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Background Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in Alzheimer’s disease (AD) have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration—at least in the dementia stage—as deposition of Aβ reaches a ceiling. In this study, we examined in vivo the association between fibrillar Aβ deposition and synaptic density in early AD using positron emission tomography (PET). We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI; a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau). Methods We measured SV2A binding ([ 11 C]UCB-J) and Aβ deposition ([ 11 C]PiB) in 14 participants with aMCI due to AD and 24 participants with mild AD dementia. Distribution volume ratios ( DVR ) with a cerebellar reference region were calculated for both tracers to investigate the association between global Aβ deposition and SV2A binding in hippocampus. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches. Results We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI ( r  = − 0.55, P  = 0.04), but not mild dementia ( r  = 0.05, P  = 0.82; difference statistically significant by Fisher z  = − 1.80, P  = 0.04). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a “paradoxical” positive association between local Aβ deposition and SV2A binding in the hippocampus. Conclusions Our findings lend support to a model in which fibrillar Aβ is still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research should investigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers.

Background and Purpose This study evaluated associations of brain amyloid with 2‐year objective and subjective cognitive measures in a trial‐ready older general population at risk for dementia. Methods Forty‐eight participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability underwent 11C‐Pittsburgh compound B (PiB) positron emission tomography (PET) scans and assessment of cognition (modified Neuropsychological Test Battery [NTB]) and subjective memory complaints (Prospective and Retrospective Memory Questionnaire). Results Mean age was 71.4 ± 5.06 years, and 20 participants (42%) had positive baseline PiB‐PET scans. Amyloid positivity was associated with lower NTB executive function at baseline and less favorable 2‐year NTB total score and memory trajectories, but not with other objective or subjective cognitive measures. Overall, there was little cognitive decline during 2 years. Conclusions Amyloid accumulation may affect objective but not necessarily subjective cognition from a very early at‐risk stage, although substantial decline likely requires >2 years to occur.

INTRODUCTION We aimed to compare gait between individuals with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and cognitively unimpaired (CU) individuals and to evaluate the association between gait and regional amyloid beta (Aβ) burden in AD and DLB. METHODS We included 420 participants (70 AD, 70 DLB, 280 CU) in the Mayo Clinic Study of Aging (MCSA). Gait was assessed using a pressure‐sensor walkway. Aβ deposition was analyzed with Pittsburgh compound B (PiB) positron emission topography (PET). RESULTS The DLB group had reduced stride velocity, step length, and stride width variability, as well as increased double support percentage (%DS) and variability in step length, swing time, and step time compared to the AD and CU groups. Aβ burden was not associated with any gait outcomes. DISCUSSION This study provides additional evidence that gait differs between AD and DLB. Larger studies are needed to investigate associations between Aβ burden and gait outcomes in dementia. Highlights Gait was more impaired in dementia than in cognitively unimpaired (CU) controls. Compared with Alzheimer's disease (AD), Dementia with Lewy bodies (DLB) had more impaired pace, variability, and postural control. Step length and double support (%) distinguished DLB and AD with moderate accuracy.

INTRODUCTION Alzheimer's disease (AD) pathology causes corticobasal syndrome (CBS) in 21%–50% of patients. Studies have assessed hypometabolism in CBS according to β‐amyloid (A) positron emission tomography (PET), but the understanding of the association of both AD‐tau (T) and A with hypometabolism is incomplete. METHODS Thirty‐three CBS patients and 45 controls underwent fluorodeoxyglucose (FDG), flortaucipir, and Pittsburgh compound‐B PET and were classified as A± and T±. FDG‐PET uptake was extracted for 12 regions‐of‐interest in dominant (most affected) and non‐dominant hemispheres and compared across A/T groups. RESULTS A+T+ patients had greater hypometabolism in temporo‐parieto‐occipital cortices than A+T‐ and A‐T‐ groups, with no differences observed between the A+T‐ and A‐T‐ groups. FDG asymmetry was more accentuated in A+T+ patients. Medial temporal and basal ganglia metabolism were similar across AT groups. DISCUSSION Amyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in temporo‐parieto‐occipital cortices in CBS, with AD‐like patterns of hypometabolism observed only in A+T+ patients. Highlights Amyloid (A) and tau PET (T) status can be used to stratify CBS patients. A+T+ CBS patients show more hypometabolism in temporo‐parieto‐occipital cortices. Medial temporal metabolism (typical AD pattern) is similar across AT groups. Parieto‐occipital cortices should be assessed when investigating AT pathology in CBS. Amyloid and tau positivity contribute synergistically to hypometabolism and asymmetry in CBS.

INTRODUCTION Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin‐1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre‐/postcodon 200) influences these pathologic features and dementia at different stages. METHODS Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross‐sectionally evaluated regional Pittsburgh compound B‐positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging‐based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. Highlights Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre‐200 group had stronger associations between Aβ burden and disease stage. PSEN1 post‐200 group had stronger associations between SVD markers and disease stage. PSEN1 post‐200 group had worse dementia score than pre‐200 in late disease stage. Diffusion tensor imaging‐based SVD markers mediated mutation position effects on dementia in the late stage.

