New AD Guidelines Focus on Early Disease

The culmination of the work of three international work groups, the Alzheimer's Association and the National Institute on Aging have released the first new criteria and guidelines to diagnose Alzheimer's in 27 years. The new guidelines “update, refine, and broaden” the old set published in 1984. More than 40 Alzheimer's researchers and clinicians from around the world reviewed the original criteria to decide how they might be improved by incorporating research advances from the last three decades.

Presented in three PDFs available at www.alz.org, the guidelines reflect the workgroups' focus on refining the existing guidelines for diagnosing mild cognitive impairment (MCI), expansion of the conceptual framework for thinking about AD to include a ‘preclinical' stage characterized by biomarkers occurring before memory disruption, and establishing a framework for eventually adding biomarker benchmarks to the diagnosis of AD in all stages.

In a publication by McKhann et al. the authors note that earlier criteria have been dependable for the diagnosis of probable AD, “and across more than a dozen clinical pathological studies have had a sensitivity of 81 percent and specificity of 70 percent.” They have also been widely used in clinical trials and clinical research.

They write that certain features of the original criteria required revision. Among them are the following:¹

1. The fact that the histological pathology of AD (or surrogates for this pathology) may be found across a broad clinical spectrum (including individuals who are cognitively normal, those with MCI, and those with dementia). Therefore, the authors favor the term “AD pathophysiological process” to encompass the antemortem biological changes that precede the postmortem neuropathological diagnosis of AD as well as the neuropathological substrate. “AD dementia" refers to the clinical syndrome that arises as a consequence of the AD pathophysiological process.

2. Lack of acknowledgment of distinguishing features of other dementing conditions that occur in a similarly aged population, which were not completely recognized decades ago. For example, Dementia with Lewy bodies, vascular dementia, behavior variant frontotemporal dementia, and primary progressive aphasia have been characterized extensively.

3. No inclusion of results of magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, and cerebrospinal fluid (CSF) assays or biomarkers in decision-making. Incorporation of biomarkers into the diagnosis of AD dementia and MCI should be part of a comprehensive approach to the diagnostic process.

4. The implication that memory impairment is always the primary cognitive deficit in all patients with AD dementia. It is accepted that there are several nonamnestic presentations of the pathophysiological process of AD. The most common of these are posterior cortical atrophy and logopenicprimary progressive aphasia.

5. Lack of information about genetics of AD. Mutations in amyloid precursor protein, presenilin 1, and presenilin 2 are all linked to an early onset, autosomal dominantly inherited AD.

6. Proposed age cutoffs for the diagnosis of AD dementia. Although AD dementia in those aged 40 is rare, it does not differ in its pathophysiology from AD dementia in older persons. Similarly, AD dementia in persons aged 90 years part of that same spectrum as that of younger persons. In later age, clinical– pathological correlations are attenuated.

7. Extreme heterogeneity of the “Possible” AD dementia category, including a group of patients who would now be diagnosed as “Mild cognitive impairment.”

Mild Cognitive Impairment

Albert et al. worked on the MCI part of the update. They write that the core clinical criteria of the recommendation regarding AD dementia and MCI due to AD are intended to guide diagnosis in the clinical setting. Yet, “The recommendations of the preclinical AD workgroup are intended purely for research purposes,” according to Clifford et al. in an accompanying introductory piece.

The piece fine-tunes the existing guidelines for diagnosing MCI by attempting to formalize an emerging consensus that patients who eventually develop Alzheimer's experience this stage of minimal but discernable impairment, even though it's currently under-diagnosed. MCI does not always progress to Alzheimer's, “because MCI may also occur for other reasons. The guidelines designate the condition of minimal impairment preceding Alzheimer's as ‘MCI due to Alzheimer's disease,' and define four levels of certainty for arriving at this diagnosis.”

The workgroup developed the following two sets of criteria: 1.) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and 2.) research criteria that could be used in clinical research settings, including clinical trials, that incorporate the use of biomarkers based on imaging and CSF measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings.

The core clinical criteria for individuals with MCI are:

Concern regarding a change in cognition. There should be evidence of concern about a change in cognition, relative to the person's previous level.

Impairment in one or more cognitive domains. There should be evidence of lower performance in one or more cognitive domains that is greater than would be expected for the patient's age and educational background. When applicable, repeated assessments should show a decline in performance over time. An impairment in episodic memory is the most common domain change seen in patients who subsequently progress to a diagnosis of AD dementia.”

Preservation of independence in functional abilities.There may be mild problems performing complex functional tasks previously performed, such as paying bills, preparing a meal, or shopping. Such tasks may take more time, lack efficiency, or be marked by errors; however individuals will typically have preservation of daily function requiring minimal aids or assistance.

Not demented. Cognitive changes may be mild with no evidence of significant impact on social or occupational function mild,. Nonetheless, the evidence for intraindividual change may warrant the diagnosis of MCI.

Research

The third paper, by Sperling et al., reviews the biomarker, epidemiological, and neuropsychological evidence, to develop recommendations to determine the factors that best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. They propose “a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies.” They intend their recommendations for research purposes only, and it has no clinical implications at this time.

Emphasizing the urgency to battle AD on the biomarker front, they cite a study that predicts that, as the “baby boomer” generation ages, more than 13.5 million individuals in the US will manifest AD dementia by the year 2050. If the onset of AD dementia could be delayed by fve years, it would result in a 57 percent reduction in the number of patients with AD dementia and reduce the projected Medicare costs of AD from $627 to $344 billion dollars, according to the authors.

Among their many recommendations, the work group highlights the importance of redefining the earliest stages of AD. To aid the possibility of future presymptomatic/preclinical treatment of AD all three groups felt it was important to define AD “as encompassing the underlying pathophysiological disease process, as opposed to having ‘AD' connote only the clinical stages of the disease.” They suggest it may be useful to refer to evidence of the underlying brain disease process as AD-pathophysiological process (abbreviated as AD-P) and the clinical phases of the illness as “AD- Clinical” (abbreviated as AD-C), “which would include not only AD dementia but also individuals with MCI due to AD-P.” They hypothesize that AD starts its course with a lengthy asymptomatic stage during which the pathophysiological process is progressing; individuals with biomarker evidence of early AD-P are thought to be at increased risk for developing cognitive and behavioral impairment and progression to AD dementia (AD-C).

1. McKhann, G., Knopman, D., et al. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 7(3):263-269.
2. Albert, M., et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 7(3): 270-279.
3. Sperling, R., et al. Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 7(3): 280-292.