Apolipoprotein AIV codon 360 mutation increases with human aging and is not associated with Alzheimer's disease. Aksam Merched, Yongjing Xia, Anna Papadopoulou, Gerard Siest, Sophie Visvikis* Centre de Medecine Preventive UPRES, 2 rue du Doyen Jacques Parisot, F-54501 Vandoeuvre-les-Nancy, France. Received 8 December 1997; received in revised form 29 December 1997; accepted 29 December 1997.

Abstract: In order to evaluate genetic apolipoprotein polymorphisms as risk factors for Alzheimer's disease (AD), we studied apolipoprotein (apo) AIV after apoE, an apolipoprotein also present in the brain. The allelic distribution of apoAIV codon 360 polymorphism was no different in the AD group (n=120) compared with elderly healthy individuals (n=119). Surprisingly, this polymorphism was over-represented (11.40%, vs. 5.7% P, 0.005) in all these aged subjects (74.29 +/- 8.46 years) and independently of the clinical and mental status compared with the younger population (39.00 +/- 9.69 years) of the same regional recruitment. These results suggest that the apoAIV (360:His) allele could be a marker of aging and longevity.

1998 Elsevier Science Ireland Ltd.

Keywords: Longevity; Genetic marker; Alzheimer's disease; Apolipoprotein E; Apolipoprotein AIV (360:Gln:His); DNA polymorphism.

Cell culture and animal models [3,10] suggest that apoAIV may act in the CNS as a factor to control appetite during food intake [8]. Apolipoprotein (apo) AIV is a component of chylomicrons and high-density lipoproteins which show a genetic polymorphism in Caucasian populations with two common alleles, ApoAIV-1 and ApoAIV-2. Previously, we identified these alleles to be a result of glutamine (CAG) to histidine (CAT) substitution at codon 360 [1]. Postulated functions of this apolipoprotein include: acting as an activator of the enzyme lecithin:cholesterol acyltransferase (LCAT) [20], promoting removal of cellular cholesterol from extrahepatic tissue [21] and modulating the activation of lipoprotein lipase by apoC-II [9]. Genetic-association studies have demonstrated a relationship between apoAIV polymorphism and interindividual variability in plasma cholesterol, triglyceride and glucose levels in supposedly healthy populations, but the results have been somewhat controversial [15-17,25]. Little is known about the function of this apolipoprotein at the level of the central nervous system (CNS). Some studies have attributed roles to apoAIV during degenerative and regenerative processes in the peripheral and central nervous systems, as well as during development in cell culture and animal models [3,10]. It was reported that apoAIV was first supposed to cross the blood-brain barrier [6,14]. However, the recent localization of apoAIV within the brain [12] and in the CSF [2] increases the potential role of this protein in the CNS. Unchanged apoAIV expression in Alzheimer's disease (AD) brains compared with controls suggests that qualitative rather than quantitative change may be linked to this pathology. Collectively, these data led us to investigate the common apoAIV polymorphism implication in AD. We report our findings as a response to very recent results reporting an association of the apoAIV codon 360 mutation with AD [4].

The population studied included 120 patients (88 females, 32 males) with probable AD established according to the criteria of the NINCDS-ADRDA work group. All patients with AD had a mini-mental state (MMS) score of less than 25. Moreover, we included a population of 119 presumed-healthy elderly subjects (62 females, 57 males) participating in systematic health screening at the Center for Preventive Medicine in Nancy, France. These subjects were supposed to be free of AD symptoms after clinical examinations performed by general clinicians. The results of this study were compared with those previously described from the general population of the same region [23].

Genotyping was performed with DNA isolated from nucleated blood cells [18]. The ApoE genotype was determined as described elsewhere [13]. ApoAIV codon 360 genotyping was performed with a technique using a bispecific-allele primer amplification established in our laboratory [26]. In this technique, simple electrophoresis of PCR products is used for typing the variation at codon 360. When DNA was not available, apoE and apoThe scope of this study is to investigate whether the apoAIV allele frequency differs between Alzheimer's disease (AD) patients and elderly control groups. The results show that there was no significant difference in the frequency of apoAIV alleles between AD patients and the elderly control group (Table 1). However, both groups had a higher frequency of apoAIV (360:His) alleles compared to the general population, with a mean age of 39.00 ± 9.69 years and 70.68 ± 6.52 years for elderly and 77.87 ± 8.47 years for AD patients (P<0.05 and P<0.001, respectively). These findings suggest that the mutation is over-represented at an advanced age and not associated with AD risk. 

Next, the results were examined concerning apoE polymorphism and the presence or absence of the e4-allele, which is a major genetic risk factor for AD (Table 2). Regardless of whether an individual had the e4-allele or not, the apoAIV allelic distribution was similar, and there was no significant additional risk for AD for the apoAIV (360:Gln:His) allele carriers. In the AD group, the apoAIV 360 polymorphism did not influence the mini-mental score [7] (not shown).

Table 2 displays the ApoAIV 360 allelic distribution according to e4-allele presence between AD patients and elderly control groups.