Plasma P-tau in combination with brief and accessible measures predict future AD dementia in two independent cohorts with high accuracy that is clearly superior to specialists' clinical diagnostic prediction.

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer’s disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T− and A−T− groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9–33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1–26.4) and A+T− (HR = 2.4, 95% CI = 1.4–4.3) groups versus the A−T− (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4–10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7–13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T− group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = −0.056 ± 0.005, T = −11.55, P < 0.001), A+TMTL+ (β = −0.024 ± 0.005, T = −4.72, P < 0.001) and A+T− (β = −0.008 ± 0.002, T = −3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A−T− (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T− group. In summary, evidence of advanced Alzheimer’s disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3–5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.

A combination of plasma phospho-tau (P-tau) and other accessible biomarkers may provide accurate prediction about the risk of developing Alzheimer’s disease (AD) dementia. We examined this in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) who were consecutively recruited in the BioFINDER study (n=340). The results were validated in SCD/MCI participants in the ADNI study (n=543). Plasma P-tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and MRI (cortical thickness in AD-specific regions) were examined as predictors of progression to AD dementia primarily within 4 years. The accuracy was determined using the area under the ROC curve (AUC) from logistic regression models. Within 4 years, plasma P-tau217 predicted AD dementia accurately (AUC 0.83) in BioFINDER. A model of plasma P-tau217, memory, executive function, and APOE had higher accuracy (AUC 0.91, p<0.001). In ADNI, this model produced a similar AUC (0.90) using plasma P-tau181 instead of P-tau217. A cross-validated version of this model was implemented online for prediction of the individual probability of progressing to AD dementia. Within 2 and 6 years, parsimonious models performed similar in both cohorts (AUCs 0.90-0.91). Using cerebrospinal fluid P-tau, Aβ42/Aβ40 and neurofilament light instead of plasma biomarkers did not improve the accuracy. The clinical prediction by memory clinic physicians had significantly lower accuracy than all models (4-year AUC 0.71). In summary, plasma P-tau in combination with brief cognitive tests and APOE genotyping may greatly improve the diagnostic prediction of AD dementia and facilitate recruitment for AD trials.

ImportanceAlzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.ObjectiveTo evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals.Design, Setting, and ParticipantsThis prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses.ExposuresBaseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.Main Outcomes and MeasuresThe primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion.ResultsAmong 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P &amp;lt; .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.Conclusions and RelevanceIn this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.