H. Michael Arrighi

Forecasting the global burden of Alzheimer's disease.

Our goal was to forecast the global burden of Alzheimers disease and evaluate the potential impact of interventions that delay disease onset or progression.

Mild cognitive impairment: Disparity of incidence and prevalence estimates

The purpose of conducting this study was to identify areas of concordance and sources of variation for the published rates of prevalence and incidence associated with various definitions for mild cognitive impairment (MCI).

Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis

BACKGROUND Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimers disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors. METHODS Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patients treatment, APOE ɛ4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA. FINDINGS 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of APOE ɛ4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001). INTERPRETATION ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE ɛ4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden. FUNDING Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth Pharmaceuticals, and Pfizer.

Worldwide variation in the doubling time of Alzheimer's disease incidence rates

The doubling time is the number of chronological years for the age‐specific incidence rate to double in magnitude. Doubling times describe the rate of increase of the risk of Alzheimers disease (AD) with advancing age. Estimates of doubling times of AD assist in understanding disease etiology and forecasting future disease prevalence. The objective of this study was to investigate regional and gender differences in the doubling of AD age‐specific incidence rates.

Hip fracture risk and subsequent mortality among Alzheimer's disease patients in the United Kingdom, 1988–2007

BACKGROUND hip fractures result in a significant burden to the patient, their caregivers and the health care system. Patients with Alzheimers disease (AD) have a higher incidence of hip fracture compared with other older people without AD, although it is not clear if AD is an independent risk factor for hip fracture. METHODS a retrospective cohort study was conducted using anonymised electronic medical records from primary care practices in the United Kingdom. Proportional hazards regression modelling with adjustment for potential confounders was used to evaluate AD as an independent risk factor for predicting hip fractures. RESULTS the incidence of hip fracture among patients with and without AD was 17.4 (95% CI, 15.7-19.2) and 6.6 (95% CI, 5.8-7.6) per 1,000 person years, respectively. Patients with AD had a hazard that was 3.2 (95% CI, 2.4-4.2) times that of non-AD patients after controlling for potential confounders. AD patients who experienced a hip fracture also had an increased mortality rate compared with non-AD patients who experienced a hip fracture (hazard ratio = 1.5; 95% CI, 1.1-1.9). CONCLUSION patients with AD and their caregivers should be advised on how to prevent hip fractures and more attention should be given to AD patients who are undergoing rehabilitation following a hip fracture.

Apolipoprotein E ε4 Prevalence in Alzheimer’s Disease Patients Varies across Global Populations: A Systematic Literature Review and Meta-Analysis

Background: The Ε4 allele of apolipoprotein E (APOE) is associated with Alzheimer’s disease (AD). However, attributable risk due to APOE4 varies by region and by race/ethnicity. Methods: A literature review and meta-analysis were conducted to estimate the prevalence of APOE4 by geographic area among AD patients. Results: Although estimates varied significantly by study design and case definition, AD patients recruited in Asian and southern European/Mediterranean communities seemed to have significantly lower E4 carrier status estimates (37 and 43%) than those recruited in North America (58%) or northern Europe (64%; all: p < 0.05). Conclusions: APOE4 genotype frequency varies among AD patients in regional patterns similar to that of the general population. Study level differences may also contribute to the heterogeneity of published estimates of APOE4 in AD cases.

Rate of Conversion from Prodromal Alzheimer's Disease to Alzheimer's Dementia: A Systematic Review of the Literature

Background: The purpose of this study was to summarize published estimates for conversion from mild cognitive impairment or amnestic mild cognitive impairment to Alzheimers dementia. We carried out a systematic review of English language publications to identify cohort studies published since January 2006 that reported the risk or rate of conversion. Summary: Thirty-two cohort studies were identified, of which 14 reported annualized conversion rates (ACRs). Conversions over 1 year ranged from 10.2 to 33.6% (5 studies, median: 19.0%), and over 2 years from 9.8 to 36.3% (7 studies, median: 18.6%). ACRs ranged from 7.5 to 16.5% (7 studies, median: 11.0%) per person-year for studies recruiting from clinics, and from 5.4 to 11.5% (7 studies, median: 7.1%) for community samples. Key Message: Extensive variation was observed in conversion rates due to the population sampled, diagnostic criteria, and duration, and because many studies did not account for loss to follow-up.

The Impact of Alzheimer's Disease on the Chinese Economy

Background Recent increases in life expectancy may greatly expand future Alzheimers Disease (AD) burdens. Chinas demographic profile, aging workforce and predicted increasing burden of AD-related care make its economy vulnerable to AD impacts. Previous economic estimates of AD predominantly focus on health system burdens and omit wider whole-economy effects, potentially underestimating the full economic benefit of effective treatment. Methods AD-related prevalence, morbidity and mortality for 2011–2050 were simulated and were, together with associated caregiver time and costs, imposed on a dynamic Computable General Equilibrium model of the Chinese economy. Both economic and non-economic outcomes were analyzed. Findings Simulated Chinese AD prevalence quadrupled during 2011–50 from 6–28 million. The cumulative discounted value of eliminating AD equates to Chinas 2012 GDP (US

Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer's disease treated with bapineuzumab: a historical, prospective secondary analysis

8 trillion), and the annual predicted real value approaches US AD cost-of-illness (COI) estimates, exceeding US

Age-Stratified Prevalence of Mild Cognitive Impairment and Dementia in European Populations: A Systematic Review

1 trillion by 2050 (2011-prices). Lost labor contributes 62% of macroeconomic impacts. Only 10% derives from informal care, challenging previous COI-estimates of 56%. Interpretation Health and macroeconomic models predict an unfolding 2011–2050 Chinese AD epidemic with serious macroeconomic consequences. Significant investment in research and development (medical and non-medical) is warranted and international researchers and national authorities should therefore target development of effective AD treatment and prevention strategies.