Skip to main content
    • Aa
    • Aa

Most rapid cognitive decline in APOE ε4 negative Alzheimer's disease with early onset

  • A. E. van der Vlies (a1), E. L. G. E. Koedam (a1), Y. A. L. Pijnenburg (a1), J. W. R. Twisk (a2), P. Scheltens (a1) and W. M. van der Flier (a1)...

We aimed to compare the rate of cognitive decline in patients with early and late onset Alzheimer's disease (AD) and to investigate the potentially modifying influence of the apolipoprotein E (APOE) genotype.


We included 99 patients with early onset AD (age ⩽65 years) and 192 patients with late onset AD (age >65 years) who had at least two scores on the Mini-Mental State Examination (MMSE) (range 2–14) obtained at least 1 year apart. Linear mixed models were performed to investigate the rate of cognitive decline dependent on age at onset (AAO) and APOE genotype.


The mean (s.d.) age for patients with early onset AD was 57.7 (4.5) years, and 74.5 (5.1) years for patients with late onset AD. AAO was not associated with baseline MMSE [β (s.e.)=0.8 (0.5), p=0.14]. However, patients with early onset showed a faster decline on the MMSE [β (s.e.)=2.4 (0.1) points/year] than those with late onset [β (s.e.)=1.7 (0.1) points/year, p=0.00]. After stratification according to APOE genotype, APOE ε4 non-carriers with early onset showed faster cognitive decline than non-carriers with late onset [2.4 (0.3) v. 1.3 (0.3) points/year, p=0.01]. In APOE ε4 carriers, no difference in rate of cognitive decline was found between patients with early and late onset [β (s.e.)=0.2 (0.2), p=0.47].


Patients with early onset AD show more rapid cognitive decline than patients with late onset, suggesting that early onset AD follows a more aggressive course. Furthermore, this effect seems to be most prominent in patients with early onset who do not carry the genetic APOE ε4 risk factor for AD.

Corresponding author
*Address for correspondence: A. E. van der Vlies, Department of Neurology and Alzheimer Centre, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. (Email:
Hide All
K Blennow , MJ de Leon , H Zetterberg (2006). Alzheimer's disease. Lancet 368, 387403.

Y Davidson , L Gibbons , A Pritchard , J Hardicre , J Wren , C Stopford , C Julien , J Thompson , A Payton , SM Pickering-Brown , N Pendleton , MA Horan , A Burns , N Purandare , CL Lendon , D Neary , JS Snowden , DM Mann (2007). Apolipoprotein E epsilon4 allele frequency and age at onset of Alzheimer's disease. Dementia and Geriatric Cognitive Disorders 23, 6066.

GB Frisoni , S Govoni , C Geroldi , A Bianchetti , L Calabresi , G Franceschini , M Trabucchi (1995). Gene dose of the epsilon-4 allele of apolipoprotein-E and disease progression in sporadic late onset Alzheimer's disease. Annals of Neurology 37, 596604.

D Jacobs , M Sano , K Marder , K Bell , F Bylsma , G Lafleche , M Albert , J Brandt , Y Stern (1994). Age at onset of Alzheimer's disease: relation to pattern of cognitive dysfunction and rate of decline. Neurology 44, 12151220.

T Kleiman , K Zdanys , B Black , T Rightmer , M Grey , K Garman , M MacAvoy , J Gelernter , C van Dyck (2006). Apolipoprotein E e4 allele is unrelated to cognitive or functional decline in Alzheimer's disease: retrospective and prospective analysis. Dementia and Geriatric Cognitive Disorders 22, 7382.

J Kuusisto , K Koivisto , K Kervinen , L Mykkanen , EL Helkala , M Vanhanen , T Hanninen , K Pyorala , YA Kesaniemi , P Riekkinen , M Laakso (1994). Association of apolipoprotein-E phenotypes with late onset Alzheimer's disease: population-based study. British Medical Journal 309, 636638.

CAR Martins , A Oulhaj , CA de Jager , JH Williams (2005). APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model. Neurology 65, 18881893.

G McKhann , D Drachman , M Folstein , R Katzman , D Price , EM Stadlan (1984). 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. Neurology 34, 939944.

A Ruitenberg , S Kalmijn , MAJ de Ridder , WK Redekop , F van Harskamp , A Hofman , LJ Launer , MMB Breteler (2001). Prognosis of Alzheimer's disease: the Rotterdam Study. Neuroepidemiology 20, 188195.

B Seltzer , I Sherwin (1983). A comparison of clinical features in early- and late-onset primary degenerative dementia: one entity or two? Archives of Neurology 40, 143146.

AJ Slooter , JJ Houwing-Duistermaat , F van Harskamp , M Cruts , C Van Broeckhoven , MM Breteler , A Hofman , T Stijnen , CM van Duijn (1999). Apolipoprotein E genotype and progression of Alzheimer's disease: the Rotterdam Study. Journal of Neurology 246, 304308.

AJC Slooter , M Cruts , S Kalmijn , A Hofman , MMB Breteler , C Van Broeckhoven , CM van Duijn (1998). Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. Archives of Neurology 55, 964968.

JD Sluimer , H Vrenken , MA Blankenstein , NC Fox , P Scheltens , F Barkhof , WM van der Flier (2008). Whole-brain atrophy rate in Alzheimer's disease: identifying FAST progressors. Neurology 70, 18361841.

WJ Strittmatter , AM Saunders , D Schmechel , M Pericak-Vance , J Enghild , GS Salvesen , AD Roses (1993). Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late onset familial Alzheimer disease. Proceedings of the National Academy of Sciences USA 90, 19771981.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 1
Total number of PDF views: 50 *
Loading metrics...

Abstract views

Total abstract views: 341 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 18th October 2017. This data will be updated every 24 hours.