A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling.

After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.

Economic Impact of Progression from Mild Cognitive Impairment to Alzheimer Disease in the United States.

BACKGROUND: Limited evidence exists on the economic burden of individuals who progress from mild cognitive impairment (MCI) to Alzheimer disease and related dementia disorders (ADRD). OBJECTIVES: To assess the all-cause health care resource utilization and costs for individuals who develop ADRD following an MCI diagnosis compared to those with stable MCI. DESIGN: This was a retrospective cohort study from January 01, 2014, to December 31, 2019. SETTING: The Merative MarketScan Commercial and Medicare Databases were used. PARTICIPANTS: Individuals were included if they: (1) were aged 50 years or older; (2) had ≥1 claim with an MCI diagnosis based on the International Classification of Diseases, Ninth Revision (ICD-9) code of 331.83 or the Tenth Revision (ICD-10) code of G31.84; and had continuous enrollment. Individuals were excluded if they had a diagnosis of Parkinson's disease or ADRD or prescription of ADRD medication. MEASUREMENTS: Outcomes included all-cause utilization and costs per patient per year in the first 12 months following MCI diagnosis, in total and by care setting: inpatient admissions, emergency department (ED) visits, outpatient visits, and pharmacy claims. RESULTS: Out of the total of 5185 included individuals, 1962 (37.8%) progressed to ADRD (MCI-to-ADRD subgroup) and 3223 (62.2%) did not (Stable MCI subgroup). Adjusted all-cause utilization was higher for all care settings in the MCI-to-ADRD subgroup compared with the Stable MCI subgroup. Adjusted all-cause mean total costs ($34 599 vs $24 541; mean ratio [MR], 1.41 [95% CI, 1.31-1.51]; P<.001), inpatient costs ($47 463 vs $38 004; MR, 1.25 [95% CI, 1.08-1.44]; P=.002), ED costs ($4875 vs $3863; MR, 1.26 [95% CI, 1.11-1.43]; P<.001), and outpatient costs ($16 652 vs $13 015; MR, 1.28 [95% CI, 1.20-1.37]; P<.001) were all significantly higher for the MCI-to-ADRD subgroup compared with the Stable MCI subgroup. CONCLUSIONS: Individuals who progressed from MCI to ADRD had significantly higher health care costs than individuals with stable MCI. Early identification of MCI and delaying its progression is important to improve patient and economic outcomes.

Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment.

BACKGROUND: Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI. Method Subjects with MCI (n=268) were selected from the 'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease' (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid ß(1-42) protein (Aß42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory. RESULTS: Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aß42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.3] and t-tau (OR 2.6, 95% CI 1.9-3.6) concentrations and with the combination of abnormal concentrations of both Aß42 and t-tau (OR 3.1, 95% CI 2.0-4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aß42 (agitation: OR 1.6, 95% CI 1.1-2.3; irritability: OR 2.2, 95% CI 1.5-3.3). Symptoms of depression and apathy were not related to any of the CSF markers. CONCLUSIONS: In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not.

Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer.

The lifetime risk of breast cancer may approach 80-90% in women who have germline mutations of either of two genes, BRCA1 or BRCA2. A single BRCA1 mutation, 185delAG, has been noted in approximately 20% of Ashkenazi Jewish women with early onset breast cancer and in 0.9% of the Ashkenazi population. We recently detected a 6174delT frameshift mutation in BRCA2 in an hereditary breast cancer kindred of Ashkenazi Jewish ancestry. Here, we investigated the frequency of this mutation in 200 women with early-onset breast cancer. Six of 80 Ashkenazi Jewish women (8%) diagnosed with breast cancer before the age of 42, wer heterozygous for the 6174delT mutation, compared to none of 93 non-Jewish women diagnosed with breast cancer at the same age (P = .005). These cases were ascertained without regard to family history. Two of 27 (7%) additional Jewish families in which the proband was diagnosed with breast cancer at age 42 to 50 and had a family history of breast or ovarian cancer had germline 6174delT mutations. The results of this report suggest that a recurrent mutation of BRCA1 and a recurrent mutation BRCA2 together may account for over a quarter of all early-onset breast cancer in the setting of a personal or family history of ovarian cancer in Ashkenazi Jewish women.

Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC.

