Prodromal Alzheimer's Disease Research Articles

Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring

Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4–6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer’s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.

Mining CSF_tau associated genes with deep learning in AD patients

AbstractBackgroundTau protein abnormalities have been attracting more and more attention in Alzheimer’s disease (AD) pathophysiology. Tau spreads in a hierarchical pattern in the AD brain, likely by trans‐synaptic propagation between neurons. Discovering genetic risk factors associated with tau pathology could be key for improving our ability to predict and treat AD. In this study, we leveraged the non‐linear analytic approach of deep learning to identify genes that are associated with cerebrospinal fluid (CSF) total tau levels.MethodWe selected 384 subjects [118 normal control and 266 mild cognitive impairment (MCI)] from ADNI cohort. We designed a deep neuron network model that predicted CSF total tau levels using peripheral blood transcriptomic data. More specifically, we developed an occlusion map approach to rank 2,364 transcripts, which were initially selected from 49,386 transcripts by dimension reduction. The occlusion map aimed to rank the transcripts and identified the critical ones.ResultOur deep neural network successfully predicted CSF total tau levels with an accuracy of 67% and the occlusion map identified the critical genes for the prediction. The list included genes like TTL5, AKIRIN2, CPEB1, PTPN7, CIRBP and RPS23, which have been previously reported to be related to AD. For example, TTL5 relates to missorting of tau protein. AKIRIN2 is essential for the formation of the cerebral cortex. CPEB is found to be an interacting factor of amyloid‐precursor protein (APP). PTPN7 belongs to protein tyrosine phosphatases family, among which PTPN1& PTPN5 has been reported to tau pathology and amyloid pathology. CIRBP is reported to exert protective effects against neuronal amyloid toxicity. RPS23 regulates amyloid level and tau phosphorylation.ConclusionUncovering the genes that have critical association with tau protein abnormalities is critically important for improving our understanding of the drivers of neurodegeneration in prodromal AD. Our deep learning algorithm has shown promising results in identifying the critical genes for tau pathology. This study has demonstrated the effectiveness of deep learning in genetic analysis for AD research.1. Bahureksa, L., et al. (2017)2. Wilcockson, T.D.W., et al. (2019)3. Tomoeda, C. K. (2001)4. Feldman, H. H., et al. (2008)5. Winblad, B., et al. (2016)6. Thomann, A. E., et al. (2018)

Topographical differences in white matter hyperintensity burden and cognition in aging, MCI, and AD

AbstractBackgroundWhite matter hyperintensities (WMHs) are pathological changes that develop with increased age and are associated with cognitive decline. Most research on WMHs has neglected to examine regional differences and instead focuses on using a whole‐brain approach. This study examined regional WMH differences and their association with different cognition domains in normal controls (NCs), people with mild cognitive impairment (MCI), and Alzheimer’s disease (AD).Methods We included participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Few studies using ADNI data have examined the most recent cohort, ADNI‐3. Our study included datapoints from this recently released cohort. Participants were selected from ADNI and were included if they had at least one WMH measurement and cognitive scores examining global cognition (Alzheimer’s Disease Assessment Scale‐13), executive functioning (Trail Making Test‐Part B, and memory (Rey Auditory Verbal Learning Test). MCI and AD participants were included only if they were amyloid positive. A total of 1573 participants with 7381 follow‐ups met inclusion criteria. Linear mixed‐effects models were completed to examine group differences in WMH burden and the association between WMH burden and cognition in aging, MCI, and AD.ResultsPeople with MCI and AD had increased total and regional WMH burden compared to cognitively healthy older adults. An association between WMH and cognition was observed for global cognition, executive functioning, and memory in NCs in all regions of interest. A steeper decline (stronger association between WMH and cognition) was observed in MCI compared to NCs for all cognitive domains in all regions. A steeper decline was observed in AD compared to NCs for global cognition in only the temporal region.Conclusion Including ADNI‐3 data in this study is a novel strength to this study. These results suggest WMH burden increases from aging to AD. A strong association is observed between all cognitive domains of interest and WMH burden in healthy aging and MCI, while those with AD only had a few associations between and WMH and global cognition. These findings indicate that WMH burden is associated with changes in cognition in healthy aging and prodromal AD but not AD.

