scholarly journals Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer’s Disease Dementia

2021 ◽  
pp. 1-16
Author(s):  
Albert C. Lo ◽  
Cynthia Duggan Evans ◽  
Michele Mancini ◽  
Hong Wang ◽  
Sergey Shcherbinin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Functional Decline ◽  
Neurofibrillary Tangle ◽  
Amyloid Β ◽  
System Organ Class ◽  
Serious Adverse Events ◽  
Study Results ◽  
Significant Difference

Background: LY3202626 is a small molecule inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-β (Aβ)1–40 and Aβ1–42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer’s disease (AD). Objective: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild. Methods: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. Results: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. Conclusion: LY3202626 tested at doses generating 70–90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.

scholarly journals The Alzheimer’s Disease THErapy with NEuroaid II (ATHENE) Study: A Double-Blind Randomized Delayed-Start Trial to Assess the Safety and Efficacy of MLC901 (NeuroAiD™II) as an add-on Treatment to Cholinesterase Inhibitors or Memantine in Patients With Mild to Moderate Alzheimer's Disease

2021 ◽  
Author(s):  
Christopher Chen ◽  
Qingshu Liu ◽  
Rejesh Babu Moorakonda ◽  
Nagaendran Kandiah ◽  
Boon Yeow Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Cognitive Assessment ◽  
Standard Treatment ◽  
Serious Adverse Events ◽  
Significant Difference ◽  
Early Starters ◽  
Modifying Effect ◽  
Disease Modifying

Abstract BackgroundPreclinical and clinical studies indicate a role for MLC901 (NeuroAiDTMII) in Alzheimer’s Disease (AD). We investigated its safety and efficacy as add-on therapy to standard treatment and evaluated a disease modifying effect in mild to moderate AD.MethodsMild-moderate probable AD patients by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n=125) were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months during which all patients received MLC901, in a delayed-start design. The primary outcome measure was serious adverse events at 6 months, secondary outcomes included the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) and other cognitive assessment scales.ResultsThere was no significant difference in the risk of serious adverse events between early and delayed starters at month (M) 6 (22.6% vs. 27.0%, risk difference = -4.4%, 90% CI -16.9 to 8.3%). Furthermore, there was no significant difference in the risk of adverse events, including the occurrence of stroke or vascular events, between early and delayed starters throughout the 12-month study period. The early-starters differed significantly on ADAS-Cog from the delayed-starters at M9 (mean difference -3.36, 95% CI -5.64 to -1.09) and M12 (mean difference -2.35, 95% CI -5.45 to 0.74). Other cognitive assessment scales showed trends in favor of MLC901.ConclusionsMLC901 is a safe adjunct to standard treatment for mild-moderate AD. There is no indication that the risk of any adverse events, including vascular, is increased with MLC901 in the study population. The cognitive outcomes provide support for a disease-modifying effect of MLC901 which requires confirmation in further studies. Clinical trial registration: ClinicalTrials.gov, NCT03038035. https://clinicaltrials.gov/ct2/show/NCT03038035

scholarly journals 416 - Risk of Mortality Associated with Antipsychotics in Alzheimer's Disease

2020 ◽  
Vol 32 (S1) ◽  
pp. 132-132
Author(s):  
Liliana P. Ferreira ◽  
Núria Santos ◽  
Nuno Fernandes ◽  
Carla Ferreira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Mortality Risk ◽  
Antipsychotic Treatment ◽  
Serious Adverse Events ◽  
Risk Of Death ◽  
Mesh Terms ◽  
Risk Of Mortality ◽  
Increased Risk

