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Alzheimer’s Disease (AD) is a neurodegenerative condition affecting millions worldwide. Defining early pathobiological events remains challenging, in part due to inaccessibility of neural tissue. Because olfactory neurons are accessible, and olfactory loss is prevalent in AD, we evaluated olfactory brush biopsies from controls, individuals with cerebrospinal fluid (CSF) biomarker-confirmed AD, and cognitively typical individuals whose positive CSF biomarkers signal a pre-clinical AD stage. Here we show via single cell RNA-sequencing ( n  = 22 subjects) conserved neuroinflammatory T cell, myeloid cell, and olfactory neuron changes detectable even in pre-clinical AD subjects, and corroborate heightened CD8 T-cell activation by flow cytometry. Activated memory T cell states in the olfactory epithelium were a hallmark of pre-clinical AD, paralleling CSF T cell phenotypes seen in advanced disease, accompanied by both microglia-like inflammatory programs and evidence of olfactory neuron inflammatory injury. Together, our findings establish a platform permitting analysis of neural tissue in AD at its earliest stages. Using nasal brush biopsies from the olfactory region, single-cell profiling revealed neuroimmune alterations in Alzheimer’s Disease detectable at a pre-clinical stage, offering an accessible window into early neurodegenerative disease in humans.

We aimed to understand clinician views regarding gene therapy as a future treatment for Alzheimer's disease (AD) and potential barriers and facilitators to its use. We interviewed ten clinicians who treat patients with AD. Clinicians helped design a semi-structured interview including the following domains: establishing understanding, cost/access, quality of life, and religion/spirituality. Transcripts were analyzed by a coding team using descriptive content analysis with inductive approach. Clinicians identified three main areas of concern: 1) potential clinician and patient understanding of gene therapy and Alzheimer's disease 2) consideration of inequity (i.e., care access, disease awareness along with education level, family support, trust in care systems); and 3) considerations in decision-making (i.e., religious/spiritual beliefs and method of treatment delivery as a decision-making tools). Findings highlight areas for knowledge-building for patients and clinicians alike. Clinicians must be aware of patient/family educational needs and gaps in their own clinical knowledge before engaging patients/families with new technology. Allowing time for questions is crucial to building rapport and trust.

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that affects the frontal and temporal lobes of the brain, leading to cognitive decline and personality changes. The objective of this cross-sectional study was to characterize angioarchitectural changes in the retina and choroid of individuals with FTD compared to cognitively normal controls using optical coherence tomography (OCT) and OCT angiography (OCTA). Cross-sectional comparison of patients with FTD and controls with normal cognition. All participants underwent Mini-Mental State Examination (MMSE) at the time of imaging. Outcome measures included OCT parameters: retinal nerve fiber layer (RNFL) thickness, ganglion cell layer-inner plexiform layer (GC-IPL) thickness, central subfield thickness (CST), subfoveal choroidal thickness (SFCT), choroidal vascularity index (CVI); and OCTA superficial capillary plexus parameters: foveal avascular zone (FAZ) area, 3x3mm and 6x6mm macular perfusion density (PD) and vessel density (VD), 4.5x4.5mm peripapillary capillary perfusion density (CPD) and capillary flux index (CFI). Generalized estimating equation analysis was used to account for the inclusion of 2 eyes from the same participant. 29 eyes of 19 patients with FTD and 85 eyes of 48 controls were analyzed. In FTD, 3x3mm macular PD (p = 0.02) and VD (p = 0.02) and CFI (p = 0.01) were reduced compared to controls. There was no difference in average 4.5x4.5mm CPD, RNFL thickness, GC-IPL thickness, CST, SFCT, CVI, FAZ, or 6x6mm VD or PD between FTD and controls (all p > 0.05); however, there was a trend toward lower macular 6x6mm PD and VD in patients with FTD. Decline of peripapillary and macular OCT and OCTA parameters merit further investigation as potential biomarkers for FTD detection. Noninvasive retinal and choroidal imaging may hold promise for earlier detection, and future longitudinal studies will clarify their role in monitoring of FTD.

[This corrects the article DOI: 10.1371/journal.pone.0312118.].