Approximately 130,000 cases of colorectal cancer (CRC) are diagnosed in the United States each year, and about 15% of these have a hereditary component. Two well-defined syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), account for up to 5% of the total new cases of CRC. Truncating APC mutations are responsible for FAP, and defective mismatch repair genes cause HNPCC. However, the genes responsible for most of the familial cases are unknown. Here we report a mutation (T to A at APC nucleotide 3920) found in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of CRC. Rather than altering the function of the encoded protein, this mutation creates a small hypermutable region of the gene, indirectly causing cancer predisposition.

Alzheimer disease: from biomarkers to diagnosis.

The discovery of biomarkers, considered as surrogate markers of the underlying pathological changes, led an international work group (IWG) to propose a new conceptual framework for AD in 2007 Dubois et al. (2007). According to the IWG, AD is now defined as a dual clinico-biological entity that can be recognized in vivo, prior to the onset of the dementia syndrome, on the basis of: i) a specific core clinical phenotype comprised of an amnestic syndrome of the hippocampal type and ii) supportive evidence from biomarkers reflecting the location or the nature of Alzheimer-type changes. Therefore, AD is diagnosed with the same criteria throughout all symptomatic phases of the disease based on the biologically-based approach to diagnosis independent of clinical expression of disease severity. The definitions were further clarified in 2010 (Dubois et al., 2010). Although the new criteria are proposed for research purposes, we encourage expert centres with adequate resources to begin to use the proposed algorithm in order to move the field forward and facilitate translation into clinical practice.

Body size and dispersal mode as key traits determining metacommunity structure of aquatic organisms.

Relationships between traits of organisms and the structure of their metacommunities have so far mainly been explored with meta-analyses. We compared metacommunities of a wide variety of aquatic organism groups (12 groups, ranging from bacteria to fish) in the same set of 99 ponds to minimise biases inherent to meta-analyses. In the category of passive dispersers, large-bodied groups showed stronger spatial patterning than small-bodied groups suggesting an increasing impact of dispersal limitation with increasing body size. Metacommunities of organisms with the ability to fly (i.e. insect groups) showed a weaker imprint of dispersal limitation than passive dispersers with similar body size. In contrast, dispersal movements of vertebrate groups (fish and amphibians) seemed to be mainly confined to local connectivity patterns. Our results reveal that body size and dispersal mode are important drivers of metacommunity structure and these traits should therefore be considered when developing a predictive framework for metacommunity dynamics.

Subjective memory complaints in community dwelling healthy older people: the influence of brain and psychopathology.

OBJECTIVES: Subjective memory complaints (SMC) are common. We aimed to characterize the relationship between psychiatric illness and white matter disease to SMC in a sample of healthy older people. MEASUREMENTS: Cognitively normal subjects between 55 and 90 years had age-adjusted and education-adjusted Consortium to Establish a Registry for Alzheimer's disease (CERAD) scores ≤1.5 SD from standard mean. ApoE genotyping was performed using polymerase chain reaction. Sixty subjects (30 SMC, 30 controls) underwent 3T MRI, which was rated by two raters blinded to the diagnosis, for periventricular (PVH) and deep white matter hyperintensities (DWMH) using the Fazekas scale. Subjective memory was assessed by asking the participant, Do you feel like your memory or thinking is becoming worse? RESULTS: Two hundred and fifteen volunteers were assessed. Ninety-six were cognitively normal (mean age 62.5 years). SMC were reported by 52/96 subjects (54%). These were compared with subjects who denied SMC. Participants with a history of depression or anxiety were more likely to have SMC (p = 0.02). The frequency distribution of ApoE4 allele and CERAD scores were similar. White matter load was similar (p ≤ 0.47), with a high prevalence of PVH and DWMH seen (100% and 88% of scans, respectively). CONCLUSION: Both SMC and white matter disease were common. SMC were associated with a history of depression or anxiety but not with white matter disease. Evaluation for a history of depression and anxiety in people with SMC is supported by these findings.

Longitudinal changes of fractional anisotropy in Alzheimer's disease patients treated with galantamine: a 12-month randomized, placebo-controlled, double-blinded study.

