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Few studies can address how adulthood cognitive trajectories relate to brain health in 70-year-olds. Participants (n = 468, 49% female) from the 1946 British birth cohort underwent 18F-Florbetapir PET/MRI. Cognitive function was measured in childhood (age 8 years) and across adulthood (ages 43, 53, 60–64 and 69 years) and was examined in relation to brain health markers of β-amyloid (Aβ) status, whole brain and hippocampal volume, and white matter hyperintensity volume (WMHV). Taking into account key contributors of adult cognitive decline including childhood cognition, those with greater Aβ and WMHV at age 70 years had greater decline in word-list learning memory in the preceding 26 years, particularly after age 60. In contrast, those with smaller whole brain and hippocampal volume at age 70 years had greater decline in processing search speed, subtly manifest from age 50 years. Subtle changes in memory and processing speed spanning 26 years of adulthood were associated with markers of brain health at 70 years of age, consistent with detectable prodromal cognitive effects in early older age.

A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age.Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy.Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD.Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility.Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

Background and ObjectivesThe goals of this work were to quantify the independent and interactive associations of β-amyloid (Aβ) and white matter hyperintensity volume (WMHV), a marker of presumed cerebrovascular disease (CVD), with rates of neurodegeneration and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British Birth Cohort.MethodsParticipants underwent brain MRI and florbetapir-Aβ PET as part of Insight 46, an observational population-based study. Changes in whole-brain, ventricular, and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI with the boundary shift integral. Linear regression was used to test associations with baseline Aβ deposition, baseline WMHV, APOE ε4, and office-based Framingham Heart Study Cardiovascular Risk Score (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53, and 69 years.ResultsThree hundred forty-six cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time points (mean [SD] scan interval 2.4 [0.2] years). Being Aβ positive at baseline was associated with 0.87–mL/y faster whole-brain atrophy (95% CI 0.03, 1.72), 0.39–mL/y greater ventricular expansion (95% CI 0.16, 0.64), and 0.016–mL/y faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10-mL additional WMHV at baseline was associated with 1.07–mL/y faster whole-brain atrophy (95% CI 0.47, 1.67), 0.31–mL/y greater ventricular expansion (95% CI 0.13, 0.60), and 0.014–mL/y faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent, and there was no evidence that Aβ and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjustment for Aβ status and WMHV, no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, and no evidence that FHS-CVS or systolic BP acted synergistically with Aβ.DiscussionAβ and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways.

ObjectiveTo investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study.MethodsCognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to18F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant’s perspective on SCD was evaluated in relation to MyCog score.ResultsAnxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) −0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant’s perception of SCD was generally in accordance with that of the participant.ConclusionsThis cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer’s disease pathology and SCD.

Objective To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later‐life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia‐free individuals. Methods Participants (n = 502, age = 69–71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18F‐florbetapir Aβ‐PET and MR imaging. Measures include Aβ‐PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer’s disease (AD)‐related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71. Results Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69–71, taking into account premorbid cognition, particularly on the digit‐symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD‐related cortical thickness or NFL (all p > 0.01). Interpretation Having a LOC HI aged 50’s and younger was linked with lower later‐life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).

Background The insulin/insulin-like signaling (IIS) pathways, including insulin-like growth factors (IGFs), vary with age. However, their association with late-life cognition and neuroimaging parameters is not well characterized. Methods Using data from the British 1946 birth cohort, we investigated associations of IGF-I, IGF-II and IGF binding protein 3 (IGFBP-3; measured at 53 and 60-64 years of age) with cognitive performance [word-learning test (WLT) and visual letter search (VLS) at 60-64 years and 69 years of age] and cognitive state [Addenbrooke’s Cognitive Exam III (ACE-III) at 69-71 years of age], and in a proportion, quantified neuroimaging measures [whole brain volume (WBV), white matter hyperintensity volume (WMHV), hippocampal volume (HV)]. Regression models included adjustments for demographic, lifestyle, and health factors. Results Higher IGF-I and IGF-II at 53 years of age was associated with higher ACE-III scores [ß 0.07 95% confidence interval (CI) (0.02, 0.12); scoreACE-III 89.48 (88.86, 90.1), respectively). IGF-II at 53 years of age was additionally associated with higher WLT scores [scoreWLT 20 (19.35, 20.65)]. IGFBP-3 at 60 to 64 years of age was associated with favorable VLS score at 60 to 64 and 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.02, 0.12), respectively], higher memory and cognitive state at 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.01, 0.13), respectively], and reduced WMHV [ß −0.1 (−0.21, −0.00)]. IGF-I/IGFBP-3 at 60 to 64 years of was associated with lower VLS scores at 69 years of age [ß −0.08 (−0.15, −0.02)]. Conclusions Increased measure in IIS parameters (IGF-I, IGF-II, and IGFBP-3) relate to better cognitive state in later life. There were apparent associations with specific cognitive domains (IGF-II relating to memory; IGFBP-3 relating to memory, processing speed, and WMHV; and IGF-I/IGFBP-3 molar ratio related to slower processing speed). IGFs and IGFBP-3 are associated with favorable cognitive function outcomes.

