Accelerated forgetting has been proposed as the first sign in preclinical and early Alzheimer's disease (AD). The authors investigated learning and retention in participants who later developed AD with free and cued selective reminding (FCSR; H. Buschke, 1984; E. Grober & H. Buschke, 1987), a test that maximizes learning by inducing deep semantic processing and by controlling study and test conditions. AD patients in the preclinical stage recalled significantly fewer words than did matched control participants, indicating an impairment of learning; nonetheless, patients' retention was identical to that of control participants. A retention deficit was documented 3 years later for AD patients but not for control participants, whose retention was still perfect. Thus, a retention deficit is not present in preclinical AD when hallmark learning deficits can be documented. Detection of preclinical and very early AD may be best accomplished by using robust learning tests that control cognitive processing.

The present work explored the loss of semantic attributes that is said to occur in dementia. In the first two experiments, subjects had to select attributes that went with concepts like airplane and church. The finding that demented subjects maintained high levels of accuracy when selecting attributes suggested that the semantic content of their concepts was relatively well preserved. The organization of the content was explored in a third experiment by having subjects order attributes according to their relative importance in defining concepts. While demented subjects performed better than chance, they did not rank attributes as well as healthy aged subjects, suggesting a disruption in organization whereby the importance of central attributes is reduced. The hypothesized disruption in organization is viewed in relation to the learning and memory deficit that is the hallmark of the dementias.

Objective

To examine trajectories of declines in learning and retention during the predementia phase of Alzheimer's disease (AD) using the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT+IR).

Method

Learning was defined by the sum of free recall over three test trials. Retention was defined in two ways: by delayed free recall (DFR) and by savings; DFR adjusted for learning. The performances of 217 incident AD cases from the Baltimore Longitudinal Study of Aging (BLSA) were aligned based on the time that AD was first diagnosed. The predementia phase of learning and retention decline was assessed using change point models in which cognitive trajectories are described by a series of linear components with knots delineating times of accelerating decline.

Results

Trajectories for both learning and DFR had two change points: the first at 6.58 (95% confidence intervals (CI): 6.56, 6.60) to 7.29 (95% CI: 6.13, 8.46) years before diagnosis followed by gradual decline over the next 4 years, and a second acceleration of decline 1.89 (0.56, 3.24) to 2.93 (95% CI: 1.56, 4.30) years before diagnosis. The change points for DFR were not significantly earlier in the predementia phase than the change points for learning. Savings had one change point, 5.3 (95% CI: 3.56, 7.04) years before diagnosis.

Conclusion

Both learning and DFR showed similar profiles of decline in the years prior to the clinical diagnosis of AD. When delayed recall was adjusted for initial learning, the measure was less sensitive to early disease. (JINS, 2019, 25, 699-705).

Objective

To compare the predictive validity of learning and retention measures from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR) for identifying incident mild cognitive impairment (MCI).

Methods

Learning was defined by the sum of free recall (FR) and retention by delayed free recall (DFR) tested 15-20 min later. Totally, 1422 Baltimore Longitudinal Study of Aging (BLSA) participants (mean age 69.6 years, 54% male, mean 16.7 years of education) without dementia or MCI received the pFCSRT + IR at baseline and were followed longitudinally. Cox proportional hazards models were used to evaluate the effect of baseline learning and retention on risk of MCI.

Results

In total, 187 participants developed MCI over a median of 8.1 years of follow-up. FR and DFR each predicted incident MCI adjusting for age, sex, and education. Also, each independently predicted incident MCI in the presence of the other with similar effect sizes: around 20% decrease in the hazard of MCI corresponding to one standard deviation increase in FR or DFR.

Conclusion

The practice of preferring retention over learning to predict incident MCI should be reconsidered. The decision to include retention should be guided by time constraints and patient burden.

In the Baltimore Longitudinal Study of Aging (BLSA), we examined the temporal unfolding of declining performance on tests of episodic memory (Free Recall on the Free and Cued Selective Reminding Test), executive function (Category Fluency, Letter Fluency, and Trails), and Verbal Intelligence (Nelson, 1982; American Version of the Nelson Adult Reading Test [AMNART]) before the diagnosis of dementia in 92 subjects with incident Alzheimer's disease (AD) followed for up to 15 years before diagnosis. To examine the preclinical onset of cognitive decline, we aligned subjects at the time of initial AD diagnosis and examined the cognitive course preceding diagnosis. We found that declines in performance on tests of episodic memory accelerated 7 years before diagnosis. Declining performance on tests of executive function accelerated 2-3 years before diagnosis, and verbal intelligence declined in close proximity to diagnosis. This cognitive profile is compatible with pathologic data suggesting that structures which mediate memory are affected earlier than frontal structures during the preclinical onset of AD. It also supports the view that VIQ as estimated by the AMNART does not decline during the preclinical onset of AD.

