Predicting Alzheimer's disease

This is another long post with studies utilizing diverse methodologies. First, Frei et al. (2022) published “Can You Find It? Novel oddity detection task for the early detection of Alzheimer’s disease” in Neuropsychology. The edited abstract and impact statements follow:

We aimed to develop a measure to specifically assess the functioning of the perirhinal cortex (PRC), a brain structure affected very early in Alzheimer’s disease (AD) pathology. In this novel task, participants were shown arrays of six complex figures and had to identify the “odd-one.” The pilot study included 50 normal controls (NCs) and 50 patients in very early stages of AD. Participants completed the task and received MRI scanning. Best differentiating items were determined and applied in a validation study including 25 NCs, 27 early-stage AD patients, and 26 patients with major depression. Logistic regression models investigated if task performance predicted group membership. Task performance was then related to whole-brain gray matter integrity. As proof of concept, cortical thickness values of four regions of interest (ROIs; e.g., medial PRC and entorhinal cortex [ERC]) were compared between the groups. The associations of task performance and cortical thickness of the ROIs were investigated using linear models. Task performance showed good discriminative ability between early-stage AD patients and NCs. Whole-brain analyses revealed four significant clusters (p < .001) with peak voxels in parahippocampal regions including PRC and ERC. ROI analyses showed distinctly reduced cortical thickness in the AD group compared to both other groups in the medial PRC and ERC (p ≤ .001). Task performance modeled by ROI cortical thickness did not achieve significant results. AD patients showed distinct lower performance in the discrimination task compared to healthy adults and task performance was associated with gray matter integrity in areas including the perirhinal and entorhinal cortex. It supports the use of functional and structural measures of the perirhinal and entorhinal cortex for the early detection of AD and its differentiation from other etiologies of cognitive impairment. Further validation of this task, especially with age-matched participant groups, could contribute to refining the detection of early-stage AD and expand opportunities for targeted therapeutic intervention.

I presented this one first because it has the most expensive methodology but seems promising if the oddity detection methodology works in further studies. Next, Forno et al. (2023) published “The ‘When’ Matters: Evidence from memory markers in the clinical continuum of Alzheimer’s disease” in Neuropsychology. 

Cognitive assessment able to detect impairments in the early neuropathological stages of Alzheimer’s disease (AD) is urgently needed. The visual short-term memory binding task (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT) have been recommended by the neurodegenerative disease working group as promising tests to aid in the early detection of AD. One hundred and seventeen older adults with subjective cognitive complaint (SCC), 79 with mild cognitive impairment (MCI), 31 patients with AD dementia (ADD), and 37 cognitively unimpaired (CU) subjects, underwent assessment with the VSTMBT and the picture version of the Spanish FCSRT. After controlling for multiple comparisons, significant differences were found across groups. The VSTMBT was the only test that “marginally” differentiated between CU and SCC (d = 0.47, p = .052). Moreover, whereas the FCSRT showed a gradient (CU = SCC) > MCI > ADD, the VSTMBT gradient was CU > SCC > (MCI = ADD) suggesting that conjunctive binding deficits assessed by the latter may be sensitive to the very early stages of the disease. Our results suggest that the VSTMBT and the FCSRT are sensitive to the clinical continuum of AD. Whereas the former detects changes in the early prodromal stages, the latter is more sensitive to the advanced prodromal stages of AD. These novel tests can aid in the early detection, monitor disease progression and response to treatment, and thus support drug development programs. Are the VSTMBT and the FCSRT sensitive to the earliest cognitive impairments observed in the AD continuum? While the VSTMBT is sensitive to the early prodromal stages, the FCSRT is sensitive to the advanced prodromal stages. These findings are relevant for the stratification of the clinical stages of AD using cognitive assessment tools. 

I like this comparison of measures that seem readily available and potentially useful. The next study uses a different approach to memory in Alzheimer’s disease. Rami et al. (2023) published “Design and Validation of the 1-Week Memory Battery for Assessing Episodic Memory and Accelerated Long-term Forgetting in Cognitively Unimpaired Subjects” in Neuropsychology.  Here’s edited information:

Subtle decline in memory is thought to arise in the preclinical phase of Alzheimer’s disease (AD). However, detecting these initial cognitive difficulties cross-sectionally has been challenging, and the exact nature of the decline is still debated. Accelerated long-term forgetting (ALF) has been recently suggested as one of the earliest and most sensitive indicators of memory dysfunction in subjects at risk of developing AD. The objective of this study was to design and validate the 1-week memory battery (1WMB) for assessing episodic memory and ALF in cognitively unimpaired individuals. The 1WMB is unique in that it assesses multimodal memory and measures recall at both short delay (20 min) and at long term (1 week). Forty-five cognitively unimpaired subjects were assessed with 1WMB and standardized neuropsychological tests. Subjective cognitive decline (SCD), levels of anxiety and depression, and cognitive reserve were also measured. The tests of 1WMB showed a high internal consistency, and concurrent validity was observed with standard tests of episodic memory and executive functions. The analysis revealed a greater loss of information at 1 week compared to short-term forgetting (20 min). Performance in the 1WMB was affected by age and educational level, but was not associated with levels of anxiety and depression. Unlike standard tests, performance in the 1WMB correlated with measures of SCD. Our findings indicate that the 1WMB has good psychometric properties, and future studies are needed to explore its potential usefulness to assess cognitively unimpaired subjects at increased risk of developing AD. 

