Clinical and psychological characteristics of the initial cohort of the Dominantly Inherited Alzheimer Network (DIAN).

OBJECTIVE: The purpose was to describe clinical, cognitive, and personality characteristics at baseline assessment of 249 participants, 19 to 60 years of age, in a multinational longitudinal study of autosomal dominant Alzheimer's disease (ADAD). METHOD: Participants (74% cognitively normal) were from ADAD families with mutations in 1 of 3 genes (APP, PSEN1, or PSEN2). Mixed model analyses, including family as a random variable and controlling for years from expected time of symptomatic onset of ADAD based on parental age at onset, compared 3 groups (cognitively normal mutation noncarriers, cognitively normal mutation carriers, very mildly impaired mutation carriers). RESULTS: Global cognitive deficits similar to those observed in late-life sporadic Alzheimer's disease (AD) existed in very mild ADAD compared with cognitively normal carriers and noncarriers on all but 2 measures (Digit Span Backward, Letter Fluency for FAS) of episodic memory, semantic memory, working memory, attention, and speeded visuospatial abilities. Demented individuals were less extraverted, open, and conscientious than cognitively normal participants on the International Personality Item Pool. Differences in the relation between 3 measures (Logical Memory, Digit Symbol, attention switching) and time to expected age at symptomatic onset indicate that cognitive deficits on some measures can be detected in mutation carriers prior to symptomatic AD, and hence should be useful markers in subsequent longitudinal follow-up. CONCLUSIONS: Overall cognitive and personality deficits in very mild ADAD are similar to those seen in sporadic AD. Cognitive deficits also occur in asymptomatic mutation carriers who are closer to the expected time of dementia onset.

Progression of Alzheimer's disease as measured by Clinical Dementia Rating Sum of Boxes scores.

BACKGROUND: This study examined rates of dementia progression as ascertained by the Clinical Dementia Rating Sum of Boxes (CDR-SB) for symptomatic Alzheimer's disease (sAD), and assessed participant characteristics as predictors of CDR-SB progression. METHODS: Participants (n = 792) were enrolled in longitudinal studies at an Alzheimer's Disease Research Center, received a diagnosis of sAD with a global CDR of 0.5 (n = 466) or 1 (n = 326), and had at least one follow-up assessment. Progression in CDR-SB over time as a function of baseline global CDR was examined. RESULTS: A longitudinal increase (P < .0001) in CDR-SB was observed. The annual rate of change in CDR-SB scores was 1.43 (standard error [SE] = 0.05) in the CDR 0.5 sample and 1.91 (SE = 0.07) in the CDR 1 sample. For participants followed from the beginning of the CDR stage, time to progression to a higher global CDR was longer for individuals who were CDR 0.5 (3.75 years; 95% confidence interval [CI]: 3.18-4.33) than those who were CDR 1 at baseline (2.98 years; 95% CI: 2.75-3.22). In the total CDR 0.5 sample, the significant predictors of progression to the next global CDR stage (P < .01) were age at first sAD diagnosis and apolipoprotein E4 genotype. CONCLUSIONS: The study findings are relevant to sAD clinical trial design and accurate, reliable ascertainment of the effect of disease-modifying treatments.

Toward a multifactorial model of Alzheimer disease.

Relations among antecedent biomarkers of Alzheimer disease (AD) were evaluated using causal modeling; although correlation cannot be equated to causation, causation does require correlation. Individuals aged 43 to 89 years (N = 220) enrolled as cognitively normal controls in longitudinal studies had clinical and psychometric assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and brain amyloid imaging via positron emission tomography with Pittsburgh Compound B (PIB) obtained within 1 year. CSF levels of Aß(42) and tau were minimally correlated, indicating they represent independent processes. Aß(42), tau, and their interaction explained 60% of the variance in PIB. Effects of APOE genotype and age on PIB were indirect, operating through CSF markers. Only spurious relations via their common relation with age were found between the biomarkers and regional brain volumes or cognition. Hence, at least 2 independent hypothesized processes, one reflected by CSF Aß(42) and one by CSF tau, contribute to the development of fibrillar amyloid plaques preclinically. The lack of correlation between these 2 processes and brain volume in the regions most often affected in AD suggests the operation of a third process related to brain atrophy.

