Prospective memory (PM) is the ability to remember to perform an action at a specific point in the future. Regarded as multidimensional, PM involves several cognitive functions that are known to be impaired in normal ageing. In the present study we set out to investigate the cognitive correlates of PM impairment in normal ageing. Manipulating cognitive load, we assessed event- and time-based PM, as well as several cognitive functions, including executive functions, working memory, and retrospective episodic memory, in healthy participants covering the entire adulthood. We found that normal ageing was characterised by PM decline in all conditions and that event-based PM was more sensitive to the effects of ageing than time-based PM. Whatever the conditions, PM was linked to inhibition and processing speed. However, while event-based PM was mainly mediated by binding and retrospective memory processes, time-based PM was mainly related to inhibition. The only distinction between high- and low-load PM cognitive correlates lies in an additional, but marginal, correlation between updating and the high-load PM condition. The association of distinct cognitive functions, as well as shared mechanisms with event- and time-based PM, confirm that each type of PM relies on a different set of processes.

IMPORTANCE Fluid and imaging biomarkers of Alzheimer disease (AD) are often used interchangeably, but some biomarkers may reveal earlier stages of disease.OBJECTIVE To characterize individuals with tau abnormality indicated by cerebrospinal fluid (CSF) assay or positron emission tomography (PET). Between 2010 and 2019, 322 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent CSF and PET assessments of tau pathology. Data-driven, clinically relevant thresholds for CSF phosphorylated tau (P-tau) (Ն26.64 pg/mL) and flortaucipir-PET meta-regions of interest (ROI) (standard uptake value ratio Ն1.37) indicated participants' tau status as CSF − /PET − , CSF + /PET − , CSF − /PET + , and CSF + /PET + . Of 1659 ADNI participants with a CSF or flortaucipir assessment, 588 had both measures (1071 were excluded). Among these, 266 were further excluded because they did not have flortaucipir and CSF testing within less than 25 months, leaving 322 for analysis. Of these, 213 were cognitively unimpaired (CU); 98 had mild cognitive impairment (MCI); and 11 had AD dementia. DESIGN, SETTING, AND PARTICIPANTS MAIN OUTCOMES AND MEASURESWe compared tau-positive vs tau-negative groups as indicated by either modality or demographic and clinical variables, amyloid β-PET burden, and flortaucipir-PET binding across Braak stage-related ROIs. We also compared 5-year rates of CSF P-tau accumulation and cognitive decline prior to flortaucipir-PET scanning.RESULTS Among the 322 study participants, 180 were women (56%), and the mean (SD) age was 73.08 (7.37) years. Two hundred ten participants were CSF − /PET − (65%); 63 were CSF + /PET − (19.5%); 15 were CSF − /PET + (4.6%); and 34 were CSF + /PET + (10.5%). Most CSF − /PET + participants had measures near CSF or PET tau thresholds. The CSF + /PET − participants showed faster 5-year accrual of P-tau and increased flortaucipir-PET binding in early Braak ROIs but similar memory decline compared with CSF − /PET − participants. Tau-positive individuals by either measure showed increased amyloid β-PET burden. All CSF + /PET + individuals were amyloid-positive, and 26 had MCI or AD dementia (76%). Compared with the CSF − /PET − group, CSF + /PET + individuals had experienced faster 5-year accrual of CSF P-tau and decline in memory and executive function, resulting in reduced cognitive abilities at the time of flortaucipir-PET assessment.CONCLUSIONS AND RELEVANCE Suprathreshold CSF P-tau without flortaucipir-PET abnormality may indicate a stage of AD development characterized by early tau abnormality without measurable loss in cognitive performance. Persons with both tau CSF and PET abnormality appear to have reduced cognitive capacities resulting from faster antecedent cognitive decline. Elevation of CSF P-tau appears to precede flortaucipir-PET positivity in the progression of AD pathogenesis and related cognitive decline.

Introduction White matter hyperintensities (WMH) are often described in Alzheimer's disease (AD), but their topography and specific relationships with cognition remain unclear. Methods Regional WMH were estimated in 54 cognitively impaired amyloid beta–positive AD (Aβpos‐AD), compared to 40 cognitively unimpaired amyloid beta–negative older controls (Aβneg‐controls) matched for vascular risk factors. The cross‐sectional association between regional WMH volume and cognition was assessed within each group, controlling for cerebral amyloid burden, global cortical atrophy, and hippocampal atrophy. Results WMH volume was larger in Aβpos‐AD compared to Aβneg‐controls in all regions, with the greatest changes in the splenium of the corpus callosum (S‐CC). In Aβpos‐AD patients, larger total and regional WMH volume, especially in the S‐CC, was strongly associated with decreased cognition. Discussion WMH specifically contribute to lower cognition in AD, independently from amyloid deposition and atrophy. This study emphasizes the clinical relevance of WMH in AD, especially posterior WMH, and most notably S‐CC WMH.