Woodruff, Bryan K.

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.

This letter comments on the letter by Luis Aguera‐Ortiz et al .

Introduction: Roughly 4% to 23% of the population embody stress prone personality and other traits characterizing a subclinical “broad autism phenotype” (BAP). Subjective cognitive impairment (SCI) among healthy elderly is associated with psychological distress leading us to predict BAP would be associated with SCI. Methods: The Autism Spectrum Quotient, a self-administered 50 item questionnaire, was completed by 419 consecutive members of the Arizona APOE Cohort who underwent neuropsychological testing every 2 years. SCI was assessed with self and informant versions of the Multidimensional Assessment of Neurodegenerative Symptoms (MANS) Questionnaire. Results: A total of 45 individuals scored in the BAP range, designated BAP+, and the rest were BAP−. At entry, both Multidimensional Assessment of Neurodegenerative Symptoms Questionnaire Self and Informant scores were higher in the BAP+ group (P<0.0001). After age 60, the BAP+ group had greater annual increases in Multidimensional Assessment of Neurodegenerative Symptoms Questionnaire Self scores (0.05 vs. 0.02; difference=0.03; 95% confidence interval, 0.004-0.05; P=0.02) yet there was no difference between groups in memory decline. Over ~10 years 33 individuals developed mild cognitive impairment: 4 in the BAP+ group (8.9%) and 29 in the BAP− group (7.8%), P=0.77. Discussion: Individuals who meet criteria for the BAP have escalating SCI with age, but no greater rate of memory decline or clinical progression to mild cognitive impairment.

AbstractIntroductionLittle empirical work has been done to examine differences between mild cognitive impairment (MCI) diagnosed in research settings with longitudinal data (incident MCI) and MCI diagnosed in clinical settings (prevalent MCI). Because Alzheimer's disease progresses over a clinicopathological continuum, we examined the cognitive differences between these two different sources of MCI patients.MethodsWe compared 52 consecutively identified patients with prevalent amnestic MCI with 53 incident amnestic MCI participants from the Arizona APOE study. Neuropsychological data from common tests were compared encompassing four cognitive domains and one global indicator.ResultsPrevalent MCI cases performed significantly worse than incident MCI cases on global as well as domain‐specific measures.DiscussionBy the time patients seek evaluation for memory loss, they have more severe single domain, amnestic MCI than research subjects with incident MCI. Studies of MCI should distinguish incident and prevalent not just single‐ and multiple‐domain MCI.

Background/Objectives Behavioral problems in individuals with Alzheimer's disease ( AD ) impose major management challenges. Current prevention strategies are anchored to cognitive outcomes, but behavioral outcomes may provide another, clinically relevant opportunity for preemptive therapy. We sought to determine whether personality changes that predispose to behavioral disorders arise during the transition from preclinical AD to mild cognitive impairment ( MCI ). Design Longitudinal observational cohort study. Setting Academic medical center. Participants Members of an apolipoprotein E ( APOE ) ɛ4 genetically enriched cohort of Maricopa County residents who were neuropsychiatrically healthy at entry (N = 277). Over a mean interval of 7 years, 25 who developed MCI and had the Neuroticism, Extraversion, and Openness Personality Inventory—Revised ( NEO ‐ PI ‐R) before and during the MCI transition epoch were compared with 252 nontransitioners also with serial NEO ‐ PI ‐R administrations. Intervention Longitudinal administration of the NEO ‐ PI ‐R and neuropsychological test battery. Measurements Change in NEO ‐ PI ‐R factor scores (neuroticism, extraversion, openness, agreeableness, conscientiousness) from entry to the epoch of MCI diagnosis or an equivalent follow‐up duration in nontransitioners. Results NEO ‐ PI ‐R neuroticism T‐scores increased significantly more in MCI transitioners than in nontransitioners (mean 2.9, 95% confidence interval ( CI ) = 0.9–4.9 vs 0, 95% CI = −0.7–0.7, P = .02), and openness decreased more in MCI transitioners than in nontransitioners (−4.8, 95% CI = −7.3 to −2.4 vs −1.0, 95% CI = −1.6 to −0.4, P < .001). Concurrent subclinical but statistically significant changes in behavioral scores worsened more in MCI transitioners than nontransitioners for measures of depression, somatization, irritability, anxiety, and aggressive attitude. Conclusion Personality and subclinical behavioral changes begin during the transition from preclinical AD to incident MCI and qualitatively resemble the clinically manifest behavioral disorders that subsequently arise in individuals with frank dementia.