In a group of more than 2,000 old people followed annually for up to 16 years, we assessed change in cognitive function during the prodromal phases of AD and its precursor, MCI. Rate of cognitive decline increased sharply about 5 to 6 years before dementia was diagnosed and showed a modest increase approximately of 4 to 6 years before MCI was diagnosed. The results indicate that dementia in AD is preceded by many years of progressively accelerating cognitive decline.
We are aware of only one previous study of cognitive change preceding development of MCI and results were comparable to the present study, with accelerated cognitive decline 3 to 4 years before the MCI diagnosis [9
]. In addition, we found that the prodromal period for amnestic MCI began 1 to 2 years earlier than the nonamnestic MCI prodrome and was characterized by more rapid cognitive decline. These findings are consistent with neuroimaging [29
] and neuropathologic [19
] data suggesting that many people with amnestic MCI actually have mild AD.
As noted above, estimates of the temporal course of cognitive decline prior to dementia onset in AD have varied widely. The 5 to 6 years of cognitive decline preceding dementia observed in the present study is close to the midpoint of comparable studies [3
]. Several factors are probably contributing to this variability. One suggested by the present analyses is the extent to which symptomatic individuals are included. When we excluded people with MCI at baseline, the prodromal period was briefer and the acceleration of cognitive decline was more marked. This may be because individuals with more mild disease take longer to transition from no cognitive impairment to dementia and so are less likely to be identified with observation periods of less than 2 or 3 decades. Another factor contributing to variability in findings is study differences in the effective cutpoint for dementia. Thus, in a diagnostic system that regards MCI as mild AD [30
], the cognitive prodromal period is relatively brief [6
]. By contrast, in the study with the longest estimate of the prodromal period [5
], the mean Mini-Mental State Examination score in the pre-AD group declined below 20 before the diagnosis was made, a relatively low dementia cutpoint.
There is also evidence that prodromal cognitive decline in AD varies across cognitive domains. We found that prodromal decline in semantic memory and working memory preceded decline in other cognitive domains, consistent with findings from the PAQUID study [5
]. However, the differences between domains in this study were not large and other studies suggest that prodromal decline in AD begins in other domains, including episodic memory [8
] and visuospatial ability [6
]. Thus, cognition is clearly globally affected in the prodromal phase of AD, and some of the variability between cognitive outcomes probably reflects metric factors including retest effects [31
] rather than the cognitive domain being assessed. On the other hand, prodromal cognitive decline in amnestic MCI began earlier and progressed more rapidly than in nonamnestic MCI, in line with neuropathologic [32
] and neuroimaging [34
] data suggesting that medial temporal lobe structures that support episodic memory are among the first brain regions affected by the disease.
These data show that by the time individuals meet clinical criteria for a diagnosis of AD, they have already experienced many years of accelerating cognitive decline. This has important public health implications because it is generally assumed that treatments for AD will be more effective if introduced before this prodromal period begins and cognitive systems are manifestly dysfunctional. Further, an effective early treatment could compress the cognitive morbidity of AD [36
] whereas effective treatment after dementia onset might prolong it, underscoring the need for biologic and behavioral markers to aid in early diagnosis.
Little cognitive decline was evident in people who did not develop MCI or AD. This observation is consistent with prior research [5
] and suggests that cognitive decline may not be an inevitable consequence of old age.
Strengths and limitations of this study should be noted. Clinical classification of MCI, dementia, and AD was based on a uniform clinical evaluation and widely accepted criteria applied by experienced clinicians, thereby minimizing diagnostic error. The large cohort, high rate of follow-up participation, and availability of previously established psychometrically sound measures of cognition allowed us to capture subtle nonlinear changes in function. The principal limitation is that subjects are selected and so the generalizability of the findings will need to be established.