The slope of decline exhibited by the noncarriers represents normal, age-related memory loss, Dr. Caselli said. The sharper post-60-year decline in apo ϵ4 carriers probably reflects a direct or indirect effect of the ϵ4 gene.
But although these cognitive changes appeared mainly after age 60, imaging studies on some of the younger carriers suggest that some brain areas may be vulnerable much earlier in life. PET scanning of presymptomatic 50- to 59-year-old homozygotes showed areas of decreased glucose metabolism in brain regions associated with Alzheimer's disease pathology: the posterior cingulate gyrus, parietal and temporal lobes, and prefrontal cortex. PET scans of 20- to 39-year-olds with one copy of the allele showed similar, although smaller, areas of decreased metabolism.
“So what does that mean?” asked Dr. Caselli. “If you look at all the work out there–the Nun Study, brain imaging, and pathology studies of apo ϵ4 carriers–you get the idea that little pieces of AD pathology happen throughout young adult life, but we don't see young people developing progressive dementia unless there's an autosomal dominant mutation. The fact is, we don't know whether these early changes reflect a sort of nonprogressive pathology or some basic biologic vulnerability that marks the territory of later decline.”
There are plenty of theories about the possible connection between apo ϵ4 status and Alzheimer's pathology, Dr. Caselli said. Most focus on the pathologic function of the apo ϵ4 isoform. Research from the 1990s suggests that it enhances amyloid deposition, reduces neurite outgrowth and protection against oxidative stress, and cuts the efficiency of neuronal and synaptic repair. Most recently, researchers at the University of California, San Francisco, have suggested that the apo ϵ4 isoform can generate a cytotoxic carboxyl fragment. This truncated form of the protein is thought to induce neuronal inclusions that are similar to neurofibrillatory tangles, containing phosphorylated tau and high-molecular-weight neurofilaments (Proc. Natl. Acad. Sci. USA 2001;98:8838–43).
“The science on this is pretty well established, but whether it's key to AD pathogenesis is still undergoing further study,” Dr. Caselli said. Another recently proposed connection is the relationship between apo ϵ4 status and the demyelination in the frontal lobe and corpus callosum, Dr. Caselli noted. These brain regions, which continue to lay down myelin until middle age, also appear most susceptible to myelin breakdown, wrote Dr. George Bartzokis, director of the UCLA Memory Disorders and Alzheimer's Disease Clinic in Los Angeles.
Dr. Bartzokis's study of 104 healthy subjects aged 75 years and younger found that those with the apo ϵ4 genotype had the highest level of demyelination in frontal lobe white matter and the genu of the corpus callosum. The apo ϵ2 genotype appeared protective of demyelination, while those who were apo ϵ3 positive had an intermediate level of demyelination.
The connection may be the dearth of apo ϵ molecules in the ϵ4 genotypes. Apo ϵ helps maintain neuronal health by degrading damaged myelin and recycling the lipids for rapid repair. Those who are apo ϵ2 positive have the highest number of apo ϵ molecules available for this constant repair process; those who are apo ϵ4 positive have the lowest number, while apo ϵ3-positive subjects have an intermediate number (Arch. Gen. Psychiatry 2006;63:63–72; Proc. Natl. Acad. Sci. USA 2006;103:5641–3).