter, Leslie C., Rapcsak, Steven Z. +7 more·2009·New England Journal of Medicine
DOI 10.1056/nejmoa0809437PMC PMC2928998
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: The APOE epsilon4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE epsilon4 allele, those who are heterozygous for the allele, and noncarriers is unknown. METHODS: Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE epsilon4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE epsilon4 allele, using a mixed model for longitudinal change with age. RESULTS: We analyzed 815 subjects: 317 APOE epsilon4 carriers (79 who were homozygous for the APOE epsilon4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele-dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status. CONCLUSIONS: Age-related memory decline in APOE epsilon4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1056/nejmoa0809437

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • The well-established association between APOE genotype and cognition - whereby APOEε4 accelerates age-related cognitive decline and APOEε2 delays it - is largely mediated by genotype-specific effects on Alzheimer disease neuropathological changes and, to a lesser extent, on comorbid pathologies.

    “The well-established association between APOE genotype and cognition — whereby APOEε4 accelerates age-related cognitive decline76 and APOEε2 delays it77 — is largely mediated by genotype-specific effects on AD neuropathological changes and, to a lesser extent, on comorbid pathologies46–48,78,79.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [76]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Cognitively normal individuals carrying the ε4 allele have a faster decline in age-related memory than non-ε4-carriers.

    “Cognitively normal individuals that carry the ε4 allele have a faster decline in age-related memory than non-ε4-carriers [101].”

    From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [101]

  • ApoE4 carriers exhibit accelerated rates of cognitive decline related to aging and Alzheimer's disease.

    “Clinically, ApoE4 carriers exhibit accelerated rates of cognitive decline related to aging and AD (Craft et al., 1998;Martins et al., 2005;Caselli et al., 2009Caselli et al., , 2011)).”

