Health economic evaluation of treatments for Alzheimer's disease: impact of new diagnostic criteria.

The socio-economic impact of Alzheimer's disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost-effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease-modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost-effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD-dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end-points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long-term effects. To improve cost-effectiveness studies, long-term population-based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end-points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered.

Advances in the prevention of Alzheimer's disease and dementia.

BACKGROUND: Definitions and diagnostic criteria for all medical conditions are regularly subjected to reviews and revisions as knowledge advances. In the field of Alzheimer's disease (AD) research, it has taken almost three decades for diagnostic nomenclature to undergo major re-examination. The shift towards presymptomatic and pre-dementia stages of AD has brought prevention and treatment trials much closer to each other than before. METHODS: Here we discuss: (i) the impact of diagnostic reliability on the possibilities for developing preventive strategies for AD; (ii) the scientific evidence to support moving from observation to action; (iii) ongoing intervention studies; and (iv) the methodological issues and prospects for balancing strategies for high-risk individuals with those for broad population-based prevention. RESULTS: The associations between neuropathology and cognition are still not entirely clear. In addition, the risk factors for AD dementia and the neuropathological hallmarks of AD may not necessarily be the same. Cognitive impairment has a clearer clinical significance and should therefore remain the main focus of prevention. Risk/protective factors for dementia/AD need to be studied from a life-course perspective. New approaches in prevention trials include enrichment strategies based on genetic risk factors or beta-amyloid biomarkers (at least four ongoing pharmacological trials), and multidomain interventions simultaneously targeting various vascular and lifestyle-related risk factors (at least three ongoing trials). Experience from prevention programmes in other chronic diseases can provide additional methodological improvements. CONCLUSIONS: Building infrastructures for international collaborations is necessary for managing the worldwide public health problem of AD and dementia. The International Database on Aging and Dementia (IDAD) and the European Dementia Prevention Initiative (EDPI) are examples of ongoing international efforts aiming to improve the methodology of preventive studies and provide the basis for larger intervention trials.

Using Clinical Decision Intelligence Applications to Improve Pathways For Earlier Detection Of Underrecognized Cognitive Disorders.

Cost estimates for care for those with dementia and other cognitive impairments are rising globally, estimated to reach US $1 trillion by 2025. Lack of specialized personnel, infrastructure, diagnostic capabilities, and healthcare access impedes the timely identification of patients progressing to dementia, particularly in underserved populations. International healthcare infrastructure may be unable to handle existing cases in addition to a sudden increase due to undiagnosed cognitive impairment and dementia. Healthcare bioinformatics offers a potential route for quicker access to healthcare services; however, a better preparedness plan must be implemented now if expected demands are to be met. The most critical consideration for implementing artificial intelligence/machine learning (AI/ML) -driven clinical decision intelligence applications (CDIA) is ensuring patients and practitioners take action on the information provided.

Revisiting the Cholinergic Hypothesis in Alzheimer's Disease: Emerging Evidence from Translational and Clinical Research.

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "Cholinergic Hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

Incidence of AD may decline in the early 90s for men, later for women: The Cache County study.

OBJECTIVES: To characterize the incidence of AD among the elderly population of Cache County, UT, noted for its longevity and high response rates; to explore sex differences; and to examine whether AD incidence plateaus or declines in extreme old age. METHODS: Using a multistage screening process in 1998 and 1999, and re-examining 122 individuals who had been identified 3 years earlier as cognitively compromised but not demented, the authors found 185 individuals with incident dementia (123 with AD) among 3,308 participants who contributed 10,541 person-years of observation. Adjusting for nonresponse and screening sensitivity, the authors estimated the incidence of dementia and of AD for men and women in 3-year age intervals. Multivariate discrete time survival analysis was used to examine influences of age, sex, education, and genotype at APOE, as well as interactions of these factors. RESULTS: The incidence of both dementia and AD increased almost exponentially until ages 85 to 90, but appeared to decline after age 93 for men and 97 for women. A statistical interaction between age and the presence of two APOE-epsilon 4 alleles indicated acceleration in onset of AD with this genotype; the interaction of age and one epsilon 4 suggested more modest acceleration. A statistical interaction of sex and age indicated greater incidence of AD in women than in men after age 85. CONCLUSIONS: The incidence of AD in the Cache County population increased with advancing age, but then peaked and declined among the extremely old. The presence of APOE-epsilon 4 alleles accelerated onset of AD, but did not appreciably alter lifetime incidence apparent over a span of 100 years.

Performance characteristics of a two-stage dementia screen in a population sample.

