Neuropsychological decline up to 20 years before incident mild cognitive impairment

Abstract

Introduction Some Alzheimer's disease biomarker studies found amyloid changes 20 years or more in advance of expected symptoms, while cognitive changes lagged for more than a decade, but this apparent lag might reflect the sensitivities of the biomarker and cognitive assays used. How far in advance of incident amnestic mild cognitive impairment (MCI) does cognition begin to decline? Methods Longitudinal neuropsychological study of an apolipoprotein E e4 enriched cohort of cognitively normal individuals at entry. Linear mixed models for MCI converters (n = 65) and nonconverters (n = 719) fitted for each neuropsychological measure; annual changes compared between groups before and after linear model intersections (inflection points). Results 34 of 35 cognitive measures and 9 of 18 behavioral measures declined faster post‐inflection in the MCI converters; the earliest cognitive inflection point was nearly 20 years in advance of MCI diagnosis. Discussion The preclinical duration of cognitive and behavioral changes approaches the earliest reported biomarker changes.

An agnostic reevaluation of the amyloid cascade hypothesis of Alzheimer's disease pathogenesis: The role of APP homeostasis

“…Imaging with amyloid positron emission tomography (PET) ligands has shown that there is a decades‐long period of accumulation that occurs in the absence of any clinical deficits 21 . The earliest areas of cerebral amyloid deposition detectable with amyloid‐PET are the frontal and posterior cingulate cortices yet neuropsychological decline at this early preclinical stage reflects medial temporal lobe and not frontally mediated cognition, 22 and among those who go on to develop MCI and dementia, the earliest cognitive changes begin roughly 20 years before incident diagnosis, a duration that approaches the earliest reported biomarker changes far earlier than predicted by the current model 23 . With the advent of tau‐ligands, PET imaging has shown even more vividly that the regional distribution of tau pathology corresponds to the clinical symptomatology far better than does the regional distribution of Aβ pathology 24 …”

“…This accelerated decline is highly correlated with tau and not amyloid pathology. 24 We found preclinical memory decline begins 20 years before incident MCI diagnosis, 23 about the time when biomarkers like CSF Aβ levels start to drop and hippocampal atrophy begins to accelerate. In a recent ADNI-based study patients with subtle cognitive decline had negative amyloid PET scans that subsequently became positive.…”

“…20 22 and among those who go on to develop MCI and dementia, the earliest cognitive changes begin roughly 20 years before incident diagnosis, a duration that approaches the earliest reported biomarker changes far earlier than predicted by the current model. 23 With the advent of tau-ligands, PET imaging has shown even more vividly that the regional distribution of tau pathology corresponds to the clinical symptomatology far better than does the regional distribution of Aβ pathology. 24…”

“…Subclinical memory decline is coincident or very nearly so with the onset of medial temporal tau pathology in the absence of locally aggregated Aβ. 23,55…”

“…Clinical symptoms are a practical but biologically arbitrary definition of “onset.” Subclinical memory decline is coincident or very nearly so with the onset of medial temporal tau pathology in the absence of locally aggregated Aβ 23,55 …”