Prospective validation and implementation of high-performing blood biomarkers and digital cognitive tests for detection of Alzheimer's disease in specialist memory clinic and primary care settings

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SUMMARY The recent major breakthroughs in the development of accurate blood-based Alzheimer’s disease (AD) biomarkers, including phospho-tau217 (pTau217), have the potential to truly revolutionize AD diagnostics. However, these novel biomarkers must now be thoroughly validated in a prospective fashion in clinical practice before they can be implemented in the diagnostic and prognostic work-up of AD in specialist clinics and primary care globally. This validation is urgently needed because of the relatively low accuracy of the clinical diagnostic work-up without support of accurate AD biomarkers, resulting in misdiagnoses of 25-30% of AD patients in specialist memory clinics and >50% in primary care. Furthermore, it is important to determine in which patients and real-world clinical settings these novel blood AD biomarkers clearly improve diagnosis, treatment, and care, which is essential for reimbursement in many countries. Finally, we also need accurate prognostic tools to identify those individuals with early AD who are most likely to show imminent clinical decline, because this group may benefit most from targeted interventions. This is highly timely considering the recent advent of disease-modifying AD therapies that may soon become widely available. Given the excellent infrastructure of the primary care system in Sweden and research biomarker protocols already approved and fully integrated in clinical practice, we have a unique opportunity to test these novel blood AD markers in broad, diverse, and unselected populations that are generalizable to other real-world settings. To achieve this ambitious goal, we will conduct two novel and unique prospective studies in specialist memory clinic (n=800) and general primary care (n=800) settings. First, we aim to prospectively validate plasma AD biomarkers for the diagnosis of patients with cognitive symptoms evaluated in either specialist memory clinics or in primary care. Following recent expert consensus recommendations, we will use i) predefined biomarker cut-offs, ii) bi- weekly analysis of the plasma samples and iii) appropriate reference standards (i.e., PET/CSF). We anticipate that we will identify - within 48 months - AD blood biomarkers with high potential for implementation in memory clinic and/or primary care settings. Second, we will determine whether blood-based AD biomarkers improve patient management in specialist memory clinic settings and general primary care settings. Demonstrating improvements of the AD diagnostic work-up and treatment when compared to “care-as-usual” is essential for regulatory authorities to approve future reimbursement of blood-based biomarkers. Third, we aim to optimize the prognosis of patients with early AD by combining (prospectively analyzed) plasma AD biomarkers with brief digital cognitive tests. The expected outcome is a combination of easily accessible and time- and cost-effective blood biomarkers and digital cognitive tests that can predict short-term cognitive decline and progression to AD dementia in primary care. At the end of this project, our expected goal is that blood-based biomarkers and prognostic algorithms will be ready for clinical implementation in both specialist clinics and primary care.