The Brain Health Registry: Lessons learned and next steps for remote, online AD and aging clinical research

AbstractBackgroundRemote, internet‐based methods for recruitment, screening, and longitudinally assessing older adults have the potential to greatly facilitate Alzheimer’s disease and related research, including clinical trials and observational studies.MethodsThe Brain Health Registry (BHR) is an online website and registry that includes a comprehensive battery of self‐ and study partner‐report questionnaires and online neuropsychological tests. Participants are asked to return at 6‐month intervals for longitudinal follow‐up. Recently, new online infrastructure for managing remote biomarker (saliva, blood) collection and for linking in‐clinic and online data were added. Multiple current initiatives aim to increase recruitment and engagement of underrepresented populations using digital, community engaged research strategies to improve generalizability of results. These include the recent launch of a Spanish‐language website, and projects focused on increasing enrollment and task completion of Black/African American and Hispanic/Latinx individuals.ResultsBHR includes >95,000 participants, >9000 of whom have enrolled study partners, 40% return for longitudinal follow up, 64% are age 55+, 80% are female, 80% identify as Non‐Latinx White, and 10% identify as Hispanic/Latinx. Participants have an average of 16.2 years of education. BHR has made >86,000 referrals to other studies, resulting in >5000 BHR participants enrolled in 25 different aging and AD observational studies and treatment trials. Over 2400 participants are co‐enrolled in BHR and collaborator studies, with online data linked to in‐clinic data. 573 participants have undergone APOE genotyping using remote saliva collection, and 629 have had blood collected using local phlebotomy for AD plasma biomarker analysis. Accumulating evidence supports the feasibility and validity of the approach, including associations with in‐clinic assessments, the ability to accurately detect MCI and enrichment for amyloid positivity.ConclusionsMajor advantages of the BHR approach are scalability and accessibility. Challenges include compliance, retention, and cohort diversity. Lessons learned from BHR, and components of the existing infrastructure, can be used to inform future remote clinical trial design. One such future effort is ADNI4. To facilitate enrollment of new participants, ADNI4 will establish an online recruitment and screening portal, with a remote phlebotomy component, to efficiently identify those from underrepresented populations, and those likely to have preclinical and prodromal AD.

18F‐MK6240 tau in ento‐ and perihinal cortex is related to episodic memory in the earliest stages of Alzheimer’s disease

AbstractBackgroundIn a previous study, we showed the sensitivity of the Buschke Selective Reminding test Total Retention (BSRT TR) for detecting and predicting 4‐year cognitive change in cognitively intact older adults. Here, we examined how BSRT TR related to tau load.MethodThe study sample consisted of 29 cognitively intact participants of the Flemish Prevent AD cohort KU Leuven (CDR global=0, MMSE=28‐30, mean age=68.5 year) and eight memory‐clinic recruited patients with prodromal AD (CDR global=0.5, MMSE=21‐30, mean age=71 year). All participants underwent neuropsychological testing, MRI and 18F‐MK6240 PET. Structural T1‐weighted MRI images were processed using CAT12. Tau load was quantified as 18F‐MK6240 DVR with the inferior cerebellum used as reference region. The primary analysis was based on voxel‐wise regression analysis between 18F‐MK6240 DVR scans and BSRT TR mean scores, with age as covariate. The second primary endpoint was the correlation between BSRT TR mean scores and tau DVR in an entorhinal and perirhinal volume of interest (VOI) based on the Brainnetome atlas. The secondary analysis was a VOI analysis based on an early metaVOI also containing hippocampus, parahippocampus, fusiform gyrus and inferior temporal cortex. Results were compared to those obtained for other episodic memory scores (BSRT delayed recall (DR), Auditory Verbal Learning Test (AVLT) total learning (TL) and AVLT DR), and an MRI volumetric analysis.ResultVoxel‐wise regression analysis showed a negative correlation between BSRT TR mean and DVR in ento‐ and perirhinal cortex bilaterally (x=22, y=‐4, z=‐32, extent=612 voxels, cluster level pcorr<0.001) (x=‐30, y=‐22, z=‐20, extent=2910 voxels, cluster level pcorr<0.001) (Figure A). This was confirmed by the analysis of the entorhinal/perirhinal VOI (rho=‐0.44, p=0.0063; Figure B). Significant correlations with ento‐ and perirhinal DVR were also present for BSRT DR (rho=‐0.39, p=0.017) and AVLT TL (rho=‐0.41, p=0.012), but not for AVLT DR (rho=‐0.29, p=0.084). No significant correlation was found with tau in the early metaVOI for any of the verbal episodic memory measures. Voxel‐wise regression analysis between gray matter volume and BSRT TR mean scores did not show significant results.ConclusionThe earliest measurable tau aggregate levels in ento‐ and perirhinal cortex correlate with classical episodic memory parameters.

