ÌÇÐÄvlog

Key Points

QuestionÌý What is the prevalence of amyloid abnormality assessed in cerebrospinal fluid or on positron emission tomography scans across the clinical Alzheimer disease (AD) spectrum?

FindingsÌý This cross-sectional study of 19 097 individuals across the AD spectrum found that, in persons without dementia, the cerebrospinal fluid–based amyloid abnormality prevalence estimate that used data-driven cutoffs was 10% higher than the positron emission tomography–based prevalence estimate that used cohort-provided cutoffs.

MeaningÌý Findings from this study suggest that preclinical and prodromal AD may be more prevalent today than previously anticipated; these updated estimates may inform health care planning and recruitment strategies for clinical trials of AD therapies.

ImportanceÌý One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.

ObjectiveÌý To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.

Design, Setting, and ParticipantsÌý This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.

ExposuresÌý Alzheimer disease biomarkers detected on PET or in CSF.

Main Outcomes and MeasuresÌý Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.

ResultsÌý Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling–based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, −2% to 9%; P = .18).

Conclusions and RelevanceÌý This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Pathologic change in Alzheimer disease (AD) is characterized by cerebral amyloid aggregation, as indicated by amyloid biomarkers on positron emission tomography (PET) scans or in cerebrospinal fluid (CSF).^1,2 With emerging disease-modifying antiamyloid therapies, estimating the prevalence of amyloid abnormality in persons across the AD clinical spectrum is important to reduce screening failure rates and improve recruitment efficiency.^3-5 Previous studies analyzed 56 Amyloid Biomarker Study cohorts to estimate age, sex, educational level, and apolipoprotein E (APOE; GenBank 348)–associated prevalence of amyloid abnormality on PET scans and in CSF in 7583 individuals without dementia and on PET scans in 1359 individuals with clinical AD dementia.^6,7 Much more biomarker data have become available in recent years, providing the possibility of increasing estimate robustness and examining previously unaddressed factors that could alter amyloid abnormality prevalence estimates.

One such factor is the method for defining amyloid abnormality cutoffs. In a previous analysis, cohort-provided cutoffs were used; however, different methods to calculate amyloid abnormality cutoffs were applied.^8-10 Moreover, values from a specific CSF amyloid-β 42 analysis tool appeared to have gradually increased over the past 2 decades such that older available CSF amyloid–abnormality cutoffs may have been too conservative.^11-13 Therefore, we recalculated the cutoffs using an unbiased mixture modeling approach and examined whether these adjusted cutoffs affected amyloid abnormality prevalence estimates. Furthermore, in a previous study, amyloid abnormality in persons with clinical AD dementia was assessed only with PET measures,⁷ whereas CSF measures are now available for this group in the Amyloid Biomarker Study. The large number of participants in this combined analysis of Amyloid Biomarker Study cohort data enabled us to study whether PET and CSF prevalence estimates differed in persons with both measurements. We also examined whether amyloid abnormality prevalence differed by geographical region or between individuals with mild, moderate, or severe dementia, which could be important factors to consider in trial planning.

In this study, we aimed to refine the 2015 results by estimating the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and examining the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.

This cross-sectional study included participants from the 85 cohorts of the Amyloid Biomarker Study, an ongoing, worldwide data-pooling initiative that started in 2013.^6,7 A flow diagram of the included studies and participants is shown in eFigure 1 in the Supplement. None of the 85 included studies required evidence of amyloid abnormality as an eligibility criterion to enroll in the study. Written informed consent was obtained from all participants in each study, and data were deidentified by the respective cohorts. The study protocol for each cohort was approved by the local ethics committee at each site. The present study was approved by the Medical Ethics Committee of the Maastricht University Medical Center, which declared that the Medical Research Involving Human Subjects Act (WMO) does not apply to the study and waived the informed consent requirement because deidentified data were used. We followed the Strengthening the Reporting of Observational Studies in Epidemiology () reporting guideline.

The present pooled analysis consisted of 19 097 participants, of whom 9908 had normal cognition, which was defined by normal scores on cognitive tests and/or absence of cognitive complaints; 1524 had subjective cognitive decline defined by cognitive complaints without objective confirmation on tests; 5405 had mild cognitive impairment^14,15; and 2260 had clinical AD dementia. Clinical AD dementia was subcategorized as follows according to Mini-Mental State Examination scores (range 0-30, with higher scores indicating better performance): mild (score: ≥20; n = 1525), moderate (score: 11-20; n = 488), or severe (score: ≤10; n = 61). The characteristics of all cohorts are shown in eTable 1 in the Supplement, and an overview of data availability is provided in eTable 2 in the Supplement. Compared with the 2015 analyses of the Amyloid Biomarker Study cohorts, the present study included more people, with 7804 persons without dementia and 737 persons with clinical AD dementia from 29 new cohorts as well as 1205 additional cases from 10 cohorts, who also participated in the 2015 studies (which involved 812 persons without dementia and 737 persons with clinical AD dementia).

Data collection was performed from January 1, 2013, to December 31, 2020. Race and ethnicity data were not collected because this study used existing data, and many of the cohorts we analyzed did not collect this information.

Amyloid measures per cohort are detailed in eTables 3 and 4 in the Supplement. We selected the biomarker modality that resulted in the greatest number of participants per cohort for the primary analyses. Both PET amyloid and CSF amyloid were measured at baseline, and the interval between diagnosis and biomarker assessment did not exceed 6 months.

We calculated cohort-specific, data-driven cutoffs independent of diagnosis to ascertain amyloid abnormality using gaussian mixture modeling in those cohorts that provided continuous amyloid values. Gaussian mixture modeling–based cutoffs may better capture amyloid abnormality than clinical diagnosis–based cutoffs.^12,13,16 We evaluated the number of distributions that provided the best fit on the data using the R function boot.comp (R Foundation for Statistical Computing). Next, we visually inspected the normality of distributions and chose the cutoff as the value where 2 fitted normal distributions intersected. When there were more than 2 distributions, we forced the data into 2 distributions or chose the cutoff of 2 of the 3 distributions after visual inspection (eTable 3 in the Supplement). When there was a single distribution, cohort-provided cutoffs were used.

Descriptive data were analyzed using independent-samples, unpaired, 2-tailed t tests for continuous variables and χ² tests for categorical variables. Differences in observed percentages were analyzed using McNemar tests. Amyloid abnormality was the dichotomous outcome variable (normal or abnormal) in generalized estimating equations¹⁷ using the genlin command in SPSS, version 26 (IBM). We assumed a logit-link function with an exchangeable correlation structure. The outcome of amyloid abnormality was defined using cohort-provided cutoffs and adjusted cutoffs.

We performed 6 analyses. First, we examined the prevalence of amyloid abnormality defined using cohort-provided cutoffs according to age, diagnosis, and biomarker modality, testing up to 3-way interactions with a forward selection method. Second, we repeated the analyses after cutoff adjustments. Third, we assessed the characteristics of participants who had discordant amyloid-positive results based on cohort-provided vs adjusted cutoffs. Fourth, we conducted separate analyses based on adjusted cutoffs to examine the dependencies on sex; educational level; APOE ε4 carrier status (carrier vs noncarrier); APOE genotype (ε2ε2, ε2ε3, ε2ε4, ε3ε3, ε3ε4, or ε4ε4); and geographical region of amyloid abnormality prevalence, which were tested with up to 3-way interactions with age, cognitive status, APOE ε4 carrier status, and biomarker modality using forward selection. Interaction terms were retained in the model if they appeared significant by the Wald statistical test; a 2-sided P < .05 indicated statistical significance. From these separate analyses, we excluded small subgroups of participants with ε2ε2 (44 with normal cognition, 2 with subjective cognitive decline, 6 with mild cognitive impairment, and 1 with clinical AD dementia) and 16 participants with subjective cognitive decline and ε2ε4. Among persons with clinical AD dementia, we examined the association of amyloid abnormality with APOE ε4 gene dose (0/1/2 alleles) instead of APOE genotype, because the ε2ε2 (0.2%), ε2ε3 (2.5%), and ε2ε4 (2.5%) genotypes were infrequent. Fifth, we investigated whether amyloid abnormality prevalence depended on mild, moderate, or severe AD dementia. Sixth, we assessed PET-CSF concordance for participants who had values for both measurements available.

We performed all 6 analyses separately in persons without dementia (normal cognition, subjective cognitive decline, or mild cognitive impairment) and in persons with clinical AD dementia because the 2015 studies were also conducted in these groups separately^6,7 and because age and biomarker modality associations differed for these groups. Age was included as a continuous variable centered at the median (70 years). Educational level was dichotomized at the median (14 years). Cohorts were subdivided into geographical regions: North America, Europe, Asia, and Australia.

