Two decades of investigation have led to a mature understanding of the brain regions that are consistently atrophic in patients with AD dementia. Here we looked further back in the trajectory of AD and demonstrated that subtle neuroanatomic abnormalities are detectable in asymptomatic individuals nearly a decade before they are diagnosed with AD dementia, and are useful not only for assessing risk of AD dementia but also for predicting time to onset. Despite the small sample size, the striking consistency of these findings in 2 independent samples supports their generalizability.
Although sophisticated tools are now available for investigating changes in brain structure, function, molecular profiles, and behavior, the challenges of longitudinal research have made it difficult to study the full course of AD from preclinical to prodromal to dementia. Partly because they are time-, labor-, and cost-intensive, very few longitudinal studies have been completed of CN individuals who are followed until a clinical diagnosis of AD dementia. In one of the earliest studies of the decline of elderly individuals without dementia to AD dementia, smaller baseline hippocampal volume was present,10
as also observed in a more recent epidemiologic study.14
Another investigation of CN individuals demonstrated that ventricular volume was predictive of cognitive decline (11 converted to MCI, 2 to AD), but hippocampal, entorhinal, or whole brain volume were not.20
A voxel-based morphometry study found reduced MTL and parietal gray matter in 23 CN individuals who later developed MCI,13
and another analysis of the same sample using manual ROIs demonstrated hippocampal/entorhinal atrophy.15
Two other investigations found subtle shape abnormalities in hippocampal subregions in CN individuals who progressed to MCI.16,17
Very recently, a group of 9 CN individuals harboring brain amyloid who progressed to very mild AD dementia were shown to have lower baseline parahippocampal volumes compared to a stable CN group.8
We previously demonstrated that CN adults with brain amyloid have subtle AD-signature cortical thinning compared to CN adults without brain amyloid, but these individuals had not yet been followed longitudinally.18
Finally, a few studies have identified MTL and whole brain atrophy in the presymptomatic stage of genetically determined early-onset familial AD, again supporting the concept that atrophy, while subtle, may be present for years before AD symptoms.9,11,12
From the perspective of quantitative imaging biomarkers, the present study adds to prior literature in several ways. First, most prior work has employed manual tracings of one or a few ROIs. While neuropathologic studies21–23
made MTL structures a logical place to focus when investigating brain regions in which the earliest atrophy occurs in AD, recent imaging research has highlighted ventrolateral temporal, lateral parietal, and the posterior cingulate/precuneus as also involved early in the disease course.11,13,24,25
Here a relatively new technique for quantitative neuroanatomic measurement (cortical thickness analysis)—employed using a novel a priori approach focusing on brain regions known to be consistently affected early in AD—enabled the detection of statistically robust (large effect sizes due to small measurement error), replicable group differences of very subtle absolute magnitude (~¼ mm) in MRI scans now considered previous generation technology. Such observations highlight the value of returning to older MRI datasets when new measurement technology is developed.
More importantly, these measures can be efficiently, reliably obtained from single individuals. A determination of whether AD-signature thickness is low, average, or high relative to similarly aged individuals appears valuable in assessing risk of future AD dementia, a finding replicated across both samples. Furthermore, the Cox regression model results are powerful in that they augment the risk assessment with an estimate of the potential time to AD dementia. Whether such an approach will prove useful in a generalizable manner is an important research topic.