Objectives: Alzheimer's disease (AD) is the most common cause of dementia and it is associated with increased mortality. The use of antipsychotics is common among the elderly, especially in those with dementia. Evidence suggests an increased risk of mortality associated with antipsychotic use. Despite the short-term benefit of antipsychotic treatment to reduce the behavioral and psychological symptoms of dementia, it increases the risk of mortality in patients with AD. Our aim is to discuss the findings from the literature about risk of mortality associated with the use of antipsychotics in AD.Methods: We searched Internet databases indexed at MEDLINE using following MeSH terms: "Antipsychotic Agents" AND "Alzheimer Disease" OR "Dementia" AND "Mortality" and selected articles published in the last 5 years.Results: Antipsychotics are widely used in the pharmacological treatment of agitation and aggression in elderly patients with AD, but their benefit is limited. Serious adverse events associated with antipsychotics include increased risk of death. The risk of mortality is associated with both typical and atypical antipsychotics. Antipsychotic polypharmacy is associated with a higher mortality risk than monotherapy and should be avoided. The mortality risk increases after the first few days of treatment, gradually reducing but continues to increase after two years of treatment. Haloperidol is associated with a higher mortality risk and quetiapine with a lower risk than risperidone.Conclusions: If the use of antipsychotics is considered necessary, the lowest effective dose should be chosen and the duration should be limited because the mortality risk remains high with long-term use. The risk / benefit should be considered when choosing the antipsychotic. Further studies on the efficacy and risk of adverse events with antipsychotics are needed for a better choice of treatment and adequate monitoring with risk reduction.

scholarly journals Potentially inappropriate medication use in older adults with mild-moderate Alzheimer’s disease: prevalence and associations with adverse events

2020 ◽  
Vol 49 (4) ◽  
pp. 580-587
Author(s):  
Claire Murphy ◽  
Adam H Dyer ◽  
Brian Lawlor ◽  
Sean P Kennelly ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Inappropriate Medication ◽  
Potentially Inappropriate Medication ◽  
Randomised Control Trial ◽  
Vulnerable Group ◽  
Serious Adverse Events

Abstract Aim Potentially inappropriate medication (PIM) use is prevalent in older adults and is associated with adverse events, hospitalisation and mortality. We assessed the patterns and associations of PIM use in older adults with mild-to-moderate Alzheimer’s Disease (AD), who may represent a particularly vulnerable group. Design Analysis of data from NILVad, an 18-month Randomised Control Trial of Nilvadapine in mild-to-moderate AD. The v2 STOPP criteria were applied in duplicate to identify PIM use. Associations between PIM use and adverse events/unscheduled healthcare visits in addition to the associations between PIM use and AD progression were evaluated. Setting and Participants 448 older adults with mild-to-moderate AD from 23 centres in nine European countries. Results Of 448 participants (mean age: 72.56 ± 8.19 years), over half (55.8%) were prescribed a PIM with 30.1% being prescribed 2+ PIMs. The most frequent PIMs were (i) long-term benzodiazepines (11.6% N = 52/448), (ii) selective serotonin reuptake inhibitors without appropriate indication (11.1% N = 50/448), and (iii) Proton-Pump Inhibitors (PPIs) without appropriate indication (10.7% N = 48/448). Increasing number of PIMs was associated with a greater risk of adverse events (IRR 1.17, 1.13–1.19, P < 0.001), serious adverse events (IRR 1.27; 1.17–1.37, P < 0.001), unscheduled hospitalisations (IRR 1.16, 1.03–1.30, P = 0.016) and GP visits (IRR 1.22, 1.15–1.28, P < 0.001). PIM use was not associated with dementia progression. Conclusions and Implications PIM use is highly prevalent in mild-to-moderate AD and is associated with adverse events and unscheduled healthcare utilisation. Further attention to de-prescribing in this vulnerable group is warranted.

Commentary on: L-Methylfolate, Methylcobolamine, and N-Acetylcysteine in the Treatment of Alzheimer's Disease-Related Cognitive Decline

CNS Spectrums ◽  
2010 ◽  
Vol 15 (S1) ◽  
pp. 7-7 ◽  
Author(s):  
Jeffrey L Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Methylation Status ◽  
Neurofibrillary Tangle ◽  
Amyloid Β ◽  
Vitamin B ◽  
Amyloid Β Protein ◽  
In Vivo Models ◽  
The Impact