Probabilities and 95% CIs that were estimated by generalized estimating equations were used in figures and tables. Statistical comparisons were reported at the mean age unless otherwise specified.

Of the 19 097 participants included in the study, 10 148 were women (53.1%) and 8949 were men (46.9%) with a mean (SD) age of 69.1 (9.8) years. Participant characteristics according to cognitive status and biomarker modality are shown in Table 1. A total of 3858 participants (20.2%) had missing data for APOE ε4 carrier status, 132 (0.7%) for sex, and 1803 (9.4%) for educational level (eTable 5 in the Supplement). Participants with missing data were excluded from the respective subanalyses. Of the 19 097 total participants, 1571 (8.2%) underwent both CSF and PET measurements. The characteristics of persons who underwent PET vs CSF measurement are shown in eTable 6 in the Supplement.

A total of 10 139 of 19 097 participants (53.1%) in 50 cohorts underwent an amyloid-PET measurement (26 quantitative reading, 23 visual reading, and 1 combined), and 15 of 26 cohorts provided continuous amyloid load values. In addition, 8958 participants (46.9%) in 51 cohorts had an amyloid-CSF measurement; 50 cohorts provided continuous values, and 2 of these cohorts did not provide study-specific cutoffs.

Of the 50 cohorts with continuous CSF values, 27 showed a bimodal distribution, and 7 showed 3 distributions. In 19 subsets, gaussian mixture modeling of CSF amyloid values did not show distinctive distributions such that the cutoffs could be determined; eTable 7 in the Supplement shows methodological considerations for the cohorts without distinctive distributions. Compared with cohort-provided cutoffs, the adjusted cutoffs in the 34 cohorts with distinctive distributions were higher in 24 cohorts (n = 6299 participants; mean Innotest difference, 108.44 pg/mL), lower in 3 cohorts (n = 741 participants; mean Innotest difference, 48.24 pg/mL), and did not differ in 7 cohorts. Furthermore, 3832 participants (42.8%) had abnormal amyloid with cohort-provided cutoffs and 4467 participants (49.9%) had abnormal amyloid with adjusted cutoffs (mean difference, 7.1%; P < .001) (eTable 8 in the Supplement).

Of the 50 cohorts with PET values, 14 provided continuous PET values, 10 of which had a bimodal distribution and 4 did not show distinctive distributions because of small sample sizes (<28 participants). The difference between cohort-provided cutoffs and adjusted cutoffs was less than 0.1 SUVR (standardized uptake value ratio) for 7 cohorts (lower in 3 cohorts [n = 5055 participants], higher in 3 cohorts [n = 1275 participants], and no difference in 1 cohort [n = 279 participants]) and was less than 0.4 SUVR for 3 cohorts (lower in 2 cohorts [n = 312 participants] and higher in 1 cohort [n = 279 participants]). In these 10 cohorts, 2174 participants (30.2%) had abnormal amyloid with the cohort-provided cutoff and 2146 participants (29.8%) had abnormal amyloid with the adjusted cutoff (mean difference, 0.4%; P = .07). Given this nonsignificant difference and the limited number of cohorts with continuous data, amyloid abnormality on PET scans was defined using cohort-provided cutoffs for quantitatively rated scans.

With cohort-provided cutoffs for both PET and CSF measures, amyloid abnormality prevalence estimates in normal cognition, subjective cognitive decline, and mild cognitive impairment were similar to the 2015 estimates. Specifically, prevalence estimates increased with older age, were similar for participants with normal cognition and subjective cognitive decline at any age (mean difference, 2%; 95% CI, −7% to 2%; P = .31), were approximately 25% higher in participants with mild cognitive impairment vs normal cognition and subjective cognitive decline (mean difference, 25%-27%; 95% CI, 19%-30%; P < .001), and were similar for PET and CSF (mean difference, 0% [95% CI, −4% to 4%; P = .99]; normal cognition: 24% [95% CI, 21%-28%]; subjective cognitive decline: 27% [95% CI, 21%-33%]; and mild cognitive impairment: 51% [95% CI, 46%-56%]) (Figure 1; eFigure 2A and eTable 9 in the Supplement).

With adjusted CSF cutoffs, CSF-based amyloid abnormality estimates were, on average, 10% higher than PET-based estimates in persons with normal cognition (CSF vs PET mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004) and were similarly associated with age compared with cohort-provided cutoffs (Table 2 and Figure 1; eFigure 2B in the Supplement). Given this association of biomarker modality with the prevalence of amyloid abnormality when adjusted CSF cutoffs were included, we included biomarker modality in further analyses. Table 3 shows observed amyloid abnormality prevalence.

Amyloid abnormality estimates had a steeper increase with age among APOE ε4 carriers than noncarriers, regardless of clinical diagnosis and biomarker modality (Figure 2A and B; eTable 10 in the Supplement). Similarly, APOE ε4ε4 carriers aggregated amyloid at the youngest age, followed by ε3ε4, ε2ε4, ε3ε3, and ε2ε3 (eFigure 3A and B, eFigure 4 in the Supplement). The PET-based amyloid abnormality prevalence was 10% (95% CI, 4%-16%; P = .001) higher in ε3ε4 compared with ε2ε4 (normal cognition: 46% vs 36%; subjective cognitive decline: 44% vs 34%; mild cognitive impairment: 66% vs 56%), whereas in the 2015 study, these groups had similar amyloid abnormality frequencies. Of the 44 APOE ε2ε2 carriers with normal cognition, 5 had an abnormal amyloid marker. In APOE ε4ε4 carriers, CSF-based estimates were 15% (95% CI, 5%-25%; P = .005) higher than PET-based estimates, whereas this difference was approximately 8% for the other APOE genotypes (modality × APOE P = .008). Sex was not associated with amyloid abnormality prevalence (PET in female vs male: normal cognition, 25% vs 25%; subjective cognitive decline, 27% vs 27%; mild cognitive impairment, 50% vs 50%; CSF in female vs male: normal cognition, 34% vs 33%; subjective cognitive decline, 36% vs 36%; mild cognitive impairment, 60% vs 60%; P = .45), and there were no interactions between sex and age, diagnosis, biomarker modality, or APOE ε4 carrier status. Higher educational level was associated with higher prevalence of amyloid abnormality regardless of age, cognitive status, APOE ε4 carrier status, and biomarker modality (mean difference, 2%-3%; 95% CI, 1%-5%; P = .001) (eFigure 5A and B in the Supplement). Amyloid abnormality prevalence was similar across geographical regions (eg, PET in normal cognition: North America, 24% [95% CI, 21%-29%]; Asia, 24% [95% CI, 16%-35%]; Europe, 24% [95% CI, 18%-31%]; Australia, 29% [95% CI, 27%-32%]; P = .12).

With cohort-provided cutoffs, amyloid abnormality estimates were higher with PET vs CSF biomarkers (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04) and decreased with age (from 91% at age 50 years to 83% at age 90 years for PET vs from 84% at age 50 years to 72% at age 90 years for CSF; P = .03) (Figure 1; eFigure 2A and eTable 9 in the Supplement).

With adjusted CSF cutoffs, CSF-based amyloid abnormality estimates increased and became similar to PET-based estimates (mean difference, 4%; 95% CI, −2% to 9%; P = .18; further analyses were not corrected for biomarker modality). The decrease of amyloid abnormality prevalence with older age became no longer significant (Table 2, Figure 1; eFigure 2B and eTable 11 in the Supplement).

