J. Scott Andrews

The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.

INTRODUCTION: This study estimated the minimal clinically important difference (MCID) for Mini Mental State Examination, Clinical Dementia Rating Scale sum of boxes, and Functional Activities Questionnaire across the Alzheimer's disease (AD) spectrum. METHODS: Retrospective analysis of the National Alzheimer's Coordinating Center Uniform Data Set (9/2005-9/2016) and MCID for clinical outcomes were estimated using anchor-based (clinician's assessment of meaningful decline) and distribution-based (1/2 baseline standard deviation) approaches, stratified by severity of cognitive impairment. RESULTS: On average, a 1-3 point decrease in Mini Mental State Examination, 1-2 point increase in Clinical Dementia Scale sum of boxes, and 3-5 point increase in Functional Activities Questionnaire were indicative of a meaningful decline. The MCID values generally increased by disease severity; the effect size and standardized response mean for those with meaningful decline were consistently in the acceptable ranges for MCID. DISCUSSION: These findings can inform design and interpretation of future clinical trials.

Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18-month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified.

BACKGROUND: Costs associated with early stages of Alzheimer's disease (AD; mild cognitive impairment [MCI] and mild dementia [MILD]) are understudied. OBJECTIVE: To compare costs associated with MCI and MILD due to AD in the United States. METHODS: Data included baseline patient/study partner medical history, healthcare resource utilization, and outcome assessments as part of a prospective cohort study. Direct, indirect, and total societal costs were derived by applying standardized unit costs to resources for the 1-month pre-baseline period (USD2017). Costs/month for MCI and MILD cohorts were compared using analysis of variance models. To strengthen the confidence of diagnosis, amyloid-β (Aβ) tests were included and analyses were replicated stratifying within each cohort by amyloid status [+ /-]. RESULTS: Patients (N = 1327) with MILD versus MCI had higher total societal costs/month ($4243 versus $2816; p < 0.001). These costs were not significantly different within each severity cohort by amyloid status. The largest fraction of overall costs were informal caregiver costs (45.1%) for the MILD cohort, whereas direct medical patient costs were the largest for the MCI cohort (39.0%). Correspondingly, caregiver time spent on basic activities of daily living (ADLs), instrumental ADLs, and supervision time was twice as high for MILD versus MCI (all p < 0.001). CONCLUSION: Early AD poses a financial burden, and despite higher functioning among those with MCI, caregivers were significantly impacted. The major cost driver was the patient's clinical cognitive-functional status and not amyloid status. Differences were primarily due to rising need for caregiver support.

OBJECTIVE: To identify, in caregivers of patients with Alzheimer's disease (AD) dementia, factors associated with subjective (personal, physical, emotional, and social) and objective (informal caregiver time and costs) caregiver burden. DESIGN: Prospective longitudinal European observational study: post-hoc analysis. SETTING: Clinic. PARTICIPANTS: Community-dwelling patients in France and Germany aged ≥ 55 years (n = 969) with probable AD and their informal caregivers. MEASUREMENTS: Mini-Mental State Examination (MMSE), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), 12-item Neuropsychiatric Inventory (NPI-12), Zarit Burden Interview (ZBI), informal caregiver basic and instrumental ADL hours (Resource Utilization in Dementia instrument), and informal caregiver costs. Mixed-effect models of repeated measures (MMRM) were run, including baseline and time-dependent covariates (change from baseline [CFB] to 18 months in MMSE, ADCS-ADL, and NPI-12 scores) associated with CFB in ZBI score/informal caregiver time over 36 months (analyzed using linear regression models) and informal caregiver costs over 36 months (analyzed using generalized linear models). RESULTS: Greater decline in patient function (ADCS-ADL) over 18 months was associated with increased subjective caregiver burden (ZBI), hours, and costs over 36 months. Increased behavioral problems (NPI-12) over 18 months also negatively impacted ZBI. Cognitive decline (MMSE) over 18 months did not affect change in caregiver burden. CONCLUSIONS: Long-term informal caregiver burden was driven by worsening functional abilities and behavioral symptoms but not cognitive decline, over 18 months in community-dwelling patients with AD dementia. Identifying the drivers of caregiver burden could highlight areas in which interventions may benefit both caregivers and patients.