Drs. McCaddon and Hudson provide a thorough review of the multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hey) are implicated in the pathogenesis of Alzheimer's disease (AD). They noted that Hey is more often elevated in AD and in mild cognitive impairment (MCI) than in cognitively healthy elderly; phosphatases needed to limit tau hyperphosphoryalation and neurofibrillary tangle formation require methylation and are dependent on folate and methylation status; cerebrospinal fluid (CSF) tau levels correlated with markers of methylation status; reduced folate and B12 levels lead to increase β-secretase and pesenilin 1 (PS1) actions leading to greater amyloid-β production in in vitro models; elevated Hey levels in rates are associated with increased PS1 activity and spatial memory deficits that are reversed following treatment with B12 and folate; raised Hey levels in vitro increase amyloid-β protein neurotoxicity; methylation impacts transmitters and transmitter function relevant to AD; in cultured neurons, Hey induces injury in DNA and stimulates cell death pathways. B12 deficiency leads to accumulation of methyl malonic acid, which inhibits mitochondrial function and may compromise energy generation and impair maintenance of synaptic plasticity. Methylation abnormalities result in excessive generation of reactive oxygen species that contribute importantly to cell injury. Biomarkers of oxidative injury, such as isoprostanes, are elevated in AD and suggest excess oxidation. Thus, there are multiple pathways through which deficient methylation may contribute to AD. In some cases, the observations are derived from models with B12 or folate deficiency and some in vitro observations have not been tested in in vivo models. There are no biomarkers specific to some of the pathways implicated and the magnitude of the impact of the deficiency or its treatment has not been established for all the relationships. Two open-label experiments in early- and late-stage AD patients have suggested benefit.

scholarly journals Efficacy, Safety and tolerability of the once-daily 10 cm² rivastigmine patch formulation in the patients with dementia (with probable Alzheimer’s disease)

2013 ◽  
Vol 29 (1) ◽  
pp. 5-14
Author(s):  
Anisul Haque ◽  
Quazi Deen Mohammad ◽  
Nirmalendu Bikash Bhowmik ◽  
Biplob Kumar Roy ◽  
Md Rafiqul Islam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Event ◽  
Adverse Events ◽  
Patch Size ◽  
Tolerability Profile ◽  
Rivastigmine Patch ◽  
Significant Difference ◽  
Lost To Follow Up

Back ground: Treatment compliance in patients with Alzheimer’s disease is particularly important as patients receiving regular treatment have a greater chance of slowing or delaying disease progression. Transdermal delivery has the potential for providing continuous drug delivery and steady plasma levels. Current study aimed to evaluate safety and tolerability of rivastigmine patch, to assess patient compliance and to assess the efficacy of treatment in patients with dementia (with probable Alzheimer’s disease). Methods: A total of 112 dementia patients (with a diagnosis of probable Alzheimer’s disease) from 12 centers were enrolled who were residing with someone in the communities throughout the study. After eligibility, and baseline assessments, patients were entered a 24-week open label treatment phase. All patients were started with application of one 5 cm² patch, followed by an up-titration to the target dose of 10 cm² patch size. Efficacy assessments were performed at weeks 12 and 24 in terms of MMSE and GDS score. Safety was monitored at all assessment points based mainly on the frequency of adverse events. Results: Analysis of baseline and available data until the drop out revealed no significant differentials. Around 95% of the study participants could receive 10 cm² patch size, showing a very high tolerability of the patch. Concurrent medication use also showed significant reduction to 16.3% patient in the end from 25% at baseline. The average MMSE score increased to 19.3 (±3.1) at 12th week and to 20.6(±3.4) at 24th week from 16.8 (±3.2) at baseline. GDS score reduced to 3.7 (±1.4) at 12th week and to 3.2 (±1.3) at 24th week from 4.3 (±1.5) at baseline. Only eight occasions of adverse event was reported (8.2%); no serious adverse event (SAE) were reported. Lost to follow up in the study was 14 (12.5%). Analysis of baseline data shows no significant difference. Their withdrawal seems to be unrelated to the adverse events and treatment outcome. Among the lost to follow up only one 1 (7.1%) had some side effect. Conclusion: Our study supports the pharmacokinetic rationale for the rivastigmine patch, indicating that smooth and continuous delivery of rivastigmine translates into an improved tolerability profile versus conventional oral administration, while maintaining clinical effectiveness. Bangladesh Journal of Neuroscience 2013; Vol. 29 (1) : 5-14