APOE ε4 carrier status was associated with higher amyloid abnormality prevalence, with a mean prevalence of 80% for noncarriers, 87% for heterozygotes, and 97% for homozygotes (mean difference: noncarriers vs heterozygotes, 7% [95% CI, −7% to 21%; P = .33]; noncarriers vs homozygotes, 17% [95% CI, 7%-28%; P = .002]; heterozygotes vs homozygotes, 10% [95% CI, 4%-17%; P = .002]) (eFigure 6 in the Supplement). APOE ε4 noncarriers no longer showed a steeper decrease in amyloid abnormality than APOE ε4 carriers, as previously observed (age × APOE P = .37). Sex was not associated with amyloid abnormality (AD dementia in female vs male, 86% vs 85%; P = .47). The association of educational level with amyloid abnormality depended on age (age × education P = .02). Higher educational level was associated with higher amyloid abnormality prevalence at age 60 years (mean difference, 7%; 95% CI, 1%-13%; P = .02), whereas at older ages, educational level was not associated with amyloid abnormality (mean difference, 4%; 95% CI, −1% to 9%; P = .11) (eFigure 5 in the Supplement). Among persons with clinical AD dementia, amyloid abnormality prevalence was higher in Australia at 98% than in Europe at 84%, Asia at 85%, and North America at 85% (mean difference, 13%-14%; 95% CI, 7%-24%; P = .002) (eFigure 7 in the Supplement). However, the number of participants with clinical AD dementia from Australia was relatively small (n = 107), with data from only 2 cohorts (1 population-based and 1 clinical) compared with 535 participants from 8 North American cohorts, 242 participants from 5 Asian cohorts, and 1376 participants from 28 European cohorts. The prevalence of amyloid abnormality was similar across mild (85%; 95% CI, 81%-88%), moderate (88%; 95% CI, 84%-91%), and severe (87%; 95% CI, 78%-92%) AD dementia cases; taking into account APOE ε4 carrier status, the prevalence rates for those with noncarrier status vs carrier status were 74% (95% CI, 68%-79%) vs 92% (95% CI, 89%-95%) for mild, 84% (95% CI, 73%-91%) vs 96% (95% CI, 92%-98%) for moderate, and 84% (95% CI, 64%-94%) vs 96% (95% CI, 88%-98%) for severe AD dementia (P = .17 vs P = .09) (eTable 12 and eFigure 8 in the Supplement).

In 21 cohorts with amyloid abnormality measured by both CSF and PET biomarkers in the same individuals (n = 1571 of 19 097 [8.2%]), 83% of the individuals (1304) had a concordant amyloid abnormality status (eTable 13 in the Supplement for comparison of individuals with concordant or discordant status). Amyloid abnormality prevalence using adjusted CSF cutoffs in persons with normal cognition (n = 477) was 34% (95% CI, 27%-42%) for CSF and 24% (95% CI, 17%-32%) for PET; in persons with subjective cognitive decline (n = 194), it was 31% (95% CI, 23%-40%) for CSF and 33% (95% CI, 26%-41%) for PET; in persons with mild cognitive impairment (n = 627), it was 53% (95% CI, 46%-59%) for CSF and 53% (95% CI, 45%-61%) for PET; and in persons with clinical AD dementia (n = 273), it was 67% (95% CI, 52%-80%) for CSF and 81% (95% CI, 68%-90%) for PET.

In a post hoc analysis, we compared amyloid abnormality estimates in cohorts with quantitatively vs visually rated PET scans but did not find a difference (mean difference quantitive vs visual in persons without dementia and those with dementia: 4% [95% CI, −6% to 13%; P = .46] vs 5% [95% CI, −2% to 12%]; P = .14).

In this study, we estimated the prevalence of amyloid abnormality among 19 097 persons from 85 studies participating in the Amyloid Biomarker Study. Prevalence estimates based on cohort-provided PET and CSF cutoffs for participants with normal cognition, subjective cognitive decline, or mild cognitive impairment remained largely similar to the 2015 estimates, which included fewer cases.⁶ The narrower CIs in the present study indicate more precise estimates especially in younger age groups. The CSF cutoff adjustment based on an unbiased gaussian mixture modeling approach identified 10% higher prevalence rates in persons without dementia, indicating that preclinical and prodromal AD may be more prevalent than previously estimated.

The higher prevalence of amyloid abnormality in individuals with normal cognition, subjective cognitive decline, or mild cognitive impairment, which was measured using adjusted CSF cutoffs compared with PET imaging, is in line with previous findings in individuals without dementia.^18-21 This finding could mean that CSF assessment of amyloid abnormality is more sensitive than PET assessment. Because most PET studies applied a visual reading, which may be less sensitive than a quantitative reading,^22,23 we compared differences in amyloid abnormality between the 2 methods but did not find a difference. In the subsample with both biomarker modalities available, CSF estimates were higher than PET estimates in persons with normal cognition only. The question of whether CSF-based estimates are more sensitive than PET-based estimates for amyloid abnormality among people without dementia should be explored in studies that use both modalities and monitor the point at which PET abnormality follows CSF abnormality.

In clinical AD dementia, amyloid abnormality prevalence was lower with cohort-provided cutoffs for CSF than for PET estimates, whereas after CSF cutoff adjustment estimates were similar, suggesting again that uncorrected cutoffs might be too conservative. In a direct comparison of PET to CSF in persons with dementia, more than 90% of the results were concordant and the prevalence of amyloid abnormality in CSF was lower than on PET scans. Although both PET and CSF measurements in persons with dementia were available from relatively few cohorts, this result may reflect lower production of soluble amyloid forms in CSF as opposed to cumulative amyloid burden measured with PET in the dementia stage.^24-26

The amyloid abnormality prevalence estimates in individuals without dementia are partly in line with the PET-based estimates from the population-based Mayo Clinic Study of Aging (MCSA), which was not included in the Amyloid Biomarker Study.²⁷ The PET-based estimates at age 85 years in individuals with normal cognition and subjective cognitive decline (38% and 41%, respectively, as shown in eTable 9 in the Supplement) were similar to that of the MCSA estimate (41%) at age 80 to 89 years. However, at age 50 to 59 years, the estimate was only 3% in the MCSA compared with 15% to 17% in the present study (as shown in eTable 9 in the Supplement). Also, the amyloid abnormality prevalence estimates in persons with mild cognitive impairment were much higher in this study than those in the MCSA: 34% vs 0% at age 50 to 59 years, and 65% vs 16% at age 80 to 89 years. These higher prevalence estimates may reflect the population-based design of the MCSA compared with the mostly research or clinical study settings of the present study.

Older age and APOE ε4 carrier status were associated with higher amyloid abnormality prevalence, in accordance with the 2015 results^6,7 and with previous studies.^28-30 The finding that the prevalence in APOE ε4 homozygous carriers started increasing first, followed by ε3ε4, ε2ε4, ε3ε3, and ε2ε3, fits largely with the previous findings.^6,7 In addition, we found approximately 10% higher prevalence of PET-based amyloid abnormality in ε3ε4 compared with ε2ε4, which is consistent with the protective effect of ε2.^31,32 In clinical AD dementia, amyloid abnormality prevalence was also higher in APOE ε4 homozygotes than APOE ε4 heterozygotes. The 2015 study observed that the prevalence of PET-based amyloid abnormality in those with dementia decreased with age, particularly for APOE ε4 noncarriers.⁷ In the present study, however, this age-related decline was less prominent and no longer differed between APOE ε4 carriers and noncarriers.

Sex was not associated with amyloid abnormality in any disease stage, which is in line with previous studies and the MCSA.^6,7,33 Higher educational level was associated with a higher amyloid abnormality prevalence in persons without dementia, which is in accordance with previous findings.^6,7 This finding can be explained by delayed expression of amyloid-related cognitive decline because of higher cognitive reserve.^6,34,35

No associations were found between geographical location and amyloid abnormality in persons without dementia, indicating no ethnicity-based difference in amyloid pathology prevalence. The higher prevalence in persons with clinical AD dementia in Australia should be interpreted cautiously and further investigated because relatively few cases originated from this region. Dementia severity was not associated with amyloid abnormality prevalence, which is in line with the notion that amyloid aggregation is an early marker that becomes abnormal years before dementia onset.^20,36These estimates may guide health care planning, providing potential eligible patient population sizes for antiamyloid therapies, and recruitment strategies for clinical trials.

We combined data that were collected on persons across the AD spectrum within many cohorts in various settings and geographical locations. Studying individual participant-level data rather than aggregated data increased the statistical power to detect subgroup and interaction outcomes³⁷; however, multiple cohorts also used different amyloid assessment methods, cutoff definitions, and study designs. The study showed that the potential bias introduced by these variations between cohorts might be reduced when using the same method to identify the cutoffs in CSF.^12,13,16 Nonetheless, we could only apply this method to a subset of cohorts that provided continuous data, and some cohorts did not show a multimodal distribution.

The use of cohort-specific cutoffs to define abnormal amyloid for cohorts for which no data-driven cutoff could be calculated may have led to an underestimation of amyloid abnormality in these cohorts. We expect this potential underestimation to be limited given that the sample sizes for most of these Amyloid Biomarker Study cohorts included were small. Another limitation is the cross-sectional design of the study, which might underestimate amyloid abnormality as opposed to lifetime risk estimates. Furthermore, generalizability of the findings to the general population might be limited. In addition, persons with AD dementia were clinically diagnosed, and it remains unknown whether these diagnoses were correct on histopathological examination.