Diffusion tensor imaging (DTI) demonstrates decline of fractional anisotropy (FA) as a marker of fiber tract integrity in Alzheimer's disease (AD). We aimed to assess the longitudinal course of white matter microstructural changes in AD and healthy elderly control (HC) subjects and to evaluate the effects of treatment with the cholinesterase inhibitor galantamine on white matter microstructure in AD patients. We enrolled 28 AD patients and 11 healthy elderly control subjects (HC). AD patients were randomly assigned to 6-month double-blind galantamine treatment or placebo, with a 6-month open-label extension phase. DTI was performed at baseline, as well as at 6 and 12-month follow-up in AD patients. The HC subjects underwent DTI at baseline and 12-month follow-up without treatment. We measured FA in regions of interest covering the posterior cingulate and corpus callosum. At 6-month follow-up, the AD group showed significant FA decline in the left posterior cingulate. FA decline was significantly preserved in the posterior body of the corpus callosum in AD group with treatment compared to placebo. At 12-month follow-up, the AD patients showed no differences in FA decline between initial treatment and placebo groups after the 6-month open-label extension phase. A significant FA decline occurred in the left posterior cingulate across the AD and HC groups without between-group differences. DTI demonstrated FA decline in intracortically projecting fiber tracts in aging and AD over 1 year. Galantamine had limited impact on regional FA decline, which was not preserved after additional 6-month open-label treatment.

[Structural and functional neuronal connectivity in Alzheimer's disease: a combined DTI and fMRI study]. / Strukturelle und funktionelle neuronale Konnektivität bei der Alzheimer-Krankheit : Eine kombinierte DTI- und fMRT-Studie.

BACKGROUND: Cognitive performance depends on intact cortical connectivity. Important for memory processing in the human brain is the connection between posterior cingulate cortex and hippocampus, directly as well as indirectly via the parahippocampal gyrus. These brain areas are involved early in Alzheimer's disease (AD). At the same time, they belong to the default mode network (DMN), a functional network showing high functional connectivity under resting state conditions. In AD, this connectivity in specifically compromised, offering the possibility to investigate the structural basis of functional brain connectivity. METHODS: We studied 18 patients with mild to moderate AD, 16 patients with mild cognitive impairment (MCI) and 20 healthy control subjects using diffusion tensor imaging (DTI) and resting state fMRI at 3.0 Tesla. We determined the effect of structural integrity in the posterior cingulate as assessed by DTI on the functional connectivity between posterior cingulate, hippocampus and parahippocampus during resting state in these three groups. RESULTS: Structural integrity was reduced in posterior cingulate fibre tracts in patients with AD in the left hemisphere; however, this effect was partly accounted for by age differences. All three groups showed high functional connectivity between posterior cingulate cortex and hippocampus, via both the direct and the indirect pathways. Determination of effective connectivity yielded a negative fractional anisotropy (FA)-moderated correlation on the direct pathway in AD and MCI for both hemispheres, and in healthy controls for the right hemisphere. The indirect pathway showed a negative FA-moderated correlation in AD for the right hemisphere and in MCI for both hemispheres. Healthy controls showed a positive correlation on the indirect pathway for the left hemisphere. CONCLUSION: Our data suggest that under healthy conditions, effective connectivity in the DMN between posterior cingulate cortex and hippocampus is mainly maintained by the indirect pathway via the parahippocampal gyrus. Patients with AD and patients with MCI show changes in this connectivity with a partial allocation to the direct pathway, most likely reflecting early parahippocampal lesions. The combination of DTI and fMRI broadens our understanding of human brain connectivity and its pathological changes with AD.

Age, Sex, Hypertension and HDL-C Alter Serum BACE1 Activity in Cognitively Normal Subjects: Implications for Alzheimer's Disease.

BACKGROUND: Increasing evidence indicates that ß-secretase 1 (BACE1) activity and concentration in blood are candidate biomarkers for Alzheimer's disease (AD). Investigating potential demographic, biological, and clinical determinants of BACE1 in the blood matrix is the critical step to validate and qualify BACE1 bio-indicators for different contexts-of-use (CoU), such as risk assessment, early detection, diagnosis, prognosis, management of AD, and outcome of amyloid pathway targeted drugs. OBJECTIVES: To evaluate the influence of age, sex, HDL-cholesterol and comorbidities (cardiovascular diseases, hypertension, diabetes) on circulating BACE-1 activity. DESIGN: prospective analysis of serum samples, clinical, biological, and demographic variables. SETTING: Three cohorts: 1) Memory Clinic of the Department of Internal Medicine, S. Anna University Hospital, Ferrara (Italy); 2) outpatients attending the Menopause and Osteoporosis Centre (MOC) of the University of Ferrara (Ferrara, Italy); 3) Prevention Center of the University of Ferrara. PARTICIPANTS: 504 cognitively healthy individuals (median age: 62 years, interquartile range: 51-73) and 175 patients with AD (78 years, 74-82). MEASUREMENTS: serum BACE1 (sBACE1), age, sex, HDL-cholesterol, major comorbidities. RESULTS: Age was the strongest independent predictor of sBACE1 variance (ß=0.425, p<0.0001), followed by sex (ß=0.180, p<0.0001), high density lipoprotein-cholesterol (HDL-C) (ß=-0.168, p<0.0001) and hypertension (ß=0.111, p<0.05) (overall model, R2: 0.232). The probability of having elevated sBACE1 activity increased after 70 years of age, with women being more susceptible to higher sBACE1 activity than men. CONCLUSIONS: We provide evidence about potential clinical and biological determinants of sBACE1 activity with a strong association among biomarker, female sex, and older age.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study.