    From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Caselli et al., 2009

Self-check

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

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 47

  1. [1]West RL An application of prefrontal cortex function theory to cognitive aging Psychol Bull 1996 120 272 292 8831298
  2. [2]Verhaeghen P Cerella J Aging, executive control, and attention: a review of meta-analyses Neurosci Behav Rev 2002 26 849 857 12470697
  3. [3]Treitz FH Heyder K Daum I Differential course of executive control changes during normal aging Aging, Neuropsychology, and Cognition 2007 14 370 393 17612814
  4. [5]Morris JC Storandt M Miller JP McKeel DW Price JL Rubin EH Bell L Mild cognitive impairment represents early stage Alzheimer disease Arch Neurol 2001 58 397 405 11255443
  5. [6]Petersen RC Stevens JC Ganguli M Tangalos EG Cummings JL DeKosky ST Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 2001 56 1133 1142 11342677
  6. [7]Boyle PA Wilson RS Aggarwal NT Tang Y Bennett DA Mild cognitive impairment: risk of Alzheimer’s disease and rate of cognitive decline Neurology 2006 67 441 445 16894105
  7. [8]Albert M Blacker D Moss MB Tanzi R McArdle JJ Longitudinal change in cognitive performance among individuals with mild cognitive impairment Neuropsychology 2007 21 158 169 17402816
  8. [9]Howieson DB Carlson NE Moore MM Wasserman D Abendroth CD Payne-Murphy J Kaye JA Trajectory of mild cognitive impairment onset J Int Neuropsychol Soc 2008 14 192 198 18282317
  9. [10]Salthouse TA Memory aging 18 to 80 Alzeimer Dis Assoc Disord 2003 17 162 167 14512830
  10. [11]Burke D Mackay DG Memory, language, and ageing Phil Trans R Soc Lond B 1997 352 1845 1856 9460069 PMC1692140
  11. [12]Corder EH Saunders AM Strittmatter WJ Gene dose of apolipoprotein E type 4 allele and the risk of AD in late onset families Science 1993 261 5123 921 923 8346443
  12. [13]Saunders AM Strittmatter WJ Schmechel D St. George-Hyslop PH Pericak-Vance MA Joo SH Rosi BL Gusella JF Crapper-McLachlan DR Alberts MJ Hulette C Crain B Goldgaber D Roses AD Association of apolipoprotein E allele ε4 with late onset familial and sporadic Alzheimer’s disease Neurol 1993 43 1467 1472 8350998
  13. [14]Baxter LC Caselli RJ Johnson SC Reiman E Osborne D Apolipoprotein E epsilon 4 affects new learning in cognitively normal individuals at risk for Alzheimer’s disease Neurobiol Aging Nov 2003 24 7 947 52 12928055
  14. [15]Caselli RJ Reiman EM Osborne D Hentz JG Baxter LC Hernandez JL Alexander GG Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele Neurology 8 Jun 2004 62 11 1990 5 15184602
  15. [16]Caselli RJ Reiman EM Locke DE Hutton ML Hentz JG Hoffman-Snyder C Woodruff BK Alexander GE Osborne D Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment Arch Neurol Sep 2007 64 9 1306 11 17846270
  16. [17]Caselli RJ Chen K Lee W Alexander GE Reiman EM Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment Archives of Neurology 2008 65 1231 1236 18779428
  17. [18]Small SA Age-related memory decline Arch Neurol 2001 58 360 364 11255438
  18. [19]Petersen RC Smith G Kokmen E Ivnik RJ Tangalos EG Memory function in normal aging Neurol 1992 42 396 401 1736173
  19. [20]Small SA Stern Y Tang M Mayeux R Selective decline in memory function among healthy elderly Neurol 1999 52 1392 1396 10227623
  20. [21]Ferris SH Aisen PS Cummings J ADCS Prevention Instrument Project: overview and initial results Alzheimer Dis Assoc Disord 2006 20 suppl 3 S109 S123 17135805
  21. [22]Hixson JE Vernier DT Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I J Lipid Res 1990 31 545 548 2341813
  22. [23]Crum RM Anthony JC Bassett SS Folstein MF Population-based norms for the mini-mental satae examination by age and education level JAMA 1993 269 2386 2391 8479064
  23. [24]Lezak MD Howieson DB Loring DW Neuropsychological Assessment 2004 Oxford University Press New York 4th edition
  24. [25]American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 1987 American Psychiatric Association Washington DC 3rd Edition, Revised
  25. [26]McKhann G Drachman D Folstein M Clinical diagnosis of Alzheimer’s disease: report of the NINCDS/ADRDA work group under the auspices of Department of Health and Human Services task force on Alzheimer’s disease Neurol 1984 34 939 944 6610841
  26. [27]American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 1994 American Psychiatric Association Washington D.C. Fourth Edition
  27. [28]Steinberg BA Bieliauskas LA Smith GE Ivnik RJ Malec JF Mayo’s Older Americans Normative Studies: age- and IQ- adjusted norms for the Auditory Verbal Learning Test and the Visual Spatial Learning Test The Clinical Neuropsychologist 2005 19 464 523 16120537
  28. [30]Fitzmaurice GM Laird NM Ware JH Applied Longitudinal Analysis 2004 John Wiley & Sons, Inc. Hoboken (Section 15.4)
  29. [31]Ware JH Dockery DW Louis TA XU X Ferris BG Speizer FE Longitudinal and cross-sectional estimates of pulmonary function decline in never-smoking adults Am J Epidemiology 1990 132 685 700 2403109
  30. [32]Reiman EM Chen K Liu X Bandy D Yu M Lee W Fibrillar amyloid-β burden in cognitively normal people homozygous for the apolipoprotein E ε4 allele (manuscript under review)
  31. [35]Crystal HA Dickson D Sliwinski M Masur D Blau A Lipton RB Associations of status and change measures of neuropsychological function with pathologic changes in elderly, originally nondemented subjects Arch Neurol 1996 53 82 87 8599564
  32. [36]Alafuzoff I Helisalmi S Mannermaa A Soininen H Severity of cardiovascular disease, apolipoprotein E genotype, and brain pathology in aging and dementia Ann NY Acad Sci 2000 903 244 251 10818513
  33. [37]Snowden DA Healthy aging and dementia: findings from the nun study Ann Intern Med 2003 139 450 454 12965975
  34. [38]Knopman D Parisi JE Salviati A Floriach-Robert M Boeve BF Neuropathology of cognitively normal elderly J Neuropathol Exp Neurol 2003 62 1087 1095 14656067
  35. [40]Bennett DA Schneider JA Wilson RS Bienias JL Berry-Kravis E Arnold SE Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people J Neurol Neurosurg Psychiatry 2005 76 1194 1199 16107349 PMC1739810
  36. [41]Lambert JC Mann D Richard F IsAlzheimer’s disease J Neurol Neurosurg Psychiatry 2005 76 928 933 15965197 PMC1739723
  37. [42]Horsburgh K McCarron MO White F The role of apolipoprotein E in Alzheimer’s disease, acute brain injury, and cerebrovascular disease: Evidence of common mechanisms and utility of animal models Neurobiol Aging 2000 21 245 255 10867209
  38. [43]Olichney JM Sabbagh MN Hofstetter CR The impact of apolipoprotein E4 on cause of death in Alzheimer’s disease Neurology 1997 49 76 81 9222173
  39. [44]Schneider JA Bienias JL Wilson RS Berry-Kravis E Evans DA Bennett DA The apolipoprotein E epsilon4 allele increases the odds of chronic cerebral infarction detected at autopsy Stroke 2005 36 954 959 15774818
  40. [45]Hayden KM Zandi PP Lyketsos CG Apolipoprotein E genotype and mortality: findings from the Cache County Study J Am Geriatr Soc 2005 53 935 942 15935014
  41. [46]Lane KA Gao S Hui SL Murrell JR Hall KS Hendrie HC Apolipoprotein E and mortality in African-Americans and Yoruba J Alzheimers Dis 2003 5 383 390 14646029 PMC3212028
  42. [48]Snowden DA Healthy aging and dementia: findings from the nun study Ann Intern Med 2003 139 450 454 12965975
  43. [49]Whalley LJ Starr JM Athawes R Hunter D Pattie A Deary IJ Childhood mental ability and dementia Neurology 2000 55 1455 1459 11094097
  44. [50]McGurn B Deary IJ Starr JM Childhood cognitive ability and risk of late-onset Alzheimer and vascular dementia Neurology 2008 71 1051 1056 18579804
  45. [51]Caselli RJ Hentz JG Osborne D Apolipoprotein E and intellectual achievement J Am Ger Soc 2002 50 49 54 12028246
  46. [52]Caselli RJ Reiman EM Hentz JG Osborne D Alexander GE Boeve BF A distinctive interaction between memory and chronic daytime somnolence in asymptomatic APOE e4 homozygotes Sleep 2002 25 447 53 12071547
  47. [53]Caselli RJ Reiman EM Hentz JG Osborne D Alexander GE A distinctive interaction between chronic anxiety and problem solving in asymptomatic APOE e4 homozygotes J Neuropsychiatry Clin Neurosci 2004 16 320 9 15377739