Role of family history for Alzheimer biomarker abnormalities in the adult children study.

OBJECTIVE: To assess whether family history (FH) of Alzheimer disease (AD) alone influences AD biomarker abnormalities. DESIGN: Adult Children Study. SETTING: Washington University's Charles F. and Joanne Knight Alzheimer's Disease Research Center. PARTICIPANTS: A total of 269 cognitively normal middle- to older-aged individuals with and without an FH for AD. MAIN OUTCOME MEASURES: Clinical and cognitive measures, magnetic resonance imaging-based brain volumes, diffusion tensor imaging-based white matter microstructure, cerebrospinal fluid biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography using the [(11)C] benzothiazole tracer, Pittsburgh compound B. RESULTS: A positive FH for AD was associated with an age-related decrease of cerebrospinal fluid Aß42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted cerebrospinal fluid Aß42 was decreased for individuals with APOE4 compared with the level for those without, and the decrease was larger for individuals with a positive FH compared with the decrease for those without. The variation of cerebrospinal fluid tau and Pittsburgh compound B mean cortical binding potential increased by age. For individuals younger than 55, an age-related increase in mean cortical binding potential was associated with APOE4 but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in mean cortical binding potential. A positive FH was associated with decreased fractional anisotropy from diffusion tensor imaging in the genu and splenium of the corpus callosum. CONCLUSION: Independent of APOE4, FH is associated with age-related change of several cerebrospinal fluid, Pittsburgh compound B, and diffusion tensor imaging biomarkers in cognitively normal middle- to older-aged individuals, suggesting that non- APOE susceptibility genes for AD influence AD biomarkers.

Ascertainment bias in the clinical diagnosis of Alzheimer disease.

BACKGROUND: The clinical diagnosis of Alzheimer disease (AD) is often based, at least in part, on poor cognitive test performance compared with normative values. OBJECTIVE: To examine the presence and extent of an ascertainment bias (omission of affected individuals) produced by such criteria when applied as early as possible in the course of the disease. DESIGN: Longitudinal study (1979-2008). SETTING: Washington University Alzheimer Disease Research Center, St Louis, Missouri. PARTICIPANTS: Of 78 individuals aged 65 to 101 years enrolled as healthy controls, 55 later developed autopsy-confirmed AD; 23 remained cognitively healthy and did not have neuropathologic AD. MAIN OUTCOME MEASURES: Criteria for the diagnosis of AD based on various cutoff points (1.5, 1.0, and 0.5 SDs below the mean for robust test norms) for 2 standard psychometric measures from each of 3 cognitive domains (episodic memory, visuospatial ability, and working memory) were applied to data from the first assessment associated with an independent clinical diagnosis of cognitive impairment for those who developed symptomatic AD and from the last assessment for those who did not. RESULTS: Areas under the curve from receiver operating characteristic analyses ranged from 0.71 to 0.49; sensitivities and specificities were unsatisfactory even after adjusting for age and education, using combinations of tests, or examining longitudinal decline before clinical diagnosis. CONCLUSION: Reliance on divergence from group normative values to determine initial cognitive decline caused by AD results in failure to include people in the initial symptomatic stage of the illness.

Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease.

