In this prospective study of subjects who fulfilled the criteria for MCI due to AD1
and prodromal AD2
based on abnormal CSF Aβ1–42
, we found that during a mean follow-up of 2.2 years 63 subjects (57%) progressed to AD-type dementia. High CSF levels of t-tau and p-tau and hippocampal atrophy predicted progression to dementia and declines in MMSE score.
The overall annual conversion rate to dementia of approximately 20% in this study was higher than the conversion rate typically observed in subjects with MCI unselected for biomarker status.25
For comparison, subjects with MCI and a normal concentration of CSF Aβ1–42
in our dataset had an annual conversion rate of less than 10% (data not shown). Still, a considerable percentage of our subjects did not develop AD-type dementia within the follow-up period. Because abnormal Aβ is suggested to be an early marker for AD,3
higher progression rates to AD-type dementia might be expected with a longer follow-up period.
The rapid decline to dementia in subjects with high CSF levels of t-tau and p-tau and hippocampal atrophy could mean that these subjects either had a more aggressive course of the disease or were already in a more advanced stage when assessed at baseline. Slope analyses suggested that they had a more aggressive course of the disease because they showed a more rapid decline in MMSE score than subjects with normal values of these markers at baseline. This finding is in line with previous studies that showed a more rapid cognitive decline in subjects with AD-type dementia with high levels of CSF tau.26,27
Subjects with hippocampal atrophy may have also already been in a more advanced stage of the disease at baseline because they had lower MMSE scores at baseline than subjects without hippocampal atrophy. This result is consistent with the previously suggested order of events in the amyloid cascade,3,4
with hippocampal atrophy being a relatively late feature of AD pathology. In a previous study in subjects with MCI and biomarker evidence of Aβ pathology, hippocampal atrophy also predicted time to dementia.28
In another study in subjects with MCI who all progressed to AD-type dementia, CSF t-tau, CSF p-tau, and hippocampal atrophy were also associated with rapid progression from MCI to AD-type dementia, whereas CSF Aβ1–42
Our finding that the predictive value of the respective CSF and MRI markers for progression to AD-type dementia remained after correction for baseline MMSE score indicates that AD biomarkers can have prognostic value in addition to clinical measures alone.
The predictive accuracy of CSF t-tau and p-tau and hippocampal atrophy we observed in our MCI subjects with abnormal CSF Aβ1–42
was lower than that reported in studies conducted in subjects with MCI regardless of amyloid biomarker status7–9,23
Most likely this is because in our analyses only the additional predictive effect relative to abnormal amyloid was tested, although differences could partly also be due to differences in setting and other study characteristics.
We found no differences in age, gender, and APOE status between subjects with and without dementia at follow-up, although age, gender, and APOE genotype are known risk factors for AD in the general population. A possible explanation for this finding is that advanced age and APOE ϵ4 genotype are risk factors for development of abnormal Aβ processing but do not influence clinical progression once abnormal Aβ processing is established.
We included subjects with MCI and abnormal amyloid. According to the criteria of the National Institute on Aging and the Alzheimer Association,1
these subjects would meet the criteria for “MCI due to AD−intermediate likelihood.” Of the 65 subjects with both CSF and MRI data available, 9 subjects (14%) had both normal CSF t-tau and normal hippocampal volume and met the criteria for “MCI, biomarker evidence uninformative.” The course of the disease in these subjects was relatively benign with a 27% conversion rate to AD-type dementia after 4 years, although the interpretation is limited by the small sample size. Twenty-eight subjects (43%) had both abnormal CSF t-tau and hippocampal atrophy and fulfilled the criteria for “MCI due to AD−high likelihood.”1
Their prognosis was poor, with 91% progressing to AD-type dementia after 4 years. In 28 subjects (43%), the injury markers were conflicting, with either CSF t-tau abnormal or hippocampal volume abnormal. According to the National Institute on Aging and the Alzheimer Association criteria, it is not clear whether these subjects should be diagnosed as “MCI, biomarker evidence uninformative” or “MCI due to AD−high likelihood.”1
Our data suggest that these subjects should be considered as “MCI due to AD−high likelihood” because the decline in MMSE score and progression rate to AD-type dementia (81%) was similar to that of subjects with both markers abnormal, whereas the rate of decline on the MMSE was worse than that of subjects with both markers normal, although group comparisons are hampered by the small sample size.
Two subjects included in the study progressed to other types of dementia, despite abnormal CSF Aβ1–42
levels at baseline. One subject, aged 75 years, had extrapyramidal signs at baseline and was later diagnosed with Parkinson disease dementia. CSF Aβ1–42
was 326 pg/mL, CSF t-tau and CSF p-tau were normal, and hippocampal volume was not available. Decreased CSF Aβ1–42
has been described before in subjects with alpha-synucleinopathies.29
This finding highlights the importance of ruling out causes for the cognitive symptoms other than AD before the criteria for MCI due to AD can be applied.1
The other subject, aged 61 years, was diagnosed with vascular dementia at follow-up. She had a CSF Aβ1–42
concentration of 357 pg/mL and abnormal CSF t-tau and p-tau concentrations. On the MRI scan she had multiple vascular white matter lesions and parietal atrophy, in the absence of hippocampal atrophy. In retrospect, this subject may have had mixed dementia with both vascular and AD pathology.
A major limitation of our study is that we did not have MRI data available for all subjects, which limited the possibilities for multivariate analyses. Another limitation is the limited follow-up. Studies with longer clinical follow-up are needed to assess whether all subjects with MCI due to AD will indeed develop dementia eventually.
Our results indicate that markers of AD-related neuronal injury, such as CSF levels of t-tau and p-tau and hippocampal atrophy, could help to identify those subjects with MCI due to AD who will more rapidly progress to dementia. Subjects with both abnormal CSF Aβ1–42 and abnormal injury markers, thereby fulfilling the criteria for “MCI due to AD−high likelihood,” showed the most rapid cognitive decline and a high progression rate to AD-type dementia, even within our limited follow-up period.