Objectives We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists’ accuracy and confidence in detecting volume loss, and in differentiating Alzheimer’s disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone. Methods Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52–81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, ‘non-clinical image analysts’) assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as ‘normal’ or ‘abnormal’ and if ‘abnormal’ as ‘AD’ or ‘FTD’. Results The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group’s accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters’ agreement (Cohen’s κ) with the ‘gold standard’ was not significantly affected by the QReport; only the consultant group improved significantly (κs 0.41➔0.55, p = 0.04*). Cronbach’s alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from ‘good’ to ‘excellent’. Conclusion Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses. Key Points • The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone. • Consultant neuroradiologists’ assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports. • First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.

PurposeThe Centiloid scale provides a systematic means of harmonising amyloid-β PET measures across different acquisition and processing methodologies. This work explores the Centiloid transformation of [18F]florbetapir PET data acquired on a combined PET/MR scanner and processed with methods that differ from the standard Centiloid pipeline.MethodsThe Standard PiB and Florbetapir Calibration datasets were processed using a standardised uptake value ratio (SUVR) pipeline with MRI parcellations from the Geodesic Information Flow (GIF) algorithm in native PET space. We generated SUVRs using whole cerebellum (GIF_WCSUVR) and eroded white matter (GIF_WMSUVR) reference regions, with and without partial volume correction (PVC). Linear regression was used to calibrate these processing pipelines to the standard Centiloid approach. We then applied the resulting transformation to 432 florbetapir scans from the Insight 46 study of mostly cognitively normal individuals aged ∼70 years, and defined Centiloid cutpoints for amyloid-β positivity using Gaussian-mixture modelling.ResultsGIF-based SUVR processing pipelines were suitable for conversion according to Centiloid criteria. For GIF_WCSUVR, cutpoints translated to 14.2 Centiloids, or 11.8 with PVC. There was a differential relationship between florbetapir uptake in WM and WC regions in Florbetapir Calibration and Insight 46 datasets, causing implausibly low Centiloid values for GIF_WMSUVR. Linear adjustment to account for this difference resulted in Centiloid cutpoints of 18.1 for GIF_WMSUVR (17.0 with PVC).ConclusionOur results show florbetapir SUVRs acquired on PET/MR scanners can be reliably converted to Centiloids. Acquisition or biological factors can have large effects on Centiloid values from different datasets, we propose a correction to account for these effects.

Although APOE-ε4 carriers are at significantly higher risk of developing Alzheimer’s disease than non-carriers(1), controversial evidence suggests that APOE-ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)(2,3). In a population-based cohort born in one week in 1946 (assessed aged 69-71), we assessed differential effects of APOE-ε4 and β-amyloid pathology (quantified using (18)F-Florbetapir-PET) on visual working memory (object-location binding). In 398 cognitively normal participants, APOE-ε4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall respectively. ε4-carriers also recalled locations more precisely, with a greater advantage at higher β-amyloid burden. These results provide evidence of superior visual working memory in ε4-carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer’s disease.

Although APOE e4 carriers are at substantially higher risk of developing Alzheimer’s disease than noncarriers1, controversial evidence suggests that APOE e4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)2,3. In a population-based cohort born in one week in 1946 (assessed aged 69–71 years), we assessed differential effects of APOE e4 and β-amyloid pathology (quantified using 18F-Florbetapir-PET) on visual working memory (object–location binding). In 398 cognitively normal participants, APOE e4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall, respectively. e4 carriers also recalled locations more precisely, with a greater advantage at higher β-amyloid burden. These results provide evidence of superior visual working memory in e4 carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer’s disease. In a sample of about 400 cognitively normal older adults, APOE e4 genotype and β-amyloid pathology predicted better and poorer visual working memory, respectively, suggesting some benefits of e4 in older age, even in the preclinical stages of Alzheimer’s disease.