This study found that the prevalence of amyloid abnormality based on data-driven CSF cutoffs among persons with normal cognition, subjective cognitive decline, or mild cognitive impairment appeared to be 10% higher compared with cohort-provided CSF and PET cutoffs. The CSF- and PET-based estimates were similar for those with clinical AD dementia. Older age, APOE ε4 gene dose, and higher educational level were associated with higher prevalence of amyloid abnormality. These updated estimates suggest that preclinical and prodromal AD are more prevalent than previously estimated. The findings may be useful in health care planning, providing potential eligible patient population sizes for antiamyloid therapies, and in recruitment strategies for clinical trials.

Accepted for Publication: October 28, 2021.

Published Online: January 31, 2022. doi:10.1001/jamaneurol.2021.5216

Correction: This article was corrected on March 14, 2022, to fix the affiliations for Agneta Nordberg, MD, PhD and the Figure 1 caption.

Corresponding Authors: Olin Janssen, MSc (olin.janssen@maastrichtuniversity.nl), and Willemijn J. Jansen, PhD (willemijn.jansen@maastrichtuniversity.nl), Alzheimer Centre Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands.

The Amyloid Biomarker Study Group Authors: Dag Aarsland, MD, PhD; Daniel Alcolea, MD; Daniele Altomare, PhD; Christine von Arnim, PhD; Simone Baiardi, MD, PhD; Ines Baldeiras, PhD; Henryk Barthel, MD, PhD; Randall J. Bateman, PhD; Bart Van Berckel, MD, PhD; Alexa Pichet Binette, PhD; Kaj Blennow, MD, PhD; Merce Boada, MD, PhD; Henning Boecker, MD, PhD; Michel Bottlaender, MD, PhD; Anouk den Braber, PhD; David J. Brooks, MD, PhD; Mark A. Van Buchem, MD, PhD; Vincent Camus, MD, PhD; Jose Manuel Carill, PhD; Jiri Cerman, PhD; Kewei Chen, PhD; Gaël Chételat, PhD; Elena Chipi, MSc; Ann D. Cohen, PhD; Alisha Daniels, MD, MHA; Marion Delarue, MSc; Mira Didic, PhD; Alexander Drzezga, MD, PhD; Bruno Dubois, MD, PhD; Marie Eckerström, MD; Laura L. Ekblad, MD, PhD; Sebastiaan Engelborghs, MD, PhD; Stéphane Epelbaum, PhD; Anne M. Fagan, PhD; Yong Fan, PhD; Tormod Fladby, MD, PhD; Adam S. Fleisher, MD, MAS; Wiesje M. Van der Flier, PhD; Stefan Förster, MD, PhD; Juan Fortea, PhD; Kristian Steen Frederiksen, MD, PhD; Yvonne Freund-Levi, MD, PhD; Lars Frings, PhD; Giovanni B. Frisoni, MD; Lutz Fröhlich, MD, PhD; Tomasz Gabryelewicz, MD, PhD; Hermann-Josef Gertz, PhD; Kiran Dip Gill, PhD; Olymbia Gkatzima, MSc; Estrella Gómez-Tortosa, PhD; Timo Grimmer, PhD; Eric Guedj, MD, PhD; Christian G. Habeck, PhD; Harald Hampel, MD, PhD; Ron Handels, PhD; Oskar Hansson, MD, PhD; Lucrezia Hausner, MD, PhD; Sabine Hellwig, MD; Michael T. Heneka, MD, PhD; Sanna-Kaisa Herukka, MD, PhD; Helmut Hildebrandt, PhD; John Hodges, MD, PhD; Jakub Hort, MD, PhD; Chin-Chang Huang, MD, PhD; Ane Juaristi Iriondo, PhD; Yoshiaki Itoh, PhD; Adrian Ivanoiu, MD, PhD; William J. Jagust, MD, PhD; Frank Jessen, PhD; Peter Johannsen, MD, PhD; Keith A. Johnson, PhD; Ramesh Kandimalla, PhD; Elisabeth N. Kapaki, MD, PhD; Silke Kern, MD, PhD; Lena Kilander, PhD; Aleksandra Klimkowicz-Mrowiec, PhD; William E. Klunk, MD, PhD; Norman Koglin, PhD; Johannes Kornhuber, MD; Milica G. Kramberger, MD, PhD; Hung-Chou Kuo, MD, PhD; Koen Van Laere, MD, PhD; Susan M. Landau, PhD; Brigitte Landeau, MSc; Dong Young Lee, MD, PhD; Mony de Leon, MD, PhD; Cristian E. Leyton, MD, PhD; Kun-Ju Lin, PhD; Alberto Lleó, MD, PhD; Malin Löwenmark, PhD; Karine Madsen, MD, PhD; Wolfgang Maier, MD, PhD; Jan Marcusson, MD, PhD; Marta Marquié, MD, PhD; Pablo Martinez-Lage, PhD; Nancy Maserejian, ScD; Niklas Mattsson, MD, PhD; Alexandre de Mendonça, MD, PhD; Philipp T. Meyer, MD, PhD; Bruce L. Miller, MD; Shinobu Minatani, MD; Mark A. Mintun, MD; Vincent C. T. Mok, MD; Jose Luis Molinuevo, MD, PhD; Silvia Daniela Morbelli, MD, PhD; John C. Morris, MD; Barbara Mroczko, MD, PhD; Duk L. Na, MD, PhD; Andrew Newberg, MD, PhD; Flavio Nobili, PhD; Agneta Nordberg, MD, PhD; Marcel G. M. Olde Rikkert, MD, PhD; Catarina Resende de Oliveira, MD, PhD; Pauline Olivieri, MSc; Adela Orellana, PhD; George Paraskevas, MD, PhD; Piero Parchi, PhD; Matteo Pardini, PhD; Lucilla Parnetti, MD, PhD; Oliver Peters, MD; Judes Poirier, MD, PhD; Julius Popp, MD; Sudesh Prabhakar, MD, PhD; Gil D. Rabinovici, MD; Inez H. Ramakers, PhD; Lorena Rami, PhD; Eric M. Reiman, PhD; Juha O. Rinne, MD, PhD; Karen M. Rodrigue, PhD; Eloy Rodríguez-Rodriguez, MD, PhD; Catherine M. Roe, PhD; Pedro Rosa-Neto, MD, PhD; Howard J. Rosen, MD; Uros Rot, MD, PhD; Christopher C. Rowe, MD, PhD; Eckart Rüther, MD, PhD; Agustín Ruiz, MD, PhD; Osama Sabri, MD, PhD; Jayant Sakhardande, MSc; Pascual Sánchez-Juan, MD, PhD; Sigrid Botne Sando, MD, PhD; Isabel Santana, MD, PhD; Marie Sarazin, MD, PhD; Philip Scheltens, MD, PhD; Johannes Schröder, MD, PhD; Per Selnes, MD, PhD; Sang Won Seo, MD, PhD; Dina Silva, PhD; Ingmar Skoog, PhD; Peter J. Snyder, PhD; Hilkka Soininen, MD, PhD; Marc Sollberger, PhD; Reisa A. Sperling, PhD; Luisa Spiru, MD, PhD; Yaakov Stern, PhD; Erik Stomrud, MD, PhD; Akitoshi Takeda, MD; Marc Teichmann, MD; Charlotte E. Teunissen, PhD; Louisa I. Thompson, PhD; Jori Tomassen, MSc; Magda Tsolaki, MD, PhD; Rik Vandenberghe, MD, PhD; Marcel M. Verbeek, PhD; Frans R. J. Verhey, MD, PhD; Victor Villemagne, MD, PhD; Sylvia Villeneuve, PhD; Jonathan Vogelgsang, MSc; Gunhild Waldemar, MD, DMsc; Anders Wallin, MD, PhD; Åsa K. Wallin, MD, PhD; Jens Wiltfang, PhD; David A. Wolk, MD; Tzu-Chen Yen, MD, PhD; Marzena Zboch, MD, PhD; Henrik Zetterberg, MD, PhD.

