Alzheimer’s disease is the most common form of dementia, affecting about 10% of the elderly population. Four genetic loci have so far been implicated in Alzheimer’s disease, either in rare family pedigrees in which the defective gene (amyloid precursor protein, presenilin-1, presenilin-2) cosegregates with early onset Alzheimer’s disease, or in late onset cases in which polymorphism of the apolipoprotein E (ApoE) gene on the chromosome 19 is identified as an important individual risk trait. Apolipoprotein E is a normal constituent of plasma lipoproteins and has an important role in the maintenance of the integrity of the neuronal membrane and myelin sheath, but is also deposited in senile plaques in Alzheimer’s disease. Three allelic forms of the ApoE gene have been characterised—Apo ε2, Apo ε3, and Apo ε4. In a previous study, we found that the Apo ε4 allele constitutes a major risk factor for Alzheimer’s disease in the Portuguese population,1similar to that described for other populations.2 In the present study, we tested the hypothesis that different ApoE genotypes might be associated with distinct clinical phenotypes in Alzheimer’s disease.

Consecutive patients with sporadic Alzheimer’s disease from the dementia study group outpatient clinic were studied. The diagnosis of probable Alzheimer’s disease was established according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRADA). All patients were submitted to neurological history and examination (including mental status examination), laboratory analytical tests, and brain CT according to the recommendations of the American Academy of Neurology to exclude other causes of dementia. For ApoE genotyping, genomic DNA was extracted from peripheral blood, and allelic variants identified by the polymerase chain reaction (PCR) amplification.1 Relevant clinical characteristics were compared in the patients with Alzheimer’s disease with different ApoE genotypes. Age of onset was defined as the age at which the first symptoms required for the diagnosis of Alzheimer’s disease were noticed. Information provided by the patient was always checked by questioning the spouse or a close relative. The interviewing neurologist was unaware of the ApoE genotype of the patient.

Sixty eight patients with sporadic probable Alzheimer’s disease were studied. Twenty eight were Apo ε3/ε3, 31 ε3/e4, and nine ε4/ε4. The age of onset of disease was significantly higher in the patients bearing the Apo e4 allele (ε3/e4 and ε4/e4, 65.7 (7.1), n=40), compared with patients without the Apo e4 allele (ε3/ε3, 61.6 (7.6), n=28, p<0.05, two tailed Student’s t test). The time from the onset of the disease to the first outpatient interview, which may reflect the initial progression of the disorder, was not different between the two genotype groups. No significant differences in relation to the sex, education, disease installation, disease course, interference with professional or social life, arterial hypertension, diabetes mellitus, dyslipidaemia, and CT were found.

The main finding of the present study was that the age of onset in Alzheimer’s disease was higher in patients bearing the Apo ε4 allele. The table shows data from different studies on the age of onset according to the ApoE genotype. Studies looking specifically at familial or early onset cases were not considered, as these might represent subsets of patients with particular forms of Alzheimer’s disease. Various studies found that patients bearing the Apo ε4 allele were either younger or older at the onset, whereas others could detect no significant difference (table). It is noteworthy that the two studies that found a higher age of onset for patients bearing the Apo ε4 allele were those including relatively younger patients with Alzheimer’s disease (Dal Forno, 1995 and the present study, table). Furthermore, analysis of the 10 studies in the table shows that the difference between the ages of onset in patients without and with the Apo ε4 allele significantly relates to the mean age of patients with Alzheimer’s disease (linear regression, slope 0.46 (0.13), 95% confidence interval 0.16–0.77). A possible interpretation is that the presence of the Apo ε4 allele could represent a particularly high risk in the older patients of a relatively young Alzheimer’s disease population, and the reverse would be true for a comparatively older Alzheimer’s disease sample. This interpretation is consistent with the previously reported data showing that the Apo ε4 allele might exert its effect as a risk factor for Alzheimer’s disease mainly in the 60–69 decade of life, and less so in the preceding and subsequent decades.3

In conclusion, the present study reinforces the idea that the importance of the Apo ε4 allele as a risk factor for Alzheimer’s disease depends on the age of the person, although conclusive evidence can only result from large epidemiological studies.4