ObjectiveTo investigate predictors of performance on a range of cognitive measures including the Preclinical Alzheimer Cognitive Composite (PACC) and test for associations between cognition and dementia biomarkers in Insight 46, a substudy of the Medical Research Council National Survey of Health and Development.MethodsA total of 502 individuals born in the same week in 1946 underwent cognitive assessment at age 69–71 years, including an adapted version of the PACC and a test of nonverbal reasoning. Performance was characterized with respect to sex, childhood cognitive ability, education, and socioeconomic position (SEP). In a subsample of 406 cognitively normal participants, associations were investigated between cognition and β-amyloid (Aβ) positivity (determined from Aβ-PET imaging), whole brain volumes, white matter hyperintensity volumes (WMHV), and APOE ε4.ResultsChildhood cognitive ability was strongly associated with cognitive scores including the PACC more than 60 years later, and there were independent effects of education and SEP. Sex differences were observed on every PACC subtest. In cognitively normal participants, Aβ positivity and WMHV were independently associated with lower PACC scores, and Aβ positivity was associated with poorer nonverbal reasoning. Aβ positivity and WMHV were not associated with sex, childhood cognitive ability, education, or SEP. Normative data for 339 cognitively normal Aβ-negative participants are provided.ConclusionsThis study adds to emerging evidence that subtle cognitive differences associated with Aβ deposition are detectable in older adults, at an age when dementia prevalence is very low. The independent associations of childhood cognitive ability, education, and SEP with cognitive performance at age 70 have implications for interpretation of cognitive data in later life.

Background In view of reported associations between high adiposity, particularly in midlife and late-life dementia risk, we aimed to determine associations between body mass index (BMI), and BMI changes across adulthood and brain structure and pathology at age 69–71 years. Methods Four hundred sixty-five dementia-free participants from Insight 46, a sub-study of the British 1946 birth cohort, who had cross-sectional T1/FLAIR volumetric MRI, and florbetapir amyloid-PET imaging at age 69–71 years, were included in analyses. We quantified white matter hyperintensity volume (WMHV) using T1 and FLAIR 3D-MRI; β-amyloid (Aβ) positivity/negativity using a SUVR approach; and whole brain (WBV) and hippocampal volumes (HV) using 3D T1-MRI. We investigated the influence of BMI, and BMI changes at and between 36, 43, 53, 60–64, 69 and 71 years, on late-life WMHV, Aβ-status, WBV and mean HV. Analyses were repeated using overweight and obese status. Results At no time-point was BMI, change in BMI or overweight/obese status associated with WMHV or WBV at age 69–71 years. Decreasing BMI in the 1–2 years before imaging was associated with an increased odds of being β-amyloid positive (OR 1.45, 95% confidence interval 1.09, 1.92). There were associations between being overweight and larger mean HV at ages 60–64 (β = 0.073 ml, 95% CI 0.009, 0.137), 69 (β = 0.076 ml, 95% CI 0.012, 0.140) and 71 years (β = 0.101 ml, 95% CI 0.037, 0.165). A similar, albeit weaker, trend was seen with obese status. Conclusions Using WMHV, β-amyloid status and brain volumes as indicators of brain health, we do not find evidence to explain reported associations between midlife obesity and late-life dementia risk. Declining BMI in later life may reflect preclinical Alzheimer’s disease.

BackgroundThe insulin/insulin-like signalling (IIS) pathways, including Insulin-like Growth Factors (IGFs), varies with age. However, their association with late-life cognition and neuroimaging parameters is not well characterised.MethodsUsing data from the British 1946 birth cohort we investigated associations of IGF-I, -II and IGFBP-3 (measured at 53 and 60-64 years) with cognitive performance (word learning test (WLT) and visual letter search (VLS) – at 60-64y and 69y) and cognitive state (Addenbrooke’s Cognitive Exam-III (ACE-III) - at 69-71y), and in a proportion, quantified neuroimaging measures (whole brain volume (WBV); white matter hyperintensity volume (WMHV); hippocampal volume (HV)). Regression models included adjustments for demographic, lifestyle and health factors.ResultsHigher IGF-I and IGF-II at 53y was associated with higher ACE-III scores (ß 0.07 95%CI [0.02,0.12]; scoreACE-III 89.48 [88.86,90.1], respectively). IGF-II at age 53y was additionally associated with higher WLT scores (scoreWLT 20 [19.35,20.65]). IGFBP-3 at 60-64y was associated with favourable VLS score at 60-64y and 69y (ß 0.07 [0.01,0.12]; ß 0.07 [0.02,0.12], respectively), higher memory and cognitive state at 69y (ß 0.07 [0.01,0.12]; ß 0.07 [0.01,0.13], respectively) and reduced WMHV (ß -0.1, [-0.21,-0.00]). IGF-I/IGFBP-3 at 60-64y was associated with lower VLS scores at 69y (ß -0.08, [-0.15,-0.02]).ConclusionsIncreased measure in IIS parameters (IGF-I, -II and IGFBP-3) relate to better cognitive state in later life. There were apparent associations with specific cognitive domains (IGF-II relating to memory; IGFBP-3 to memory, processing speed and WMHV; and IGF-I/IGFBP-3 molar ratio with slower processing speed). IGFs and IGFBP-3 are associated with favourable cognitive function outcomes.

