Early detection of Alzheimer's disease and dementia in the general population : results from the Kungsholmen project

Abstract

This doctoral thesis investigates early predictors of Alzheimer's disease (AD) and dementia in the general population, and verifies the accuracy of different syndromes of cognitive impairment for predicting progression to dementia in a dementia-free cohort of 1435 persons aged 75-95 from the Kungsholmen Project, Stockholm, Sweden. Persons were reexamined after 3 and 6 years to detect incident cases of dementia and AD (DSM-III-R criteria).

In Study I, the evolution of persons with Cognitive Impairment, No Dementia (CIND) was explored. CIND was defined as scoring I standard deviation below age- and education- specific norms on a test of global cognitive functioning. The evolution was heterogeneous; similar proportions of persons with CIND died, progressed to dementia, and remained stable or improved. Subjects with CIND had a 3-fold increased risk of progressing to dementia over 3 years compared to cognitively intact elderly, and a 2-fold increased risk of death. Individuals who improved at I' follow-up did not have a significantly higher risk of later progressing to dementia than persons who had never been impaired.

In Study II, persons with CIND were more likely to have an anxiety disorder and symptoms of suspiciousness than cognitively intact elderly. In Study III, a simple 3-step procedure, analogous to clinical practice, was evaluated to detect persons who would develop dementia after 3 years. A high positive predictive value was found; between 88- 100% of persons with memory complaints (step 1), global cognitive impairment (step 2), and deficits in episodic memory or verbal fluency (step 3) progressed to dementia over 3 years. However, the sensitivity of the procedure was poor, as only 18% of persons in the preclinical stage of dementia exhibited impairment on all 3 measures.

In Study IV, the occurrence and predictivity for dementia of 7 syndromes of cognitive impairment were examined, including previously proposed criteria for Mild Cognitive Impairment (MCI) subtypes, and modified versions, which relaxed the criterion for normal general cognitive functioning. MCI-amnestic was the least common MCI type, and MCI-single-nonmemory was the most frequent. Modified criteria increased the occurrence of all MCI subtypes and increased predictivity of MCIamnestic for future AD. Persons with MCI-multidomains and MCI-amnestic had significantly increased relative risks for future AD. Original and modified criteria for MCI subtypes were not able to identify 3.6% of the population who only have global cognitive deficits, but have a 16-fold risk for AD.

In Study V, the presence of neuropsychiatric symptoms in persons with different subtypes of MCI was examined, and their contribution to the prediction of AD was evaluated. Compared to cognitive intact elderly, elevated neuropsychiatric symptoms were found in persons with MCI-amnestic and MCImultidomains. Motivation-related depressive symptoms were associated with a nondegenerative outcome in persons with MCI-multidomains. Anxiety symptoms were predictive of 3-year progression to AD in persons with MCI-amnestic or MCI-multidomains. In persons with no detectable cognitive deficits, mood-related depressive symptoms predicted impending AD.

In summary, at the population level, cognitive impairment in nondemented elderly is a heterogeneous condition, dementia being one of 3 main outcomes. A 3-step procedure that simulates routine clinical practice can identify with high predictivity those persons who will progress to dementia, but the sensitivity of this procedure is low, as less than one fifth of future dementia cases can be identified. Previously proposed criteria for MCI can detect only half of the persons with cognitive deficits in the general population, but subtypes of MCI-amnestic and MCI-multidomains have high predictive power for identifying persons who will develop AD. A simple modification of the criteria increases the occurrence without diminishing the predictivity. Furthermore, psychiatric evaluation of persons with MCI can help to better identify a neurodegenerative progression in syndromes of cognitive impairment.