Background We assess the relationships between retinal and choroidal structural and microvascular parameters and brain volumetric magnetic resonance imaging (MRI) parameters in individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). Methods Participants underwent optical coherence tomography (OCT) and OCT angiography (OCTA) imaging using the Zeiss Cirrus HD-5000 AngioPlex (Carl Zeiss Meditec, Dublin, CA) and volumetric brain MRI imaging with NeuroQuant (CorTechs Labs, San Diego, CA) analysis. Retinal and choroidal structural and microvascular parameters were extracted from OCT and OCTA scans. Superficial capillary plexus perfusion density and vessel density in the 3 × 3 mm and 6 × 6 mm circles and rings centered on the fovea were determined. Hippocampal, superior lateral ventricle (SLV), and inferior lateral ventricle (ILV) volumes were determined. Correlations between OCT, OCTA, and volumetric MRI parameters in patients with aMCI and AD were explored using Spearman partial correlation analysis. Results 68 eyes of 37 aMCI participants and 64 eyes of 33 AD participants were analyzed. In the eyes with aMCI, hippocampal volume negatively correlated with FAZ area and positively correlated with perfusion density and vessel density in the 3 mm OCTA scan. In the aMCI cohort, SLV and ILV volume inversely correlated with perfusion density in the 3 mm and 6 mm OCTA scans, respectively. In the eyes with AD, SLV and ILV volume inversely correlated with perfusion density and vessel density in the 3 mm and 6 mm OCTA scans. Central subfield thickness, ganglion cell-inner plexiform layer thickness, RNFL thickness, and choroidal vascularity index did not significantly correlate with SLV, ILV, or hippocampal volume in any cohorts ( p  > 0.05). Conclusions Decline in retinal microvascular parameters significantly correlated with hippocampal volume loss and ventricular expansion, suggesting that these parameters may mirror cerebral neurodegeneration in individuals with aMCI and AD. Trial registration Clinical trial identifier: NCT03233646, registration date: July 20, 2017.

The objective of this study was to examine clinicians' patient selection and result interpretation of a clinically validated mass spectrometry test measuring amyloid beta and ApoE blood biomarkers combined with patient age (PrecivityAD® blood test) in symptomatic patients evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. The Quality Improvement and Clinical Utility PrecivityAD Clinician Survey (QUIP I, ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm cohort study among 366 patients evaluated by neurologists and other cognitive specialists. Participants underwent blood biomarker testing and received an amyloid probability score (APS), indicating the likelihood of a positive result on an amyloid positron emission tomography (PET) scan. The primary study outcomes were appropriateness of patient selection as well as result interpretation associated with PrecivityAD blood testing. A 95% (347/366) concordance rate was noted between clinicians' patient selection and the test's intended use criteria. In the final analysis including these 347 patients (median age 75 years, 56% women), prespecified test result categories incorporated 133 (38%) low APS, 162 (47%) high APS, and 52 (15%) intermediate APS patients. Clinicians' pretest and posttest AD diagnosis probability changed from 58% to 23% in low APS patients and 71% to 89% in high APS patients (p < 0.0001). Anti-AD drug therapy decreased by 46% in low APS patients (p < 0.0001) and increased by 57% in high APS patients (p < 0.0001). These findings demonstrate the clinical utility of the PrecivityAD blood test in clinical care and may have added relevance as new AD therapies are introduced.

INTRODUCTION Anti‐amyloid monoclonal antibodies (mAbs) slow cognitive decline in Alzheimer's disease but may cause amyloid‐related imaging abnormalities (ARIA), which can rarely be disabling or fatal. This qualitative study investigates how clinicians communicate the benefits and risks of mAbs to patients and caregivers. METHODS Semi‐structured interviews with clinicians who prescribe mAbs at seven academic medical centers. Hybrid inductive‐deductive thematic analysis by interdisciplinary researchers. RESULTS In 27 clinician interviews (women [n = 17], White individuals [n = 19], neurologists [n = 17]), three themes emerged. First, clinicians varied in techniques used and concepts emphasized, including using analogies, discussing statistics, and emphasizing versus de‐emphasizing risks. Second, patient contextual factors (e.g., comorbidities), hopes, and fears shaped communication. Third, clinician communication varied by training, personal style, and ambivalence. While clinicians honor patients’ choices to pursue treatment, many do not “recommend” it (but may recommend against it). DISCUSSION Preliminary insights about how clinicians communicate tradeoffs can guide future shared decision‐making interventions for mAbs. Highlights This qualitative study among 27 clinicians across seven academic medical centers examined how clinicians communicate with people with Alzheimer's disease about risks and benefits of anti‐amyloid therapy, which can influence treatment decisions. Clinicians varied in what techniques they employed and how they portrayed risks and benefits, and whether they incorporated patients’ values. They cited comorbidities, eligibility criteria fit, and degree of social support or family involvement in decisions as factors used in framing discussions, while fewer used patients’ goals to guide discussion. The professional training, individual practice style, and personal sense of ambivalence of clinicians shaped conversations. These findings can guide future interventions to improve communication and shared decision‐making.

