Knopman, David S.

Objective The newly proposed National Institute on Aging–Alzheimer's Association (NIA‐AA) criteria for mild cognitive impairment (MCI) due to Alzheimer disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known. Methods The Mayo Clinic Study of Aging (MCSA) is a population‐based longitudinal study of nondemented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI‐1) to assess the applicability of the criteria in both settings and to assess their outcomes. Results Fourteen percent of MCSA and 16% of ADNI‐1 of subjects were biomarker negative. In addition, 14% of MCSA and 12% of ADNI‐1 subjects had evidence for amyloid deposition only, whereas 43% of MCSA and 55% of ADNI‐1 subjects had evidence for amyloid deposition plus neurodegeneration (magnetic resonance imaging atrophy, fluorodeoxyglucose positron emission tomography hypometabolism, or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model; for example, 29% of MCSA subjects and 17% of ADNI‐1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone. Interpretation The NIA‐AA criteria apply to most MCI subjects in both the community and clinical trials settings; however, a sizeable proportion of subjects had conflicting biomarkers, which may be very important and need to be explored. Ann Neurol 2013;74:199–208

BackgroundThe purpose of this study was to estimate differences in rates of functional decline in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia (VaD) and whether differences vary by age or sex.MethodsData came from 32 U.S. Alzheimer's Disease Centers. The cohort of participants (n = 5848) were ≥60 years of age and had clinical dementia with a primary etiologic diagnosis of probable AD, DLB, or probable VaD; a Clinical Dementia Rating‐Sum of Boxes score <16; and a duration of symptoms ≤10 years. Dementia diagnoses were assigned using standard criteria. Annual mean rate of change of the Functional Activities Questionnaire (FAQ) score was modeled using multiple linear regression with generalized estimating equations adjusted for demographics, comorbidities, years since onset, and cognitive status (mean follow‐up = 2.0 years).ResultsFAQ declined more slowly over time in those with VaD compared with AD (difference in mean annual rate of change: −0.91; 95% confidence interval [CI]: −1.68, −0.14). VaD participants also declined at a slower rate than DLB participants, but this difference was not statistically significant (−0.61; 95% CI: −1.45, 0.24). There was no significant difference between DLB and AD. Within each group, rate of decline was more rapid for the youngest participants.ConclusionsIn this sample, findings suggested that VaD patients declined in their functional abilities at a slower rate compared with AD patients and that there were no significant differences in rate of functional decline between patients with DLB compared with those with either AD or VaD. These results may provide guidance to clinicians about average expected rates of functional decline in three common dementia types.

AbstractBackgroundType 2 diabetes may increase the risk of amnestic mild cognitive impairment (aMCI) through Alzheimer's disease (AD)‐related and vascular pathology and may also increase the risk of nonamnestic MCI (naMCI) through vascular disease mechanisms. We examined the association of type 2 diabetes with mild cognitive impairment (MCI) and MCI subtype (aMCI and naMCI) overall and by sex.MethodsParticipants were Olmsted County, Minnesota residents (70 years and older) enrolled in a prospective, population‐based study. At baseline and every 15 months thereafter, participants were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of normal cognition, MCI, and dementia by a consensus panel. Type 2 diabetes was ascertained from the medical records of participants at baseline.ResultsOver a median 4.0 years of follow‐up, 348 of 1450 subjects developed MCI. Type 2 diabetes was associated (hazard ratio [95% confidence interval]) with MCI (1.39 [1.08–1.79]), aMCI (1.58 [1.17–2.15]; multiple domain: 1.58 [1.01–2.47]; single domain: 1.49 [1.09–2.05]), and the hazard ratio for naMCI was elevated (1.37 [0.84–2.24]). Diabetes was strongly associated with multiple‐domain aMCI in men (2.42 [1.31–4.48]) and an elevated risk of multiple domain naMCI in men (2.11 [0.70–6.33]), and with single domain naMCI in women (2.32 [1.04–5.20]).ConclusionsDiabetes was associated with an increased risk of MCI in elderly persons. The association of diabetes with MCI may vary with subtype, number of domains, and sex. Prevention and control of diabetes may reduce the risk of MCI and Alzheimer's disease.

AbstractObjectiveA National Institute on Aging–sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.MethodsSeventy‐one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups.ResultsThere was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross‐sectional comparisons did not discriminate the groups.ConclusionsAlthough cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory‐sensitive measures and longitudinal design.