Skip to main content Accessibility help

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
Blennow, K, de Leon, MJ, Zetterberg, H (2006). Alzheimer's disease. Lancet 368, 387403.
Davidson, Y, Gibbons, L, Pritchard, A, Hardicre, J, Wren, J, Stopford, C, Julien, C, Thompson, J, Payton, A, Pickering-Brown, SM, Pendleton, N, Horan, MA, Burns, A, Purandare, N, Lendon, CL, Neary, D, Snowden, JS, Mann, DM (2007). Apolipoprotein E epsilon4 allele frequency and age at onset of Alzheimer's disease. Dementia and Geriatric Cognitive Disorders 23, 6066.
Folstein, MF, Folstein, SE, McHugh, PR (1975). ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189198.
Fratiglioni, L, Launer, LJ, Andersen, K, Breteler, MM, Copeland, JR, Dartigues, JF, Lobo, A, Martinez-Lage, J, Soininen, H, Hofman, A (2000). Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54, S10S15.
Frisoni, GB, Govoni, S, Geroldi, C, Bianchetti, A, Calabresi, L, Franceschini, G, Trabucchi, M (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.
Greicius, MD, Geschwind, MD, Miller, BL (2002). Presenile dementia syndromes: an update on taxonomy and diagnosis. Journal of Neurology, Neurosurgery and Psychiatry 72, 691700.
Huff, FJ, Growdon, JH, Corkin, S, Rosen, TJ (1987). Age at onset and rate of progression of Alzheimer's disease. Journal of the American Geriatrics Society 35, 2730.
Jacobs, D, Sano, M, Marder, K, Bell, K, Bylsma, F, Lafleche, G, Albert, M, Brandt, J, Stern, Y (1994). Age at onset of Alzheimer's disease: relation to pattern of cognitive dysfunction and rate of decline. Neurology 44, 12151220.
Kleiman, T, Zdanys, K, Black, B, Rightmer, T, Grey, M, Garman, K, MacAvoy, M, Gelernter, J, van Dyck, C (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.
Kuusisto, J, Koivisto, K, Kervinen, K, Mykkanen, L, Helkala, EL, Vanhanen, M, Hanninen, T, Pyorala, K, Kesaniemi, YA, Riekkinen, P, Laakso, M (1994). Association of apolipoprotein-E phenotypes with late onset Alzheimer's disease: population-based study. British Medical Journal 309, 636638.
Lobo, A, Launer, LJ, Fratiglioni, L, Andersen, K, Di Carlo, A, Breteler, MM, Copeland, JR, Dartigues, JF, Jagger, C, Martinez-Lage, J, Soininen, H, Hofman, A (2000). Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54, S4S9.
Mann, DM, Yates, PO, Marcyniuk, B (1984). Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age-related continuum of pathological changes. Neuropathology and Applied Neurobiology 10, 185207.
Martins, CAR, Oulhaj, A, de Jager, CA, Williams, JH (2005). APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model. Neurology 65, 18881893.
McKhann, G, Drachman, D, Folstein, M, Katzman, R, Price, D, Stadlan, EM (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.
Petersen, RC, Thomas, RG, Grundman, M, Bennett, D, Doody, R, Ferris, S, Galasko, D, Jin, S, Kaye, J, Levey, A, Pfeiffer, E, Sano, M, van Dyck, CH, Thal, LJ (2005). Vitamin E and donepezil for the treatment of mild cognitive impairment. New England Journal of Medicine 352, 23792388.
Poirier, J, Davignon, J, Bouthillier, D, Kogan, S, Bertrand, P, Gauthier, S (1993). Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342, 697699.
Ruitenberg, A, Kalmijn, S, de Ridder, MAJ, Redekop, WK, van Harskamp, F, Hofman, A, Launer, LJ, Breteler, MMB (2001). Prognosis of Alzheimer's disease: the Rotterdam Study. Neuroepidemiology 20, 188195.
Seltzer, B, Sherwin, I (1983). A comparison of clinical features in early- and late-onset primary degenerative dementia: one entity or two? Archives of Neurology 40, 143146.
Slooter, AJ, Houwing-Duistermaat, JJ, van Harskamp, F, Cruts, M, Van Broeckhoven, C, Breteler, MM, Hofman, A, Stijnen, T, van Duijn, CM (1999). Apolipoprotein E genotype and progression of Alzheimer's disease: the Rotterdam Study. Journal of Neurology 246, 304308.
Slooter, AJC, Cruts, M, Kalmijn, S, Hofman, A, Breteler, MMB, Van Broeckhoven, C, van Duijn, CM (1998). Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. Archives of Neurology 55, 964968.
Sluimer, JD, Vrenken, H, Blankenstein, MA, Fox, NC, Scheltens, P, Barkhof, F, van der Flier, WM (2008). Whole-brain atrophy rate in Alzheimer's disease: identifying FAST progressors. Neurology 70, 18361841.
Stern, Y, Brandt, J, Albert, M, Jacobs, DM, Liu, XH, Bell, K, Marder, K, Sano, M, Albert, S, Castenada, CD, Bylsma, F, Tycko, B, Mayeux, R (1997). The absence of an apolipoprotein epsilon 4 allele is associated with a more aggressive form of Alzheimer's disease. Annals of Neurology 41, 615620.
Strittmatter, WJ, Roses, AD (1995). Apolipoprotein E and Alzheimer's disease. Proceedings of the National Academy of Sciences USA 92, 47254727.
Strittmatter, WJ, Saunders, AM, Schmechel, D, Pericak-Vance, M, Enghild, J, Salvesen, GS, Roses, AD (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.
Teri, L, McCurry, SM, Edland, SD, Kukull, WA, Larson, EB (1995). Cognitive decline in Alzheimer's disease: a longitudinal investigation of risk factors for accelerated decline. Journals of Gerontology, Series A. Biological Sciences and Medical Sciences 50, M49M55.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed