The global fight against Alzheimer's disease (AD) poses unique challenges for the field of neuropsychology. Along with the increased focus on early detection of AD pathophysiology, characterizing the ...earliest clinical stage of the disease has become a priority. We believe this is an important time for neuropsychology to consider how our approach to the characterization of cognitive impairment can be improved to detect subtle cognitive changes during early-stage AD. The present article aims to provide a critical examination of how we define and measure cognitive status in the context of aging and AD. First, we discuss pitfalls of current methods for defining cognitive impairment within the context of research shifting to earlier (pre)symptomatic disease stages. Next, we introduce a shift towards a more continuous approach for identifying early markers of cognitive decline and characterizing progression and discuss how this may be facilitated by novel assessment approaches. Finally, we summarize potential implications and challenges of characterizing cognitive status using a continuous approach.
Background
Subjective cognitive decline (SCD) indicates a likelihood of the presence of cerebral beta‐amyloid burden associated with preclinical Alzheimer’s disease (AD), future objective cognitive ...decline, and clinical progression to dementia. The applicability of SCD as a preclinical AD marker in diverse ethnoracial groups has not been validated. In the few studies with diverse samples, participants from under‐represented populations such as Latinx and Black, tend to endorse differing levels of SCD than Non‐Hispanic White (NHW) individuals. Better understanding of ethnoracial differences in SCD and addressing potential cultural biases in existing measures are critical to validate its use as a preclinical AD marker in diverse samples. In this study, we examined two SCD instruments to evaluate measurement invariance across ethnoracial groups.
Method
807 participants aged ≥55 who reside in the United States (298 Latinx, 270 Black, 239 NHW) were recruited through Amazon’s Mechanical Turk and Qualtrics Panel. We examined the psychometric properties of the Cognitive Change Index (CCI) and Cognitive Function Index (CFI) across ethnoracial groups. First, we evaluated the factor structure of each measure using split‐half exploratory and confirmatory factor analyses (EFA/CFA). Next, we used multiple‐group CFA to evaluate configural, metric, and scalar invariance via a step‐wise approach.
Results
Participants (mean age of 65), were mostly women (63%) and received education beyond high school (83%). Split‐half EFA/CFA on the whole sample supported a one‐factor solution for both measures. Multiple‐group CFA revealed that when race/ethnicity was considered, model fit was negatively impacted. Neither measure achieved metric invariance, indicating that factor loadings were not equivalent across groups. For example, the CFI item “memory has declined substantially” had the highest loading for NHW and Latinx, but was low for the Black group. Conversely, “trouble following the news” loaded high for Latinx and Black, but low for NHW.
Conclusion
Measurement invariance was not supported for either instrument, indicating that it cannot be assumed that the same construct is being measured across NHW, Latinx and Black individuals. Scale refinement, such as abbreviating SCD measures to include only items that perform well across all groups, may minimize biases and facilitate cross‐cultural comparison in preclinical AD research.
Background
Cognitive dispersion refers to the within‐person variability across tasks. Relative to the normative approach, cognitive dispersion may be more sensitive to subtle changes in preclinical ...Alzheimer’s disease. Greater dispersion has been associated with increased risk for conversion to mild cognitive impairment and faster rates of medial temporal lobe atrophy. This metric can be derived from a regular neuropsychological assessment and complement traditional outcome approaches, particularly in those underrepresented in normative data. This study evaluated cognitive dispersion as an independent predictor of clinical status across racial and ethnic groups.