Gantenerumab treatment increases plasma beta‐amyloid(1–42) and decreases plasma pTau

AbstractBackgroundGantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer’s disease (AD). SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) were two Phase III trials which assessed the efficacy and safety of subcutaneous, low‐dose gantenerumab in participants with prodromal and mild AD, respectively, for up to 2 years. Following a gap period gantenerumab treatment was continued with uptitration to a dose of 1,200 mg monthly in open‐label extensions (OLE), which demonstrated substantial Abeta removal by positron emission tomography without new or unexpected safety findings. The aim of this work is to investigate the pharmacodynamic effects of gantenerumab on plasma markers for amyloid and tau during both double‐blind and OLE periods.MethodWe evaluated the pharmacodynamic effects of subcutaneous gantenerumab on blood‐based biomarkers for amyloid and tau proteins in plasma samples collected once every year from participants who completed the double‐blind periods of SCarlet RoAD and Marguerite RoAD and participated in the OLE for up to 3 years. We measured Abeta(1–42) and phosphorylated Tau (pTau) in plasma samples using prototype Elecsys® immunoassays from Roche Diagnostics.ResultPlasma Abeta(1–42) increases by 106% (95% confidence interval [CI]: 48% to 163%) in SCarlet RoAD and 63% (95% CI: 49% to 77%) in Marguerite RoAD after 3 years of OLE treatment. Plasma pTau decreases by 24% (95% CI: –44% to –4%) in SCarlet RoAD and 11% (95% CI: –23% to +2%) in Marguerite RoAD after 3 years of OLE treatment.ConclusionChronic treatment with 1,200 mg subcutaneous injections of gantenerumab every 4 weeks increases levels of plasma Abeta(1–42) and decreases levels of plasma pTau consistently across both studies.

Chemical ablation of locus coeruleus terminals in mice dysregulates behavioral features reminiscent of prodromal Alzheimer’s disease

AbstractBackgroundThe prodromal stages of Alzheimer’s disease (AD), which precede cognitive impairment by decades, are characterized by neuropsychiatric symptoms such as anxiety, agitation, impulsivity, and sleep disturbances that significantly impair quality of life. The brainstem noradrenergic locus coeruleus (LC) modulates behaviors that are reminiscent of these prodromal symptoms. Furthermore, the loss of norepinephrine (NE) terminals in LC‐projecting regions is a prominent feature of early AD, implicating LC dysfunction as a possible contributor to prodromal symptoms. However, the behavioral and pathological consequences of LC terminal loss have not been fully investigated.MethodAdult male and female C57BL/6 mice aged 4‐6 months were administered either saline or the LC‐specific neurotoxin, N‐(2‐chloroethyl)‐N‐ethyl‐bromo‐benzylamine (DSP‐4) (50 mg/kg, i.p.) on day 1 and day 7 (12 animals/group). Performance in behavioral tests that assess arousal (sleep latency), locomotor activity (novelty‐induced and circadian), anxiety (novelty‐suppressed feeding), and associative memory (contextual fear conditioning) commenced one week following the last treatment. In addition, brain sections consisting of LC, hippocampus, and cortical areas were immunostained for tyrosine hydroxylase (TH) to evaluate LC integrity, NE transporter (NET) to determine fiber/terminal density to LC‐projecting regions, and glial fibrillary acidic protein (GFAP) to assess astrogliosis. Fluorescence immunoreactivity (IR) was analyzed with ImageJ.ResultAnimals treated with DSP‐4 displayed significantly increased latency to feed in a novel environment compared to saline‐treated animals, with no treatment differences in the home cage, suggesting elevated neophobic behavior. Furthermore, DSP‐4‐treated animals trended towards decreased locomotor activity in the center of the environment over 1 hour and 23 hours, indicating increased thigmotaxis. No behavioral treatment differences were observed for sleep latency and contextual fear conditioning paradigms. Immunofluorescence revealed no treatment differences in TH IR in the LC but reduced NET IR in LC‐projecting regions of DSP‐4‐treated animals, demonstrating preserved LC cell bodies and LC fiber loss. No significant treatment differences were found for GFAP.ConclusionThese data suggest that chemical ablation of LC terminals with DSP‐4 can contribute to neophobia and anxiogenic responses, implicating LC terminal loss in mediating prodromal symptoms relevant to AD. Further studies are warranted to identify the physiological and molecular mechanisms underlying LC dysfunction for alleviating prodromal AD symptoms.

