In this longitudinal community-based clinical-pathologic study of 483 older persons we found that clinically probable AD is a heterogeneous and often mixed disorder. While nearly all persons with clinically probable AD were pathologically-confirmed to have AD at autopsy, almost half had AD pathology mixed with cerebral infarcts or neocortical Lewy bodies. The pathology underlying MCI is also heterogeneous; though AD is the most common pathology; infarcts and mixed pathologies also occur in many persons with MCI. We found that the cooccurrence of infarcts and neocortical Lewy bodies with AD pathology is not trivial but rather significantly increases the likelihood of a diagnosis of MCI or probable AD. Finally, we found that AD was the most frequent pathology in both amnestic and non-amnestic MCI; whereas “pure” infarct pathology (without a concomitant pathologic diagnosis of AD) was less frequent even in non-amnestic MCI.
Mixed pathologies have been identified as the most common substrate for dementia in several community-dwelling cohorts (2
). Because AD is the most common clinical diagnosis in older persons with dementia it is not unexpected that mixed pathologies would also be common in this group. Indeed, in this study, though nearly 90% of persons with clinically probable AD met pathologic criteria for AD, mixed pathologies were as common as “pure” AD pathology. Furthermore, mixed pathologies were associated with a marked increase in the odds of cognitive impairment. In other words, these additional pathologies were not innocent bystanders in the aging brain, but rather added to the likelihood that someone meeting pathologic criteria for AD would also meet clinical criteria for probable AD.
There have been few reports on the neuropathology of MCI (12
). Though the operational definitions of MCI between studies differed, they similarly showed that persons with MCI often meet the minimal pathologic criteria for AD (12
) and their level of AD pathology is typically intermediate between persons with and without clinical AD (12
). While most studies have focused on AD pathology, additional pathologies, particularly vascular pathologies, appear to be common (11
). Prior studies had relatively few persons with MCI, with the largest study including 57 subjects (16
); further, they either included both amnestic and non-amnestic MCI as a single group (14
) or were restricted to amnestic MCI (12
). Two additional studies focused on the neuropathology of MCI after conversion to dementia; these showed the pathology of AD (33
) and mixed pathologies (34
). Thus, the current study markedly extends and adds to these prior observations. Overall, there was substantial pathologic heterogeneity in MCI. In contrast to probable AD which was found to be almost always associated with a pathologic diagnosis of AD, about half of persons with MCI met pathologic criteria for AD, and few had high levels of pathology as reflected by a low proportion with high likelihood AD by NIA-Reagan criteria compared to probable AD. Interestingly, a pathologic diagnosis of AD was the most common pathology in both amnestic MCI and non-amnestic MCI; whereas, “pure” infarct pathology or Lewy body pathology accounted for less than a quarter of amnestic and non-amnestic MCI cases. This lack of specificity may be partly due to the observation that infarcts can damage brain regions associated with episodic memory while AD pathology frequently accumulates in non-memory regions. Indeed, we (35
) and others (36
) have shown that infarcts can affect episodic memory; and that AD pathology may affect non-memory functions (38
We found that mixed pathologies are not an infrequent finding in MCI, particularly amnestic MCI. It is interesting to note the conceptual similarities between amnestic MCI and probable AD. A pathologic diagnosis of AD is common in both amnestic MCI and probable AD, and additional pathology increases the likelihood of cognitive impairment. Indeed, the proportion of persons with a single pathology in MCI differs little from persons with no cognitive impairment; yet, the number of persons with mixed pathology was twice that in comparison to those no cognitive impairment. These findings support the contention that MCI, especially amnestic MCI is often a synonym for early clinical AD. Finally, compared to amnestic MCI, non-amnestic MCI has a somewhat lower proportion of mixed pathologies; this is likely due to the fact that somewhat fewer persons had a pathologic diagnosis of AD. Larger numbers will be needed to determine the significance of these findings.
The observation that clinical AD is a pathologically heterogeneous and often mixed disorder has implications for the public health and medical research of our aging population. First, because infarcts are the most common unrecognized contributing pathology in clinical AD, prevention of infarcts is likely to be important for delaying onset and slowing cognitive decline in persons with AD pathology. From a public health perspective, measures that can improve vascular health, such as life style changes, and prevention and treatment of hypertension and diabetes, could decrease both the incidence and severity of clinical AD in the population.
Second, the prominent role of vascular disease in the clinical expression of MCI and AD means that inferences from epidemiologic studies that find associations between vascular risk factors and clinical AD need to be made with caution. In particular, one cannot assume that risk factors for clinical AD are also risk factors for AD pathology. For instance, diabetes, a known risk factor for stroke, has been linked to clinical AD (39
); yet a relationship between diabetes and the pathology of AD remains unclear (41
). Indeed, we previously found that diabetes is related to post-mortem cerebral infarctions but not to AD pathology (43
). The biological mechanisms of other diverse posited risk factors for clinical AD such as hypertension, diet, and estrogen supplementation raises similar questions. To separate the vascular and degenerative aspects of the disease process will likely require studies that include both structural and amyloid neuroimaging, in addition to clinical-pathologic studies.
Finally, mixed pathologies in clinically probable AD and amnestic MCI also have implications for the implementation and interpretation of clinical trials. Given that many persons with clinically probable AD have unrecognized mixed pathologies, and a clinical diagnosis of probable AD does not ascertain pathologically “pure” disease, it's not clear that persons with known vascular disease should be excluded from AD clinical trials. Moreover, if a drug trial shows a clinical effect, interpretation of the biological mechanism could potentially be through a vascular mechanism. Indeed, if the conversion of MCI to AD and the progression of clinical AD in some individuals include vascular insults, then drugs with primarily vascular mechanisms could be beneficial for the prevention, slowing, and treatment of a subset of cognitive decline in persons with clinical AD, i.e. those with unrecognized mixed pathologies.
This study has important strengths. We used two community based studies that use standard, uniform clinical and pathologic procedures. Participants had high follow-up rates, high autopsy rates and were evaluated proximate to death. Clinical diagnoses were made blinded to pathology results, while final pathologic diagnoses were made without knowledge of clinical diagnoses.
There are also limitations. Selection of subjects who volunteer may introduce bias by effectively decreasing pathology; this, however, is partially mitigated by high follow-up and autopsy rates. Another potential source of bias is inherent to autopsy studies; subjects who are impaired and have pathology are at greater risk of death and deceased subjects are a nonrandom subset of the cohort. Thus, it is possible that persons with multiple brain pathologies may be more prone to come to autopsy than persons with only a single or no pathology. Thus, one should use caution when extrapolating findings from autopsy studies to the general population. Another limitation is the lack of routine neuroimaging. While neuroimaging would not likely have affected the classification of probable AD since most criteria for vascular cognitive impairment require a temporal relation between a clinical vascular event and cognitive decline (44
), it is likely that some persons with possible AD would not have been found to have vascular disease and would have been included in the probable AD group. While the numbers are likely to be small, it's not clear how this would have affected our findings. Conversely, we did not include microscopic infarcts in our tables or analyses; and these would have further increased the numbers with mixed pathologies. Moreover, imaging studies suggest that white matter changes, some of which appears to be of vascular origin (45
), also contribute to cognitive impairment. Finally, we included neocortical Lewy bodies, but not limbic or nigral Lewy bodies as a mixed pathology. Together, these data suggest that we may be underestimating the extent to which co-existing conditions contribute to probable AD and MCI.