We analyzed the performance of a two-stage screening protocol [the Modified Mini-Mental State Exam (3MS) or the Informant Questionnaire for Cognitive Decline (IQCODE), and the Dementia Questionnaire (DQ)] in a weighted stratified sample of 839 subjects from a population survey of dementia in Cache County, UT. The subjects were subsequently examined using a standardized diagnostic assessment protocol. Using the method of receiver operating characteristic (ROC) analysis, the main outcome measure was area under the ROC curve (AUC). The overall AUC estimates were 0.956 (95% confidence interval 0.943-0.968) for the 3MS/IQCODE and 0.945 (0.931-0.960) for the DQ. After adjustment for age, the efficiency of the both 3MS/IQCODE and the DQ was better for subjects with genotype epsilon4/epsilon4 at APOE, better among women, and better in those with two or more years duration of dementia. The optimal threshold for this two-stage screen yielded sensitivity and specificity estimates of 91.0% and 92.0%, respectively.

Does NSAID use modify cognitive trajectories in the elderly? The Cache County study.

BACKGROUND: Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful for the prevention of Alzheimer disease (AD). By contrast, clinical trials have not supported NSAID use to delay or treat AD. Few studies have evaluated cognitive trajectories of NSAID users over time. METHODS: Residents of Cache County, UT, aged 65 or older on January 1, 1995, were invited to participate in the study. At baseline, participants provided a detailed inventory of their medications and completed a revised Modified Mini-Mental State Examination (3MS). Participants (n = 3,383) who were cognitively normal at baseline were re-examined after 3 and 8 years. The association between NSAID use and 3MS scores over time was estimated using random effects modeling. RESULTS: Associations depended upon when NSAIDs were started and APOE genotype. In participants who started NSAID use prior to age 65, those with no APOE epsilon4 alleles performed similarly to nonusers (a difference of 0.10 points per year; p = 0.19), while those with one or more epsilon4 allele(s) showed more protection (0.40 points per year; p = 0.0005). Among participants who first used NSAIDs at or after age 65, those with one or more epsilon4 alleles had higher baseline scores (0.95 points; p = 0.03) but did not show subsequent difference in change in score over time (0.06 points per year; p = 0.56). Those without an epsilon4 allele who started NSAID use after age 65 showed greater decline than nonusers (-0.16 points per year; p = 0.02). CONCLUSIONS: Nonsteroidal anti-inflammatory drug use may help to prevent cognitive decline in older adults if started in midlife rather than late life. This effect may be more notable in those who have one or more APOE epsilon4 alleles.

Major depression and cancer: the 13-year follow-up of the Baltimore epidemiologic catchment area sample (United States).

OBJECTIVE: The relationship between depression and development of cancer is not well understood, with some studies finding a significant but small increase in risk for cancer among persons with depression. No studies have employed standardized interviews keyed to the diagnostic criteria for Major Depression. Our objective was to evaluate the relationship between Major Depression at baseline and new onset of cancer at follow-up. METHOD: The study was based on a population-based 13-year follow-up survey of community-dwelling adults living in East Baltimore in 1981. After excluding 372 persons with a history of cancer or those whom reported their health as poor at the baseline interview, 3109 adults remained. Information on baseline depression status and cancer at follow-up was available for 2017 persons. A diagnosis of cancer was ascertained at follow-up through interview of survivors and from death certificates. RESULTS: There were 203 new cases of cancer among 2017 persons at risk. Neither Major Depression (relative risk (RR) = 1.0, 95% confidence interval (CI) 0.5-2.1) nor dysphoric episode (RR = 1.3, 95% CI 0.9-1.9) were significantly associated with increased risk of cancer at follow-up. However, among women with Major Depression, the risk of breast cancer was increased (adjusted RR = 3.8, 95% CI 1.0-14.2). CONCLUSIONS: We found no overall association of depression with cancer. However, among women, Major Depression (but not dysphoric episode alone) was associated with the onset of breast cancer.

Dementia: the leading predictor of death in a defined elderly population: the Cache County Study.

OBJECTIVE: To examine the relative risk and population attributable risk (PAR) of death with dementia of varying type and severity and other risk factors in a population of exceptional longevity. METHODS: Deaths were monitored over 5 years using vital statistics records and newspaper obituaries in 355 individuals with prevalent dementia and 4,328 without in Cache County, UT. Mean age was 83.3 (SD 7.0) years with dementia and 73.7 (SD 6.8) years without. History of coronary artery disease, hypertension, diabetes, and other life-shortening illness was ascertained from interviews. RESULTS: Death certificates implicated dementia as an important cause of death, but other data suggested a stronger association. Adjusted Cox relative hazard and PAR of death were higher with dementia than with any other illness studied. Relative hazard of death with dementia was highest at ages 65 to 74, but the high prevalence of dementia after age 85 resulted in 27% PAR among the oldest old. Mortality increased substantially with severity of dementia. Alzheimer disease shortened survival time most dramatically in younger participants, but vascular dementia posed a greater mortality risk among the oldest old. CONCLUSION: In this population, dementia was the strongest predictor of mortality, with a risk two to three times those of other life-shortening illnesses.