Individuals with Alzheimer's disease and low tau burden: Characteristics and implications.

INTRODUCTION: Abnormal amyloid-beta (Aß) and tau deposition define Alzheimer's Disease (AD), but non-elevated tau is relatively frequent in patients on the AD pathway. METHODS: We examined characteristics and regional patterns of 397 Aß+ unimpaired and impaired individuals with low tau (A+T-) in relation to their higher tau counterparts (A+T+). RESULTS: Seventy-one percent of Aß+ unimpaired and 42% of impaired Aß+ individuals were categorized as A+T- based on global tau. In impaired individuals only, A+T- status was associated with older age, male sex, and greater cardiovascular risk. α-synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T- status. DISCUSSION: Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aß- and tau-modifying therapies.

Optimizing quantification of MK6240 tau PET in unimpaired older adults.

Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aß)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aß and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aß+> Aß- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

Quantification of amyloid beta and tau PET without a structural MRI.

INTRODUCTION: Relying on magnetic resonance imaging (MRI) for quantification of positron emission tomography (PET) images may limit generalizability of the results. We evaluated several MRI-free approaches for amyloid beta (Aß) and tau PET quantification relative to MRI-dependent quantification cross-sectionally and longitudinally. METHODS: We compared baseline MRI-free and MRI-dependent measurements of Aß PET ([18F]florbetapir [FBP], N = 1290, [18F]florbetaben [FBB], N = 290) and tau PET ([18F]flortaucipir [FTP], N = 768) images with respect to continuous and dichotomous agreement, effect sizes of Aß+ impaired versus Aß- unimpaired groups, and longitudinal standardized uptake value ratio (SUVR) slopes in a subset of individuals. RESULTS: The best-performing MRI-free approaches had high continuous and dichotomous agreement with MRI-dependent SUVRs for Aß PET and temporal flortaucipir (R2 ≥0.95; ± agreement ≥92%) and for Alzheimer's disease-related effect sizes; agreement was slightly lower for entorhinal flortaucipir and longitudinal slopes. DISCUSSION: There is no consistent loss of baseline or longitudinal AD-related signal with MRI-free Aß and tau PET image quantification.

Abnormal tau in amyloid PET negative individuals.

We examined the characteristics of individuals with biomarker evidence of tauopathy but without ß-amyloid (Aß) (A-T+) in relation to individuals with (A+T+) and without (A-T-) evidence of Alzheimer's disease (AD). We included 561 participants with Aß and tau PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We compared A-T- (n = 316), A-T+ (n = 63), and A+T+ (n = 182) individuals on demographics, amyloid, tau, hippocampal volumes, and cognition. A-T+ individuals were low on apolipoprotein E ɛ4 prevalence (17%) and had no evidence of subtly elevated brain Aß within the negative range. The severity of tau deposition, hippocampal atrophy, and cognitive dysfunction in the A-T+ group was intermediate between A-T- and A+T+ (all p < 0.001). Tau uptake patterns in A-T+ individuals were heterogeneous, but approximately 29% showed tau deposition in the medial temporal lobe only, consistent with primary age-related tauopathy and an additional 32% showed a pattern consistent with AD. A-T+ individuals also share other features that are characteristic of AD such as cognitive impairment and neurodegeneration, but this group is heterogeneous and likely reflects more than one disorder.