Although presence of one or more APOE
ε4 alleles has been the most robust genetic risk factor for LOAD, this study found that in asymptomatic late middle-aged ε3/ε3 individuals, another genetic polymorphism in TOMM40
, poly-T length at rs10524523, is associated with cognitive and gray matter volume differences that are suggestive of incipient AD. This same TOMM40
poly-T polymorphism has previously been shown to be associated with age of onset in LOAD (8
), and the present study suggests that AD-related brain and cognitive changes may be occurring years before the onset of clinical symptoms in APOE ε3 homozygotes.
homozygous Short and homozygous Very Long groups had different serial position curves on a list learning task. Deficits in learning and memory are distinguishing features of mild and very mild LOAD and amnestic MCI. Further, mild learning and memory dysfunction have been shown to presage development of clinical AD in community and population cohorts (20
). Normal aging does not affect the basic shape of the serial position curve, even though the total amount recalled is typically lower for older persons (24
). By contrast, patients with AD, even in very mild stages, show an increase in recency and decrease in primacy (25
), likely reflecting AD-associated changes in episodic memory systems for encoding and retrieval that are seen in the hippocampus (28
), entorhinal cortex (28
), and ventral posterior aspects of the cingulate including the isthmus and retrosplenial area (13
). Although there was a medium effect size in the primacy effect, no group was abnormally low, which is to be expected in an asymptomatic population. Replication of these preliminary cognitive trends and MRI findings with independent samples is needed, as is longitudinal study to determine whether variation in intronic poly-T length at TOMM40
rs10524523 is associated with progressive changes in cognition and regional brain volume in this cohort.
The difference in ventral posterior cingulate volume in this study is particularly intriguing as this region is not only implicated in memory retrieval, it is also atrophic and hypometabolic in mild AD (14
) and MCI (32
). Dose-dependent hypometabolism in asymptomatic APOE
ε4 carriers (15
) has been found in this region. It is also one of the earliest regions to show increased amyloid burden measured using Positron Emission Tomography with Pittsburgh Compound B (34
). The gray matter finding in this study is complementary to GWAS studies using the chronologically older ADNI cohort in which a separate TOMM40
polymorphism was associated with gray matter volume differences in normal persons and those with a diagnosis of mild cognitive impairment or AD (10
The VL/VL group was 4 years older than the S/S group and thus age was included as a covariate. To further alleviate the potential concern that age is unduly influencing the result, we conducted a secondary analysis in which we trimmed the tails of the age distribution to include only those subjects between ages 56 and 66. Age was no longer significantly different, while the group effect in the posterior cingulate remained significant at an uncorrected voxel level alpha of .005 and 200 contiguous voxels.
In prior studies, we and others have found laboratory, cognitive and neuroimaging evidence for presumptive AD in asymptomatic persons with a first degree family history of AD (13
). Some studies report interactions with APOE
genotype, others report independent family history effects, suggesting the presence of an unknown gene(s) that may be responsible for the family history effect. In this study the S/S and VL/VL groups did not differ on the proportion of subjects with parental FH. However the S/VL group had a greater proportion with FH. Persons with a FH have a high prevalence of APOE
ε4 alleles (17
), which may interact in some way with TOMM40
to explain FH genetic risk. The interplay of FH, TOMM40
genotype is the topic of ongoing studies.
In conclusion, this study suggests that a subgroup of late middle-aged APOE ε3/3 homozygotes who carry the TOMM40 VL/VL genotype may be at higher risk for AD than current paradigms for AD risk would predict. These asymptomatic subjects performed worse on a measure of episodic learning and also exhibited smaller volume in the posterior cingulate, a region well-known to be affected early in the course of AD. The study is limited by the relatively small number of subjects who were APOE ε3/ε3 and had both TOMM40 genotyping and structural imaging. The VL/VL group was also older than the other groups, though the analyses were statistically adjusted for age. If confirmed in independent studies, these findings suggest that TOMM40 poly-T length may help to explain residual AD risk among the most common APOE genotype in the population. The clinical significance of TOMM40 variants in this population will be elucidated with further longitudinal study to clinical endpoints of MCI and AD.