Research Article: White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes

Date Published: May 24, 2018

Publisher: BioMed Central

Author(s): Grégory Operto, Raffaele Cacciaglia, Oriol Grau-Rivera, Carles Falcon, Anna Brugulat-Serrat, Pablo Ródenas, Rubén Ramos, Sebastián Morán, Manel Esteller, Nuria Bargalló, José Luis Molinuevo, Juan Domingo Gispert.


The ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer’s disease. During middle age, cognitively healthy APOE-ε4 carriers already show several brain alterations that resemble those of Alzheimer’s disease (AD), but to a subtler degree. These include microstructural white matter (WM) changes that have been proposed as one of the earliest structural events in the AD cascade. However, previous studies have focused mainly on comparison of APOE-ε4 carriers vs noncarriers. Therefore, the extent and magnitude of the brain alterations in healthy ε4 homozygotes, who are the individuals at highest risk, remain to be characterized in detail.

We examined mean, axial, and radial water diffusivity (MD, AxD, and RD, respectively) and fractional anisotropy in the WM as measured by diffusion-weighted imaging in 532 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 207 heterozygotes, and 257 noncarriers). We examined the impact of age and APOE genotype on these parameters using tract-based spatial statistics.

Healthy APOE-ε4 homozygotes display increased WM diffusivity in regions known to be affected by AD. The effects in AxD were much smaller than in RD, suggesting a disruption of the myelin sheath rather than pure axonal damage.

These findings could be interpreted as the result of the reduced capacity of the ε4 isoform of the APOE protein to keep cholesterol homeostasis in the brain. Because cerebral lipid metabolism is strongly related to the pathogenesis of AD, our results shed light on the possible mechanisms through which the APOE-ε4 genotype is associated with an increased risk of AD.

The online version of this article (10.1186/s13195-018-0375-x) contains supplementary material, which is available to authorized users.

Partial Text

The ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer’s disease. Compared with those individuals with an APOE ε3/ε3 genotype, white individuals with one copy of the ε4 allele show an increased lifetime risk of developing Alzheimer’s disease (AD) (ε2/ε4, OR 2.6; ε3/ε4, OR 3.2). The risk is much higher for carriers of two copies (ε4/ε4, OR 14.9) [1]. The main roles of the ApoE protein, encoded by the APOE gene, include lipid transport and clearance of amyloid deposition. However, the ε4 isoform of the ApoE protein shows an impaired capacity to perform these functions compared with the other isoforms [2]. Such impaired function may underlie the observed effects of APOE-ε4 on the brain throughout the lifespan. In particular, APOE-ε4 has been related to earlier and increased amyloid-β deposition, one of the neuropathological hallmarks of AD [3, 4]. However, the effects on brain morphology have been reported to be subtler [5]. Most of the studies so far have stratified individuals in only two levels of risk (APOE-ε4 carriers vs noncarriers). However, APOE-ε4 homozygotes, who completely lack expression of the most efficient isoform of the ApoE protein, are an interesting population to study to gain a better understanding of the mechanisms through which APOE genotype modulates the risk of AD. Given the essential implication of ApoE in the transport of cholesterol, the main component of the myelin sheath, it is conceivable that alterations in white matter (WM) microstructure may be one of these mechanisms.

The present study points to the existence of WM microstructural changes in cognitively normal adults carrying the ε4 allele. This effect was significant when we tested both the recessive and additive models. These results suggest that the ε4 allele adds extra burden to known age-related changes, especially for those individuals carrying two copies of the risk allele. In the brain, the APOE protein mediates neuronal delivery of cholesterol, which is an essential component for axonal growth, synaptic formation, and remodeling [2]. Because the ApoE-ε4 isoform of the protein is less efficient than ApoE-ε3 and ApoE-ε2 in transporting brain cholesterol [41], our findings could be interpreted as the result of a dysregulation in cholesterol homeostasis, which might contribute to the increased risk of AD observed in the ε4-homozygous group.

Our results confirm that carrying the APOE-ε4 allele confers an additional burden to the normal age-related changes observed in WM in cognitively healthy individuals. This burden emerges as differential changes in dMRI parameters, essentially in diffusivity, suggesting early affection of the fibers of the myelin sheath at a stage predating axonal loss and typically resulting in decreases of anisotropy. With the uniquely high number of homozygotes in our dataset, our study shows that carrying two copies of the ε4 allele is also associated with a significantly higher impact on the WM microstructure.




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