Geir Bråthen

Alzheimer’s disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050¹. AD is highly heritable, with twin-based heritability estimates of 60–80%². Although 1,200 causal loci are predicted to exist for AD³, approximately 80 loci have been associated with AD in two recent studies^4,5. Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be found⁶. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.

Alzheimer’s disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050¹. AD is highly heritable, with twin-based heritability estimates of 60-80%². While 1,200 causal loci are predicted to exist for AD³, approximately 80 have been associated with AD in two recent studies^4,5, suggesting that many loci remain to be discovered⁶. Here, we analyzed data from 183,620 AD cases and 2.6 million controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and identified microglia and, for the first time, several neuronal cell types enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a single-nucleotide polymorphism (SNP) heritability of 19%. Together, our findings offer insights into the genetic architecture and potential pathobiology of AD, as well as specific targets for future drug development research.

Importance Detecting early Alzheimer’s disease (AD) biological and clinical changes is crucial for early diagnostic and therapeutic interventions. Objective To explore the associations between plasma p-tau biomarkers, cognitive- and biological profiles in predementia AD. Design, Setting, and Participants In this study (n=619), we examined two independent cohorts consisting of preclinical and prodromal AD. Cohort-1 included 431 participants classified as either cognitively normal (CN) or mild cognitive impaired (MCI) with normal or abnormal cerebrospinal fluid (CSF) Aβ42/40 ratio (A) and p-tau181 (T) [CN A-/T-, n=169; A+/T-, CN=26; MCI=24; A+/T+, CN=40; MCI=105; CN=34; MCI=33]. A total of n=418 of the participants had longitudinal assessments of verbal memory up to 9.67 years from baseline. Cohort-2 included 190 participants in whom amyloid status was determined using Aβ positron emission tomography (PET) [Aβ- CN= 118; Aβ+ CN= 49; Aβ+ MCI= 21]. Exposure CSF and plasma p-tau181, p-tau217 and p-tau231. Main Outcomes and Results In cohort-1, plasma p-tau217 showed a moderate correlation with its corresponding CSF biomarker (rho=0.65, p<.001) and high accuracy identifying Aβ+ participants (AUC: 0.85). Diagnostic accuracy of plasma p-tau217 was significantly greater for MCI Aβ+ (AUC: 0.89) versus CN Aβ+ (AUC: 0.79, p<.05) and for A+/T+ (AUC: 0.88) versus A+/T- (AUC: 0.78, p<.05). P-tau181 and p-tau231 showed significantly weaker CSF-plasma correlations (rho= 0.47, and rho=0.32, p<.001, respectively) and levels were not as tightly associated with cognitive status in the Aβ+ group. Moreover, p-tau217 was the only plasma marker that associated with future memory decline (β=0.05, pConclusions Our findings show that, unlike p-tau181 and p-tau231, plasma p-tau217 aligns consistently with cognitive status in Aβ+ individuals, potentially reducing disagreements between clinical and biochemical findings. Plasma p-tau217 associations with baseline and future cognitive decline make it a valuable complement to clinical evaluation in preclinical and prodromal AD. Question Do levels of plasma p-tau markers reflect cognitive performance in preclinical and prodromal Alzheimer’s disease (AD)? Findings In two independent cohorts (n=619) we observed that among AD participants, higher plasma p-tau217, but not p-tau181 or p-tau231, was significantly associated with worse cognitive performance. Furthermore, plasma p-tau217 was the only blood p-tau marker associated with future cognitive decline in predementia AD. Meaning Plasma p-tau217 detects early AD pathology, determined either by CSF Aβ42/40 ratio or Aβ positron emission tomography, and beyond its diagnostic capabilities, p-tau217 levels are linked to clinical severity and future cognitive deterioration in preclinical and prodromal AD.

Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer’s disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ (“A”) and neurodegeneration (“N”) abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.

Introduction: Given that exercise training reduces the risk of developing Alzheimer’s disease (AD), induces changes in the blood composition and has widespread systemic benefits, it is reasonable to hypothesise that exercised plasma (ExPlas) may have rejuvenative properties. The main objective is to test safety and tolerability of transfusing ExPlas from young, healthy, fit adults to patients with mild cognitive impairment (MCI) or early AD. The study is a pilot for a future efficacy study. The key secondary objectives are examining the effect of plasma transfusions on cognitive function, fitness level, vascular risk profile, assessment of cerebral blood flow and hippocampal volume, quality of life, functional connectivity assessed by resting state functional MRI and biomarkers in blood and cerebrospinal fluid. Methods and analysis: ExPlas is a double-blinded, randomised controlled clinical single-centre trial. Patients up to 75 years of age with diagnosis early symptomatic phase AD will be recruited from two Norwegian hospitals. ExPlas is plasma drawn by plasmapheresis once a month for 4 months, from a total of 30 fit male donors (aged 18–40, BMI≤27 kg/m ² and maximal oxygen uptake>55 mL/kg/min). All units will be virus inactivated by the Intercept method in accordance with procedures at St. Olavs University Hospital. Comparison with isotonic saline allows differentiation from a non-blood product. The main study consists of 6 rounds of examinations in addition to 12 plasma transfusions divided over three 4-week periods during study year-1. It is also planned to conduct follow-up examinations 2 and 5 years after baseline Ethics and dissemination: Written informed consent will be obtained from all participants and participation is voluntary. All participants have a next of kin who will follow them throughout the study to represent the patient’s interest. The study is approved by the Regional Committee for Medical and Health Research Ethics (REK 2018/702) and the Norwegian Medicines Agency (EudraCT No. 2018-000148-24). The study will be published in an open access journal and results will be presented at numerous national and international meetings as well as on social media platforms. Trial registration number: EudraCT No. 2018-000148-24. ClinicalTrials.gov, NCT05068830

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.