This study of a population-based, incident cohort of persons with AD found: first, that 30–58% of those who survived 5–7 years after dementia onset declined slowly; second, that AD progressed faster in women than in men; third, that number and severity of NPS increased over time, but the course was variable and episodic; and fourth, that rate of change in NPS was correlated weakly, if at all, with rate of change in cognition or function.
Several studies have noted a contrast between “fast” and “slow” progressors in AD (e.g.,(25
)), but studies of incident cases from populations are lacking. Approximately one-third to one-half of persons in the Cache County DPS fell into the slow progression category. By contrast, the multi-center French Network on Alzheimer Disease (REAL-FR) consisting of a volunteer sample of 686 individuals reported that 23% of their sample could be characterized as “slow” progressors.(27
) The French study also reported that 89% of their participants were receiving treatment for AD (cf.
, 22% of DPS participants). The lower figure is similar to estimates (26%) reported among Medicare beneficiaries with dementia.(28
) Nonetheless, our analyses suggest that slow dementia progression is not attributable to treatment with anti-dementia medications.
In the DPS sample, the mean ARC on the MMSE was considerably lower than was found in clinical or other convenience samples. For example, a mean ARC of −3.9 (SD=3.7) has been reported from the multicenter Consortium to Establish a Registry in AD,(8
) and rates of −2.97 (SD=4.26) for Possible AD and −3.05 (SD=3.86) for Probable AD in patients at California AD Centers.(29
) A meta-analysis of studies primarily from clinical/university research centers or hospitals reported a pooled ARC on the MMSE of of −3.3 (95% CI:−2.9 to −3.7).(30
) To our knowledge, the Kungsholmen project is the only population-based study that has reported an ARC on the MMSE. This was somewhat greater than in the DPS (−2.75 at the study’s first 3-year follow-up and −3.03 at the second follow-up after 3–7 more years).(31
) We speculate that the Kungsholmen cases may not have entered the longitudinal analysis as shortly after diagnosis as the DPS cases, and that their case cohorts may therefore show some of the same phenomena (survival bias, entry into study when MMSE decline was more rapid) as is likely in convenience samples.
Functional change in DPS participants was also quite variable. The REAL-FR study reported a mean change in CDR-sb of 4.17 over two years (2.09/year),(27
) an approximately 0.65 point faster rate of progression than was observed in DPS. However, differences in CDR versions used between studies make comparisons problematic.
In the behavioral domain, we observed increasing occurrence, rate, and overall severity of NPS over time, consistent with other studies (reviewed in (4
)). Change in severity of symptoms in the DPS was higher than that reported in REAL-FR. However, again, comparisons between studies are hampered due to differences in the NPI versions and baseline differences in NPI scores (mean=4.30 in DPS vs. 15.11 in REAL-FR). In the DPS, rate of change in NPS was marginally associated with change in CDR-sb, but not with change in MMSE. Although the lack of correspondence between dementia domains is consistent with other reports,(33
) these results may also reflect the crude measurements of change employed here. Alternate methods that characterize the non-linear nature of progression in each domain may reveal stronger associations.(34
) We also note that the occurrence of NPS varies with severity of dementia,(35
) creating problems for cross-study comparisons, and that symptoms tend to be correlated.(36
) Hence, a global summary score may not be optimal for examining associations between NPS and other clinical features of AD.
Among the variables examined, there was no consistent set of factors that influenced change across domains. In cognition, carriers of the APOE ε4
allele performed worse at baseline than did non-carriers but APOE
status did not affect rate of decline. Studies examining the effect of APOE
after dementia onset have found inconsistent results. Our findings are consistent with recent work suggesting that APOE ε4
exerts deleterious effects early in the disease course.(12
) In DPS, education was associated with higher MMSE scores at onset, but not with decline on any of the outcomes. This finding contrasts with studies reporting more rapid decline among those with more years of education,(37
) but is consistent with higher education conferring advantages early in the disease course.(38
) Differences in results may also reflect sample differences in years of education and the timing of observations along the course of dementia.
Older age was associated with worse cognition and function at baseline, while women declined more rapidly (in cognition) than men. More rapid decline among women with AD has been reported in some,(31
) but not all studies.(32
) The reasons for gender differences on rates of decline in AD are unclear and warrant further study.
Among the study limitations are the use of single measures of cognition, function and NPS. Some measures (e.g., MMSE) have been criticized for differential performance in classifying the cognitive status of individuals from different ages and educational backgrounds, and for significant floor effects when studying persons with severe dementia (reviewed in (43
)). We do not believe these issues substantially affected the results as a somewhat more sensitive measure, the 3MS, was employed in dementia screening in the Cache County population, and dementia diagnoses were based on rigorous clinical examination. Additionally, because we followed individuals with incident dementia, the majority (89%) of our participants did not reach the floor of this measure over the period of observation.
Other limitations included the missing MMSE scores at baseline and/or follow-up owing to sensory/motor impairments among 9% of the sample, the lack of follow-up among 29% of the sample (mostly due to death(44
)), and our cursory examination of the effects of anti-dementia medications on dementia progression. Here, we did not consider duration or consistency of medication use; a thorough examination of the effects of anti-dementia medications will be the topic of a subsequent paper on dementia treatments. Finally, the Cache County population is primarily Caucasian and of northern European descent. Thus, the results obtained here may not generalize to populations with different ethnic representation.
The study strengths include its population base, its focus on incident cases, the characterization of course in the three domains of dementia, the extended follow-up after dementia onset, and the high participation rates observed in dementia ascertainment and over the period of observation.
In conclusion, a significant proportion of individuals with AD exhibit a slowly progressive course. The present results in general suggest important differences between population- vs. clinic-based samples. As the DPS continues to accrue additional observations, we will focus our efforts on identifying factors that moderate dementia progression, in addition to those we have described earlier (e.g.,(39