Building on the efforts of the late Dr. William Markesbery, we have been able to apply similar protocols in ACT, HAAS, NS, and OBAS for evaluation of NPs, NFTs, LBs, and CMIs; however, to date databasing and analyses have been done independently among these studies. Since these lesions are the standard means to assess the most common diseases that contribute to dementia in community- or population-based cohorts, we undertook an evaluation in CN individuals to estimate the occurrence and interaction of clinically silent diseases in cohorts drawn from multiple regions of the US.
Our resource for this analysis was 1672 brain autopsies from participants in ACT, HAAS, NS, and OBAS from which we selected 424 CN individuals whose last clinical examination was performed on average about one year before death; average age at death was in the mid 80’s. Since not all studies used comprehensive neuropathologic examinations from their inception, 336 brain autopsies from among these 424 CN cases were eligible to be included. Our major conclusions are (i) AD, μVBI, and LBD were prevalent among CN older adults, (ii) the burden of these three diseases varied widely, and (iii) co-morbidity among these three diseases is quite variable among individuals. Many others have reported on neuropathologic evidence of usually one or two of these diseases, mostly in research clinic cohorts, and less commonly in community- or population-based cohorts. Any interval between last clinical evaluation and autopsy creates a potential for misclassification, especially since progression to dementia typically seems to be preceded by a prodrome.33
We made an effort to minimize inclusion of people with prodromal dementia by selecting only those performing within the upper four quintiles on a cognitive screening test at last evaluation, rather than simply individuals without a diagnosis of dementia. To our knowledge, ours is the first to report evidence of clinically silent dementia-associated neuropathologic changes among CN individuals from multiple independent community- or population-based cohorts. Our results show an intricate complexity among clinically silent diseases. We hope these data on the ecology of aging brain will be useful in guiding expectations of future neuroimaging or biomarker studies as well as clinical trials with cognitively normal older individuals in the community setting.
Using similar but not directly comparable methods of histopathologic assessment, others have reported on clinically silent lesions of AD, μVBI, and LBD in older individuals without dementia in the Religious Orders Study (ROS) and Memory and Aging Project (MAP) (n = 202, average age = 84 years) and observed prevalence of these lesions similar to our cohorts, although with somewhat less co-morbidity.15
Indeed, the concordance among the four cohorts analyzed in this study as well as the ROS and MAP mitigates the serious concern about generalizability among cohorts that focused on specific populations such as men or women in religious orders, or ethnic Japanese on Oahu; indeed the neuropathologic outcomes from all these diverse studies are remarkably similar. Nevertheless, we should be cautious in extrapolating these validated findings in non-demented or CN individuals to other ethnic or racial groups or other societies.
Cerebral NP accumulation was the most common disease process among CN older adults. The proportion of CN older adults with moderate or frequent CERAD NP score, a metric significantly correlated with Aβ peptide-immunoreactive plaque area and detergent-insoluble Aβ42
accumulation, matches well with reports using fibrillar Aβ PET imaging in cognitively normal individuals. Indeed, these neuroimaging reports from CN older individuals observe a prevalence of PET-positive fibrillar Aβ ranging from about one-fifth to about one-half, the variance related at least in part to age, APOE
, and socio-economic status, with the latter perhaps related to education level or cognitive reserve.34, 35
CMIs were the next most prevalent clinically silent lesion in our cohorts, present in about one-third of CN older adults. High burden of CMIs, meaning lesions at the magnitide significantly associated with dementia,19
was present in approximately one in ten CN older adults. This screening protocol for CMIs has been shown independently in HAAS and ACT to be correlated with others forms of VBI, such as lacunes and territorial infarcts. However, among these forms of VBI, increased CMIs are most strongly and independently associated with increased risk of dementia.18, 19
These results are consistent with neuroimaging estimates of white matter hyperintensities, imaging abnormalities that appear to derive at least in part from pathogenic mechanisms overlapping with those that produce CMIs (reviewed in 36
LBD was the least prevalent clinically silent disease in our cohorts. Our data suggest that future imaging modalities for LBD should expect to detect medullary LBD in approximately one in six CN individuals; about one-half of these also will have nigral LBD, and about one-half of those with midbrain LBD will have isocortical LBD. Amygdala-only LBD appears to be uncommon in CN individuals as was hippocampal sclerosis. Finally, it is important to stress that while we are evaluating lesions that are diagnostic for specific underlying diseases, our neuropathologic protocols likely have varying sensitivities and this should be remembered when considering our estimates of disease burden. Nevertheless, evaluating these histologic lesions currently remains the only means of which we are aware to assess simultaneously the presence and extent of AD, μVBI, and LBD.
Many of the studies referenced above have noted extensive co-morbidity among AD, μVBI, and/or LBD, especially with advancing age, but with somewhat different protocols for histologic assessment. Our results validate this very important point in multiple population- or community-based cohorts from different regions of the US. Importantly, we add to this body of work by showing that the extent of co-morbidity was remarkably similar in CN older adults among the four studies. In further accord with work of others, including work from our individual cohorts, we observed that approximately 10 to 15% of CN individuals across the four studies harbored clinically silent AD, μVBI, and/or LBD at levels that equaled or exceeded the average burden of lesions in individuals diagnosed with dementia, a finding that may be interpreted as suggesting some form of compensation or reserve capacity. Although not a focus of this analysis, it is at least interesting to note that a similarly sized subset of individuals with dementia have a burden of lesions in cerebrum that is less than the average burden in CN individuals. Since this is an autopsy study and not limited by technologies focused on a particular disease process, we have demonstrated that these individuals with dementia and low burden of AD, μVBI, and/or LBD do not instead have less common diseases that also can cause dementia, such as fronto-temporal lobar degeneration or prion disease. These are the opposite of the “cognitive reserve” group and raise questions about heightened susceptibility or additional contributing disease mechanisms not captured by neuropathologic examination in a small subset of patients that meet clinical criteria for dementia.
Our results from four independent community- or population-based studies of brain aging and dementia demonstrate that clinically silent AD, μVBI, and LBD are prevalent and commonly co-morbid but with extensive individual variation. While it is a challenge to generalize from any research study to the primary medical setting, these results at least should guide expectations for neuroimaging and biomarker studies as well as clinical trials focused on disease prevention that will be populated with community-dwelling CN subjects. Moreover, our results suggest that the aging brain is experiencing multiple simultaneous stressors, injuries, and responses to injury that likely interact with each other to generate a complex convergent environment. Importantly, our results also suggest that there are yet-to-be identified factors that in some individuals may suppress and in others promote clinical expression of disease. Although autopsy-based studies provide important insight, further studies of the ecology of aging brain will require intra vitam disease- and mechanism-specific markers that will be critical to the efficient conduct of research focused on disease prevention or neuroprotection.