INTRODUCTION Imaging biomarkers are fundamental in diagnosing neurodegenerative diseases, but their use in FTD remains limited. This study examines PET biomarkers in Argentine bvFTD patients. METHODS We studied a cohort of bvFTD patients (n = 20) and controls (n = 21) with three different PET radiotracers (18F‐FDG, 11C‐PiB, and 18F‐AV1451). RESULTS In bvFTD patients, 18F‐FDG PET showed significant hypometabolism in frontotemporal regions, along with hypermetabolism in the precentral gyrus, compared to normal controls. 11C‐PIB did not reveal a pattern typical of Alzheimer's disease, yet increased uptake was notably observed in the precentral region. We found 18F‐AV1451 uptake in frontal lobe, parietal, precuneus, cuneus, posterior cingulum, highly significant in bvFTD with respect to NCs. DISCUSSION PET biomarkers are a crucial tool in diverse real‐world clinical scenarios. However, their utility in revealing questions about the underlying pathology in FTD is still limited. Highlights First bvFTD study using 18F‐FDG, 11C‐PIB, and 18F‐AV1451 PET in a Latin American cohort. Frontotemporal hypometabolism with compensatory precentral hypermetabolism due to amyloid. Amyloid deposits observed in the precentral gyrus without an Alzheimer's‐like pattern. 18F‐AV1451 shows limitations in specificity for bvFTD pathology. Study provides new insights into PET biomarker utility for bvFTD clinical assessment.

INTRODUCTION Monoclonal anti‐amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS In the DIAN‐TU‐001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [11C]‐Pittsburgh compound‐B (PiB) positron emission tomography (PET), [18F]‐fluoro‐2‐deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS Gantenerumab significantly reduced PiB‐PET uptake overall and in most regions and showed no changes in FDG‐PET or MRI measures. Drug effects were associated with baseline PiB‐PET uptake, and the largest effects occurred in medial regions. DISCUSSION Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB‐PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. Highlights Gantenerumab unevenly decreased Aβ burden as measured by PiB‐PET across brain regions. The strongest decrease in PiB‐PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG‐PET metabolism or MRI volumetrics after 4 years.

Although deposition of β-amyloid (Aβ), a pathological hallmark of Alzheimer's disease (AD), has also been reported in cognitively intact older people, its influence on brain structure and cognition during normal aging remains controversial. Using PET imaging with the radiotracer Pittsburgh compound B (PIB), structural MRI, and cognitive measures, we examined the relationships between Aβ deposition, gray matter volume, and cognition in older people without AD. Fifty-two healthy older participants underwent PIB–PET and structural MRI scanning and detailed neuropsychological tests. Results from the whole-brain voxel-based morphometry (VBM) analysis revealed that gray matter volume in the left inferior frontal cortex was negatively associated with amyloid deposition across all participants whereas reduced gray matter volume was shown in the posterior cingulate among older people with high amyloid deposition. When gray matter density measures extracted from these two regions were related to other brain regions by applying a structural covariance analysis, distinctive frontal and posterior brain networks were seen. Gray matter volume in these networks in relation to cognition, however, differed such that reduced frontal network gray matter volume was associated with poorer working memory performance while no relationship was found for the posterior network. The present findings highlight structural and cognitive changes in association with the level of Aβ deposition in cognitively intact normal elderly and suggest a differential role of Aβ-dependent gray matter loss in the frontal and posterior networks in cognition during normal aging. ►Aβ deposition relates to gray matter volume reduction in the lIFG and PCC. ►Structural covariance patterns with lIFG reveal the frontal network. ►Structural covariance patterns with PCC reveal the posterior network. ►Effects of frontal and posterior networks on cognition differ in normal aging.

Background Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive dysfunction in the elderly, and frequently coexists with Alzheimer's disease and tau pathology. Dual‐phase 11C‐PiB PET detects amyloid deposition and cerebral perfusion changes and may have diagnostic value for identifying tau in CAA. Methods We prospectively enrolled patients with probable CAA for dynamic PiB and AV1451 scans. We compared early‐phase (0–6 min after tracer injection) and late‐phase (40–70 min) PiB PET between the tau(+) and tau(−) groups (based on AV1451 PET) and investigated their diagnostic values for detecting tau. Results CAA/tau(+) had lower early‐phase temporal PiB uptake than CAA/tau(−) (p = 0.014) and higher late‐phase uptake in the whole cortex and temporal and parietal lobes (all p < 0.05). Early‐phase temporal PiB SUVR correlated with tau burden (r = −0.34, p = 0.038). Using Youden's cut‐off, early‐phase and late‐phase PET had sensitivities of 55% and 80% and specificities of 85% and 65% for detecting tau, respectively. Combining early‐ and late‐phase scans provided a rule‐out sensitivity of 90% and rule‐in specificity of 100% for tau pathology in CAA. Conclusions Dual‐phase 11C‐PiB PET represents a reliable approach for assessing tau and could potentially identify CAA patients for tau biomarker testing.

Animal models of Alzheimer's disease show that exercise may modify β-amyloid (Aβ) deposition. We examined the effect of a 16-week exercise intervention on cortical Aβ in patients with mild-to-moderate Alzheimer's disease. Thirty-six patients with Alzheimer's disease were randomized to either one hour of aerobic exercise three times weekly for 16 weeks or usual care. Pre and post intervention, 11Carbon-Pittsburgh compound B positron emission tomography was carried out to assess cortical Aβ, and quantified using standardized uptake value rations (SUVRs). The intervention showed no effect on follow-up SUVRs in a covariance analysis with group allocation, baseline intervention SUVR, age, sex, and baseline Mini–Mental State Examination as predictors. Change in SUVRs did not correlate with changes in measures of physical or aerobic fitness. The present findings do not support an effect of exercise on Aβ. However, the relatively short intervention period may account for a lack of efficacy. Further studies should test earlier and longer interventions.