OBJECTIVE: To determine whether preclinical Alzheimer disease (AD), as detected by the amyloid-imaging agent Pittsburgh Compound B (PiB) in cognitively normal older adults, is associated with risk of symptomatic AD. DESIGN: A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PiB and followed up with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT). SETTING: The Alzheimer's Disease Research Center, Washington University, St Louis, Missouri. PARTICIPANTS: One hundred fifty-nine participants with a mean age of 71.5 years with a Clinical Dementia Rating (CDR) of 0 on a PET PiB scan at baseline. MAIN OUTCOME MEASURE: Progression from CDR 0 to CDR 0.5 status (very mild dementia). RESULTS: Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range, 1-5 assessments after PET PiB). Of these, 9 also were diagnosed with DAT. Higher mean cortical binding potential values for PiB (hazard ratio, 4.85; 95% confidence interval, 1.22-19.01; P = .02) and age (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in 3 cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained at CDR 0. CONCLUSION: Preclinical AD as detected by PET PiB is not benign, as it is associated with progression to symptomatic AD.

Cognitive decline and brain volume loss as signatures of cerebral amyloid-beta peptide deposition identified with Pittsburgh compound B: cognitive decline associated with Abeta deposition.

OBJECTIVE: To examine the relation of amyloid-beta peptide (Abeta) levels in the cerebral cortex with structural brain integrity and cognitive performance in cognitively healthy older people. DESIGN: Longitudinal study from May 22, 1985, through October 15, 2008. SETTING: Washington University Alzheimer Disease Research Center. PARTICIPANTS: A total of 135 individuals aged 65 to 88 years with a Clinical Dementia Rating of 0. MAIN OUTCOME MEASURES: The relations between mean cortical carbon 11 ((11)C)-labeled Pittsburgh compound B (PiB) binding potential values, proportional to the density of fibrillar Abeta binding sites in the brain, concurrent regional brain volumes as assessed by magnetic resonance imaging, and both concurrent and longitudinal cognitive performance in multiple domains. RESULTS: Elevated cerebral Abeta levels, in some cases comparable to those seen in individuals with Alzheimer disease, were observed in 29 participants, who also had smaller regional volumes in the hippocampus, temporal neocortex, anterior cingulate, and posterior cingulate. Concurrent cognitive performance was unrelated to Abeta levels but was related to regional brain volumes with the exception of the caudate. Longitudinal cognitive decline in episodic and working memory and visuospatial ability was associated with elevated Abeta levels and decreased hippocampal volume. CONCLUSION: The in vivo measure of cerebral amyloidosis known as [(11)C]PiB is associated with cross-sectional regionally specific brain atrophy and longitudinal cognitive decline in multiple cognitive domains that occur before the clinical diagnosis of Alzheimer disease. These findings contribute to the understanding of the cognitive and structural consequences of Abeta levels in cognitively healthy older adults.

Absence of Pittsburgh compound B detection of cerebral amyloid beta in a patient with clinical, cognitive, and cerebrospinal fluid markers of Alzheimer disease: a case report.

BACKGROUND: To date, there have been no reports of individuals who have been characterized longitudinally using clinical and cognitive measures and who transitioned from cognitive normality to early symptomatic Alzheimer disease (AD) during a period when both cerebrospinal fluid (CSF) markers and Pittsburgh Compound B (PiB) amyloid imaging were obtained. OBJECTIVE: To determine the temporal relationships of clinical, cognitive, CSF, and PiB amyloid imaging markers of AD. DESIGN: Case report. SETTING: Alzheimer disease research center. PARTICIPANT: Longitudinally assessed 85-year-old man in a memory and aging study who was cognitively normal at his initial and next 3 annual assessments. MAIN OUTCOME MEASURES: Serial clinical and psychometric assessments over 6 years in addition to PiB imaging with positron emission tomography (PET) and CSF biomarker assays before autopsy. RESULTS: Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB PET amyloid imaging was negative at age 88(1/2) years, but at age 89(1/2) years there was reduced amyloid beta 42 and elevated levels of tau in the CSF. Beginning at age 89 years, very mild cognitive and functional decline reported by his collateral source resulted in a diagnosis of very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse amyloid beta plaques sufficient to fulfill Khachaturian neuropathologic criteria for definite AD, but other neuropathologic criteria for AD were not met because only sparse neuritic plaques and neurofibrillary tangles were present. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB PET binding was below the level needed for in vivo detection. CONCLUSION: Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral amyloid beta using amyloid imaging agents such as PiB that primarily label fibrillar amyloid beta plaques.