Method
Baseline data on 1811 cognitively unimpaired older adults with high vascular risk from the U.S. POINTER multisite lifestyle intervention study were examined. Sample characteristics included mean age of 68 (SD = 5.2), 70% female, 30% less‐than‐college education, and 29% underrepresented groups (301 Black, 231 Other). Correlations between cognitive dispersion and other brain health risks (vascular, subjective cognitive decline (SCD), physical activity) were tested. Cognitive dispersion was defined as the standard deviation of individuals’ z‐transformed scores of 8 cognitive tests. Vascular risk burden was the sum of 5 conditions (hypertension, diabetes, hypercholesterolemia, heart disease, obesity). Self‐report SCD was measured by the Cognitive Function Instrument (CFI) and Measurement of Everyday Cognition (ECOG12). Logistic Regression Models were fitted to predict Clinical Dementia Global Ratings (CDR 0.5 vs. 0) to evaluate cognitive dispersion as an independent predictor in the whole sample, White participants and Black participants, controlled for demographics, vascular risk, and physical activity. Logistic Regression Models were also evaluated with CFI or ECOG12 as additional covariate.
Result
Greater cognitive dispersion was correlated with older age, greater vascular burden and less physical activity, but not SCD. Cognitive dispersion was significantly higher in men, Black participants, and participants with less education. Cognitive dispersion predicted CDR in Black participants (OR = 4.7, p<0.01), and trended in the whole sample (OR = 1.6, p = 0.05), but was not significant in White participants (OR = 1.2, p = 0.63). Results hold when controlled for SCD (Table 1).
Conclusion
Results supported cognitive dispersion as a sensitive objective metric, in addition to self‐report SCD, to identify individuals showing the earliest clinical signs of decline, particularly among those underrepresented in traditional norms.
Background
The U.S. POINTER study is a phase 3, multicenter, 2‐year randomized controlled trial (RCT) of two lifestyle interventions varying in intensity and format, conducted in older adults living ...in the U.S. who do not have objective cognitive impairment at study entry, but have increased risk of cognitive decline and dementia. Inclusion criteria included specific risk factors (e.g., family history of dementia, vascular risk factors) but not subjective cognitive concerns (SCCs). However, SCCs are likely to be common in this group of at‐risk individuals. U.S. POINTER provides a unique opportunity to evaluate the prevalence of SCCs and their demographic and clinical correlates in an at‐risk group.
Methods
Recruitment for the U.S. POINTER study is still ongoing, and the following is based on a partial sample. The sample includes 1811 U.S. POINTER participants with complete baseline data (collected by December 2022), mean age = 68.2y (SD = 5.2), 73.5% are female, 70.2% have18+ years education, and 29.3% are from underrepresented groups. SCCs were measured by the brief 12‐item Everyday Cognition (ECog) questionnaire which includes two items in each of 6 domains: everyday memory, language, visuospatial abilities, planning, organization and divided attention. Responses on the ECog range from 0 = no change/better compared to baseline, 1 = questionably/inconsistently worse, 2 = consistently a little worse, 3 = much worse. Neuropsychological performance was measured using a global composite and episodic memory, executive functioning, and processing speed composites. Other variables included demographics, depression (Geriatric Depression Scale total score; GDS) and sleep (Insomnia severity index (ISI)) and vascular disease burden index.
Results
Thirty‐five percent of the cohort endorsed having a subjective complaint on the ECog (score ≥2 on any item). The most frequent complaint was “Remembering where I have placed objects” (23%). SCCs did not differ by age, sex or education. ECog‐12 Total were related to insomnia and depression (p<.0001). After adjusting for age, sex, education, vascular risk burden, GDS and ISI, greater SCC (ECog‐12 Total) was still associated with the global composite and all three domains (ps < 0.003).
Conclusions
SCCs, particularly everyday memory complaints, were relatively common in this at‐risk cohort. While SCCs were related to depression and sleep, they were also independently associated with slightly worse cognitive function.
Background
There has been little investigation into the relationship between physical, cognitive, and social activity and subjective concern about cognition (SCD) in the absence of objective ...cognitive decline. This concern about subjective change is an important concept in the field of Alzheimer’s disease as it independently confers risk for developing MCI/AD. However, the exact relationship between SCD and engagement in positive daily activities is poorly understood. This project examines the relationship between SCD and self‐reported engagement in these activities.
