Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities.

Spatial navigation is emerging as a critical factor in identifying preclinical Alzheimer’s disease (AD). However, the impact of interindividual navigation ability and demographic risk factors (e.g., APOE, age, and sex) on spatial navigation make it difficult to identify persons “at high risk” of AD in the preclinical stages. In the current study, we use spatial navigation big data (n = 27,108) from the Sea Hero Quest (SHQ) game to overcome these challenges by investigating whether big data can be used to benchmark a highly phenotyped healthy aging laboratory cohort into high- vs. low-risk persons based on their genetic (APOE) and demographic (sex, age, and educational attainment) risk factors. Our results replicate previous findings in APOE ε4 carriers, indicative of grid cell coding errors in the entorhinal cortex, the initial brain region affected by AD pathophysiology. We also show that although baseline navigation ability differs between men and women, sex does not interact with the APOE genotype to influence the manifestation of AD-related spatial disturbance. Most importantly, we demonstrate that such high-risk preclinical cases can be reliably distinguished from low-risk participants using big-data spatial navigation benchmarks. By contrast, participants were undistinguishable on neuropsychological episodic memory tests. Taken together, we present evidence to suggest that, in the future, SHQ normative benchmark data can be used to more accurately classify spatial impairments in at-high-risk of AD healthy participants at a more individual level, therefore providing the steppingstone for individualized diagnostics and outcome measures of cognitive symptoms in preclinical AD.

We propose that boredom, a state associated with a sense of meaninglessness, leads to a psychological search for meaning in life, which in turn elevates affirmation of heroes. This hypothesis builds on the notion that heroes function, in part, as sources of meaning in life.Using a correlational model, we found that boredom proneness predicted more positive perceptions of heroes via searches for meaning in one's own life. In addition, hero perceptions seemed to prevent boredom by offering a sense of meaning in life. These findings contribute to an understanding of the psychologically existential qualities of boredom and functions of heroes. The results are consistent with the assumption that boredom triggers the existential process of searching for meaning in life. It is this search that influences perceptions of heroes as vehicles for a sense of meaning in life. Our data suggest that heroes grant a sense of meaningfulness, and in so doing, may serve as a tool to counteract the lack of meaning signaled by boredom. These findings implicate novel avenues for future research on boredom and on heroes, and more precisely, they shed light on perception and affirmations of heroes as part of existential self-regulatory processes.

Objective With the rising burden of dementia globally, there is a need to harmonize dementia research across diverse populations. The Addenbrooke’s Cognitive Examination-III (ACE-III) is a well-established cognitive screening tool to diagnose dementia. But there have been few efforts to standardize the use of ACE-III across cohorts speaking different languages. The present study aimed to standardize and validate ACE-III across seven Indian languages and to assess the diagnostic accuracy of the test to detect dementia and mild cognitive impairment (MCI) in the context of language heterogeneity. Methods The original ACE-III was adapted to Indian languages: Hindi, Telugu, Kannada, Malayalam, Urdu, Tamil, and Indian English by a multidisciplinary expert group. The ACE-III was standardized for use across all seven languages. In total, 757 controls, 242 dementia, and 204 MCI patients were recruited across five cities in India for the validation study. Psychometric properties of adapted versions were examined and their sensitivity and specificity were established. Results The sensitivity and specificity of ACE-III in identifying dementia ranged from 0.90 to 1, sensitivity for MCI ranged from 0.86 to 1, and specificity from 0.83 to 0.93. Education but not language was found to have an independent effect on ACE-III scores. Optimum cut-off scores were established separately for low education (≤10 years of education) and high education (>10 years of education) groups. Conclusions The adapted versions of ACE-III have been standardized and validated for use across seven Indian languages, with high diagnostic accuracy in identifying dementia and MCI in a linguistically diverse context.

Research suggests that tests of memory fidelity, feature binding and spatial navigation are promising for early detection of subtle behavioural changes related to Alzheimer’s disease. In the absence of longitudinal data, one way of testing the early detection potential of cognitive tasks is through the comparison of individuals at different genetic risk for Alzheimer’s dementia. Most studies have done so using samples aged 70 years or older. Here, we tested whether memory fidelity of long-term object-location binding may be a sensitive marker even among cognitively healthy individuals in their mid-60s by comparing participants at low and higher risk based on presence of the ε4-allele of the apolipoprotein gene (n = 26 ε3ε3, n = 20 ε3ε4 carriers). We used a continuous report paradigm in a visual memory task that required participants to recreate the spatial position of objects in a scene. We employed mixture modelling to estimate the two distinct memory processes that underpin the trial-by-trial variation in localization errors: retrieval success which indexes the proportion of trials where participants recalled any information about an object’s position and the precision with which participants retrieved this information. Prior work has shown that these memory paradigms that separate retrieval success from precision are capable of detecting subtle differences in mnemonic fidelity even when retrieval success could not. Nonetheless, Bayesian analyses found good evidence that ε3ε4 carriers did not remember fewer object locations [F(1, 42) = 0.450, P = 0.506, BF01 = 3.02], nor was their precision for the spatial position of objects reduced compared to ε3ε3 carriers [F(1, 42) = 0.12, P = 0.726, BF01 = 3.19]. Because the participants in the sample presented here were a subset of a study on apolipoprotein ε4-carrier status and spatial navigation in the Sea Hero Quest game [Coughlan et al., 2019. PNAS, 116(9)], we obtained these data to contrast genetic effects on the two tasks within the same sample (n = 33). Despite the smaller sample size, wayfinding deficits among ε3ε4 carriers could be replicated [F(1, 33) = 5.60, P = 0.024, BF10 = 3.44]. Object-location memory metrics and spatial navigation scores were not correlated (all r < 0.25, P > 0.1, 0 < BF10 < 3). These findings show spared object-location binding in the presence of a detrimental apolipoprotein ε4 effect on spatial navigation. This suggests that the sensitivity of memory fidelity and binding tasks may not extend to individuals with one ε4-allele in their early to mid-60s. The results provide further support to prior proposals that spatial navigation may be a sensitive marker for the earliest cognitive changes in Alzheimer’s disease, even before episodic memory.

