Cognitive Changes Preceding Clinical Symptom Onset of Mild Cognitive Impairment and Relationship to ApoE Genotype

Abstract

Background This study had two goals (1) to evaluate changes in neuropsychological performance among cognitively normal individuals that might precede the onset of clinical symptoms, and (2) to examine the impact of Apolipoprotein E (ApoE) genotype on these changes. Methods Longitudinal neuropsychological, clinical assessments and consensus diagnoses were completed prospectively in 268 cognitively normal individuals. The mean duration of follow-up was 9.2 years (+/− 3.3). 208 participants remained normal and 60 developed cognitive decline, consistent with a diagnosis of MCI or dementia. Cox regression analyses were completed, for both baseline scores and rate of change in scores, in relation to time to onset of clinical symptoms. Analyses were completed both with and without ApoE-4 status included. Interactions with ApoE-4 status were also examined. Results Lower baseline test scores, as well as greater rate of change in test scores, were associated with time to onset of clinical symptoms (p<0.001). The mean time from baseline to onset of clinical symptoms was 6.15 (+/− 3.4) years. The presence of an ApoE-4 allele doubled the risk of progression. The rate of change in two of the test scores was significantly different in ApoE-4 carriers vs. non-carriers. Conclusions Cognitive performance declines prior to the onset of clinical symptoms that are a harbinger of a diagnosis of MCI. Cognitive changes in normal individuals who will subsequently decline may be observed at least 6.5 years prior to symptom onset. In addition, the risk of decline is doubled among individuals with an ApoE-4 allele.

Investigating the influence of KIBRA and CLSTN2 genetic polymorphisms on cross-sectional and longitudinal measures of memory performance and hippocampal volume in older individuals

“…In a second step we investigated the interaction between KIBRA and CLSTN2. is negatively related to memory performance in older individuals (Albert et al, 2014;Nilsson et al,2006). We did not include APOE H4 status as a covariate in the hippocampal volume analyses based on studies showing that APOE H4 status is not associated with reduced HC volume in older individuals (Taylor et al, 2014;Mather et al, 2015).…”

Alpha-2 macroglobulin in Alzheimer’s disease: a marker of neuronal injury through the RCAN1 pathway

“…Annual clinical and cognitive evaluations of the BIOCARD participants included a comprehensive neuropsychological battery, family history of dementia, history of symptom onset and a clinical dementia rating. Consensus diagnosis criteria and protocol have been described previously, 24 and followed the NINCDS/ADRDA criteria for AD dementia 25,26 and the Petersen criteria for MCI. 27 For participants with MCI or AD, age of onset of clinical symptoms was estimated primarily based on the report of the subject and collateral obtained during the clinical dementia rating interview.…”

“…Additional BIOCARD study design and participant recruitment details are described elsewhere. 24,29 All study participants provided written informed consent, and the Johns Hopkins School of Medicine Institutional Review Board approved all study protocols.…”

Cognitive reserve and cortical thickness in preclinical Alzheimer’s disease

“…The overarching goal was to identify variables among cognitively normal individuals that could predict the subsequent development of mild to moderate symptoms of dementia due to AD. Recruitment procedures, baseline evaluations, and annual clinical and cognitive assessments have been described in detail elsewhere (Albert et al 2014). Briefly, the study was initiated at the National Institutes of Health (NIH), with recruitment conducted by the staff of the Geriatric Psychiatry Branch of the intramural program of the National Institute of Mental Health, beginning in 1995 and ending in 2005.…”

“…Since the study was re-established at Johns Hopkins, annual visits have included comprehensive neuropsychological testing and a clinical evaluation consisting of a physical and neurological examination, record of medication use, behavioral and mood assessments, family history of dementia, history of symptom onset, and a Clinical Dementia Rating (CDR), based on a semi-structured interview (Hughes et al 1982; Morris 1993) (for further detail, see Albert et al 2014). Clinical assessments given at the NIH covered similar domains.…”