Longitudinal study of the transition from healthy aging to Alzheimer disease.

BACKGROUND: Detection of the earliest cognitive changes signifying Alzheimer disease is difficult. OBJECTIVE: To model the cognitive decline in preclinical Alzheimer disease. DESIGN: Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory. SETTING: Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri. PARTICIPANTS: One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented. MAIN OUTCOME MEASURES: Inflection point in longitudinal cognitive performance. RESULTS: The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n = 44) with autopsy-confirmed Alzheimer disease. CONCLUSIONS: There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease.

Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness.

BACKGROUND: Persistent postoperative cognitive decline is thought to be a public health problem, but its severity may have been overestimated because of limitations in statistical methodology. This study assessed whether long-term cognitive decline occurred after surgery or illness by using an innovative approach and including participants with early Alzheimer disease to overcome some limitations. METHODS: In this retrospective cohort study, three groups were identified from participants tested annually at the Washington University Alzheimer's Disease Research Center in St. Louis, Missouri: those with noncardiac surgery, illness, or neither. This enabled long-term tracking of cognitive function before and after surgery and illness. The effect of surgery and illness on longitudinal cognitive course was analyzed using a general linear mixed effects model. For participants without initial dementia, time to dementia onset was analyzed using sequential Cox proportional hazards regression. RESULTS: Of the 575 participants, 214 were nondemented and 361 had very mild or mild dementia at enrollment. Cognitive trajectories did not differ among the three groups (surgery, illness, control), although demented participants declined more markedly than nondemented participants. Of the initially nondemented participants, 23% progressed to a clinical dementia rating greater than zero, but this was not more common after surgery or illness. CONCLUSIONS: The study did not detect long-term cognitive decline independently attributable to surgery or illness, nor were these events associated with accelerated progression to dementia. The decision to proceed with surgery in elderly people, including those with early Alzheimer disease, may be made without factoring in the specter of persistent cognitive deterioration.

Older adults' responses to emotional stimuli: a cautionary note.

Thirty younger (mean age = 21 years) and 30 older (mean age = 73 years) adults were compared to determine if they had similar affective experiences to eight emotion films previously validated with young adults (Gross & Levenson, 1995). Participants rated their emotions, and heart rate was collected during two films of each emotion: amusement, anger, sadness, and fear. Older and younger adults were generally similar in their physiological and subjective responses to films, but with a few exceptions. Older adults reported more intense anger in response to one film and more intense nontarget negative emotions for both anger films compared with young adults. Some older adults also reported a negative response compared with young adults to one of the films designed to elicit amusement. Thus it is inappropriate to assume that emotional stimuli produce the same response across the adult life span.

The power of personality in discriminating between healthy aging and early-stage Alzheimer's disease.

This study examined differences in personality in the earliest stages of dementia of the Alzheimer type (DAT) relative to healthy aging, and the power of personality in discriminating healthy aging from early-stage DAT. Four groups of participants (middle-aged controls, older controls, persons with very mild DAT, and persons with mild DAT) and their families were administered Costa and McCrae's NEO Five-Factor Inventory. On the basis of both self-report and informant report, there was an increase in neuroticism and a decrease in conscientiousness in persons with very mild DAT relative to healthy individuals without it, and in persons with mild DAT relative to those with very mild DAT. Moreover, informant reports of neuroticism and conscientiousness capture substantial unique variance in discriminating healthy aging and very mild DAT, above and beyond standard neuropsychological tests. Discussion focuses on the importance of personality traits as a noncognitive indicator of early-stage DAT.

Model stability of the 15-item Geriatric Depression Scale across cognitive impairment and severe depression.