Affiliations of The Amyloid Biomarker Study Group Authors: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden (Aarsland, Nordberg); Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway (Aarsland, Nordberg); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain (Alcolea, Fortea, Lleó); Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (Alcolea, Fortea, Lleó); Laboratory Alzheimer’s Neuroimaging and Epidemiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fatebenefratelli, Brescia, Italy (Altomare); Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (Altomare); Division of Geriatrics, University of Goettingen Medical School, Goettingen, Germany (von Arnim); Clinic for Neurogeriatrics and Neurological Rehabilitation, University and Rehabilitation Hospital Ulm, Ulm, Germany (von Arnim); Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Spain (Baiardi); Center for Neuroscience and Cell Biology (CIBB), University of Coimbra, Coimbra, Portugal (Baldeiras, de Oliveira, Santana); Neurology Department and Laboratory of Neurochemistry, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, Coimbra, Portugal (Baldeiras, Santana); Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Coimbra, Portugal (Baldeiras, Santana); Department of Nuclear Medicine, University Hospital of Leipzig, Leipzig, Germany (Barthel, Sabri); Department of Neurology and the Alzheimer’s Disease Research Center, Washington University School of Medicine in St Louis, St Louis, Missouri (Bateman); Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (Van Berckel); Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada (Binette, Villeneuve); Douglas Mental Health University Institute, Montreal, Quebec, Canada (Binette, Villeneuve); Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgren’s University Hospital, Mölndal, Sweden (Blennow); Research Center and Memory Clinic of Fundació Alzheimer Centre Educacional, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain (Boada, Marquié, Orellana, Ruiz); CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain (Boada, Marquié, Orellana, Ruiz); Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany (Boecker, Drzezga); Université Paris-Saclay, Service Hospitalier Frédéric Joliot (CEA), French National Centre for Scientific Research (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), BioMaps, Service Hospitalier Frederic Joliot, Orsay, France (Bottlaender); Department of Neurology, Alzheimer Centre Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (den Braber, Van der Flier, Scheltens, Teunissen, Tomassen); Translational and Clinical Research Institute, University of Newcastle upon Tyne, United Kingdom (Brooks); Department of Nuclear Medicine, Positron Emission Tomography Centre, Aarhus University, Aarhus, Denmark (Brooks); Department of Brain Sciences, Imperial College London, London, United Kingdom (Brooks); Department of Neurology, University Hospital Leiden, Leiden, the Netherlands (Van Buchem); Unite Mixte de Recherche, INSERM U930, French National Centre for Scientific Research (CNRS) ERL, Tours, France (Camus); Nuclear Medicine Department, University Hospital Marqués de Valdecilla, Molecular Imaging, Instituto de Investigación Sanitaria Valdecilla (IDIVAL), University of Cantabria, Santander, Spain (Carill); Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic (Cerman, Hort); Banner Alzheimer’s Institute, Phoenix, Arizona (Chen, Reiman); Normandie University, University of Caen Normandie (UNICAEN), INSERM, U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Institut Blood and Brain at Caen-Normandie, Cyceron, Caen, France (Chételat, Delarue, Landeau); Centro Disturbi della Memoria, Laboratorio di Neurochimica Clinica, Clinica Neurologica, Università di Perugia, Perugia, Italy (Chipi, Parnetti); Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Cohen); Department of Neurology, Washington University School of Medicine in St Louis, St Louis, Missouri (Daniels); Assistance Publique Hôpitaux de Marseille (AP-HM), Timone, Service de Neurologie et Neuropsychologie, Hôpital Timone Adultes, Marseille, France (Didic); Aix Marseille Univ, INSERM, Institut de Neurosciences des Systèmes (INS), Marseille, France (Didic); Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany (Drzezga); Department of Neurology, Institut de la Mémoire et de la Maladie d’Alzheimer, Centre de Référence Démences Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France (Dubois, Epelbaum, Teichmann); Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden (Eckerström); Turku PET Centre, University of Turku, Turku, Finland (Ekblad); Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium (Engelborghs); Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium (Engelborghs); Department of Neurology and the Alzheimer’s Disease Research Center, Washington University School of Medicine in St Louis, St Louis, Missouri (Fagan, Morris, Roe); Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Fan); Department of Neurology, Akershus University Hospital, Lorenskog, Norway (Fladby, Selnes); Eli Lilly and Company, Indianapolis, Indiana (Fleisher); Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (Förster); Department of Nuclear Medicine, Klinikum Bayreuth, Bayreuth, Germany (Förster); Danish Dementia Research Center, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (Frederiksen, Waldemar); School of Medical Sciences, Örebro University, Örebro, Sweden (Freund-Levi); Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet Center for Alzheimer Research, Stockholm, Sweden (Freund-Levi); Department of Old Age Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom (Freund-Levi); Department of Nuclear Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany (Frings, Meyer); Memory Clinic, University Hospitals and University of Geneva, Geneva, Switzerland (Frisoni); Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany (Fröhlich); Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland (Gabryelewicz); Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Leipzig, Leipzig, Germany (Gertz); Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India (Gill, Kandimalla); Greek Association of Alzheimer’s Disease and Related Disorders, Thessaloniki, Greece (Gkatzima); Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain (Gómez-Tortosa); Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany (Grimmer); Aix Marseille University, AP-HM, CNRS, Centrale Marseille, Institut Fresnel, Timone Hospital, Centre Européen de Recherche en Imagerie Médicale (CERIMED), Nuclear Medicine Department, Marseille, France (Guedj); Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York (Habeck); Sorbonne University, Clinical Research Group no. 21, Alzheimer Precision Medicine, AP-HP, Pitié-Salpêtrière Hospital, Paris, France (Hampel); Alzheimer Centre Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands (Handels, Ramakers, Verhey); Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden (Hansson, Mattsson, Stomrud, Å. K. Wallin); Universität Heidelberg, Abteilung Gerontopsychiatrie, Zentralinstitut für Seelische Gesundheit Mannheim, Mannheim, Germany (Hausner); Department of Psychiatry and Psychotherapy Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany (Hellwig); Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germany (Heneka); Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester (Heneka); Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland (Herukka); Neurocenter, Neurology, Kuopio University Hospital, Kuopio, Finland (Herukka); Klinikum Bremen-Ost, University of Oldenburg, Institute of Psychology, Oldenburg, Germany (Hildebrandt); Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia (Hodges); Chang Gung Memorial Foundation-Linkou, Taoyuan, Taiwan (Huang); Center for Research and Advanced Therapies, Centro de Investigación y Ciencias Avanzadas–Alzheimer Foundation, Donostia-San Sebastian, Spain (Iriondo); Department of Neurology, Osaka City University Graduate School of Medicine, Osaka, Japan (Itoh, Minatani, Takeda); Department of Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium (Ivanoiu); Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley (Jagust); Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, California (Jagust); Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germany (Jessen); Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany (Jessen); DZNE, Bonn, Germany (Jessen); Memory Disorder Unit, Copenhagen University Hospital, Copenhagen, Denmark (Johannsen); Department of Radiology, Massachusetts General Hospital, Boston (Johnson); Department of Radiation Oncology, Emory University, Atlanta, Georgia (Kandimalla); Applied Biology, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana State, India (Kandimalla); Department of Biochemistry, Kakatiya Medical College/Mahatma Gandhi Memorial Hospital, Warangal, Telangana State, India (Kandimalla); National and Kapodistrian University of Athens, School of Medicine, 1st Department of Neurology, Eginition Hospital, Athens, Greece (Kapaki); Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden (Kern, Skoog, A. Wallin, Zetterberg); Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden (Kilander); Department of Internal Medicine and Gerontology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland (Klimkowicz-Mrowiec); Department of Psychiatry, Massachusetts General Hospital, Boston (Klunk); Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania (Klunk); Life Molecular Imaging GmbH, Berlin, Germany (Koglin); Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany (Kornhuber); Department of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia (Kramberger); Department of Neurology, Chang Gung Memorial Hospital at Linkou Medical Center, Chang Gung University College of Medicine, Taoyuan, Taiwan (Kuo); Division of Nuclear Medicine and Molecular Imaging, University Hospitals Leuven, Leuven, Belgium (Van Laere); Department of Imaging and Pathology, Katholieke Universiteit Leuven, Leuven, Belgium (Van Laere); Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley (Landau); Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Korea (Lee); Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York, New York (de Leon); School of Psychology, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia (Leyton); Healthy Aging Research Center and Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan (Lin); Department of Nuclear Medicine and Molecular Imaging Center, Linkou Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan (Lin); Memory Clinic, Department of Geriatrics, Uppsala University Hospital, Uppsala, Sweden (Löwenmark); Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark (Madsen); Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany (Maier); Acute Internal Medicine and Geriatrics, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden (Marcusson); Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, Donostia-San Sebastian, Spain (Martinez-Lage); Biogen, Cambridge, Massachusetts (Maserejian); Faculty of Medicine, University of Lisboa, Lisboa, Portugal (de Mendonça); Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco (Miller); Avid Radiopharmaceuticals, Philadelphia, Pennsylvania (Mintun); Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China (Mok); Margaret K.L. Cheung Research Centre for Management of Parkinsonism, Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China (Mok); BrainNow Research Institute, Guangdong Province, Shenzhen, China (Mok); Alzheimer’s Disease and Other Cognitive Disorders Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Clinic University Hospital, Barcelona, Spain (Molinuevo); Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy (Morbelli); Ospedale Policlinico San Martino, IRCCS, Genoa, Italy (Morbelli); Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, Poland (Mroczko); Department of Biochemical Diagnostics, University Hospital of Białystok, Białystok, Poland (Mroczko); Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (Na); Neuroscience Center, Samsung Medical Center, Seoul, South Korea (Na); Myrna Brind Center of Integrative Medicine, Thomas Jefferson University and Hospital, Philadelphia, Pennsylvania (Newberg); Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), University of Genoa, Genoa, Italy (Nobili); Ospedale Policlinico San Martino, IRCCS, Genoa, Italy (Nobili); Radboudumc Alzheimer Centre, Radboud University Medical Center, Nijmegen, the Netherlands (Olde Rikkert); Department of Neurology of Memory and Language, Groupe Hospitalier Universitaire Paris Psychiatry and Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France (Olivieri, Sarazin); National and Kapodistrian University of Athens, School of Medicine, 1st Department of Neurology, Eginition Hospital, Athens, Greece (Paraskevas); Istituto delle Scienze Neurologiche di Bologna, IRCCS, Bologna, Italy (Parchi); DIMES, University of Bologna, Bologna, Italy (Parchi); DINOGMI, University of Genoa, Genoa, Italy (Pardini); Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Berlin-CBF, Berlin, Deutschland (Peters); Studies on Prevention of Alzheimer’s Disease (StOP-AD) Centre, Montreal, Quebec, Canada (Poirier, Rosa-Neto); Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich and University of Zürich, Zürich, Switzerland (Popp); Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland (Popp); Department of Neurology, Nehru Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh, India (Prabhakar); Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco (Rabinovici); Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic of Barcelona, IDIBAPS, Barcelona, Spain (Rami); Turku PET Centre, Turku, Finland (Rinne); Center for Vital Longevity, School of Behavioral and Brain Sciences, The University of Texas at Dallas, Dallas (Rodrigue); Neurology Department, Hospital Universitario Marqués de Valdecilla and IDIVAL, Santander, Spain (Rodríguez-Rodriguez); Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco (Rosen); Department of Neurology, Medical Center, Zaloska 7, Ljubljana, Slovenia (Rot); Department of Molecular Imaging, Austin Health, Melbourne, Victoria, Australia (Rowe, Villemagne); Florey Department of Neuroscience, University of Melbourne, Melbourne, Victoria, Australia (Rowe); Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany (Rüther); Cognitive Neuroscience Division, Department of Neurology and the Taub Institute, Columbia University, New York, New York (Sakhardande, Stern); Service of Neurology, University Hospital Marqués de Valdecilla-IDIVAL, CIBERNED, Santander, Spain (Sánchez-Juan); Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway (Sando); Department of Neurology, University Hospital of Trondheim, Trondheim, Norway (Sando); Université de Paris, Paris, Université Paris-Saclay, BioMaps, CEA, CNRS, INSERM, Orsay, France (Olivieri, Sarazin); Section for Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germany (Schröder); Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea (Seo); Faculty of Medicine, University of Lisboa, Lisboa, Portugal (Silva); Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston (Snyder); Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland (Soininen); Neurocenter, Department of Neurology, Kuopio University Hospital, Kuopio, Finland (Soininen); Memory Clinic, University Department of Geriatric Medicine, Felix Platter-Hospital, Basel, Switzerland (Sollberger); Department of Neurology, University Hospital Basel, Basel, Switzerland (Sollberger); Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Sperling); Harvard Aging Brain Study, Department of Neurology, Harvard Medical School, Boston, Massachusetts (Sperling); Geriatrics, Gerontology and Old Age Psychiatry Clinical Department, Carol Davila University of Medicine and Pharmacy-Elias, Emergency Clinical Hospital, Bucharest, Romania (Spiru); Memory Clinic and Longevity Medicine, Ana Aslan International Foundation, Bucharest, Romania (Spiru); Centre de Référence Démences Rares, Pitié-Salpêtrière University Hospital, AP-HP, Paris, France (Teichmann); Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island (Thompson); Aristotle University of Thessaloniki, Memory and Dementia Center, 3rd Department of Neurology, George Papanicolau General Hospital of Thessaloniki, Thessaloniki, Greece (Tsolaki); Laboratory for Cognitive Neurology, Department of Neurosciences, University of Leuven, Leuven, Belgium (Vandenberghe); Neurology Department, University Hospitals Leuven, Leuven, Belgium (Vandenberghe); Departments of Neurology and Laboratory Medicine, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Nijmegen, the Netherlands (Verbeek); Molecular Biomarkers in Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania (Villemagne); McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Quebec, Canada (Villeneuve); Translational Neuroscience Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts (Vogelgsang); Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark (Waldemar); Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany (Wiltfang); Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany (Wiltfang); Department of Neurology, University of Pennsylvania, Philadelphia (Wolk); Department of Nuclear Medicine and Molecular Imaging Center, Linkou Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan (Yen); Healthy Aging Research Center and Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan (Yen); Research-Scientific-Didactic Centre of Dementia-Related Diseases in Scinawa, Medical University of Wroclaw, Wroclaw, Poland (Zboch); Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden (Zetterberg); Department of Neurodegenerative Disease, University College London (UCL) Queen Square Institute of Neurology, Queen Square, London, United Kingdom (Zetterberg); UK Dementia Research Institute, London, United Kingdom (Zetterberg); Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China (Zetterberg).