scholarly journals Automatic Prediction of Cognitive and Functional Decline Can Significantly Decrease the Number of Subjects Required for Clinical Trials in Early Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Neda Shafiee ◽  
Mahsa Dadar ◽  
Simon Ducharme ◽  
D. Louis Collins ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Decline ◽  
Functional Decline ◽  
Amyloid Β ◽  
Cognitive Test ◽  
Disease Heterogeneity ◽  
Early Alzheimer’S Disease

Background: While both cognitive and magnetic resonance imaging (MRI) data has been used to predict progression in Alzheimer’s disease, heterogeneity between patients makes it challenging to predict the rate of cognitive and functional decline for individual subjects. Objective: To investigate prognostic power of MRI-based biomarkers of medial temporal lobe atrophy and macroscopic tissue change to predict cognitive decline in individual patients in clinical trials of early Alzheimer’s disease. Methods: Data used in this study included 312 patients with mild cognitive impairment from the ADNI dataset with baseline MRI, cerebrospinal fluid amyloid-β, cognitive test scores, and a minimum of two-year follow-up information available. We built a prognostic model using baseline cognitive scores and MRI-based features to determine which subjects remain stable and which functionally decline over 2 and 3-year follow-up periods. Results: Combining both sets of features yields 77%accuracy (81%sensitivity and 75%specificity) to predict cognitive decline at 2 years (74%accuracy at 3 years with 75%sensitivity and 73%specificity). When used to select trial participants, this tool yields a 3.8-fold decrease in the required sample size for a 2-year study (2.8-fold decrease for a 3-year study) for a hypothesized 25%treatment effect to reduce cognitive decline. Conclusion: When used in clinical trials for cohort enrichment, this tool could accelerate development of new treatments by significantly increasing statistical power to detect differences in cognitive decline between arms. In addition, detection of future decline can help clinicians improve patient management strategies that will slow or delay symptom progression.

Regional Hypoperfusion Predicts Decline in Everyday Functioning at Three-Year Follow-Up in Older Adults without Dementia

2020 ◽  
Vol 77 (3) ◽  
pp. 1291-1304
Author(s):  
Danielle L. Sanchez ◽  
Kelsey R. Thomas ◽  
Emily C. Edmonds ◽  
Mark W. Bondi ◽  
Katherine J. Bangen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cerebral Metabolism ◽  
Functional Decline ◽  
Amyloid Β ◽  
Cognitive Status ◽  
White Matter Hyperintensity ◽  
Everyday Functioning

Background: Increasing evidence indicates that cerebrovascular dysfunction may precede cognitive decline in aging and Alzheimer’s disease (AD). Reduced cerebral blood flow (CBF) is associated with cognitive impairment in older adults. However, less is known regarding the association between CBF and functional decline, and whether CBF predicts functional decline beyond cerebrovascular and metabolic risk factors. Objective: To examine the association between regional CBF and functional decline in nondemented older adults. Method: One hundred sixty-six (N = 166) participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent neuropsychological testing and neuroimaging. Pulsed arterial spin labeling magnetic resonance imaging was acquired to quantify resting CBF. Everyday functioning was measured using the Functional Assessment Questionnaire at baseline and annual follow-up visit across three years. Results: Adjusting for age, education, sex, cognitive status, depression, white matter hyperintensity volume, cerebral metabolism, and reference (precentral) CBF, linear mixed effects models showed that lower resting CBF at baseline in the medial temporal, inferior temporal, and inferior parietal lobe was significantly associated with accelerated decline in everyday functioning. Results were similar after adjusting for conventional AD biomarkers, including cerebrospinal fluid (CSF) amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) and apolipoprotein E (APOE) ɛ4 positivity. Individuals who later converted to dementia had lower resting CBF in the inferior temporal and parietal regions compared to those who did not. Conclusion: Lower resting CBF in AD vulnerable regions including medial temporal, inferior temporal, and inferior parietal lobes predicted faster rates of decline in everyday functioning. CBF has utility as a biomarker in predicting functional declines in everyday life and conversion to dementia.