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

Regional differences in effects of APOE ε4 on cognitive impairment in non-demented subjects.

BACKGROUND: The APOE ε4 allele is a risk factor for Alzheimer's disease (AD). APOE ε4 is common in non-demented subjects with cognitive impairment. In both healthy people and people with AD, its prevalence has a north-south gradient across Europe. In the present study, we investigated whether the relation between the APOE ε4 allele and cognitive impairment varied across Northern, Middle and Southern Europe. We also investigated whether a north-south gradient existed in subjects with subjective cognitive impairment (SCI), amnestic mild cognitive impairment (MCI) and non-amnestic MCI. METHODS: Data from 16 centers across Europe were analyzed. RESULTS: A north-south gradient in APOE ε4 prevalence existed in the total sample (62.7% for APOE ε4 carriers in the northern region, 42.1% in the middle region, and 31.5% in the southern region) and in subjects with SCI and amnestic MCI separately. Only in Middle Europe was the APOE ε4 allele significantly associated with poor performance on tests of delayed recall and learning, as well as with the amnestic subtype of MCI. CONCLUSION: The APOE ε4 allele frequencies in subjects with SCI and amnestic MCI have a north-south gradient. The relation between the APOE ε4 allele and cognition is region dependent.

Effects of aging on default mode network activity in resting state fMRI: does the method of analysis matter?

UNLABELLED: Functional MRI (fMRI) of default mode network (DMN) brain activity during resting state is gaining attention as a potential non-invasive biomarker to diagnose incipient Alzheimer's disease. The aim of this study was to identify effects of normal aging on the DMN using different methods of fMRI processing and evaluation. METHODS: fMRI was acquired in 17 young and 21 old healthy subjects and the data were analyzed with (a) volumes of interest (VOI)-based signal time course and (b) independent component analyses (ICA). In the first approach, the strength of DMN region inter-connectivity (as expressed with correlation coefficients) was of primary interest, the second method provided a measure of the magnitude of DMN co-activation. RESULTS: The older subjects exhibited significantly lower DMN activity in the posterior cingulate (PCC, t-test P<.001) as well as a tendency to lower activity in all other DMN regions in comparison to the younger subjects. We found no significant effect of age on DMN inter-connectivity. CONCLUSION: Effects of normal aging such as loss of PCC co-activity could be detected by ICA, but not by signal time course correlation analyses of DMN inter-connectivity. This either indicates lower sensitivity of inter-connectivity measures to detect subtle DMN changes or indicate that ICA and time course analyses determine different properties of DMN co-activation. Our results, therefore, provide fundamental knowledge for a potential future use of functional MRI as biomarker for neurodegenerative dementias where diminished DMN activity needs to be reliably differentiated from that observed in health aging.

A novel MRI-biomarker candidate for Alzheimer's disease composed of regional brain volume and perfusion variables.

BACKGROUND: Earlier evidence indicates that regional cerebral volume (rVOL) and blood flow (rCBF) variables carry independent information on incipient and early Alzheimer's disease (AD) and combining these modalities may increase discriminant performance. We compared single variables and combinations regarding their power for optimizing diagnostic accuracy. METHODS: Twelve cognitively normal elderly controls (CN), 30 subjects with mild cognitive impairment (MCI) and 15 with mild AD were examined by structural and perfusion-weighted magnetic resonance imaging (MRI) in single sessions at 1.5 Tesla. rVOLs were measured by manual volumetry, and rCBFs were calculated with a ROI-based co-localization technique. RESULTS: Applying single MRI variables for the differentiation of AD versus CN, the area under curve (AUC) of receiver operating characteristic curves (ROCCs) was highest for rVOL variables (maximum of 0.972 for right amygdala). A composite marker selected and weighted by logistic regression containing left amygdalar rCBF, left hippocampal and right amygdalar rVOLs gave a diagnostic accuracy for AD versus CN of 100%. Internal cross-validation revealed a reliability of 88.9%. CONCLUSIONS: Whilst external revalidation is mandatory employing a naturalistic sample containing disease controls, our phase I/II findings demonstrate that deducing composite markers from multimodal MRI acquisitions can optimize diagnostic accuracy for AD.