Author Contributions: Dr Jansen and Ms Janssen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Jansen and Ms Janssen both contributed equally.

Concept and design: Jansen, Janssen, Ossenkoppele, Aarsland, Gill, Gkatzima, Hausner, Hodges, Hort, Itoh, Jessen, Kilander, Maserejian, Miller, Mok, Molinuevo, Morris, Newberg, Olde Rikkert, Prabhakar, Rüther, Verhey, Yen, Visser.

Acquisition, analysis, or interpretation of data: Jansen, Janssen, Tijms, Vos, Ossenkoppele, Aarsland, Alcolea, Altomare, von Arnim, Baiardi, Baldeiras, Barthel, Bateman, Van Berckel, Pichet Binette, Blennow, Boada, Boecker, Bottlaender, Braber, Brooks, Camus, Carril, Cerman, Chen, Chételat, Chipi, Cohen, Daniels, Delarue, Didic, Dubois, Eckerström, Ekblad, Epelbaum, Fagan, Fan, Fladby, Fleisher, Van der Flier, Förster, Fortea, Frederiksen, Freund-Levi, Frings, Gabryelewicz, Gertz, Gkatzima, Gómez-Tortosa, Grimmer, Guedj, Habeck, Hampel, Handels, Hansson, Hausner, Hellwig, Heneka, Herukka, Hildebrandt, Hort, Huang, Iriondo, Itoh, Ivanoiu, Jagust, Johannsen, Johnson, Kandimalla, Kapaki, Kern, Klimkowicz-Mrowiec, Klunk, Koglin, Kornhuber, Kramberger, Kuo, Van Laere, Landau, Landeau, Lee, de Leon, Leyton, Lin, Lleó, Lowenmark, Madsen, Maier, Marcusson, Marquié, Martinez-Lage, Maserejian, de Mendonca, Meyer, Miller, Mintun, Mok, Morbelli, Morris, Mroczko, Na, Nobili, Nordberg, Oliveira, Olivieri, Orellana, Paraskevas, Parchi, Pardini, Parnetti, Peters, Poirier, Popp, Rabinovici, Ramakers, Rami, Reiman, Rodrigue, Rodríguez-Rodriguez, Roe, Rosa-Neto, Rosen, Rot, Rowe, Ruiz, Sabri, Sakhardande, Sánchez-Juan, Sando, Santana, Sarazin, Scheltens, Schröder, Selnes, Seo, Silva, Skoog, Snyder, Soininen, Sollberger, Sperling, Spiru, Stern, Stomrud, Takeda, Teichmann, Teunissen, Tomassen, Vandenberghe, Verbeek, Villemagne, Villeneuve, Vogelgsang, Waldemar, A. Wallin, Å. K. Wallin, Wiltfang, Yen, Zboch, Zetterberg, Visser.

Drafting of the manuscript: Jansen, Janssen, Freund-Levi, Gkatzima, Itoh, Klunk, Maserejian, Mok, Molinuevo, Scheltens, Skoog, Sperling, Yen, Zboch, Visser.

