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Inverse effect of the APOE epsilon4 allele in late- and early-onset Alzheimer’s disease

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Abstract

In Alzheimer’s disease patients (AD), the age at onset (AAO) ranges from 40 to 90. Usually, AD patients who develop symptoms before the age of 65 are classified as early onset (EO). The best known genetic risk factor for AD is the ε4 allele of the apolipoprotein E (APOE). In this study, 474 subjects with AD were consecutively recruited in the memory clinic of the Santa Lucia Foundation in Rome. The best fitting model  for the discrimination between EO and late onset (LO) was chosen based on lowest value of the Bayesian Information Criterion, which suggests the theoretical model with minimal deviation from the empirical distribution function of AAO in our sample. The FMM was used to compare EO and LO groups with respect to the following demographic and clinical variables: gender, age, education, MMSE and NPI. Furthermore a quantitative assessment of ADL and IADL was performed. Finally, the frequency of the APOE ε4 allele was compared in EO and LO groups. Using the admixture analysis, we established that the AAO discriminating EO from LO-AD was 63–64. Higher education was associated with earlier onset in the EO but not in LO, and duration of illness was associated with earlier onset only in LO. The ε4 allele was associated with later onset in EO but earlier onset in LO. Finally, increased impairment in ADL, IADL and NPI was associated with later onset only in the LO subgroup. Thus, the ε4 allele of the APOE gene was significantly associated with both EO and LO distributions but with opposite effect, suggesting genetic heterogeneity. Additional studies are needed to further clarify the genetic mechanisms differentiating EO- and LO-AD.

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Abbreviations

AAO:

Age at onset

AD:

Alzheimer’s disease

ADL:

Activities of daily living

APOE:

Apolipoprotein E

AIC:

Akaike information criterion

BIC:

Bayesian information criterion

CDR:

Dementia rating scale

DSM-IV:

Diagnostic and statistical manual IV

EO-AD:

Early-onset Alzheimer’s disease

ε4:

Epsilon4 allele

FMM:

Finite mixture model

IADL:

Instrumental activities of daily living

IRCCS:

Istituto Di Ricovero e Cura a Carattere Scientifico (Italian Research Hospital)

LO-AD:

Late-onset Alzheimer’s disease

MMSE:

Mini-mental status examination

MRI:

Magnetic resonance imaging

NINCDS–ADRDA:

National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association

NPI:

Neuropsychiatric inventory

PSEN1:

Presenilin 1

PSEN2:

Presenilin 2

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Authors and Affiliations

  1. Centre for Addiction and Mental Health (CAMH), EEG and Genetics Lab, Department of Psychiatry, University of Toronto, 250 College Street, Room R340, Toronto, ON, M5T 1R8, USA

    Vincenzo De Luca

  2. Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy

    Maria Donata Orfei, Sara Gaudenzi, Carlo Caltagirone & Gianfranco Spalletta

Authors
  1. Vincenzo De Luca
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  2. Maria Donata Orfei
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  3. Sara Gaudenzi
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  4. Carlo Caltagirone
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  5. Gianfranco Spalletta
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Correspondence to Vincenzo De Luca.

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De Luca, V., Orfei, M.D., Gaudenzi, S. et al. Inverse effect of the APOE epsilon4 allele in late- and early-onset Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci 266, 599–606 (2016). https://doi.org/10.1007/s00406-015-0663-4

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  • DOI: https://doi.org/10.1007/s00406-015-0663-4

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