Multifactor mid‐life risk for Alzheimer’s disease associated with alterations in navigation but not episodic memory: the PREVENT‐Dementia study

AbstractBackgroundThe entorhinal cortex (EC) is the first cortical brain region to exhibit neurodegeneration in Alzheimer’s disease (AD). Given that the EC contains unique grid cells underpinning path integration, tests probing this aspect of navigation may have added value in detecting AD in its earliest preclinical stages. Building on our past work showing that a VR path integration task was highly sensitive and specific for prodromal AD (Howett et al., 2019 Brain), we tested the hypothesis that path integration may be affected in asymptomatic middle‐aged individuals at increased risk of AD.Method100 cognitively healthy adults (aged 43–66) from the PREVENT Dementia cohort performed an immersive VR path integration task in a simulated environment with distal boundary cues to generate allocentric spatial representations. We manipulated EC‐dependence by pseudo‐randomly removing supportive spatial cues from the virtual environment (Figure 1). Participants additionally performed a battery of cognitive tasks including the ACE‐R and COGNITO episodic memory. Linear mixed effects models and Tukey‐corrected post‐hoc contrasts were used to explore the contributions to task performance of parental family history, APOE‐e4 status, global amyloid PET uptake value (N = 46) and CAIDE lifestyle dementia risk score, adjusted for age, sex and education.ResultIndividuals with a positive family history, APOE‐e4 allele or higher CAIDE dementia risk score showed a selective impairment in path integration only when supportive boundary cues were removed. Significant sex interactions indicated that the family history effect (t = 2.31, pTukey = 0.022, Figure 2) and APOE‐e4 effect (t = 3.18, pTukey = 0.023) was specific to males. The effect of CAIDE risk score was specific to individuals with a family history (t = 2.45, pTukey = 0.038) (Figure 3). Conversely, these AD risk factors showed no effect on performance for the other cognitive tasks. Global amyloid PET uptake values showed no association to any task performance.ConclusionThese results suggest that navigation tests based on EC grid cell function may identify the earliest cognitive changes in individuals at greater risk of AD. The additional moderation by sex indicates a future need to consider male/female differences when using family history or APOE status to inform detection of initial stages of AD.

Clinical features in prodromal disease: Comparing dementia with Lewy bodies with Alzheimer’s disease

AbstractBackgroundDementia with Lewy bodies (DLB) is a common neurodegenerative disorder; however, DLB can be difficult to differentiate from Alzheimer’s disease dementia (AD), particularly in the early stages. Research criteria for prodromal DLB were published in 2020 and further studies are needed to validate and refine future clinical criteria.MethodWe analyzed data from the Uniform Data Set from the National Alzheimer’s Coordinating Center (NACC database is funded by NIA/NIH U01‐AG016976). Annual visits occurred across 39 Alzheimer’s Disease Research Centers between September 2005 and September 2021. We identified non‐demented participants [i.e., normal cognition, impaired‐not mild cognitive impairment (MCI) or MCI] at baseline who subsequently received a clinical diagnosis of DLB or AD. Core clinical features (CCF) for DLB (i.e., motor features, visual hallucinations, probable REM sleep behavior disorder (pRBD), cognitive fluctuations), and supportive neuropsychiatric features (NPF; anxiety, apathy, and depression) were assessed through clinical exam and informant responses up to five years prior to dementia diagnosis.ResultThe sample consisted of 160 participants with DLB and 480 age/sex‐matched (1:3) participants with AD at first visit with dementia diagnosis. There was no significant difference in the number of visits prior to dementia diagnosis. The AD group was more racially and ethnically diverse than the DLB group. At the time of diagnosis, DLB participants demonstrated greater functional impairment. Descriptive results indicate CCF and NPF are common in DLB up to five years prior to conversion to dementia; however, motor slowing and NPF were reported in over 20% of the AD participants within the prodromal phase. The presence of 2 or more CCF yielded the greatest AUC (0.786; 95% CI: 0.743, 0.830) in distinguishing DLB from AD one year prior to dementia diagnosis. Combinations of 1 or more CCF with 1, 2, or 3 NPF resulted in significantly lower AUCs (0.725, 0.651, 0.547, respectively) due to decreased specificity.ConclusionCCF and supportive NPF are common in the prodromal phase of DLB; however, parkinsonism and NPF also occurred in the prodromal AD group. Parkinsonism may provide lower discrimination than cognitive fluctuations, visual hallucinations, or pRBD in differentiating DLB from AD in the prodromal phase.

Contributions of remote, unsupervised dyadic subjective measures to identify older adults with Mild Cognitive Impairment

