In a middle-aged, community-based sample of 717 Framingham Offspring participants, parental dementia was associated with poorer performance in verbal and visuospatial memory tasks, among APOE ε4 carriers only. Similar associations were found for parental AD and these associations were driven mainly by maternal dementia. Among APOE ε4 carriers, participants with parental dementia also had greater brain atrophy rates over 6 years of follow-up. Finally, parental dementia and AD were associated with worsening performance in executive function, regardless of APOE ε4 status.
To our knowledge, the finding that significant changes in verbal and visuospatial memory can be detected in asymptomatic middle-aged offspring of individuals with sporadic dementia, 2 decades before the age at onset of dementia in the affected parent, is new. The magnitude of the effect of parental AD on memory performance, corresponding to approximately 15 years of brain aging, is particularly striking. Preliminary data from previous publications lend support to our findings. Indeed, an altered memorization pattern on the Rey Auditory Verbal Learning Test in middle-aged persons with a family history of AD has been shown recently, suggesting greater reliance on immediate working memory as opposed to consolidated episodic memory, as seen in early AD.17
In another study, first-degree relatives of patients with AD more often showed evidence of decline in memory and intelligence measures compared to controls, but the sample was relatively small and included both siblings and children.18
Moreover, functional imaging data suggest modified activation patterns in asymptomatic individuals with a positive parental history of AD compared to controls, more than a decade before their parent's onset age.19
Importantly, neither the APOE
ε4 allele nor parental dementia alone was associated with impaired memory performances, while the combination of the 2 was associated with significantly worse performances in verbal and visuospatial memory. The fact that the association of parental dementia and AD with poorer performance in verbal and visuospatial memory was seen only in APOE
ε4 carriers is consistent with previous work suggesting that genetic risk factors besides APOE
ε4 contribute to the familial component of dementia and verbal memory performance,20,21
and that APOE
ε4 interacts with these genes to determine risk.22,23
The observation that parental dementia was associated with poorer memory performance only among APOE
ε4 carriers could imply either that parental dementia impacts memory only if the APOE
ε4 allele is present (via an interaction of the latter with other genetic risk factors and shared environment) or that APOE
ε4 accelerates the clinical expression of memory impairment in predisposed persons.4,24
Our finding that the association of memory performance with parental dementia was largely attributable to maternal dementia is intriguing. Previous studies have reported that maternal transmission of AD is significantly more frequent than paternal transmission,25
and that having an AD-affected mother confers a greater risk than having an AD-affected father.26
Moreover, in a recent analysis of PET scans from cognitively intact individuals, persons with affected mothers showed a modified pattern of glucose consumption, while findings were unremarkable in subjects with an AD-affected father.27
Potential explanations for a predominantly maternal inheritance include chromosome X variants, genetic imprinting, involvement of mitochondrial DNA, or intrauterine exposure to risk factors.28–30
Alternatively, the stronger association with maternal dementia could reflect the fact that women live longer, up to an age when they are more likely to develop dementia, which reduces the probability for mothers to be misclassified as having no dementia due to early death by competing causes. This is unlikely to be the only explanation, as our results were unchanged when restricting the analysis to dementia by age 85, or adjusting for age at the parent's death.
In previous publications on the Framingham Original cohort and the PAQUID study, poor performance in verbal and visuospatial memory heralded dementia approximately 10 years before it was diagnosed.31,32
However, whether the cognitive changes we observed here in middle-aged offspring of individuals with dementia are associated with subsequent dementia in these persons, or just reflect a less favorable but not necessarily ominous cognitive profile, remains to be determined.
ε4 carriers, individuals with parental dementia exhibited a significantly higher rate of global brain atrophy compared to individuals without parental dementia, suggesting that the poorer memory performance we observed in the same subgroup of participants could be related to an underlying degenerative process. Higher rates of global brain atrophy have previously been related to an increased risk of incident dementia.33
The absence of association between parental dementia and change in THV or baseline TCBV and HV does not necessarily mean that these associations do not exist. In a study on familial autosomal dominant AD, differences between mutation carriers and controls in hippocampal and total brain volume and atrophy rates became evident less than 5 years before diagnosis of AD.5
Given the young age of our population, we had little power to detect such differences. Besides, early changes from AD pathology involve the entorhinal cortex, which may be missed when looking at a global measure of hippocampal size. The absence of a significant association with annual increase in THV ought to be interpreted with particular caution, as THV is only a surrogate marker of HV.
The significant association of parental dementia and AD with a steeper decline in executive function but not memory-related tests could be explained by the young age of our sample and the relatively short duration of follow-up. Previous studies suggest that in persons who subsequently develop dementia the magnitude of preclinical cognitive deficits remains relatively stable until a few years before clinical diagnosis,34
due perhaps to compensatory mechanisms.35
Besides, executive functions, especially cognitive speed, decline earlier with age than other cognitive domains such as memory.36
The strengths of this study are its population-based setting and the careful prospective surveillance and validation of dementia and AD. Although the acceptance rate was high, persons included in this study are not perfectly representative of the general population, as they are more educated with fewer risk factors and less disease than persons excluded. This limitation is common to all population-based studies involving time-consuming examinations and follow-up. Finally, our sample was largely Caucasian, reflecting the racial composition of Framingham in 1948 when the Original cohort was enrolled.
If the present findings are confirmed, their public health implications are substantial. First, they reinforce prior data suggesting a prolonged subclinical phase before the onset of dementia. Second, they suggest that in addition to age and APOE
ε4, parental dementia and its interaction with APOE
ε4 are important to consider when designing a risk score for dementia or cognitive impairment. Third, they indicate that heritable factors other than APOE
ε4 are important in determining the familial aggregation of parental dementia with memory performance, and that at least some of them interact with APOE
ε4. Fourth, our results underscore that measures of verbal and visuospatial memory are valid endophenotypes that can be used to broaden the search for genetic risk factors of sporadic dementia, as in addition to being heritable,21,37,38
and predicting an increased risk of dementia,31,32
they are also associated with parental dementia.