Spatial orientation is emerging as an early and reliable cognitive biomarker of Alzheimer’s disease (AD) pathophysiology. However, no evidence exists as to whether spatial orientation is also affected in vascular dementia (VaD).Objective: To examine allocentric (map-based) and egocentric (viewpoint-based) spatial orientation in an early stage VaD case.Methods: A spatial test battery was administered following clinical and neuropsychological cognitive evaluation.Results: Despite the patient’s complaints, little evidence of episodic memory deficits were detected when cueing was provided to overcome executive dysfunction. Similarly, medial temporal lobe-mediated allocentric orientation was intact. By contrast, medial parietal-mediated egocentric orientation was impaired, despite normal performance on standard visuospatial tasks.Conclusion: To our knowledge, this is the first in-depth investigation of spatial orientation deficits in VaD. Isolated egocentric deficits were observed. This differs from AD orientation deficits which encompass both allocentric and egocentric orientation deficits. A combination of egocentric orientation and executive function tests could serve as a promising cognitive marker for VaD pathophysiology.

Research suggests that tests of memory fidelity, feature binding and spatial navigation are promising for early detection of subtle behavioural changes related to Alzheimer’s disease (AD). In the absence of longitudinal data, one way of testing the early detection potential of cognitive tasks is through the comparison of individuals at different genetic risk for AD. Most studies have done so using samples aged 70 years or older. Here, we tested whether memory fidelity of long-term object-location binding may be a sensitive marker even among cognitively healthy individuals in their mid-60s by comparing participants at low and higher risk based on presence of the ε4-allele of the apolipoprotein gene (n=26 ε3ε3 and n=20 ε3ε4 carriers). We used a continuous report paradigm in a visual memory task that required participants to recreate the spatial position of objects in a scene. We employed mixture modelling to estimate the two distinct memory processes that underpin the trial-by-trial variation in localisation errors: retrieval success which indexes the proportion of trials where participants recalled any information about an object’s position and the precision with which participants retrieved this information. Prior work has shown that these memory paradigms that separate retrieval success from precision are capable of detecting subtle differences in mnemonic fidelity even when retrieval success could not. Nonetheless, a Bayesian analysis found good evidence that ε3ε4 carriers did not remember fewer object locations (F(1, 42)=.450, p=.506, BF01=3.02), nor was their precision for the spatial position of objects reduced compared to ε3ε3 carriers (F(1, 42)=.12, p=.726, BF01=3.19). Importantly, ε3ε4-carriers from the same sample have previously been reported to exhibit wayfinding deficits in a spatial navigation task (Coughlan et al. 2019, PNAS, 116(19)). The sensitivity of memory fidelity tasks may therefore not extend to individuals with one ε4-allele in their early to mid-60s. These results provide further support to prior proposals that spatial navigation may be a sensitive marker for the earliest AD-dependent cognitive changes, even before episodic memory. More research in preclinical AD is needed to confirm this hypothesis by direct comparison of memory fidelity and spatial navigation tasks.

The Virtual Supermarket Task (VST) and Sea Hero Quest detect high-genetic-risk Alzheimer's disease (AD). We aimed to determine their test-retest reliability in a preclinical AD population. Over two time points, separated by an 18-month period, 59 cognitively healthy individuals underwent a neuropsychological and spatial navigation assessment. At baseline, participants were classified as low-genetic-risk of AD or high-genetic-risk of AD. We calculated two-way mixed effects intraclass correlation coefficients (ICC) for task parameters and used repeated measures ANOVAS to determine whether genetic risk or sex contributed to test-retest variability. The egocentric parameter of the VST measure showed the highest test-retest reliability (ICC = .72), followed by the SHQ distance travelled parameter (ICC = .50). Post hoc longitudinal analysis showed that boundary-based navigation predicts worsening episodic memory concerns in high-risk (F = 5.01, P = 0.03), but in not low-risk, AD candidates. The VST and the Sea Hero Quest produced parameters with acceptable testretest reliability. Further research in larger sample sizes is desirable.