AbstractBackgroundDyadic (self and study partner) subjective reports of an individual’s recent cognitive and functional decline are an efficient approach to facilitate identification of older adults with, and at risk for, Mild Cognitive Impairment (MCI). Such methods can be easily adapted for remote administration, but few studies have investigated the ability of remotely‐collected, unsupervised dyadic subjective reports to accurately detect MCI and cognitive decline.MethodsIn 289 older adults enrolled in the Brain health Registry (BHR), with clinically‐confirmed diagnoses of Cognitively‐unimpaired (CU) or MCI, we identified the optimal combination of remote measures to accurately distinguish CU from MCI. We then externally validated our predictive model in 217 participants enrolled in a separate cohort, Validation of Online Methods to Predict Cognitive Decline (eVAL). Predictors included Cogstate Brief Battery One Card Learning (OCL) accuracy; self‐ and study partner‐reported memory concern (SMCs); performance on online adaptations of Everyday Cognition Scale (ECog, self‐ and study partner‐report versions), Geriatric Depression Scale Short Form (GDS); family history of AD, age, gender, and education. We calculated 10‐fold cross validated area under the ROC curves (cvAUC), 95% confidence intervals (CI), and the percentage of participants correctly classified (accuracy) for all models. Likelihood ratio (LR) tests were used to compare model fits.ResultsIn the BHR cohort, models including dyad‐report ECog, family history of AD, GDS, and Cogstate OCL scores distinguished CU from MCI with the highest accuracy (cvAUC = 0.90; 95% CI = 0.83, 0.92; accuracy = 85.5%). Models excluding study partner‐report ECog distinguished diagnostic groups with moderate accuracy (cvAUC = 0.83; 95% CI = 0.78, 0.85; accuracy = 75.9%) When applied to the validation cohort, the optimal training model including dyadic report performed with moderate accuracy ( Table 2 ). In the validation cohort, inclusion of study partner (but not self) report SMC, in addition to dyadic‐report ECog, improved model fit (LR test p<0.01).ConclusionsRemotely‐collected dyadic subjective measures, along with other remote measures, accurately distinguish CU from MCI. Subjective cognitive and functional decline and concerns about memory problems independently contribute to diagnostic discrimination. Results support future utilization of remote dyadic subjective measures to efficiently identify older adults with MCI for prodromal AD clinical trials, and in clinical care settings.

Evidence of Filamin A loss of solubility at the prodromal stage of neuropathologically-defined Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disorder diagnosed through the assessment of amyloid-beta (Aβ) and tau protein depositions. Filamin A (FLNA) could be a key partner of both Aβ and tau pathological processes and may be an important contributor to AD progression. The main aim of this study was to describe the differences in FLNA levels across clinicopathologic groups. From parietal cortex samples of 57 individuals (19 with no cognitive impairment (NCI), 19 mild cognitively impaired (MCI) and 19 with dementia) from the Religious Orders Study (ROS), we quantified total tau, phosphorylated tau (pTau), FLNA, synaptophysin, vesicular acetylcholine transporters (VAChT) and choline acetyltransferase (ChAT) by Western blot. Aβ42 and neuritic plaques (NP) were quantified by ELISA and Bielschowsky silver impregnation, respectively. AD staging was determined using ABC method combining Thal, Braak and the CERAD staging. From this, clinicopathologic stages of AD were established by subdividing subjects with neuropathological AD between preclinical AD, prodromal AD and AD dementia (ADD). Receiver operating characteristics analyses were performed to predict AD neuropathology from FLNA quantifications. Insoluble FLNA was significantly and positively correlated with Aβ42, NP, Thal stages, ABC scores and AD clinicopathologic stages (p < 0.05 False discovery rate-corrected). No correlation of FLNA with tau measures was found. Insoluble FLNA levels were significantly higher in the prodromal AD, ADD and intermediate ABC groups. This was consistent with significantly lower levels of soluble FLNA specifically in prodromal AD. Insoluble (AUC: 0.830) and soluble FLNA levels (AUC: 0.830) as well as the ratio of soluble over insoluble FLNA (AUC: 0.852), were excellent predictors of prodromal AD among subjects with MCI from the ROS cohort. We observed opposite level changes between insoluble and soluble FLNA in prodromal AD. As this stage coincides with the appearance of cognitive symptoms, this may be a key event in the transition from preclinical to prodromal AD. Insoluble FLNA could be useful to identify prodromal AD among subjects with an MCI, indicating that it might be a hallmark of prodromal AD.

Distinct reserve capacity impacts on default-mode network in response to left angular gyrus-navigated repetitive transcranial magnetic stimulation in the prodromal Alzheimer disease

Default-mode network (DMN) may be the earliest affected network and is associated with cognitive decline in Alzheimer’s disease (AD). Repetitive transcranial magnetic stimulation (rTMS) may help to modulate DMN plasticity. Still, stimulation effects substantially vary across studies and individuals. Global left frontal cortex (gLFC) connectivity, a substitute for reserve capacity, may contribute to the heterogeneous physiological effects of neuro-navigated rTMS. This study investigated the effects of left angular gyrus-navigated rTMS on DMN connectivity in different reserve capacity participants. gLFC connectivity, was computed through resting-state fMRI correlations. Thirty-one prodromal AD patients were divided into low connection group (LCG) and high connection group (HCG) by the median of gLFC connectivity. Distinct reserve capacity impacts on DMN in response to rTMS were identified in these two groups. Then, brain-behavior relationships were examined. gLFC connectivity within a certain range is directly proportional to cognitive reserve ability (i.e., LCG), and the effectiveness of functional connectivity beyond this range decreases (i.e, HCG). Moreover, LCG exhibited increased DMN connectivity and significantly positive memory improvements, while HCG showed a contrary connectivity decline and maintained or slightly improved their cognitive function after neuro-navigated rTMS treatment. The prodromal AD patients with the distinct reserve capacity may benefit differently from left angular gyrus-navigated rTMS, which may lead to increasing attention in defining personalized medicine approach of AD.