Objective To explore the value of olfactory identification deficits as a predictor of cerebral β-amyloid status and other markers of brain health in cognitively normal adults aged ~ 70 years. Methods Cross-sectional observational cohort study. 389 largely healthy and cognitively normal older adults were recruited from the MRC National Survey of Health and Development (1946 British Birth cohort) and investigated for olfactory identification deficits, as measured by the University of Pennsylvania Smell Identification Test. Outcome measures were imaging markers of brain health derived from 3 T MRI scanning (cortical thickness, entorhinal cortex thickness, white matter hyperintensity volumes); 18F florbetapir amyloid-PET scanning; and cognitive testing results. Participants were assessed at a single centre between March 2015 and January 2018. Results Mean (± SD) age was 70.6 (± 0.7) years, 50.8% were female. 64.5% had hyposmia and 2.6% anosmia. Olfaction showed no association with β-amyloid status, hippocampal volume, entorhinal cortex thickness, AD signature cortical thickness, white matter hyperintensity volume, or cognition. Conclusion and relevance In the early 70s, olfactory function is not a reliable predictor of a range of imaging and cognitive measures of preclinical AD. Olfactory identification deficits are not likely to be a useful means of identifying asymptomatic amyloidosis. Further studies are required to assess if change in olfaction may be a proximity marker for the development of cognitive impairment.

INTRODUCTION We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau measured on the fully automated Lumipulse platform with pre‐symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET). METHODS In 72 individuals from the Insight 46 study, CSF Aβ40, Aβ42, total tau (t‐tau), and phosphorylated tau at site 181 (p‐tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays and inter‐platform Pearson correlations derived. Lumipulse Aβ42 measures were adjusted to incorporate standardization to certified reference materials. Logistic regressions and receiver operating characteristics analysis generated CSF cut‐points optimizing concordance with 18F‐florbetapir amyloid PET status (n = 63). RESULTS Measurements of CSF Aβ, p‐tau181, and their ratios correlated well across platforms (r 0.84 to 0.94, P < .0001); those of t‐tau and t‐tau/Aβ42 correlated moderately (r 0.57 to 0.79, P < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut‐points of 0.075 for Lumipulse Aβ42/Aβ40, 0.087 for MSD Aβ42/Aβ40 and 17.3 for Lumipulse Aβ42/p‐tau181. DISCUSSION The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre‐symptomatic AD pathology.

Alzheimer's disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques-liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181-to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE e4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden's index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE e4 carrier status was 0.695 (95% confidence interval: 0.628-0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548-0.691) and phospho-tau181 (0.707; 0.646-0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770-0.864 and amyloid-β composite: 0.820; 0.775-0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE e4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10-50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.

Introduction:We investigated whether life-course factors and neuroimaging biomarkers of Alzheimer’s disease pathology predict reaction time (RT) performance in older adults. Methods: Insight 46 study participants, all born in the same week in 1946 (n = 501; ages at assessment = 69 to 71 years), completed a 2-choice RT task and amyloid beta (Aβ) positron emission tomography and MR imaging. We tested for associations between task outcomes (RT; error rate; intra-individual variability in RT) and lifecourse predictors including childhood cognitive ability and education. In a subsample of 406 cognitively normal participants, we investigated associations between task outcomes and biomarkers including Aβ-positivity. Results: Cognitively normal Aβ-positive participants had 10% more variable RTs than Aβ-negative participants, despite having similar mean RTs. Childhood cognitive ability and education independently predicted task performance. Discussion: This study provides novel evidence that Aβ pathology is associated with poorer consistency of RT in cognitively normal older adults, at an age when dementia prevalence is still very low.