BACKGROUND AND OBJECTIVES: To develop and test the performance of the Positive Aβ Risk Score (PARS) for prediction of β-amyloid (Aβ) positivity in cognitively unimpaired individuals for use in clinical research. Detecting Aβ positivity is essential for identifying at-risk individuals who are candidates for early intervention with amyloid targeted treatments. METHODS: We used data from 4,134 cognitively normal individuals from the Anti-Amyloid Treatment in Asymptomatic Alzheimers (A4) Study. The sample was divided into training and test sets. A modified version of AutoScore, a machine learning-based software tool, was used to develop a scoring system using the training set. Three risk scores were developed using candidate predictors in various combinations from the following categories: demographics (age, sex, education, race, family history, body mass index, marital status, and ethnicity), subjective measures (Alzheimers Disease Cooperative Study Activities of Daily Living-Prevention Instrument, Geriatric Depression Scale, and Memory Complaint Questionnaire), objective measures (free recall, Mini-Mental State Examination, immediate recall, digit symbol substitution, and delayed logical memory scores), and APOE4 status. Performance of the risk scores was evaluated in the independent test set. RESULTS: PARS model 1 included age, body mass index (BMI), and family history and had an area under the curve (AUC) of 0.60 (95% CI 0.57-0.64). PARS model 2 included free recall in addition to the PARS model 1 variables and had an AUC of 0.61 (0.58-0.64). PARS model 3, which consisted of age, BMI, and APOE4 information, had an AUC of 0.73 (0.70-0.76). PARS model 3 showed the highest, but still moderate, performance metrics in comparison with other models with sensitivity of 72.0% (67.6%-76.4%), specificity of 62.1% (58.8%-65.4%), accuracy of 65.3% (62.7%-68.0%), and positive predictive value of 48.1% (44.1%-52.1%). DISCUSSION: PARS models are a set of simple and practical risk scores that may improve our ability to identify individuals more likely to be amyloid positive. The models can potentially be used to enrich trials and serve as a screening step in research settings. This approach can be followed by the use of additional variables for the development of improved risk scores. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in cognitively unimpaired individuals PARS models predict Aβ positivity with moderate accuracy.

Background and objectives

Increasing evidence indicates that a subset of cognitively normal individuals has subtle cognitive impairment at baseline. We sought to identify them using the Stages of Objective Memory Impairment (SOMI) system. Symptomatic cognitive impairment was operationalized by a Clinical Dementia Rating (CDR) ≥0.5. We hypothesized that incident impairment would be higher for participants with subtle retrieval impairment (SOMI-1), higher still for those with moderate retrieval impairment (SOMI-2), and highest for those with storage impairment (SOMI-3/4) after adjusting for demographics and APOE ε4 status. A secondary objective was to determine whether including biomarkers of β-amyloid, tau pathology, and neurodegeneration in the models affect prediction. We hypothesized that even after adjusting for in vivo biomarkers, SOMI would remain a significant predictor of time to incident symptomatic cognitive impairment.

Methods

Among 969 cognitively normal participants, defined by a CDR = 0, from the Knight Alzheimer Disease Research Center, SOMI stage was determined from their baseline Free and Cued Selective Reminding Test scores, 555 had CSF and structural MRI measures and comprised the biomarker subgroup, and 144 of them were amyloid positive. Cox proportional hazards models tested associations of SOMI stages at baseline and biomarkers with time to incident cognitive impairment defined as the transition to CDR ≥0.5.

Results

Among all participants, the mean age was 69.35 years, 59.6% were female, and mean follow-up was 6.36 years. Participants in SOMI-1-4 had elevated hazard ratios for the transition from normal to impaired cognition in comparison with those who were SOMI-0 (no memory impairment). Individuals in SOMI-1 (mildly impaired retrieval) and SOMI-2 (moderately impaired retrieval) were at nearly double the risk of clinical progression compared with persons with no memory problems. When memory storage impairment emerges (SOMI-3/4), the hazard ratio for clinical progression increased approximately 3 times. SOMI stage remained an independent predictor of incident cognitive impairment after adjusting for all biomarkers.

Discussion

SOMI predicts the transition from normal cognition to incident symptomatic cognitive impairment (CDR ≥0.5). The results support the use of SOMI to identify those cognitively normal participants most likely to develop incident cognitive impairment who can then be referred for biomarker screening.