Alzheimer's Disease: Progress in the Development of Anti-amyloid Disease-Modifying Therapies

CNS Spectrums ◽  
2007 ◽  
Vol 12 (2) ◽  
pp. 113-123 ◽  
Author(s):  
Daniel D. Christensen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Amyloid Β ◽  
Phase Iii ◽  
Peroxisome Proliferator ◽  
Serious Adverse Events ◽  
Amyloid Disease ◽  
Aβ Aggregation ◽  
Disease Modifying

ABSTRACTThe amyloid hypothesis—the leading mechanistic theory of Alzheimer's disease—states that an imbalance in production or clearance of amyloid β (Aβ) results in accumulation of Aβ and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Aβ or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Aβ42-lowering agents; statins; anti-Aβ aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and γ-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Aβ42 production (eg, tarenflurbil), enhance the activity of α-secretase (eg, statins), and block Aβ aggregation (eg, transiposate).

scholarly journals Evaluating Effects of Glatiramer Acetate Treatment on Amyloid Deposition and Tau Phosphorylation in the 3xTg Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Dawling A. Dionisio-Santos ◽  
Berke Karaahmet ◽  
Elizabeth K. Belcher ◽  
Laura D. Owlett ◽  
Lee A. Trojanczyk ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glatiramer Acetate ◽  
Neurofibrillary Tangle ◽  
Subcutaneous Administration ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Striking Difference ◽  
Tau Pathology ◽  
Model Of Alzheimer’S Disease

Neuroinflammation driven by the accumulation of amyloid β (Aβ) can lead to neurofibrillary tangle formation in Alzheimer’s Disease (AD). To test the hypothesis that an anti-inflammatory immunomodulatory agent might have beneficial effects on amyloid and tau pathology, as well as microglial phenotype, we evaluated glatiramer acetate (GA), a multiple sclerosis drug thought to bias type 2 helper T (Th2) cell responses and alternatively activate myeloid cells. We administered weekly subcutaneous injections of GA or PBS to 15-month-old 3xTg AD mice, which develop both amyloid and tau pathology, for a period of 8 weeks. We found that subcutaneous administration of GA improved behavioral performance in novel object recognition and decreased Aβ plaque in the 3xTg AD mice. Changes in tau phosphorylation were mixed with specific changes in phosphoepitopes seen in immunohistochemistry but not observed in western blot. In addition, we found that there was a trend toward increased microglia complexity in 3xTg mice treated with GA, suggesting a shift toward homeostasis. These findings correlated with subtle changes in the microglial transcriptome, in which the most striking difference was the upregulation of Dcstamp. Lastly, we found no evidence of changes in proportions of major helper T cell (Th) subtypes in the periphery. Overall, our study provides further evidence for the benefits of immunomodulatory therapies that alter the adaptive immune system with the goal of modifying microglia responses for the treatment of Alzheimer’s Disease.

scholarly journals Protein contributions to brain atrophy acceleration in Alzheimer’s disease and primary age-related tauopathy

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3463-3476
Author(s):  
Keith A Josephs ◽  
Peter R Martin ◽  
Stephen D Weigand ◽  
Nirubol Tosakulwong ◽  
Marina Buciuc ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Atrophy ◽  
Neurofibrillary Tangle ◽  
Amyloid Β ◽  
Brain Regions ◽  
Hippocampal Atrophy ◽  
Brain Volumes ◽  
Age Related ◽  
Over Time

Abstract Alzheimer’s disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer’s disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer’s disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer’s disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer’s disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer’s disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0–16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer’s disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer’s disease and primary age-related tauopathy.

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