The 15-item Geriatric Depression Scale (GDS) is used in a wide variety of clinical and research settings. The study's purpose was to further establish the validity of the 15-item GDS by exploring the underlying factor structure in a healthy, nondemented sample of older adults and then analyzing whether this factor structure remained stable across a sample of demented individuals and a sample of individuals with a history of depression 6 months after discharge from an inpatient psychiatric setting. A 2-factor model fit the data best in the exploratory analyses. The 2 factors, Life Satisfaction and General Depressive Affect, found in the nondemented sample (r = .39) remained stable across cognitive impairment (r = .12) but merged into a 1-factor model in the psychiatric sample (r = .93). The results indicate that nondepressed older adults with poor life satisfaction may be identified as depressed on screening instruments such as the 15-item GDS.

Clinical and psychometric distinction of frontotemporal and Alzheimer dementias.

BACKGROUND: A proportion of patients who meet the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Associations criteria for Alzheimer disease (AD) have frontotemporal lobar degeneration (FTLD) confirmed at autopsy, with or without concomitant AD. Thus, the clinical phenotypes of the 2 disorders may overlap. OBJECTIVE: To identify clinical and psychometric indicators that distinguish AD from FTLD at initial presentation. DESIGN: Longitudinal study of memory and aging. SETTING: Alzheimer's Disease Research Center, Washington University School of Medicine. PARTICIPANTS: Forty-eight clinically well-characterized cases of autopsy-confirmed FTLD (27 with psychometric testing results) were compared with 27 autopsy-confirmed AD cases. RESULTS: Behavioral abnormalities, particularly impulsivity (P<.001), disinhibition (P<.001), social withdrawal (P = .01), and progressive nonfluent aphasia, distinguished individuals with FTLD from those with AD. The individuals with FTLD performed better than those with AD on a visual test of episodic memory (P = .01), but worse on word fluency (P = .02) (performance correlated with aphasic features). Other cognitive and clinical features, including executive dysfunction and memory impairment, were comparable between the FTLD and AD groups. Concomitant histopathological AD was present in 11 of the 48 individuals with FTLD. CONCLUSIONS: Clinical and cognitive features of FTLD may overlap with AD, although behavioral and language difficulties distinguish those with FTLD. Memory loss in those with FTLD may in part reflect word-finding difficulties stemming from language dysfunction. Compounding the overlap of FTLD and AD clinical phenotypes is the presence of histopathological AD in almost one fourth of individuals with FTLD.

Effects of environmental support and strategy training on older adults' use of context.

Age-related cognitive differences may be due, in part, to difficulties using task-relevant context in a proactive manner. Two studies evaluated different methods for increasing older adults' use of context in the AX-Continuous Performance Task (H. E. Rosvold, A. F. Mirsky, I. Sarason, E. D. Bransome, & L. H. Beck, 1956), which evaluates components of context processing. The results suggest that (a) age differences in the use of context are not due to reduced access to cue information, (b) directed strategy training made older adults' context processing performance more like that of young adults, and (c) similar performance changes could be observed with less directed instruction and extended practice. These results suggest that age-related differences in context processing can be ameliorated by directed strategy training or extended practice.

Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI.

OBJECTIVES: To compare the natural history of individuals classified with mild cognitive impairment (MCI) in accordance with original criteria to the natural history of individuals classified with revised MCI criteria. METHODS: The authors compared the rates of progression in 32 individuals with amnestic MCI and in 90 people with MCI according to revised criteria that allow nonamnestic deficits with progression in 276 individuals who were too minimally impaired (pre-MCI) to meet either MCI criteria. All individuals in this study were determined clinically to be very mildly cognitively impaired with a Clinical Dementia Rating (CDR) of 0.5. RESULTS: Rates of progression for the two MCI groups were similar with a decline of almost 0.50 SD per year on a psychometric composite. Decline was less (0.23 SD) in the pre-MCI group. Median survival time to CDR 1 (mild dementia) was comparable for the original (95% CI: 3.79 to 4.07 years) and revised (95% CI: 3.29 to 5.40) criteria MCI groups but approximately twice as long in the pre-MCI group (95% CI: 6.72 to 8.93). All cases from the amnestic MCI criteria group with neuropathologic diagnoses met criteria for Alzheimer disease as did more than 90% in the other two groups. CONCLUSIONS: Mild cognitive impairment as originally and currently defined is usually early stage Alzheimer disease, which can begin with a cognitive deficit other than memory. It is possible to identify Alzheimer disease at an even earlier stage than mild cognitive impairment by focusing on intraindividual change rather than comparison with group norms.