INTRODUCTION: To assess the relationship between memory performance defined by the Stages of Objective Memory Impairment (SOMI) system and the Alzheimers disease (AD) ATN (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) biomarker system. METHODS: We used data from the Harvard Aging Brain Study cohort to estimate the level of ATN biomarkers: amyloid beta (C-Pittsburgh compound B-positron emission tomography [PET]), tau (F-18-flortaucipir [FTP] PET), and neurodegeneration (magnetic resonance imaging volumetrics). We assessed the cross-sectional relationship of SOMI classification with global amyloid levels, entorhinal and inferior temporal tau deposition, and hippocampal atrophy. RESULTS: Participants with both memory storage and retrieval deficits (SOMI-3, -4) had smaller hippocampal volumes and higher entorhinal and inferior temporal tau burden than participants with no memory impairment (SOMI-0) or mild retrieval difficulty (SOMI-1). Amyloid burden did not differ among SOMI stages. DISCUSSION: This pilot supports the close relationship between tau pathology and memory impairment across the AD continuum.  SOMI may be useful to determine eligibility for randomized controlled trials prior to the assessment of biomarker status.

Aims

To examine among Hispanics in the U.S., a population with increased reliance on informal healthcare support structures, (1) the association between cognitive function and control of diabetes; and (2) whether this association is modified by family support.

Methods

The Digit Symbol Substitution Test (DSST), word fluency, and learning and delayed recall components of the Spanish English Verbal Learning Test were administered to 1794 Hispanic adults aged 45-76years with diagnosed diabetes. An executive function index and global cognitive function index (GCFI) were derived. Uncontrolled diabetes (HbA1c⩾7% [53mmol/mol]) was compared across quartiles of cognitive function using multivariable logit models with interaction terms for cognitive function and family support.

Results

After adjustment, lower DSST scores were associated with uncontrolled diabetes (P=0.03). Family support modified the relationship between other measures of cognition and diabetes control (Pinteraction: 0.002, 0.09). Among individuals with low family support, as cognitive function declined, the odds of uncontrolled diabetes increased (P-trend across quartiles of the GCFI, 0.015). Among those with low family support, persons in the lowest quartile of global cognitive function were more than twice as likely to have uncontrolled diabetes as those in the highest performing quartile (OR=2.31; 95% CI: 1.17, 4.55). There was no similar effect among those with high family support.

Conclusions

Family support may buffer the negative association between low cognitive functioning and diabetes control in US Hispanics/Latinos. Educational programs targeted at family members of middle-age and older persons with diabetes regardless of neurocognitive status may help improve population-level glycemic control.

Background and objectives

The goal of this work was to investigate the neuroimaging correlates of the Stages of Objective Memory Impairment (SOMI) system operationalized with the Free and Cued Selective Reminding Test (FCSRT), a widely used episodic memory measure.

Methods

The FCSRT begins with a study phase in which items (e.g., grapes) are identified in response to unique semantic cues (e.g., fruit) that are used in the test phase to prompt recall of items not retrieved by free recall. There are 3 test trials of the 16 items (maximum 48). Data from 4,484 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were used. All participants had amyloid PET imaging, and a subset of 1,262 β-amyloid (Aβ)-positive had structural MRIs. We compared the Aβ mean cortical standardized uptake value ratio (SUVR) and volumetric measures of hippocampus, parahippocampal gyrus, entorhinal cortex, and inferior temporal cortex between the 5 SOMI stages.

Results

Participants had a mean age of 71.3 (SD 4.6) years; 40.6% were male; and 34.6% were APOE ε4 positive. Half had no memory impairment; the other half had retrieval deficits, storage limitations, or both. Analysis of covariance in the entire sample while controlling for age, sex, education, and APOE ε4 showed that individuals in higher SOMI stages had higher global amyloid SUVR (p < 0.001). Both SOMI-4 and -3 subgroups had higher amyloid SUVR than SOMI-0 and SOMI-1 subgroups. Individuals in higher SOMI stages had smaller hippocampal volume (p = 0.003), entorhinal cortex (p < 0.05), and inferior temporal lobes (p < 0.05), but there was no difference between parahippocampal gyrus volume of different SOMI stages. Pairwise comparison of SOMI subgroups showed that the SOMI-4, -3, and -2 subgroups had smaller hippocampal volume than the SOMI-0 and -1 subgroup. The SOMI-4 subgroup had significantly smaller entorhinal cortex and smaller inferior temporal lobe compared to all other groups.

Discussion

Presence of Alzheimer disease pathology is closely related to memory impairment according to SOMI stages in the cognitively unimpaired sample of A4. Results from structural MRIs suggest that memory storage impairment (SOMI-3 and -4) is present when there is widespread medial temporal lobe atrophy.

Trial registration information

ClinicalTrials.gov identifier: NCT02008357.

Classification of evidence

This study provides Class I evidence that, in normal older individuals, higher stages of memory impairment assessed with FCSRT were associated with higher amyloid imaging burden and lower volume of hippocampus, entorhinal cortex, and inferior temporal lobes.