In this broadly defined clinical sample of cognitively impaired, non-demented patients presenting with memory complaints, each predictor’s effect was consistent with other studies that examined predictors of MCI conversion to AD (25
), with the exception of apolipoprotein E ε4 carrier status that was not significant when included with other predictors in logistic regression analyses. Sampling differences may account for discrepancies across studies; apolipoprotein E ε4 carrier status is a significant predictor in several studies (25
) but some recent reports indicate weak prediction (29
In the 3-year follow-up sample, individual baseline measures significantly predicted future conversion to AD but the five-predictor combination markedly improved prediction. The five-predictor combination led to very strong prediction at the MCI stage, exceeding consensus threshold criteria for markers of AD of sensitivity >80% and specificity > 80% (31
). The five-predictor combination markedly added predictive value above the combination of age and MMSE at a 10% false positive rate, and positive and negative likelihood ratios confirmed strong prediction. A low false positive rate is necessary when predicting likely conversion to AD, i.e., predicting AD when the patient does not develop AD can lead to adverse clinical consequences. The findings indicate that knowing the patient’s age and administering the MMSE, a combination commonly used by practicing physicians, are together insufficient to accurately predict conversion to AD.
The diagnosis of MCI requires lack of impairment in activities of daily living (17
). This is the first study to explicitly examine informant report of impairment in complex social/cognitive abilities, which can be impaired in MCI patients, and odor identification deficits together as predictors of conversion to AD. These inexpensive measures do not require prior training to administer: FAQ 2–3 minutes (can be self-report), UPSIT 12–15 min (multiple choice, can be self-administered). In the predictor models, for 10% false positives the combination of SRT immediate recall, FAQ and UPSIT, together with age and MMSE, led to strong predictive accuracy.
The combination of SRT immediate recall with age, MMSE and the MRI variables also led to fairly strong prediction. Neuropsychological testing of episodic verbal memory and other cognitive abilities is time-consuming and can be expensive. MRI volumetric evaluation of hippocampal and entorhinal cortex volumes is expensive and currently limited to research/academic centers. Nonetheless, neuropsychological and MRI assessment improve prediction of conversion to AD, provide other useful diagnostic information, and their serial assessment may clarify the MCI/AD diagnosis. A trained MRI rater, after completing image alignment, can assess hippocampal volume in 30–45 minutes and entorhinal cortex volume in 15–20 minutes using this study’s methods (22
). Since MRI hippocampal and entorhinal cortex volumetric assessment techniques vary by research group, their identified algorithm cutoffs may not apply for other assessment methods. In contrast, the SRT, UPSIT and FAQ employ uniform administration and scoring.
In other studies, combining MMSE/verbal recall measures with MRI hippocampal volume/medial temporal lobe atrophy or apolipoprotein E genotype led to moderately strong accuracy (65–84% correctly classified) in predicting conversion to AD (25
). We found that adding olfactory identification deficits and informant report of functional impairment, and entorhinal cortex volume, led to strong predictive accuracy (92.5% correctly classified) that was appreciably higher than prior reports (25
). The predictor algorithm developed from the data obtained in our study emphasizes the need to examine multiple predictors.
For the five-predictor combination, similar findings were obtained in the amnestic MCI, high baseline MMSE, and 5-year follow-up sub-samples. Strong prediction in the high MMSE (≥ 27/30) group is clinically important because diagnosis and estimation of prognosis is difficult in patients with minimal global cognitive impairment.
The individual effects of olfactory identification deficits and informant report of functional impairment were consistent with related reports (9
), and the combined effects of episodic memory deficits and MRI volumetric measures were highly consistent with the literature (14
). For the algorithm, to reduce the risk of over-fitting, the cutoff scores for the 5 predictors were identified from their individual ROC curves and not from their combined ROC curve. Since SRT immediate recall, UPSIT and hippocampal volume declined with increasing age (5
), and SRT immediate recall correlated with education in years, the optimal algorithm cutoffs for the five predictor variables may need alteration when applied in older, less educated samples. A complete independent external validation in a larger sample is needed, but to date no other study has evaluated informant report of functional impairment and odor identification deficits together with neuropsychological and MRI volumetric measures. Further, using the five-predictor combination does not preclude the need for proper subsequent verification of diagnostic classification.
The MRI, olfactory and verbal recall measures tapped into early AD pathology: neurofibrillary tangles begin in trans-entorhinal cortex and progress through limbic areas to neocortex (34
). Impairment in complex, integrated brain functions were sensitive to incipient AD: short + long-term verbal memory (SRT immediate recall incorporates encoding with recognition, comparison to a bank of memories, retrieval over 6 consecutive trials), odor identification (UPSIT incorporates odor detection, odor memory, odor naming) and complex cognitive/social functional abilities (FAQ informant report captures the behavioral output of multiple brain regions acting together).
Gender, obesity, vascular risk factors, and family history predict dementia in large-scale epidemiologic studies. Given the known small effect size of these variables, they were not hypothesized predictors in this clinical sample. In secondary analyses, we examined gender, body mass index and family history, and none were significant predictors (data not shown).
This study had some limitations. The study was conducted in a University academic medical center; the results need validation in broader clinical settings and cannot be directly applied to the general elderly population. The sample inclusion/exclusion criteria were broader than the narrowly defined amnestic MCI samples studied by other groups (3
), but they did identify a clinically relevant, heterogenous group of patients. The findings in our large amnestic MCI subsample were consistent with the results obtained in the entire sample, thus permitting direct comparison to other studies that restricted their samples to amnestic MCI patients (3
). The raters were not blind to one of the selected predictors, SRT immediate recall, which was part of the neuropsychological test battery. However, the expert raters employed strict diagnostic methods, and the diagnoses were indirectly supported by differences in global cognitive decline in converters versus non-converters. Patients with stroke or MRI cortical or large lacunar infarctions were excluded, reducing the chance of cerebrovascular disease influencing MCI conversion to AD (35
Other measures that strongly distinguish AD from controls and potentially predict MCI conversion to AD include decreased temporoparietal metabolism with FDG PET (36
) and increased uptake of ligands that label amyloid using PET (37
). PET has high costs and limited availability. PET amyloid imaging may not show disease progression because maximal brain amyloid saturation occurs early in AD (39
). Cerebrospinal fluid (CSF) elevated tau or phosphorylated tau levels, and decreased amyloid ßeta42
levels, and their ratio, have been shown to strongly predict MCI conversion to AD (40
). Future studies will need to assess these CSF measures when combined with other predictors. Lack of patient acceptability of lumbar puncture can be a limitation. A recent report showed that combining immune and related plasma markers strongly separated AD from controls and predicted MCI conversion to AD in a small MCI sample, but independent replication in a larger sample is needed (41
In our study, a combination of five measures led to strong predictive accuracy for MCI conversion to AD, and markedly added value to the combination of age and MMSE. These findings clearly need independent replication in larger samples before widespread clinical use is justified. Another potential use is to enrich patient selection in treatment trials.