New Alzheimer’s disease guidelines: Implications for clinicians

By incorporating phases of AD that precede dementia into the disease spectrum, the new guidelines are designed to move clinicians toward earlier diagnosis and treatment.^1-3 Similar to how early, pre-symptomatic detection and treatment of conditions such as diabetes and cancer can reduce mortality, improving diagnosis of AD in its early phases may allow clinicians to better test potential therapies and eventually use them to treat at-risk individuals.^2,3 Most pharmacotherapies for AD are FDA-approved only for patients diagnosed with clinical dementia. Furthermore, current pharmacotherapies do not alter the course of AD; they have a modest effect in slowing cognitive and functional decline.^7,8 If patients in the earlier phases of AD could be recruited for research studies, we may be able to develop new treatments to stop or reverse AD pathology and its clinical manifestations.

Biomarkers. The new criteria incorporate biomarkers to provide information about pathophysiologic changes underlying the disease process. These criteria define biomarkers as physiologic, biochemical, or anatomic parameters that can be measured in vivo and reflect specific features of disease-related pathophysiologic processes.¹ Presently, there are no cutoff values to demarcate “normal” levels from “abnormal,” and biomarkers are proposed primarily as research tools because they have not been studied adequately in community settings and laboratory techniques to measure biomarkers have not been standardized.^1-4,9

The 5 biomarkers incorporated into the new criteria are divided into 2 categories: biomarkers of Aβ accumulation and those of neuronal degeneration or injury (Table 2).^1-4 In the initial, preclinical phase, biomarkers are used to detect changes in the brain—such as amyloid accumulation and nerve cell degeneration—that may already be in process in an individual whose clinical symptoms are subtle or not yet evident.^1,2 In this phase, progressive evidence of biomarkers, such as both Aβ accumulation and neuronal injury rather than Aβ accumulation alone, may increase the probability that a patient will decline quickly into the MCI phase.² Biomarkers of neuronal degeneration or injury especially correlate with the likelihood that the disease will progress to clinical dementia.¹ Subtle cognitive symptoms in the preclinical phase also might predict rapid decline into MCI.²

In the MCI and dementia phases, biomarkers are used to determine the level of certainty that AD is responsible for the patient’s symptoms.^1,3,4 For example, a patient could meet criteria for a non-AD dementia such as dementia with Lewy bodies, but also meet pathologic criteria for AD on autopsy.³ The diagnostic category of possible AD dementia with evidence of the AD pathophysiologic process is intended for this type of scenario.⁴ For the MCI phase, the criteria propose levels of certainty that a patient’s MCI syndrome is caused by AD, ranging from MCI due to AD-high likelihood to MCI-unlikely due to AD.³

Research has demonstrated that a patient’s clinical picture doesn’t necessarily reflect the extent of the underlying pathology. For example, a patient could have extensive AD pathology, such as diffuse amyloid plaques, without any obvious clinical symptoms.³ Conversely, although both Aβ deposition and elevated tau are hallmarks of AD, variations in these proteins can be seen in neuropsychiatric disorders other than AD.¹⁰ That said, it appears that worsening of clinical symptoms often parallels worsening of neurodegenerative biomarkers.¹

Under the 2011 guidelines, biomarkers would not be used to diagnose or exclude AD or MCI, but instead would help improve diagnostic accuracy in individuals with cognitive decline.^1,3,4 In other words, AD remains a clinical diagnosis, but these biomarkers could raise or lower the positive predictive value of a clinician’s judgment about the etiology of a patient’s symptoms.

See the Box for a description of the potential risks and benefits of using the new diagnostic criteria.

Table 1

Comparing the 1984 and 2011 AD criteria