by Hana Saddiki, Aurore Fayosse, Emmanuel Cognat, Séverine Sabia, Sebastiaan Engelborghs, David Wallon, Panagiotis Alexopoulos, Kaj Blennow, Henrik Zetterberg, Lucilla Parnetti, Inga Zerr, Peter Hermann, Audrey Gabelle, Mercè Boada, Adelina Orellana, Itziar de Rojas, Matthieu Lilamand, Maria Bjerke, Christine Van Broeckhoven, Lucia Farotti, Nicola Salvadori, Janine Diehl-Schmid, Timo Grimmer, Claire Hourregue, Aline Dugravot, Gaël Nicolas, Jean-Louis Laplanche, Sylvain Lehmann, Elodie Bouaziz-Amar, the Alzheimer’s Disease Neuroimaging Initiative , Jacques Hugon, Christophe Tzourio, Archana Singh-Manoux, Claire Paquet, Julien Dumurgier
The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD.
Methods and findings
This case–control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44–96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44–94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1–5.2; p p p for interaction APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD.
In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65–70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.