Can we validate the 1-week memory battery (1WMB) as a comprehensive assessment to explore accelerated long-term forgetting (ALF)? The 1WMB has good psychometric properties. Performance was not associated with levels of anxiety and depression while it was correlated with measures of subjective cognitive decline (SCD). The identification and monitoring of the first cognitive manifestations within the Alzheimer’s continuum is critical for developing secondary prevention trials and allowing earlier interventions. Further research will determine whether the 1WMB will be a useful tool for the early detection of subtle cognitive dysfunction within the Alzheimer’s continuum. 

Since the last two studies look at memory, here’s one using a different approach. Reeves, Williams, Blacker & Woods (2022) published “Further Evaluation of Narrative Description as a Measure of Cognitive Function in Alzheimer’s Disease” in Neuropsychology.  Here’s an edited summary:

The narrative description (ND) test objectively measures the ability to understand and describe visual scenes. As subtle differences in speech occur early in cognitive decline, we analyzed linguistic features for their utility in detecting cognitive impairment and predicting downstream decline. Participants (n = 52) with normal cognition to mild dementia performed the ND test (watched twenty 30-s video clips and described the visual content). Cognitive function was followed for up to 5 years. We computed simple linguistic features such as content efficiency, speech rate, and part of speech and unique word counts. We examined (a) relationships between cognitive status and ND score and linguistic features; (b) ability to discriminate early cognitive impairment from normal cognition using ND score and linguistic features; and (c) whether ND score and linguistic features were associated with future cognitive functional decline. Many of the linguistic-feature metrics were related to cognitive status. Many of the linguistic features could distinguish between the cognitively normal group and the mild cognitive impairment (MCI) and Dementia groups. The area under the curve (AUC) for ND score alone was 0.74, with a nonsignificant increase to 0.78 when adding mean word length. Among participants with subjective cognitive decline (SCD) at the first visit, a smaller number of words plus more interjections or a lower ND score at baseline were predictive of future cognitive decline. While many linguistic features were associated with cognitive status, and some were able to detect early cognitive impairment or predictive of future cognitive decline, all the features we tested seem to have been captured by the ND score. Thus, adding linguistic measures to the ND test score did not add to its value in assessing current or predicting future cognitive status. 

Can we improve the narrative description test by adding detailed linguistic information? Most linguistic features were related to cognitive status, but did not substantially improve the discriminability of the narrative description test in detecting early mild cognitive impairment. There was preliminary evidence that the narrative description test might be predictive of future decline in cognitive function in people with early cognitive impairment. Further studies are needed to further develop the narrative description test to determine whether it could be employed remotely for frequent in-home testing. 

I like this one because it helps eliminate unnecessary measures. The final study is another one that is helpful because of what they didn’t find. Schaffert, Chiang, Fatima, LoBue, Hart & Cullum (2023) published “History of Traumatic Brain Injury Does Not Alter Course of Neurocognitive Decline in Older Adults With and Without Cognitive Impairment” in Neuropsychology.  

Traumatic brain injury (TBI) history is associated with dementia risk, but it is unclear whether TBI history significantly hastens neurocognitive decline in older adults. Data were derived from the National Alzheimer’s Coordinating Center (NACC) data set. Participants with a history of TBI (TBI +; n = 1,467) were matched to individuals without a history of TBI (TBI−; n = 1,467) based on age (50–97, M = 71.61, SD = 8.40), sex, education, race, ethnicity, cognitive diagnosis, functional decline, number of Apolipoprotein ε4 (APOE ε4) alleles, and number of annual visits (3–6). Longitudinal neuropsychological functioning did not differ between TBI groups. There was a significant three-way interaction (age, TBI history, time) in language and memory performance, but post hoc analyses revealed TBI history was not driving this relationship. We sought to answer whether a history of traumatic brain injury (TBI) accelerated cognitive decline later-in-life in those with and without cognitive impairment (i.e., mild cognitive impairment or dementia). Our findings did not suggest that a history of TBI altered the course of neurocognitive functioning over approximately 6 years, and it did not appear to significantly interact with demographics (age, sex, education, race), Apolipoprotein ε4 status or cognitive diagnosis to increase risk in these subgroups. Overall, we conclude that a history of TBI does not appear to alter the course of neurocognitive functioning later-in-life, and this does not appear to be the mechanism in which TBI may increase risk of dementia for some individuals. As a field, we need longitudinal neurocognitive and biomarker studies with well-characterized head injury data to clarify the mechanism in which TBI may increase dementia risk. 

I like studies that admit what doesn’t predict behavior. Taken together, these studies suggest measurement strategies for those who are attempting to help patients and their families.