Method
U.S. POINTER is a phase 3, multicenter, 2‐year randomized controlled trial of two lifestyle interventions varying in intensity and format, conducted in older adults living in the U.S. who do not have objective cognitive impairment at study entry, but have increased risk of cognitive decline and dementia. Participants completed myriad measures at baseline, including the Cognitive Function Inventory (CFI) assessing subjective cognitive decline, and the Community Healthy Activities Model Program for Seniors (CHAMPS) which assesses self‐reported engagement in social, cognitive, and physical activities over the past 4 weeks.
Results
Baseline study characteristics of the current sample (N = 1823) are: Mean age = 68.2y (5.2), 73.5% female, 29.8% with less than 18+ years education, and 29.3% from underrepresented groups (URG). In separate multivariate linear models, CFI was associated with weekly caloric expenditure in exercise (p< .001) and cognitive activity (p <.001), such that CFI scores were higher for participants with lower exercise‐related caloric expenditure and lower cognitive activity levels. Higher CFI scores also tended to predict social activity levels (p = .06). The inverse relationship between CFI and all three variables is significant in women (p = .04; .0001; .05, respectively) but not in men, and the CFI‐cognitive activity relationship is significant for URG (p = .005) but not White participants.
Conclusion
In sum, SCD and engagement in physical, cognitive, and social activities are inversely related to varying degrees, such that individuals who report lower levels of engagement in these activities report more subjective cognitive concerns. However, different patterns emerged for some subgroups. Additional modeling is needed to demonstrate the directionality of the relationships between these activities and CFI, and the relationship with demographic variables of interest.
Background
The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) will determine whether interventions that simultaneously include multiple risk reduction ...strategies can protect cognitive health in older adults. The primary outcome, a global cognitive composite score derived from the POINTER‐Modified Neuropsychological Test Battery (PmNTB), was developed to allow for outcome harmonization with its forerunner, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and other large trials (e.g., A4, EXERT). Here we describe the PmNTB and its initial validation in the baseline U.S. POINTER sample.
Method
U.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two interventions varying in intensity and format, in older adults at increased risk for cognitive decline and dementia. The PmNTB includes performance from 7 cognitive tests and is computed as the mean of three domain‐specific composites: Episodic Memory, Processing Speed, and Executive Function. The Episodic Memory Composite includes Free and Cued Selective Reminding Test, Story Recall, and Visual Paired Associates. The Processing Speed Composite includes Trail Making Test (TMTA) and Digit Symbol Substitution Test. The Executive Function Composite includes Number Span, Word Fluency, and TMTB. PmNTB was assessed in relation to age, clinical status (Clinical Dementia Rating‐CDR), and other cognitive composites able to be computed in the current sample using overlapping measures (i.e., FINGER NTB, Preclinical Alzheimer’s Cognitive Composite‐PACC‐5).
Result
2094 participants completed the baseline assessment (mean age = 68.2±5.2 years; 68.8% female, 69.1% non‐hispanic white, mean MMSE = 28.9± 1.3). Global CDR was 0 for 79.5% of participants, and 0.5 for 20.5% of participants. After adjusting for education, race, ethnicity, and sex, each additional year in age was associated with a drop in PmNTB z‐score by ‐0.064 (95%CI = ‐0.071,‐0.056, p<0.001). Likewise, global CDR = 0.5 (questionable dementia) was associated with a lower PmNTB score (z = ‐0.549) compared with global CDR = 0 (‐0.134 z‐scores). PmNTB correlated with the FINGER NTB (r = 0.858, p<0.001) and the PACC‐5 (r = 0.876, p<0.001).
Conclusion
The PmNTB is a valid measure of cognitive functioning, capturing age‐related cognitive decrements and is associated with clinically relevant, functional outcomes. It also exhibits convergent validity with established cognitive outcomes.