A critical element of studies aiming to identify biomarkers of asymptomatic AD is the cognitive assessment methodology. Contemporary study designs include the use of questionnaires or careful structured interviews to ascertain the presence and severity of symptoms of declining memory and cognition in daily life. Questions are asked of both the individual and usually a knowledgeable informant with regard to whether the individual has experienced a decline in his or her ability to remember the details of recent events or conversations, items to purchase while shopping, or how to navigate to familiar places. Changes of this sort, particularly when corroborated by an informant, are in some cases associated with atrophy in neural circuits subserving memory26
and may potentially be predictors of future decline and dementia,27
although reports are inconsistent.28
Some individuals who do not endorse symptoms of memory impairment in daily life may exhibit signs of early impairment on detailed neuropsychological performance-based testing. Verbal list learning, paired associates, and similar challenging memory tests may provide objective evidence of mild impairments in individuals who otherwise appear normal when tested but who ultimately develop cognitive decline and AD dementia after follow-up.7
With longitudinal cognitive testing, evidence of decline (or in some cases absence of a practice effect) can be seen for 5–10 years or more prior to AD dementia.1–6
Given the challenges in these types of assessments, the clinical designation of “cognitively normal” should not be used lightly and the methods for making this determination deserve further investigation and discussion.
Three points regarding the cognitive test performance characteristics of the present participants are worth discussion. First, coloring the interpretation of all of these tests, the participants were relatively well-educated with all but 3 individuals having at least a high-school education and more than half having at least a college degree. Second, no individual performed below 28 on the MMSE at baseline. Third, although the preclinical AD dementia groups performed slightly lower on baseline memory testing than those remaining stable, performance would have been considered within the normal range for nearly all individuals. Only 3 individuals performed more than 1 SD below the mean (scores were 1.0–1.5 SD below the mean), and one remained clinically stable as CN nearly a decade later. Nevertheless, episodic memory measures were useful in prediction of AD dementia, with similar predictive power in the Cox model as the MRI measure. We interpret this to mean that the CN individuals with preclinical AD may perform within the low-normal range on memory testing (presumably lower than they would have performed previously) because of the early neurodegenerative change being detected by this MRI technique. Longitudinal studies support the idea that a causal link can be detected between subtle cortical atrophy at baseline in CN individuals and subsequent decline in memory performance.29
Studies going back to the 1960s have highlighted the presence of AD pathology in individuals who die within a relatively short time after having been assessed as CN,30–34
and extensive investigations have demonstrated the dissociations that can be present between the quantitative burden of AD pathology and the degree of cognitive impairment.23,35
These and other observations illustrate the distinction between the neuropathology of AD as a biological disease as opposed to the clinical syndrome of AD dementia, which, although strongly coupled, are by no means synonymous. Factors such as cognitive reserve have been invoked to explain why some individuals may remain CN despite the presence of substantial AD neuropathology.36–38
Nevertheless, it is becoming clear that the presence of AD pathology, as ascertained via amyloid imaging or CSF analysis, in CN individuals appears to elevate the probability of subsequent cognitive decline and dementia.8,39
Efforts are increasing to elucidate relationships between the presence and severity of these surrogate molecular markers of AD neuropathology and the timing of the development of symptoms. The present data demonstrate that in CN older adults a thinner cerebral cortex in regions typically affected by AD is predictive of time to onset of AD dementia, providing an additional tool to link the biological changes of the disease with the symptoms of the illness. We conceptualize this measure as a marker of early neurodegenerative change which appears to be of potential value among the candidate biomarkers being proposed as part of the new research criteria for the diagnosis of preclinical AD.40
The major limitation of this study is the relatively small sample size. Yet most prior studies that resemble the present one also include small samples. The field is now primed for larger, prospectively designed studies of this sort, although many challenges remain in making such cumbersome investigations as efficient as possible. Such studies will require as much as 10 years of follow-up and may need to employ new methodologic advances, including not only molecular imaging and CSF analysis, but also telephone-based cognitive screening and imaging-guided neuropathologic assessment, to make them at once cost-effective and informative. Extending these investigations to more representative samples would also be a valuable goal, since prior cohorts including the present ones include highly selected, generally healthy individuals who are motivated to participate in this type of research. Another limitation is that the computational analysis technology required to produce these measurements, while publicly available, requires nontrivial expertise and computer systems. Finally, although prior work has demonstrated that cortical thickness measures are highly reliable across different scanner platforms and field strengths,41
it is not clear whether the differences between the measures in the 2 samples reported here are attributable to true biological variability, instrument variability, or other factors. Further investigation of these topics will be required.