Clinical meaningfulness of subtle cognitive decline on longitudinal testing in preclinical AD

Abstract

Introduction Demonstrating the “clinical meaningfulness” of slowing early cognitive decline in clinically normal (CN) older adults with elevated amyloid‐β (Aβ+) is critical for Alzheimer's disease secondary prevention trials and for understanding early cognitive progression. Methods Cox regression analyses were used to determine whether 3‐year slopes on the preclinical Alzheimer's cognitive composite predicted MCI diagnosis and global Clinical Dementia Rating>0 in 267 Aβ+ CN individuals participating in the Harvard Aging Brain Study, Australian Imaging, Biomarker and Lifestyle Study, and Alzheimer's Disease Neuroimaging Initiative. Results Steeper preclinical Alzheimer's cognitive composite decline over 3 years was associated with increased risk for MCI diagnosis and global Clinical Dementia Rating>0 in the following years across all cohorts. Hazard ratios using meta‐analytic estimates were 5.47 (95% CI: 3.25–9.18) for MCI diagnosis and 4.49 (95% CI: 2.84–7.09) for Clinical Dementia Rating>0 in those with subtle decline (>−.14 to −.26 preclinical Alzheimer's cognitive composite standard deviations/year) on longitudinal cognitive testing. Discussion Early “subtle cognitive decline” among Aβ+ CN on a sensitive cognitive composite demonstrably increases risk for imminent clinical disease progression and functional impairment.

Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals

“…Though the PACC and similar measures are in use in observational studies and ongoing prevention trials, it is important to note that the PACC is weighted toward memory measures and may not fully capture early disruptions in other cognitive domains 25 , 26 , 42 , 43 . Given the potential for clinically variable symptomatic presentations of AD pathology (including language and visuospatial predominant forms), further work using additional, diverse cognitive tests is needed to determine the extent to which plasma NT1 may predict changes in executive, language, and visuospatial function on the path to Alzheimer’s disease.…”

Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals

“…12 The close match of our cohort characteristics, including age, prevalence of APOE ε4, proportion with positive Aβ PET, and clinical progression rate in the Aβ positive subjects, with other longitudinal studies of older cognitively normal cohorts suggests that our findings are widely applicable. [27][28][29][30][31] For example, in our cohort, the risk of progression to MCI or dementia over a mean of 5.3 years of follow-up was 25% in the Aβ positive CN when defined as >25 CL. This is consistent with progression rates for Aβ positive CN in the Mayo Clinic Study of Aging (18% at 3.7 years), 28 the Alzheimer's Disease Neuroimaging Initiative (ADNI) (32% at 4 yrs), 29 the Washington University Knight ADRC (26% at 5 yrs), 30 and the Harvard Aging Brain Study (20% at 3 yrs).…”

Inherited risk of dementia and the progression of cerebral small vessel disease and inflammatory markers in cognitively healthy midlife adults: the PREVENT-Dementia study

“…To address the existing gaps in literature, the core objective of our study was to investigate the influence of inherited dementia risk on the longitudinal progression of SVD and inflammation in cognitively healthy midlife adults. There is also significant merit in elucidating the pathologic contributions to early cognitive decline, as evidenced by recent findings that even subtle cognitive decline in preclinical AD has robust clinical utility in predicting disease progression and conversion ( Papp et al., 2020 ). Therefore, we further examined the interaction between these pathologic markers and inherited risk factors on neuropsychological measures.…”