A comparison of narratives told by younger and older adults.

The few studies that have examined verbal discourse in both young and older adults have yielded inconsistent results with respect to talkativeness and story quality. The disparity may arise from methodological differences. In this study the authors examined word count, irrelevant utterances, and ratings of quality of stories told by 24 young (mean age = 19.21) and 24 old (mean age = 72.13) adults. The authors found minimal age differences. A separate sample of 10 young and 10 older adults of ages similar to those of the storytellers read and rated all the stories. Raters were highly variable in their subjective evaluations of story quality, although satisfactory generalizability coefficients can be achieved with a sufficiently large number of raters. Most studies of discourse quality, however, use few raters, which produces unreliable measurement that can contribute to the inconsistent results reported in the literature.

Visual search for change in older adults.

Previous research has demonstrated that younger adults are surprisingly poor at detecting substantial changes to visual scenes. Little is known, however, about age differences in this phenomenon. In the 2 experiments reported here, older adults were slower than younger adults in detecting changes to simple visual stimuli. This age difference was beyond what would be expected given known age-related changes in processing speed. Examination of eye movement behavior during the search for change suggested that age-related changes in the useful field of view and degree of cautiousness play a significant role. Speed of processing and 3 age-related eye movement behaviors explained 85% of the variance in change detection latency, eliminating the effect of age.

Driving cessation in older adults with dementia of the Alzheimer's type.

The psychometric profile of 143 drivers with dementia who stopped driving did not differ from that of 58 individuals with dementia of similar severity who still drove. The reasons given for driving cessation by drivers with dementia as reported by a collateral source are reported.

Predictors of preclinical Alzheimer disease and dementia: a clinicopathologic study.

BACKGROUND: To understand the earliest signs of cognitive decline caused by Alzheimer disease (AD) and other illnesses causing dementia, information is needed from well-characterized individuals without dementia studied longitudinally until autopsy. OBJECTIVE: To determine clinical and cognitive features associated with the development of AD or other dementias in older adults. DESIGN: Longitudinal study of memory and aging. SETTING: Alzheimer's Disease Research Center, St Louis, Mo. MAIN OUTCOME MEASURES: Clinical Dementia Rating, its sum of boxes, and neuropathologic diagnosis of dementia. PARTICIPANTS: Eighty control participants who eventually came to autopsy. RESULTS: Individuals who did not develop dementia showed stable cognitive performance. Entry predictors of dementia were age, deficits in problem solving as well as memory, slowed psychomotor performance, and depressive features. Minimal cognitive decline occurred prior to dementia diagnosis, after which sharp decline was noted. Even individuals who were minimally cognitively impaired (Clinical Dementia Rating = 0.5) typically had neuropathologic AD at autopsy. Histopathologic AD also was present in 34% of individuals who did not have dementia at death; these individuals without dementia showed an absence of practice effects on cognitive testing. CONCLUSIONS: Increased age, depressive features, and even minimal cognitive impairment, as determined clinically by Clinical Dementia Rating sum of boxes and by slowed psychomotor performance, identify older individuals without dementia who develop dementia. Older adults who do not develop dementia have stable cognitive performance. The absence of practice effects may denote the subset of older adults without dementia with histopathologic AD, which may reflect a preclinical stage of the illness.