A growing body of evidence suggests that LR11 is intricately involved in the pathogenesis of AD.4,5,7-9
This study characterized the expression of LR11 in MCI using a novel quantitative immunohistochemical procedure, which avoids limitations of semiquantitative methods and allows more powerful statistical analyses. We confirmed and extended our earlier findings that LR11 expression is reduced in AD compared with age-matched control cases with an independent and more mildly affected cohort.4,5
Surprisingly, we also found highly variable LR11 expression among MCI cases, showing two distinct MCI subgroups. The MCI-H subgroup is characterized by robust, control-like LR11 neuronal immunostaining, whereas the MCI-L subgroup exhibited a marked reduction in LR11, similar to that seen in AD. Further examination demonstrated that although both MCI subgroups showed significant AD pathology, the MCI-L subgroup showed more severe cognitive impairment. These findings suggest that LR11 expression distinguishes two MCI subgroups and that the low LR11 subgroup has greater cognitive impairment, reflecting a phenotype similar to AD.
Unlike the consistently high levels of LR11 in NCI and consistently low levels in AD, our analyses demonstrated a bimodal distribution in MCI. Although the identification of two distinct subgroups was unexpected, it is logical considering the clinical heterogeneity of MCI. Because MCI is a relatively new clinical entity with widely varying criteria11,13,33
and individuals with MCI convert to AD at a greater rate than those with normal cognition, it is often considered a prodromal stage of AD.10,14
However, individuals with MCI have heterogeneous neuropsychological profiles, and not all MCI cases progress to AD.34
The highly variable LR11 expression seen in MCI and the stratification of cases into distinct subgroups by LR11 expression is a particularly exciting finding with implications for early diagnosis of AD.
Of the demographic, clinical, and pathological measures examined, the MCI subgroups defined by LR11 expression differed only in GCS, a general measure of cognitive performance. Moreover, LR11 levels strongly correlated with GCS across all cases, suggesting that LR11 expression may serve as a marker of disease severity. Much effort has been devoted to the identification of pathological correlates for symptom severity in AD.35-37
However, the lack of correlation with amyloid pathology and the weak correlation with neurofibrillary tangles have been disappointing.38-41
The best known correlate of cognitive dysfunction in AD is synaptic density,42-44
and it is interesting to note that the loss of other low-density lipoprotein receptor family members may contribute to synaptic loss and the resultant cognitive impairment.45,46
Our findings provide evidence that reduced LR11 expression may predispose individuals to cognitive impairment and the development of AD. Given the growing body of evidence linking LR11 to amyloid pathology, additional examination of the relation between LR11 and cognitive ability should be illuminating.
Because MCI is highly heterogeneous, and not all MCI cases will ultimately progress to AD, lower LR11 levels may identify cases likely to develop AD. Memory impairment is the hallmark symptom of AD, and it has been proposed that the amnestic subtype of MCI represents the earliest stage of AD, whereas the other subtypes may presage other forms of dementia.11,13,14,34,47
However, studies focusing exclusively on amnestic MCI37,48,49
have been shown to have low predictive value,29,50,51
suggesting that concentrating on this group may lead to inadvertent exclusion of cases that progress to AD. This cohort includes a heterogeneous mix of both amnestic and nonamnestic MCI subtypes. Given the range of MCI subtypes represented in our cohort, it is compelling that the subset of MCI cases with low, AD-like LR11 expression also shows the greatest degree of cognitive impairment. Moreover, LR11 neuronal expression in MCI displayed a bimodal distribution, suggesting that those cases with lower levels of LR11 expression may be at greater risk for progression to AD.
In summary, we have shown that LR11 expression can be measured quantitatively, that LR11 expression demonstrates two distinct MCI subgroups, and that LR11 levels are related to cognitive impairment. The recent report that LR11 is genetically linked to sporadic AD provides direct evidence that LR11 is causally linked to the development of the disease.9
When combined with evidence that LR11 modulates Aβ production4,8
and our current findings that LR11 expression is reduced in a subset of MCI cases with more cognitive impairment, it appears increasingly likely that the loss of LR11 is a causal event in the AD pathological cascade.