Objective: 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.Methods: 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.Results: 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).Interpretation: 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.

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.

Background: 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. Method: 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. Result: 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 . Conclusion: 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.