Critical revision of the manuscript for important intellectual content: Jansen, Tijms, Vos, Ossenkoppele, Aarsland, Alcolea, Altomare, von Arnim, Baiardi, Baldeiras, Barthel, Bateman, Van Berckel, Pichet Binette, Blennow, Boada, Boecker, Bottlaender, Braber, Brooks, Camus, Carril, Cerman, Chen, Chételat, Chipi, Cohen, Daniels, Delarue, Didic, Dubois, Eckerström, Ekblad, Epelbaum, Fagan, Fan, Fladby, Fleisher, Van der Flier, Förster, Fortea, Frederiksen, Freund-Levi, Frings, Gabryelewicz, Gertz, Gill, Gómez-Tortosa, Grimmer, Guedj, Habeck, Hampel, Handels, Hansson, Hausner, Hellwig, Heneka, Herukka, Hildebrandt, Hodges, Hort, Huang, Iriondo, Itoh, Ivanoiu, Jagust, Jessen, Johannsen, Johnson, Kandimalla, Kapaki, Kern, Kilander, Klimkowicz-Mrowiec, Klunk, Koglin, Kornhuber, Kramberger, Kuo, Van Laere, Landau, Landeau, Lee, de Leon, Leyton, Lin, Lleó, Lowenmark, Madsen, Maier, Marcusson, Marquié, Martinez-Lage, de Mendonca, Meyer, Miller, Mintun, Mok, Molinuevo, Morbelli, Morris, Mroczko, Na, Newberg, Nobili, Nordberg, Olde Rikkert, Oliveira, Olivieri, Orellana, Paraskevas, Parchi, Pardini, Parnetti, Peters, Poirier, Popp, Prabhakar, Rabinovici, Ramakers, Rami, Reiman, Rodrigue, Rodríguez-Rodriguez, Roe, Rosa-Neto, Rosen, Rot, Rowe, Rüther, Ruiz, Sabri, Sakhardande, Sánchez-Juan, Sando, Santana, Sarazin, Scheltens, Schröder, Selnes, Seo, Silva, Skoog, Snyder, Soininen, Sollberger, Spiru, Stern, Stomrud, Takeda, Teichmann, Teunissen, Tomassen, Vandenberghe, Verbeek, Verhey, Villemagne, Villeneuve, Vogelgsang, Waldemar, A. Wallin, Å. K. Wallin, Wiltfang, Yen, Zetterberg, Visser.

Statistical analysis: Jansen, Janssen, Tijms, Cerman, Yen.

Obtained funding: Jansen, Visser, Aarsland, Alcolea, Baiardi, Barthel, Bateman, Bottlaender, Brooks, Carril, Cohen, Didic, Fladby, Fortea, Grimmer, Guedj, Hansson, Jessen, Johnson, Kapaki, Kern, Klunk, Kornhuber, Lleó, Martinez-Lage, Maserejian, Miller, Mok, Molinuevo, Morbelli, Olivieri, Poirier, Popp, Rabinovici, Reiman, Rosen, Rowe, Rüther, Ruiz, Sabri, Sánchez-Juan, Sarazin, Scheltens, Skoog, Soininen, Sperling, Vandenberghe, Villemagne, Villeneuve, A. Wallin, Wiltfang.

Administrative, technical, or material support: Jansen, Janssen, Vos, Aarsland, Baiardi, Bateman, Boecker, Braber, Chételat, Daniels, Delarue, Fagan, Förster, Frederiksen, Gertz, Gkatzima, Gómez-Tortosa, Grimmer, Handels, Hansson, Hausner, Hellwig, Heneka, Hildebrandt, Iriondo, Itoh, Jagust, Johannsen, Johnson, Kandimalla, Kapaki, Kilander, Klimkowicz-Mrowiec, Koglin, Kuo, Van Laere, Landeau, Lee, de Leon, Marcusson, Meyer, Miller, Mintun, Morris, Newberg, Orellana, Paraskevas, Pardini, Popp, Rami, Reiman, Rodrigue, Rodríguez-Rodriguez, Roe, Rosa-Neto, Rowe, Ruiz, Sabri, Sando, Scheltens, Schröder, Seo, Skoog, Snyder, Soininen, Sollberger, Stern, Tomassen, Verbeek, Vogelgsang, Å. K. Wallin, Wiltfang, Zetterberg.

Supervision: Jansen, Ossenkoppele, Aarsland, Barthel, Bateman, Van Berckel, Boada, Brooks, Dubois, Gill, Hampel, Hodges, Huang, Jessen, Johannsen, Klunk, Van Laere, Lowenmark, Maier, Marquié, Maserejian, Miller, Mok, Morris, Mroczko, Parnetti, Poirier, Popp, Rot, Ruiz, Scheltens, Spiru, Verhey, Yen, Visser.

Other: Rodríguez-Rodriguez, Zboch.

Suggestions on statistical analysis: Chen.

Analytic review and critical reading: Habeck.

Conflict of Interest Disclosures: Dr Alcolea reported participating in advisory boards from Fujirebio-Europe and Roche Diagnostics; receiving speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica SL, Zambon SAU, and Esteve Pharmaceuticals SA; and filing a patent application (WO2019175379 A1 Markers of Synaptopathy in Neurodegenerative Disease). Dr von Arnim reported receiving honoraria from serving on the scientific advisory board of Biogen, Roche, and Dr Willmar Schwabe GmbH & Co KG; funding for travel and speaker honoraria from Lilly GmbH, Daiichi Sankyo, Biogen, Roche Diagnostics AG, and Dr Willmar Schwabe GmbH & Co KG; and research support from Roche Diagnostics AG. Dr Chételat reported receiving research support from the European Union (EU)’s Horizon 2020 Research and Innovation Programme, Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation d’Entreprise MMA des Entrepreneurs du Futur, Fondation Alzheimer, Programme Hospitalier de Recherche Clinique, Région Normandie, Association France Alzheimer et Maladies Apparentées, Fondation Recherche Alzheimer, and Fondation Vaincre Alzheimer (all to INSERM), as well as personal fees from Fondation d’Entreprise MMA des Entrepreneurs du Futur. Dr Barthel reported receiving grants from Life Molecular Imaging. Dr Eckerström reported being employed as an independent reviewer at Medavante-Prophase. Dr Engelborghs reported participating in consultancy or on advisory boards of Biogen, Danone, Eisai Inc, Icometrix, Pfizer, Novartis, and Roche, and receiving unrestricted research grants (paid to his institution) from ADx Neurosciences and Janssen Pharmaceuticals. Dr Grimmer reported receiving consulting fees from AbbVie, Anavex, Biogen, Bracket, Eli Lilly and Company, Functional Neuromodulation, Iqvia/Quintiles, Novartis, Novo Nordisk, NuiCare, Roche Pharma, Toyama, and Vivoryon; lecture fees from Actelion, B. Braun, Biogen, Eli Lilly and Company, Life Molecular Imaging, Novartis, Parexel, and Roche Pharma; and grants to his institution from Actelion and Novartis. Dr Guedj reported having a scientific collaboration on amyloid positron emission tomography (PET) imaging with Life Molecular Imaging before 2018. Dr Hampel reported being an employee of Eisai Inc; being an unpaid senior associate editor for the journal Alzheimer’s & Dementia; previously receiving lecture fees from Servier, Biogen, and Roche; receiving research grants from Pfizer, Avid, and MSD Avenir (paid to the institution); receiving travel funding from Eisai Inc, Functional Neuromodulation, Axovant, Eli Lilly and Company, Takeda and Zinfandel, GE Healthcare, and Oryzon Genomics; receiving consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd, Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation; participating in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai Inc, Eli Lilly and Company, Cytox Ltd, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics; being the inventor of 11 patents (In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders, patent number 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases, patent number 8298784; Neurodegenerative Markers for Psychiatric Conditions, publication number 20120196300; In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders, publication number 20100062463; In Vitro Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders, publication number 20100035286; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases, publication number 20090263822; In Vitro Method for the Diagnosis of Neurodegenerative Diseases, patent number 7547553; CSF Diagnostic In Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases, publication number 20080206797; In Vitro Method for the Diagnosis of Neurodegenerative Diseases, publication number 20080199966; Neurodegenerative Markers for Psychiatric Conditions, publication number 20080131921; and Method for Diagnosis of Dementias and Neuroinflammatory Diseases Based on an Increased Level of Procalcitonin in Cerebrospinal Fluid, United States patent 10921330). Dr Jagust reported consulting for Biogen, Bioclinica, and Genentech. Dr Koglin reported being employed at Life Molecular Imaging. Dr Marquié reported receiving research funding from ISCIII Acción Estratégica en Salud, which was integrated in the Spanish National RCDCI Plan and financed by a grant from ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa). Dr Morris reported receiving grants from the National Institutes of Health (NIH). Dr Nobili reported receiving fees for teaching courses from GE Healthcare and Biogen, for advisory board participation from Roche and Biogen, and for consultation from Bial. Dr Popp reported receiving consultation and speaker honoraria from Nestle Institute of Health Sciences, Innovation Campus, EPFL, Ono Pharma, OM Pharma Suisse, and Fujirebio Europe. Dr Rowe reported receiving grants from Cerveau Technologies, Biogen, and AbbVie as well as serving on the scientific advisory committee of Cerveau Technologies and the medical education faculty of Biogen. Dr Ruiz reported receiving support from Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISCIII); the EU/European Federation of Pharmaceutical Industries and Associations (EFPIA) Innovative Medicines Initiative Joint Undertaking; grants from the EXIT (Exosomes Isolation Tool with Nanofluidic Concentration Device) project, EU Euronanomed3 Program, and PREADAPT project; grant from the Joint Program for Neurodegenerative Diseases; and research funding from ISCIII Acción Estratégica en Salud, which was integrated in the Spanish National RCDCI Plan and financed by a grant from ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER; Una manera de hacer Europa) by Fundación Bancaria La Caixa and Grífols SA (GR@ACE project). Dr Sabri reported receiving grants from Life Molecular Imaging. Dr Snyder reported being a consultant to Alzheon Inc, AlzeCure Pharma, and AlzPATH Inc outside the submitted work. Dr Soininen reported receiving personal consultation fees from AC Immune and Novo Nordisk outside the submitted work. Dr Sperling reported receiving honorarium for consulting from AC Immune, Acumen, Alnylam, Cytox, Genentech, Janssen, JOMDD, Oligomerix, Neuraly, Neurocentria, Renew, Prothena, and Shionogi; reported receiving research funding from the National Institute on Aging (NIA), Alzheimer’s Association, Eisai Inc, Eli Lilly and Company, and Janssen; and reported the following financial relationships for her spouse (Dr Keith Johnson): Cerveau, Janssen, AC Immune, and Novartis. Dr Teunissen reported receiving research support from the European Commission (Marie Curie International Training Network and Joint Program for Neurodegenerative Diseases grants), Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association, and ABOARD (A Personalized Medicine Approach for Alzheimer's Disease), which is a public-private partnership supported by ZonMW, Alzheimer Nederland, Health Holland, Gieskes-Strijbisfonds, and Edwin Bouw Fonds; having a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly and Company; performing contract research or receiving grants from AC Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai Inc, PeopleBio, Roche, Toyama, and Vivoryon; serving on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, and Neurology: Neuroimmunology & Neuroinflammation; and being editor of a neuromethods book from Springer. Dr van der Flier reported holding the Pasman chair and receiving funding from ABOARD. Dr A. Wallin reported receiving gratuity for lectures from Lundbeck. Dr Zetterberg reported serving at scientific advisory boards and/or as a consultant for Alector, Eisai Inc, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx, and Red Abbey Labs; giving lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen; and being a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by Biogen.