Background
Studies have shown apolipoprotein E (APOE) genotype disclosure to be safe and well tolerated in cognitively unimpaired (CU) older adults. Genotyping can be valuable to modifiable lifestyle ...intervention studies as it provides important Alzheimer’s disease (AD) risk information. As such, the goal of this study is to examine the impact of the disclosure process itself on lifestyle behaviors and decisions about future directives in community‐dwelling CU older adults from the Butler Alzheimer’s Prevention Registry (BAPR).
Method
Cognitively unimpaired APOE ε4 non‐carriers (n= 106) and carriers (n= 80) aged 58‐78 from the BAPR first completed in‐person psychological readiness screening and genotyping followed by APOE disclosure. Follow‐up assessments were completed online 3 days, 6 weeks and 6 months post disclosure. The primary outcomes were scores on self‐reported measures of physical activity, diet, and decisions about future directives.
Result
Post‐disclosure, non‐carriers were more likely to report future directive change towards decisive action on will or estate planning at 3 days follow‐up, healthcare proxy and long‐term living arrangement planning at 6 weeks, and life insurance planning at 6 months. Further, non‐carriers were more likely to report having a long‐term planning discussion with their families at 6 months than carriers. No significant differences were found between non‐carriers and carriers on any of the self‐reported measures of modifiable lifestyle factors (all p> .10).
Conclusion
In a clinical research setting, APOE genotype disclosure has been shown to be safe, well tolerated, and in one study, to increase enrollment in ongoing clinical AD research studies. Disclosure led to more decisive actions on future directives in non‐carriers. Disclosure did not lead to changes in modifiable lifestyle factors, an indication that disclosure alone may not be sufficient to inspire behavioral change. Future work will investigate whether pairing disclosure with education about the role of lifestyle factors in AD risk and providing guidelines on making risk‐lowering lifestyle modifications as an intervention approach engenders positive change.
Background
When and how to communicate effectively the results of genetic and biomarker based prediction, detection, and quantification of the brain substrates of dementia involve important ethical ...and legal issues critical for precision medicine. The urgency of the issue has increased as People Living with Dementia (PLwD) and with Risk for Dementia (PwRD) can access direct to consumer genetic testing, amyloid targeting drugs, and clinical amyloid PET scans. To address the need for effective dissemination and consultation, an advisory group was convened that welcomes all interested members.
Method
Members attend two meetings monthly via phone/computer/WebEx. One meeting is a targeted working group that focuses on the following: 1. Symptomatic (PLwD), 2. Asymptomatic (PwRD), 3. Research, 4. Ethics/Healthcare Law, 5. Trainee/Mentorship. These discussion groups hear from and present to stakeholders (PLwD/PwRD/caregivers, professional organizations, companies) to solicit feedback on the efficacy of their efforts. Members also attend a monthly “all hands” meeting where they receive updates from other groups and hear presentations on emerging research and resources.
Result
The advisory group is composed of 104 members who represent advocacy/stakeholders (21%, e.g. professional organization representatives, (PLwD/PwRD/caregivers, FDA), academia (78%, e.g. university, funders, foundations), and healthcare law (1%). Professions include geneticists, genetic counsellors, researchers, clinicians, ethicists, and lawyers. Motivations for joining include improving communication in research and clinical contexts, mitigating potential negative impacts (e.g.emotional distress or discrimination), and protecting rights to know. Topics have included DTC genomics, the impact of APOE disclosure, genetics and personalized medicine, ecological momentary assessment of response to disclosure, and ethical issues in national and international research registries (EPAD). Activities included a survey on disclosure practices in NIA funded ADCs and collaborations with ADEAR. Stakeholders varied in concerns ranging from a need to protect patients from disclosure to a need to protect the right of access.
Conclusion
Membership is increasing and is engaging diverse specialties and stakeholders who provide education and consultation around communication and use of genetic and biomarkers related to dementia. The group structure and inclusion of members from multiple organizations supports open and free collaboration. Future efforts will be developing structured education for stakeholders and publications.
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