Alzheimer Disease Spectrum

The application of biomarkers to clinical Alzheimer disease (AD) research has transformed the way we think about the disorder. Probable AD was defined as a clinical syndrome, generally amnestic, that progressed to global dementia. Poor prediction of the underlying pathology has made it clear that this approach is inadequate, particularly for patients with atypical or mild symptoms. The recent proposal of a biomarker-based framework for diagnosis has moved our thinking about AD from the syndromic to the biological.¹ In this framework, evidence of β-amyloid and tau deposition in the brain constitutes AD, regardless of clinical presentation. Using this biomarker approach with PET imaging, Therriault et al.² report in this issue of Neurology® the patterns of β-amyloid (denoted A) and tau (denoted T) PET abnormalities in a group of persons with cognitive impairment recruited from a dementia-specialty clinic population. Their observations allow us to judge the added value of the PET biomarkers and to compare clinical and biomarker diagnoses.

The neuropathology of AD remains the gold standard, but PET imaging (using tracers different from those used here) has excellent fidelity to neuropathology, justifying the use of PET as an antemortem proxy for AD neuropathology.^3,4 The authors used newer-generation tracers: ¹⁸F-AZD4694 for A PET and ¹⁸F-MK6240 for T PET. Their fidelity to neuropathology is expected but not yet confirmed to be high. While consensus approaches to define amyloid positivity (A+) with PET were used, defining tau positivity (T+) with PET is challenging because the distribution and abundance of brain tau vary with cognitive severity, in contrast to β-amyloid. The temporal lobe regions of interest used by the authors² were a reasonable choice.

This study was performed in a tertiary care setting, with skilled clinical diagnosis, expert PET interpretations, and preselection of participants, all of which may inflate accuracy relative to other practice settings. Individuals (12%, 49 of 398) whose symptomatic cognitive impairment was attributed to non-AD etiologies were excluded from the PET analyses, which undoubtedly accounted for the high sensitivity of clinical diagnoses for the biomarker category of A+T+ that represents AD. Specificity was not the focus of this report, but among persons receiving clinical diagnoses of a non-AD disorder, there will be a nontrivial proportion who are A+ but very few who are T+.⁵

Even in this cross-sectional analysis, the relationships between severity of cognitive impairment and alterations in A and T PET biomarkers can be appreciated. In the cognitively unimpaired (CU) comparison group, the majority were A−T−, and a quarter were A+ (25%), fewer were T+ (10%), and very few (8%) were A+T+. In contrast, in those diagnosed with dementia (and in whom non-AD diagnoses were excluded before PET imaging), the vast majority (85%) were A+T+. The mild cognitive impairment (MCI) group showed the most variability in A and T PET. Only half of the MCI group had elevated A PET, while a third of persons with A+ MCI were A+T−. The A+T+ pattern was >2-fold more common in dementia than MCI.

These observations are consistent with prior work in A and T PET in persons with cognitive impairment⁵ and highlight several key points:

• That a quarter of CU persons are A+ but fewer than half of those are also A+T+ is a well-replicated observation⁶ that is grounded in the claim that brain β-amyloid elevation almost certainly precedes overt cognitive impairment by decades.⁷

• The clinical diagnosis of probable AD had very good but not perfect positive predictive value for A+T+ status, meaning that highly selected patients in specialty clinics can be diagnosed accurately, obviating the need for PET imaging for diagnostic confirmation except in situations when very high positive predictive values are required such as clinical trials. The number of cases with probable AD who were not A+T+ also illustrates the imprecision of the label probable AD. PET imaging enables the approach of separating cognitive syndrome and presumed underlying pathophysiology.

• For all of the challenges in distinguishing MCI from CU or dementia on clinical grounds,⁸ PET provided considerable added value beyond the clinical diagnosis in establishing an AD etiology in people with MCI. Although there is limited experience for long-term outcomes in persons with MCI who have undergone both A and T PET, extensive experience in A PET has shown that persons who are A+ have a worse prognosis than those who are A−.⁹ We anticipate that future longitudinal studies will show that persons with MCI who are A+T+ will decline faster than those who are A+T−. If that is true, T PET would be of value in therapeutic trials by identifying persons with MCI who might have an active tauopathy and therefore experience a more rapid progressive course.

• Especially in the MCI group but also in the group with dementia, it should be obvious that other relevant etiologies contribute to cognitive impairment,¹⁰ even when those persons with clinically overt manifestations of other etiologies have been excluded. In the future, multidimensional etiologic characterization of persons with MCI and dementia may be feasible. Structural MRI adds information about cerebrovascular lesions and non-AD focal atrophy, but biomarker definition of α-synuclein and TAR DNA-binding protein 43 pathology awaits further development.

The application of A and T PET in routine clinical care is currently unclear. However, the results of the study by Therriault et al. indicate that clinical diagnostic criteria for MCI, even used by experts, imperfectly identify individuals with biological AD. Similarly, a sizable minority of older CU people have biological AD. These observations will become crucial with therapeutic trials and targeting effective therapies for mildly symptomatic and asymptomatic people.

Study Funding

Dr. Knopman was supported by NIH grants P50 AG016574, P30 AG062677, U01 AG006786, R01 AG034676, and R01 AG41851. Dr. Jagust is supported by NIH grants R01 AG034570, R01 AG062542 U24 AG067418, and U01 AG024904.

Disclosure

Dr. Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network (DIAN) study. He serves on a Data Safety Monitoring Board for a tau therapeutic for Biogen but receives no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He serves as a consultant for Samus Therapeutics, Third Rock, and Alzeca Biosciences but receives no personal compensation. Dr. Jagust serves on a Data Safety Monitoring Board for the Alzheimer's Prevention Institute. He has served as a consultant to Biogen, Grifols, CuraSen, and Bioclinica. Go to Neurology.org/N for full disclosures.