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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:
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Psychological Medicine
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