Amygdala reduction in patients with ADHD compared with major depression and healthy volunteers.

OBJECTIVE: Results in adult attention deficit hyperactivity disorder (ADHD) on structural brain changes and the clinical relevance are contradictory. The aim of this study was to investigate whether in adult patients with ADHD hippocampal or amygdala volumes differs from that in healthy controls and patients with major depression (MD). METHOD: Twenty patients with ADHD, 20 matched patients with MD and 20 healthy controls were studied with high resolution magnetic resonance imaging. RESULTS: Amygdala volumes in patients with ADHD were bilaterally smaller than in patients with MD and healthy controls. In ADHD, more hyperactivity and less inattention were associated with smaller right amygdala volumes, and more symptoms of depression with larger amygdala volumes. CONCLUSION: This study supports findings that the amygdala plays an important role in the systemic brain pathophysiology of ADHD. Whether patients with ADHD and larger amygdala volumes are more vulnerable to affective disorders needs further investigation.

The Sars-Cov-2 Pandemic and the Brave New Digital World of Environmental Enrichment to Prevent Brain Aging and Cognitive Decline.

Individuals experiencing brain aging, cognitive decline, and dementia are currently confronted with several more complex challenges due to the current Sars-Cov-2 pandemic as compared to younger and cognitively healthy people. During the first six months of the pandemic, we are experiencing critical issues related to the management of mild cognitive impairment (MCI) and dementia. The evolving, highly contagious global viral spread has created a pressure test of unprecedented proportions for the existing brain health care infrastructure and related services for management, diagnosis, treatment, and prevention. Social distancing and lock-down measures are catalyzing and accelerating a technological paradigm shift, away from a traditional model of brain healthcare focused on late symptomatic disease stages and towards optimized preventive strategies to slow brain aging and increase resilience at preclinical asymptomatic stages. Digital technologies transform global healthcare for accessible equality of opportunities in order to generate better outcomes for brain aging aligned with the paradigm of preventive medicine.

Early Detection of Mild Cognitive Impairment (MCI) in Primary Care.

Mild cognitive impairment (MCI) is significantly misdiagnosed in the primary care setting due to multi-dimensional frictions and barriers associated with evaluating individuals' cognitive performance. To move toward large-scale cognitive screening, a global panel of clinicians and cognitive neuroscientists convened to elaborate on current challenges that hamper widespread cognitive performance assessment. This report summarizes a conceptual framework and provides guidance to clinical researchers and test developers and suppliers to inform ongoing refinement of cognitive evaluation. This perspective builds upon a previous article in this series, which outlined the rationale for and potentially against efforts to promote widespread detection of MCI. This working group acknowledges that cognitive screening by default is not recommended and proposes large-scale evaluation of individuals with a concern or interest in their cognitive performance. Such a strategy can increase the likelihood to timely and effective identification and management of MCI. The rising global incidence of AD demands innovation that will help alleviate the burden to healthcare systems when coupled with the potentially near-term approval of disease-modifying therapies. Additionally, we argue that adequate infrastructure, equipment, and resources urgently should be integrated in the primary care setting to optimize the patient journey and accommodate widespread cognitive evaluation.

Early Detection of Mild Cognitive Impairment (MCI) in an At-Home Setting.

Emerging digital tools have the potential to enable a new generation of qualitative and quantitative assessment of cognitive performance. Moreover, the ubiquity of consumer electronics, such as smartphones and tablets, can be harnessed to support large-scale self-assessed cognitive screening with benefit to healthcare systems and consumers. A wide variety of apps, wearables, and new digital technologies are either available or in development for the detection of mild cognitive impairment (MCI), a risk factor for dementia. Two categories of novel methodologies may be considered: passive technologies (which monitor a user's behavior without active user input) and interactive assessments (which require active user input). Such examinations can be self-administered, supervised by a caregiver, or conducted by an informant at home or outside of a clinical setting. These direct-to-consumer tools have the potential to sidestep barriers associated with cognitive evaluation in primary care, thus improving access to cognitive assessments. Although direct-to-consumer cognitive assessment is associated with its own barriers, including test validation, user experience, and technological concerns, it is conceivable that these issues can be addressed so that a large-scale, self-assessed cognitive evaluation that would represent an initial cognitive screen may be feasible in the future.