Budget impact analysis of the use of Souvenaid in patients with prodromal Alzheimer’s Disease in Spain

IntroductionThe effectiveness, safety, and cost-effectiveness of the use of Souvenaid for Alzheimer’s disease (AD) have been previously evidenced. To complete the economic analysis, there is a need to assess whether society can afford it. The objective of this study was to carry out a budget impact analysis of the use of Souvenaid in Spain under the conditions of the LipiDidiet clinical trial from a societal perspective.MethodsWe built a population model that took into account all the cohorts of individuals with AD, their individual progression, and the potential impact of Souvenaid treatment on their trajectories. Patient progression data were obtained from mixed models. The target population was estimated based on the population forecast for 2020–2035 and the incidence of dementia. Individual progression to dementia measured by the Clinical Dementia Rating-Sum of Boxes was reproduced using mixed models. Besides the costs of treatment and diagnosis, direct costs of medical and non-medical care and indirect costs were included.ResultsThe epidemiological indicators and the distribution of life expectancy by stages validated the model. From the third year (2022), the differences in the cost of dementia offset the incremental cost of diagnosis and treatment. The costs of dependency reached €500 million/year while those of the intervention were limited to €40 million.ConclusionsSouvenaid, with modest effectiveness in delaying dementia associated with AD, achieved a positive economic balance between costs and savings. Its use in the treatment of prodromal AD would imply an initial cost that would be ongoing, but this would be offset by savings in the care system for dependency associated with dementia from the third year. These results were based on adopting a societal perspective taking into account the effect of treatment on the use of health, social, and family resources.

Candesartan-the next anti-amyloid drug?

This scientific commentary refers to 'Safety and biomarker effects of candesartan in non-hypertensive adults with prodromal Alzheimer's disease' by Hajjar et al. (https://doi.org/10.1093/braincomms/fcac270).

Plasma Phosphorylated Tau at Threonine 181 and Neuropsychiatric Symptoms in Preclinical and Prodromal Alzheimer Disease.

Plasma phosphorylated tau at threonine 181 (p-tau181), a well-validated marker of Alzheimer disease (AD) pathologic change, could be a more efficient way to diagnose AD than invasive or expensive biomarkers requiring CSF or PET. In some individuals, neuropsychiatric symptoms (NPS) are the earliest manifestation of AD, observed in advance of clear cognitive decline. However, the few studies assessing AD biomarkers in association with NPS have often had imprecision in capturing behavioral symptoms that represent sequelae of neurodegenerative disease. Thus, the mild behavioral impairment (MBI) construct was developed, framing NPS in a way to improve the precision of risk estimates for disease. MBI core criteria stipulate that NPS emerge de novo in later life and persist for at least 6 months. Here, cross-sectionally and longitudinally, we investigated associations of MBI with p-tau181, neuropsychological test performance, and incident AD. Cognitively unimpaired and mild cognitive impairment (MCI) Alzheimer's Disease Neuroimaging Initiative participants were selected. MBI status was derived from the Neuropsychiatric Inventory (NPI) using a published algorithm. NPI total scores at baseline and year 1 visits were used to operationalize MBI (score >0 at both visits), NPS not meeting the MBI criteria (NPS-not-MBI, score >0 at only 1 visit), and no NPS (score = 0 at both visits). Linear regressions were fitted for cross-sectional analyses; multilevel linear mixed-effects and Cox proportional hazards models were implemented to examine the longitudinal associations of MBI with changes in p-tau181 and cognition and incident dementia. The sample included 571 participants (age 72.2 years, 46.8% female, 64.8% MCI). Cross-sectionally (β = 8.1%, 95% CI 1.4%-15.2%, p = 0.02), MBI was associated with higher plasma p-tau181 levels compared with no NPS; NPS-not-MBI was not. Longitudinally, MBI was associated with higher p-tau181 (β = 0.014%, 95% CI 0.003-0.026, p = 0.02), in addition to a decline in memory and executive function. Survival analyses demonstrated a 3.92-fold greater dementia incidence in MBI, with no significant differences between NPS-not-MBI and no NPS. These findings extend the evidence base that MBI is associated with elevated risk of cognitive decline and dementia and a sequela of emerging Alzheimer-related proteinopathies. MBI offers a substantial improvement over current approaches that explore behavior as a proxy marker for Alzheimer-related proteinopathies, with both clinical and AD trial enrichment implications.

