Background We classified non‐demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles. Materials and methods From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut‐offs of 1000 pg/mL for amyloid beta (Aß)1‐42 and 27 pg/mL for p‐tau181 were validated using Gaussian mixture models. Given strong correlation of p‐tau and t‐tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age‐adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages. Results Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A–T–N–, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non‐Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T–N– compared to A–T–N– (P < 0.001). Discussion In non‐demented individuals along the AD continuum, p‐tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.

BACKGROUND Apolipoprotein-E (APOE) genetic testing for Alzheimer’s disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOEε4-alleles. Little is known about the interest in finding out ones genetic risk for Alzheimer’s disease in the general population. Our objective was to examine this in a sample of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOEε4 status for trial recruitment. METHODS An online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia, and the knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOEε4/ε4 genotypes). Cochran’s-Q and post-hoc McNemar tests were used to analyse differences in frequencies across scenarios. RESULTS Most participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, while lower-educated participants were more often undecided. When provided with different risk scenario’s, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e., in the 50% (79%) compared to the 10% scenario (73%;χ2(2) = 7.98; p = .005). Most individuals expected they would share their genetic risk with close relatives (77–89%), would participate in medication trials (79–88%), and would make long-term arrangements e.g. retirement, health care, will (69–82%), with larger proportions for scenarios with higher hypothetical genetic risk. CONCLUSIONS Our findings indicate that the vast majority of CN adults participating in an research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOEε4-genotype. This suggests APOEε4-screening within an online research registry is potentially a well-received method to accelerate inclusion for trials.