Role of the Funder/Sponsor: An employee of Biogen had a role in the analysis plan, review, and revision of the manuscript but had no role in the design and conduct of the study; collection, management, and interpretation of the data; approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Members of the following groups, which contributed to this article, are listed in eAppendices 1-6 in the Supplement: Alzheimer’s Disease Neuroimaging Initiative (ADNI), A4 Study group, Clin-AD Study group, Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD) research group, Dominantly Inherited Alzheimer Network (DIAN), and Fundació ACE Healthy Brain Initiative (FACEHBI).

Additional Information: Data used in preparation of the present article were obtained from the ADNI database (adni.loni.usc.edu). As such, ADNI investigators provided and contributed to the design and implementation of the ADNI data but did not participate in the analysis or writing of this article. A complete listing of ADNI investigators can be found at . The ADNI was launched in 2003 as a public-private partnership, led by principal investigator Michael W. Weiner, MD. The primary goal of ADNI is to test whether serial magnetic resonance imaging, PET, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment and early Alzheimer disease. Data collection and sharing for this project was funded by grant U01 AG024904 from the NIH and award W81XWH-12-2-0012 from the US Department of Defense. The ADNI is funded by the NIA; the National Institute of Biomedical Imaging and Bioengineering; and AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica Inc, Biogen, Bristol-Myers Squibb Company, CereSpir Inc, Cogstate, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research and Development LLC, Johnson & Johnson Pharmaceutical Research and Development LLC, Lumosity, Lundbeck, Merck & Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc, Piramal Imaging, Servier, Takeda Pharmaceutical Company, and Transition Therapeutics. The Canadian Institutes of Health Research provides support to the ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH (). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute (ATRI) at the University of Southern California. The ADNI data are disseminated by the Laboratory for Neuroimaging at the University of Southern California. The A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies are led by Dr Sperling at Brigham and Women’s Hospital, Harvard Medical School, and by Dr Paul Aisen at the ATRI. The A4 and LEARN studies are coordinated by the ATRI, and the data are made available through the Laboratory for Neuroimaging. The participants screening for the A4 Study provided permission to share their deidentified data to advance the objective to find a successful treatment for Alzheimer disease. The A4 Study is a secondary prevention trial in preclinical Alzheimer disease that aims to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. Data used in the preparation of this article were obtained from the Harvard Aging Brain Study (HABS; grant P01AG036694 from NIA). The HABS study was launched in 2010, is funded by the NIA, and is led by principal investigators Drs Sperling and Johnson at Massachusetts General Hospital, Harvard Medical School. A proportion of the data used in preparation of this article was obtained from the following: LEARN study, which was performed within the framework of the Center for Translational Molecular Medicine, a Dutch public-private partnership (project LEARN; grant 02 N-101 from Center for Translational Molecular Medicine); DIAN (grant UF01AG032438 from NIA), which was funded by the NIA, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, and partially by the research and development grants for dementia from Japan Agency for Medical Research and Development and Korea Health Technology Research and Development Project through the Korea Health Industry Development Institute; and PREVENT-AD program (; data release 5.0, November 30, 2017), which provided and contributed to the design and implementation of PREVENT-AD data but did not participate in the analysis or writing of this article. A complete listing of PREVENT-AD research group investigators can be found at . The FACEHBI study was supported by funds from Fundació ACE Institut Català de Neurociències Aplicades, Grifols, Life Molecular Imaging, Araclon Biotech, Alkahest, Laboratorio de Análisis Echevarne and IrsiCaixa. Part of the present study was supported by the European Medical Information Framework Alzheimer's Disease (EMIF-AD), which received support from the Innovative Medicines Initiative Joint Undertaking under EMIF-AD grant agreement 115372 that comprised financial contribution from the EU’s Seventh Framework Program (FP7/2007-2013) and in kind contribution from EFPIA companies. Research of Alzheimer Centre Amsterdam was part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Centre Amsterdam was supported by Stichting Alzheimer Nederland and Stichting VUmc Fonds. The SCIENCe project was supported by research grants from Gieskes-Strijbis Fonds and Stichting Dioraphte. PET scans in the Amsterdam Dementia Cohort were obtained with research grants from GE Healthcare, Life Molecular Imaging, AVID, and ZonMW-Memorabel, the research and innovation program for dementia. The Sant Pau Memory Unit received funding from CIBERNED, ISCIII, which is jointly funded by FEDER, EU, Una manera de hacer Europa; Generalitat de Catalunya; Fundació La Marató TV3 Fundació Bancària Obra Social La Caixa; Fundación BBVA; Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica; Global Brain Health Institute; Fundació Catalana Síndrome de Down; and Fundació Víctor Grífols i Lucas. The International Mind, Activities and Urban Places (IMAP) study (Dr Chételat; Caen, France) was supported by the Programme Hospitalier de Recherche Clinique (grants PHRCN 2011-A01493-38 and PHRCN 2012 12-006-0347), the Agence Nationale de la Recherche (ANR LONGVIE 2007), Fondation Plan Alzheimer (Alzheimer Plan 2008-2012), Association France Alzheimer et Maladies Apparentées AAP 2013, the Région Basse Normandie, and INSERM. The Phoenix Arizona APOE Cohort was funded by grant R01 AG031581 from the NIA. The Imabio3 and Shatau7-Imatau studies (Sarazin, Paris) were supported by grants PHRC-0054-N 2010 and PHRC-2013-0919 from the French Health Ministry, the Institut Roche de Recherche et Medecine Translationelle (Imabio3), Service Hospitalier Frédéric Joliot, Fondation pour la Recherche sur Alzheimer, Institut de Recherches Internationales Servier, and France-Alzheimer (Shatau7-Imatau). The Nijmegen cohort was supported by the BIONIC project (grant 733050822 from ZonMW-Memorabel as part of the Dutch National Deltaplan for Dementia [zonmw.nl/dementiaresearch]), the CAFÉ project (grant 5R01NS104147-02 from the NIH), and the Selfridges Group Foundation (grant NR170024). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and Rhode Island University.