Different Sides of Depression in the Elderly: An In-depth View on the Role of Aβ Peptides.

Late-onset depression (LOD) is the most common neuropsychiatric disorder associated with Alzheimer's disease (AD), often associated with structural and functional brain changes, neuropsychological impairments and negative family history for affective disorders. LOD could be a risk factor or a prodromal phase of AD; this has led to the investigation of the link between depression and amyloid-β (Aβ) peptides by measuring Aβ levels in plasma, cerebrospinal fluid (CSF) and brains of elderly depressed subjects. This study aims to clarify the complex relationship between depression, Aβ peptides and AD. We evaluated all articles published up to 2019 in PubMed in which Aβ was measured in serum (or plasma), CSF or brain in elderly with Major Depressive Disorder or depressive symptoms evaluated with standard scales. Low plasma Aβ42 levels are strongly associated with depression severity. Plasma Aβ40 levels are higher in younger depressed, drug-resistant and those with more severe symptoms. CSF Aβ42 levels are lower in depressed than controls. PET-detected global and region-specific increases in Aβ deposition are sometimes associated with LOD, cognitive impairment, anxiety but not with Cardiovascular Diseases (CVDs)/CVD risk factors. Elderly depressed with CVDs/CVD risk factors have more frequently high plasma Aβ40 levels and drug-resistance; those without Conclusion: Two specific Aβ profiles emerge in the depressed elderly. One is associated with Aβ42 reductions in plasma and CSF, possibly reflecting increased brain amyloid deposition and prodromal AD. The other one is characterized by high plasma Aβ40 levels, cerebrovascular disease and is clinically associated with increased AD risk.

Safety and biomarker effects of candesartan in non-hypertensive adults with prodromal Alzheimer's disease.

Observational studies suggest that angiotensin receptor blockers in hypertensive adults are associated with lower post-mortem indicators of Alzheimer's disease pathology. Candesartan, an angiotensin receptor blocker, has a positive cognitive effect in mild cognitive impairment with hypertension. However, its safety and effects in non-hypertensive individuals with Alzheimer's disease are unclear. This is the first double-blind randomized placebo-controlled trial aimed to assess safety and effects of 1-year therapy of candesartan on biomarkers and clinical indicators of Alzheimer's disease in non-hypertensive individuals with biomarker-confirmed prodromal Alzheimer's disease. Seventy-seven non-hypertensive participants 50 years or older (mean age: 68.1 years; 62% women; 20% African American) with mild cognitive impairment and biomarker confirmed Alzheimer's disease were randomized to escalating doses of once daily oral candesartan (up to 32 mg) or matched placebo. Main outcomes included safety and tolerability of candesartan, cerebrospinal fluid biomarkers (amyloid-β42, amyloid-β40, total tau and phospho-tau). Additional exploratory outcomes included PET imaging (Pittsburgh Compound-B (11C-PiB) and 18F-flortaucipir), brain MRI (structural and connectivity measures) and cognitive functioning. Analyses used intention-to-treat approach with group comparisons of safety measures using Chi-square test, and repeated measures mixed effects models were used to assess candesartan effects on main and exploratory outcomes (ClinicalTrials.gov, NCT02646982). Candesartan was found to be safe with no significant difference in safety measures: symptoms of hypotension, renal failure or hyperkalemia. Candesartan was also found to be associated with increases in cerebrospinal fluid Aβ40 (between-group mean difference: 1211.95 pg/ml, 95% confidence interval: 313.27, 2110.63) and Aβ42 (49.51 pg/ml, 95% confidence interval: -98.05, -0.98) reflecting lower brain amyloid accumulation. Candesartan was associated with decreased 11C-PiB in the parahippocampal region (-0.1104, 95% confidence interval: -0.19, -0.029) which remained significant after false discovery rate correction, and with an increase in functional network connectivity in the subcortical networks. Candesartan was further associated with improved executive function (Trail Making Test Part B) performance (-11.41 s, 95% confidence interval: -11.94, -10.89) and trended for an improved global cognitive functioning reflected by a composite cognitive score (0.002, 95% confidence interval: -0.0002, 0.005). We did not observe significant effects on tau levels, hippocampal volume or other cognitive measures (memory or clinical dementia rating scale-sum of boxes). In conclusion, among non-hypertensive prodromal Alzheimer's disease, candesartan is safe and likely decreases brain amyloid biomarkers, enhances subcortical brain connectivity and has favourable cognitive effects. These findings suggest that candesartan may have an important therapeutic role in Alzheimer's disease, and warrant further investigation given the lack of clear treatment options for this devastating illness.