Objective: The objective of this study was to assess clinical decision-making associated with the use of a multi-analyte blood biomarker (BBM) test among patients presenting with signs or symptoms of mild cognitive impairment or dementia. Methods: The Quality Improvement PrecivityAD2 (QUIP II) Clinician Survey (NCT06025877) study evaluated the clinical utility of the PrecivityAD2™ blood test in a prospective, single cohort of 203 patients presenting with symptoms of Alzheimer’s disease (AD) or other causes of cognitive decline across 12 memory specialists. The PrecivityAD2 blood test (C2N Diagnostics, St. Louis, MO) combines the plasma Aβ42/Aβ40 ratio and the p-tau217/np-tau217 ratio (%p-tau217) measurements in a statistical algorithm to yield an Amyloid Probability Score 2 (APS2) that informs on the likelihood of brain amyloid plaques. After receiving the BBM test results, clinicians completed surveys on management strategies for each patient. Results: Patients had a median age of 74, 53% were female, and 28% were traditionally under-represented in Black, Hispanic, and Asian groups. The composite primary endpoint, defined as a change in AD diagnostic certainty, drug therapy, or additional brain amyloid evaluation pre- and post-BBM testing, was 75% (p < 0.0001 versus the pre-specified threshold of 20% clinically meaningful change). Anti-AD medication orders decreased among negative APS2 patients and increased among positive APS2 patients (p < 0.0001). Additional brain amyloid testing decreased among negative APS2 patients (p < 0.0001). Conclusions: This blood biomarker test can help memory specialists guide patients to anti-AD therapies as well as rule out AD to allow for other diagnostic considerations.

APOE4 homozygotes with Alzheimer's have faster rates of cognitive decline and become symptomatic approximately a decade earlier. APOE2 is a protective variant with reduced likelihood of developing AD and a slower rate of decline. LX1001 is an adeno-associated viral vector investigational gene therapy (AAVrh.10hAPOE2) delivering the APOE2 gene into the central nervous system of APOE4 homozygotes to convert the brain APOE4 homozygous genotype to an APOE2/E4. This is a Phase 1/2, dose escalation study (NCT03634007) evaluating the safety and tolerability of LX1001 in four ascending single-dose cohorts (C1-C4). LX1001 was administered into the cerebrospinal fluid (CSF) at the craniocervical junction. Enrollment criteria include APOE4 homozygotes, age ≥ 50, positive amyloid PET, CSF biomarkers consistent with AD, and mild cognitive impairment (MCI) to moderate dementia. Following the one-time dose, the CSF APOE2/E4 profile, fluid and imaging biomarkers were assessed at regular intervals over 12 months. Fifteen participants were dosed: 50% MCI, 14% mild and 36% moderate dementia, at baseline. Twelve months of data are available for C1-C3 and 6 months for C4. Treatment with LX1001 was generally safe and well-tolerated. No events of amyloid related imaging abnormalities were observed. Post-treatment, APOE2 was expressed in CSF in all participants in a dose dependent manner. Interim results showed stabilization in CSF Aβ42/40 and amyloid PET. There was a decrease in CSF t-tau, p-tau, and Tau PET. Full data results including 12-month data for C4 will be presented during the meeting. LX1001 is the first investigational gene therapy for APOE4 homozygotes. Data suggest LX1001 is generally safe and well tolerated with reduction in CSF tau biomarkers and Tau PET, measures that are highly correlated with cognitive decline.

AbstractObjectiveTo determine the incidence and prevalence of dementia in a nationally representative cohort of US Medicare beneficiaries, stratified by important subgroups.DesignPopulation based study.SettingNationwide study between 2015 and 2021.ParticipantsFee-for-service Medicare beneficiaries aged 66 or older with at least one year of continuous enrollment.Main outcome measuresIncidence and prevalence of dementia, calculated as percentage per person years or percentage of beneficiaries respectively. These metrics were also calculated in key subgroups defined by age, sex, race/ethnicity, and neighborhood socioeconomic status.ResultsA total of 5 025 039 incident cases of dementia were documented from 2015 to 2021. The overall age and sex standardized incidence decreased between 2015 and 2021 from 3.5% to 2.8%. Prevalence increased during this time from 10.5% to 11.8%. Male beneficiaries had a higher age standardized incidence than did female beneficiaries in 2015 (3.5% v 3.4%), a difference that widened by 2021 (2.9% v 2.6%; estimated difference-in-difference 0.94, 95% confidence interval (CI) 0.94 to 0.95; P<0.001). Incidence was highest in 2015 for black beneficiaries (4.2%), followed by Hispanic beneficiaries (3.7%) and white beneficiaries (3.4%), and in 2021 for black beneficiaries (3.1%) followed by white beneficiaries (2.8%) and Hispanic beneficiaries (2.6%); the difference between white and black beneficiaries narrowed from 2015 to 2021 (difference-in-difference 0.92, 95% CI 0.91 to 0.93; P<0.001) as did the difference between white and Hispanic beneficiaries (difference-in-difference 0.88, 0.87 to 0.89; P<0.001).ConclusionsThe incidence of dementia decreased from 2015 to 2021, but the prevalence increased. Disparities in these measures by race/ethnicity, sex, and neighborhood socioeconomic status should motivate future measures to promote health equity.