Impact of diabetes on the progression of Alzheimer's disease via trajectories of amyloid-tau-neurodegeneration (ATN) biomarkers.

Alzheimer's disease (AD) is characterized by the accumulation of abnormal proteins, such as β-amyloid and tau, in the brain, which precedes cognitive impairment. Although diabetes mellitus (DM) is a well-established risk factor for AD, few studies have investigated how the presence of DM affects the sequential pathogenesis of AD, specifically within the amyloid-tau-neurodegeneration (ATN) and cognition framework. This study aims to investigate the trajectories of ATN biomarkers in relation to the presence of DM in the preclinical and prodromal stages of AD. Participants with normal cognition (CN) or mild cognitive impairment (MCI) at baseline were included. Subjects were followed for 12-192 months, with neuroimaging and cognitive assessments conducted at every 12 or 24 months. This study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. A total of 603 participants aged 55-90 years were included, comprising 284 CN (25 with DM, 259 without DM) and 319 MCI (39 with DM, 280 without DM) individuals. ATN biomarkers were identified using florbetapir positron emission tomography (PET), flortaucipir PET, and magnetic resonance imaging (MRI), respectively. Cognition was assessed using the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Mini-Mental State Examination (MMSE). Moderation analysis was conducted to investigate the effect of DM on the association between ATN biomarkers of AD. Elevated amyloid standardized uptake value ratios (SUVRs) were associated with increased tau levels in the hippocampus, and this association was significantly enhanced by the presence of DM in MCI participants (p = 0.021). DM also strengthened the association between increased tau SUVR levels and neurodegeneration (indicated by decreased entorhinal cortical volumes; p = 0.005) in those with MCI. Furthermore, DM enhanced the association of decreased entorhinal (p = 0.012) and middle temporal cortex (p = 0.031) volumes with increased (worsened) CDR-SB scores in MCI participants. However, DM did not predict significant longitudinal changes in ATN pathology or cognitive decline in CN participants. Our study suggests that DM may increase the risk of AD by accelerating each step of the A-T-N cascade in the prodromal stage of AD, underscoring the importance of DM management in preventing the MCI conversion to AD.

Kim EW ，Kim KY ，Kim E ，Alzheimer’s Disease Neuroimaging Initiative ... -  《-》

Longitudinal Evolution of Financial Capacity and Cerebral Tau and Amyloid Burden in Older Adults with Normal Cognition or Mild Cognitive Impairment.

Mimmack KJ ，Sprague EH ，Amariglio RE ，Vannini P ，Marshall GA ... -  《-》

Associations of tau, Aβ, and brain volume of the Papez circuit with cognition in Alzheimer's disease.

This study aimed to investigate the cross-sectional associations between regional Alzheimer's disease (AD) biomarkers, including tau, β-amyloid (Aβ), and brain volume, within the Papez circuit, and neuropsychological functioning across the preclinical and clinical spectrum of AD. We utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 251 Aβ-positive participants. Participants were categorized into three groups based on the Clinical Dementia Rating (CDR): 73 individuals with preclinical AD (CDR = 0), 114 with prodromal AD (CDR = 0.5), and 64 with clinical AD dementia (CDR ≥ 1). Linear regression analyses, adjusted for age, gender, and education years, were employed to evaluate the associations between five regions of interest (the hippocampus, para-hippocampus, entorhinal cortex, posterior cingulate cortex, and thalamus) and five neuropsychological tests across the three imaging modalities. In the preclinical stage of AD, flortaucipir PET was associated with impaired global cognition and episodic memory (range standardized β = 0.255-0.498, p < 0.05 corrected for multiple comparisons), while florbetapir PET and brain volume were marginally related to global cognition (range standardized β = 0.221-0.231, p < 0.05). In the clinical stages of AD (prodromal and dementia), both increased flortaucipir uptake and decreased brain volume were significantly associated with poorer global neuropsychological and episodic memory performance (range standardized β = 0.222-0.621, p < 0.05, most regions of interest survived correction for multiple comparisions). However, a slight relationship was observed between florbetapir uptake and poorer global cognitive function. The regions most affected by flortaucipir PET were the hippocampus, para-hippocampus, and posterior cingulate cortex. During the clinical stages, the hippocampus and entorhinal cortex exhibited the most significant volumetric changes. Tau PET and brain volume measurements within the Papez circuit are more sensitive indicators of early cognitive deficits in AD than Aβ PET. Furthermore, during the clinical stages of AD, both flortaucipir PET and brain volume of the Papez circuit are closely correlated with cognitive decline. These findings underscore the importance of integrating multiple biomarkers for the comprehensive evaluation of AD pathology and its impact on cognition.

Feng Y ，Laraib A ，Lin X ，Li Q ，Zhan J ，Li X ... -  《-》

Tau Positron Emission Tomography for Predicting Dementia in Individuals With Mild Cognitive Impairment.

Groot C ，Smith R ，Collij LE ，Mastenbroek SE ，Stomrud E ，Binette AP ，Leuzy A ，Palmqvist S ，Mattsson-Carlgren N ，Strandberg O ，Cho H ，Lyoo CH ，Frisoni GB ，Peretti DE ，Garibotto V ，La Joie R ，Soleimani-Meigooni DN ，Rabinovici G ，Ossenkoppele R ，Hansson O ... -  《-》

Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer's disease.

Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer's disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (n = 537); mild cognitive impairment (n = 48); or dementia (n = 16). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR > 1.16 equivalent to 17.1 centiloids) onset age and years of A+ duration at tau PET (i.e. amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (70-90 min, inferior cerebellar grey matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer's disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e. progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within 10 years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially cognitively unimpaired (n = 472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration, together with a higher entorhinal tau burden, increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer's disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context, which may help inform disease prognosis and timing windows for anti-amyloid therapies.

Cody KA ，Langhough RE ，Zammit MD ，Clark L ，Chin N ，Christian BT ，Betthauser TJ ，Johnson SC ... -  《-》