Monitoring Alzheimer's Disease Progression in Mild Cognitive Impairment Stage Using Machine Learning-Based FDG-PET Classification Methods.

We previously introduced a machine learning-based Alzheimer's Disease Designation (MAD) framework for identifying AD-related metabolic patterns among neurodegenerative subjects. We sought to assess the efficiency of our MAD framework for tracing the longitudinal brain metabolic changes in the prodromal stage of AD. MAD produces subject scores using five different machine-learning algorithms, which include a general linear model (GLM), two different approaches of scaled subprofile modeling, and two different approaches of a support vector machine. We used our pre-trained MAD framework, which was trained based on metabolic brain features of 94 patients with AD and 111 age-matched cognitively healthy (CH) individuals. The MAD framework was applied on longitudinal independent test sets including 54 CHs, 51 stable mild cognitive impairment (sMCI), and 39 prodromal AD (pAD) patients at the time of the clinical diagnosis of AD, and two years prior. The GLM showed excellent performance with area under curve (AUC) of 0.96 in distinguishing sMCI from pAD patients at two years prior to the time of the clinical diagnosis of AD while other methods showed moderate performance (AUC: 0.7-0.8). Significant annual increment of MAD scores were identified using all five algorithms in pAD especially when it got closer to the time of diagnosis (p &lt; 0.001), but not in sMCI. The increased MAD scores were also significantly associated with cognitive decline measured by Mini-Mental State Examination in pAD (q &lt; 0.01). These results suggest that MAD may be a relevant tool for monitoring disease progression in the prodromal stage of AD.

Longitudinal cognitive change and duration of Alzheimer’s disease stages in relation to cognitive reserve

The relationship of cognitive reserve and measures of reserve with longitudinal cognitive change and the duration of preclinical, prodromal, and mild Alzheimer disease (AD) dementia remains to be fully characterized. In our study, 660 β-amyloid-positive participants staged with preclinical AD, prodromal AD, and dementia due to AD from the Alzheimer’s Disease Neuroimaging Initiative were selected. Cognitive reserve and brain reserve were defined by conventional proxies or the residual method at baseline. We evaluated the utility of these reserves in predicting longitudinal cognitive change by mixed effects models and used a multi-state model to estimate stage duration stratified by reserve groups. Corrected for age, sex, and APOE-ε4 status, reserve was associated with cognitive decline, and the effects changed depending on the specific measures of reserve and the stage of AD. Reserves defined by the residual method were stronger predictors of cognitive change than those defined by conventional proxies. The estimated time from preclinical to mild AD dementia varied from 15–24 years based on the different reserve groups, and we observed a linear trend for the longest duration in individuals with high cognitive reserve/high brain reserve, followed by those with high cognitive reserve/low brain reserve, low cognitive reserve/high brain reserve, and low cognitive reserve/low brain reserve. This study showed a reduced risk of cognitive decline for individuals with higher level of reserve regardless of methods for measuring reserve. Interindividual differences in reserve may be important for clinical practice and trial design.

Quantitative MRI Evidence for Cognitive Reserve in Healthy Elders and Prodromal Alzheimer's Disease.

Cognitive reserve (CR) has been postulated to contribute to the variation observed between neuropathology and clinical outcomes in Alzheimer's disease (AD). We investigated the effect of an education-occupation derived CR proxy on biological properties of white matter tracts in patients with amnestic mild cognitive impairment (aMCI) and healthy elders (HC). Educational attainment and occupational complexity ratings (complexity with data, people, and things) from thirty-five patients with aMCI and twenty-eight HC were used to generate composite CR scores. Quantitative magnetic resonance imaging (qMRI) and multi-shell diffusion MRI were used to extract macromolecular tissue volume (MTV) across major white matter tracts. We observed significant differences in the association between CR and white matter tract MTV in aMCI versus HC when age, gender, intracranial volume, and memory ability were held constant. Particularly, in aMCI, higher CR was associated with worse tract pathology (lower MTV) in the left and right dorsal cingulum, callosum forceps major, right inferior fronto-occipital fasciculus, and right superior longitudinal fasciculus (SLF) tracts. Conversely higher CR was associated with higher MTV in the right parahippocampal cingulum and left SLF in HC. Our results support compensatory CR mechanisms in aMCI and neuroprotective mechanisms in HC and suggest differential roles for CR on white matter macromolecular properties in healthy elders versus prodromal AD patients.