These findings indicate that impaired cognitive performance, older age, and APOE-4 genetic risk for AD are associated with increased brain FDDNP-PET binding in persons without dementia. Moreover, the degree of cognitive impairment (ie, normal aging vs MCI) appears to influence the interactions among risk factors. For example, in the MCI group, APOE-4 carriers show higher medial temporal FDDNP binding, whereas in normal aging, APOE-4 carriers demonstrate higher frontal binding. Overall, the results are consistent with our hypotheses and with previous clinical and postmortem studies demonstrating a relationship between such risk factors and amyloid plaque and tau tangle formation in the brain. By contrast, the other risk factors we tested, family history of dementia and prior years of education, were not found to be associated with higher FDDNP binding values.
Brain deposition of plaques and tangles follows a pattern in which tau tangles accumulate initially in the entorhinal cortex in normal aging and then spread to medial temporal regions as MCI develops; concentrations of medial temporal tangles become intermediate between those of normal aging and AD.22,23,38
The finding in our study that APOE-4
status was associated with FDDNP binding in the medial temporal region of patients with MCI is interesting in light of autopsy studies showing that this region is among the earliest to demonstrate increased plaque and tangle accumulation.22,23,38
Also, neuritic and diffuse plaques and tangles in patients with MCI are widely distributed throughout the neocortex and limbic structures.38
This spatial pattern and progression of abnormal protein accumulation may be consistent with an interaction between plaque and tangle accumulation. At some critical point in neurodegeneration, β-amyloid peptides may accelerate age-related tangle accumulation, which would otherwise progress relatively slowly with age.23
Tangle load has been associated with cognitive decline in older individuals, but plaque load has not consistently demonstrated such an association.38
The findings that FDDNP binds both plaques and tangles, particularly in the medial temporal lobe, may explain, in part, the association between higher FDDNP binding values and impaired cognitive function. Moreover, the regional pattern of FDDNP binding appears consistent with plaque and tangle accumulation patterns observed in autopsy studies.22,23,28,38
This is the first study to explore and demonstrate that a genetic risk for AD is associated with increased FDDNP-PET binding in persons without dementia. These results are consistent with previous neuropathological studies demonstrating increased plaque and tangle formation in middle-aged andolderAPOE-4
carriers without dementia.39,40
For example, in a study of persons without dementia who died between the ages of 50 and 93 years, APOE-4
carriers showed a pre-mature appearance of β-amyloid and neurofibrillary tangles.40
By contrast, autopsy studies of patients with AD find that APOE-4
heterozygotes do not show increased plaque and tangle accumulation, whereasAPOE-4
homozygotes do show increased accumulation.41
Thus, the effect of the APOE-4
allele on cerebral plaque and tangle formation may only occur early in the course of neurodegeneration.
lowers the age of clinical dementia onset, but surprisingly, several studies do not demonstrate acceleration of clinical progression of the disease in APOE-4
Consistent with such findings, APOE-4
has been reported to accelerate transitions from normal aging to MCI, but not from MCI to dementia.46–49
While controversial, these results suggest that APOE-4
may have a larger effect on a central precipitating event like amyloid plaque deposition, arguably a poor correlate of clinical progression or initial pathology in medial temporal regions, as observed in this study with FDDNP.
Previous autopsy studies of individuals without dementia ranging from young adults to elderly persons also have demonstrated that plaque and tangle formation is age-related.22,50
Other research has demonstrated interactions among these various risk factors. For example, APOE-4
carrier status may lead to increased tangle accumulation in relatively young age groups. In an autopsy study of asymptomatic younger adults (mean age, 38 years), tangle formation was significantly greater in APOE-4
carriers compared with controls.51
Sex may also modify the effect of APOE-4
on the deposition of AD brain pathology; in a study of 729 brains examined by routine autopsy, an association between the APOE-4
allele and plaques was found only for women aged between 60 and 79 years, whereas the association was found for men in all age groups.52
In the present study, we did not find sex to be associated with greater FDDNP binding.
Subjective memory concerns and minimal decline in memory ability compared with young adults are expected with normal aging.2
Although cognitive impairment is a risk factor for dementia, it is also a consequence of the brain lesions causing AD. The results of this study suggest that in vivo measures of plaques and tangles are associated with increased cognitive impairment, but other factors besides plaques and tangles can contribute to cognitive impairment including cerebrovascular disease and head trauma.53,54
Revised research criteria for the diagnosis of AD have been proposed.55
These criteria include the presence of early episodic memory impairment along with 1 or more abnormal biomarker such as molecular neuroimaging with PET or cerebrospinal fluid analysis of β-amyloid or tau proteins. Our findings that FDDNP binding patterns differ according to the degree of cognitive impairment (ie, normal aging vs MCI) suggest that FDDNP-PET might be a useful tool in applying such revised research diagnostic criteria. Additional studies clarifying the patterns of FDDNP binding and other molecular imaging techniques in AD, MCI, and normal aging will likely have an effect on the use of such diagnostic criteria.
Family history of dementia was not associated with higher FDDNP binding values. Previous studies have found that family history of dementia increases the risk for neurodegeneration56
and is associated with subsequent cognitive decline57
and lower scores on neuropsychological testing.58
Family history of dementia is an established risk factor for AD,59
but not all studies have confirmed such a risk.60,61
Moreover, the effect of family history on risk for dementia may be age-dependent—some studies have found the effect in persons older than 75 years,62
while other reports suggest that the effect of familial or genetic factors on dementia risk diminishes with increasing age.17
Misclassification in the assessment of dementia history and cohort effects (ie, relatives may be more likely to report dementia in siblings than in parents) may also diminish the accuracy of family history estimates. The relatively small sample size also may explain why family history was not associated with increased FDDNP binding values.
This small sample also may explain why we did not find prior educational achievement to influence our results. In addition, the lack of variance in years of education in these subjects may have minimized any effect of education in the present analysis. Other methodological issues could have influenced these results as well, including partial volume effects63
and use of a relatively educated sample who may not be representative of the general population.
Despite such limitations, these results, that FDDNP-PET may be an informative biological marker for people at risk for dementia, are encouraging. An important potential application of emerging technologies such as FDDNP-PET is in early detection of neurodegeneration. Our finding that greater FDDNP binding is associated with increased cognitive impairment in individuals without dementia suggests that this approach might be useful in detecting people at risk for dementia, which would also be useful for identifying candidates for clinical trials of prevention treatments. These results suggest that in future clinical trials using FDDNP-PET, stratifying subject groups according to APOE-4 carrier status, age, and cognitive status may be an informative strategy.