Cited by

Sorted by citations

Authors
Caselli, R. J., Dueck, A. C., Osborne, D., Sabbagh, M. N., Connor, D. J., Ahern, G. L., Baxter, L. C., Rapcsak, S. Z., Shi, J., Woodruff, B. K., Locke, D. E. C., Snyder, C. H., Alexander, G. E., Rademakers, R., & Reiman, E. M.
Affiliations
  • Mayo Clinic in Arizona (US)
  • University of Arizona (US)
  • Barrow Neurological Institute (US)
  • Mayo Clinic in Florida (US)
  • Translational Genomics Research Institute (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2009-07-16
Volume
361
Issue
3
Pages
255-263
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa0809437
PMC
PMC2928998
OpenAlex
W2112957305
Cited by
528
References
6
Citations by year
2026: 24 · 2025: 22 · 2024: 27 · 2023: 24 · 2022: 19 · 2021: 48 · 2020: 32 · 2019: 31 · 2018: 33 · 2017: 31 · 2016: 31 · 2015: 28 · 2014: 35 · 2013: 43 · 2012: 25
FWCI
19.64
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R01AG031581, P30AG019610)
  • National Institute of Mental Health (R01MH057899)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
Keywords
APOE ε4, age-related memory decline, Alzheimer's disease risk, cognitive aging, cognitively normal older adults, longitudinal cognitive change
MeSH terms
Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Female, Heterozygote, Homozygote, Humans, Longitudinal Studies, Male, Memory, Memory Disorders, Middle Aged, Neuropsychological Tests, Apolipoprotein E4, Young Adult

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.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review