Neuropsychological measures that detect early impairment and decline in preclinical Alzheimer disease

Abstract

Identifying which neuropsychological measures detect early cognitive changes associated with Alzheimer disease (AD) brain pathology would be helpful clinically for the diagnosis of early AD and for the design of clinical trials. We evaluated which neuropsychological measures in our cognitive battery are most strongly associated with cerebrospinal fluid (CSF) biomarkers of AD brain pathology. We studied a large cohort (n=233) of middle- to older-aged community-dwelling individuals (mean age 61 years) who had no clinical symptoms of dementia and underwent baseline CSF collection at baseline. Participants completed a battery of nine neuropsychological measures at baseline and then every one to three years. CSF tau/Aβ42 was associated with baseline performance on 5/9 neuropsychological measures, especially measures of episodic memory, and longitudinal performance on 7/9 neuropsychological measures, especially measures of global cognition. The free recall portion of the Free and Cued Selective Reminding Task (FCSRT-free) detected declining cognition in the high CSF tau/Aβ42 group the earliest, followed by another measure of episodic memory and a sequencing task.

The impact of amyloid‐beta and tau on prospective cognitive decline in older individuals

“…16,17,[27][28][29] These findings are also consistent with laboratory work suggesting that tau is likely the primary mechanism of Aβrelated neurotoxicity, 30 and previous work using other imaging markers of neurodegeneration, [31][32][33][34] suggesting that Aβ pathology in isolation may be insufficient to drive imminent cognitive decline. 16,17,[27][28][29] These findings are also consistent with laboratory work suggesting that tau is likely the primary mechanism of Aβrelated neurotoxicity, 30 and previous work using other imaging markers of neurodegeneration, [31][32][33][34] suggesting that Aβ pathology in isolation may be insufficient to drive imminent cognitive decline.…”

“…Our findings using neuroimaging markers are consistent with previous reports using CSF, suggesting that greater cognitive decline is observed in CN with abnormalities of both CSF Aβ and phospho-tau. 16,17,[27][28][29] These findings are also consistent with laboratory work suggesting that tau is likely the primary mechanism of Aβrelated neurotoxicity, 30 and previous work using other imaging markers of neurodegeneration, [31][32][33][34] suggesting that Aβ pathology in isolation may be insufficient to drive imminent cognitive decline. Our findings may also be relevant to the question as to whether tau, in the setting of low Aβ, might underlie age-related decline in episodic memory, given the nearly ubiquitous presence of tau pathology in the EC (Braak stage 1-2) by age 80, 18 and the recent interest in "primary age-related tauopathy" (PART), 35 defined as early neocortical tau accumulation with absent or low Aβ pathology (Thal phase <3 corresponding approximately to PET Aβ -) in very elderly individuals (average ages, 88-90).…”

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aβ-related cognitive impairment in preclinical Alzheimer’s disease after a 27-month delay interval

“…That is, those who failed the SCT generally did not show reliable improvements in cognitive performance as a result of benefitting from repeated exposures to the cognitive test. The absence of this effect within the SCT− group corresponds to literature demonstrating a lack of practice effects in episodic memory tasks in those with preclinical AD [34,35]. Our data support the hypothesis that lack of practice effects on an episodic memory test could indicate a preclinical AD state in cognitively normal older adults.…”

Volume and Connectivity of the Ventral Tegmental Area are Linked to Neurocognitive Signatures of Alzheimer’s Disease in Humans

“…However the identification of a memory-related mechanism of clinical relevance during the preclinical stage is a hard task, as this stage is asymptomatic. Longitudinal evidence indicates that, among healthy adults, measures of episodic memory are the best predictors of subsequent conversion to the early symptomatic stage of AD [37]. The simple retrospective use of neuropsychological tests, however, does not allow a clear separation between encoding and retrieval efficiency.…”