Apolipoprotein E Genetic Testing in a New Age of Alzheimer Disease Clinical Practice.

The recent FDA approval of amyloid-lowering drugs is changing the landscape of Alzheimer disease (AD) clinical practice. Previously, apolipoprotein E (APOE) genetic testing was not recommended in the care of people with AD because of limited clinical utility. With the advent of amyloid-lowering drugs, APOE genotype will play an important role in guiding treatment recommendations. Recent clinical trials have reported strong associations between APOE genotype and the safety and possibly the efficacy of amyloid-lowering drugs. Therefore, a clinical workflow that includes biomarker and genetic testing should be implemented to provide patients with the opportunity to make informed decisions and instruct safety monitoring for clinicians. Pretest consent, education, and counseling will be an essential aspect of this process for patients and their family members to understand the implications of these tests and their results. Given that the approved amyloid-lowering drugs are indicated for patients with mild cognitive impairment or mild dementia with biomarker evidence of AD, biomarker testing should be performed before genetic testing and genetic testing should only be performed in patients interested in treatment with amyloid-lowering drugs. It is also important to consider other implications of genetic testing, including burden on and need for additional training for clinicians, the role of additional providers, and the potential challenges for patients and families.

A causal inference study: The impact of the combined administration of Donepezil and Memantine on decreasing hospital and emergency department visits of Alzheimer's disease patients.

Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug therapies attempt to delay the mental decline and improve cognitive abilities. Two of the most commonly prescribed such drugs are Donepezil and Memantine. We formally tested and confirmed the presence of a beneficial drug-drug interaction of Donepezil and Memantine using a causal inference analysis. We applied doubly robust estimators to one of the largest and high-quality medical databases to estimate the effect of two commonly prescribed Alzheimer's disease (AD) medications, Donepezil and Memantine, on the average number of hospital or emergency department visits per year among patients diagnosed with AD. Our results show that, compared to the absence of medication scenario, the Memantine monotherapy, and the Donepezil monotherapy, the combined use of Donepezil and Memantine treatment significantly reduces the average number of hospital or emergency department visits per year by 0.078 (13.8%), 0.144 (25.5%), and 0.132 days (23.4%), respectively. The assessed decline in the average number of hospital or emergency department visits per year is consequently associated with a substantial reduction in medical costs. As of 2022, according to the Alzheimer's Disease Association, there were over 6.5 million individuals aged 65 and older living with AD in the US alone. If patients who are currently on no drug treatment or using either Donepezil or Memantine alone were switched to the combined used of Donepezil and Memantine therapy, the average number of hospital or emergency department visits could decrease by over 613 thousand visits per year. This, in turn, would lead to a remarkable reduction in medical expenses associated with hospitalization of AD patients in the US, totaling over 940 million dollars per year.

Study of neuropathological changes and dementia in 100 centenarians in The 90+ Study.

INTRODUCTION: The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear. METHODS: We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians. RESULTS: A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups. DISCUSSION: Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health. HIGHLIGHTS: Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associated with dementia. There is no attenuation of this association with age.

Impact and Risk Factors of Limbic Predominant Age-Related TDP-43 Encephalopathy Neuropathologic Change in an Oldest-Old Cohort.

BACKGROUND AND OBJECTIVES: Limbic predominant age-related TAR DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is a prevalent degenerative pathology in the oldest-old who are the fastest-growing segment of our population with the highest rates of dementia. We aimed to determine the relationship between LATE-NC and cognitive impairment and to identify its potential risk factors by studying its relationship with common past medical histories in an oldest-old cohort. METHODS: Participants from The 90+ Study with longitudinal evaluations and autopsy data were included. Dementia status and impairment in 5 main cognitive domains were determined at postmortem conferences leveraging all clinical and neuropsychological data blind to neuropathologic diagnosis. Medical history information was obtained from patients and their informants. LATE-NC and Alzheimer disease neuropathologic change (ADNC) were considered present in those with TDP-43 pathology in the hippocampus and/or neocortex and those with high likelihood of ADNC according to NIA-AA guidelines, respectively. We examined the association of degenerative pathologies with cognitive outcomes and multiple comparisons-adjusted relationship of medical history variables with LATE-NC and ADNC using logistic regressions adjusted for age at death, sex, and education. RESULTS: Three hundred twenty-eight participants were included in this study. LATE-NC was present in 32% of the participants. It had a significant association with the presence of dementia (OR 2.8, 95% CI 1.7-4.6) and impairment in memory (OR 3.0, 95% CI 1.8-5.1), language (OR 2.6, 95% CI 1.6-4.3), and orientation (OR 3.5, 95% CI 2.1-5.9). The association with impaired orientation was unique to LATE-NC, and the strength and significance of the other associations were comparable to ADNC. Furthermore, we found that history of osteoarthritis (OR 0.37, adjusted 95% CI 0.21-0.66) and hypertension (OR 0.52, adjusted 95% CI 0.28-0.98) were associated with a reduced likelihood of LATE-NC, but not ADNC. DISCUSSION: Our results suggest that LATE-NC is a prevalent degenerative pathology in the oldest-old and has significant associations with dementia and impairment in cognitive domains with magnitudes that are comparable to ADNC. We also found that past medical histories of hypertension and osteoarthritis were associated with a lower likelihood of LATE-NC. This might help identify upstream mechanisms leading to this important pathology.

Cognitive resilience to three dementia-related neuropathologies in an oldest-old man: A case report from The 90+ Study.

Cognitive resilience provides insights into maintaining good cognition despite dementia-related neuropathologic changes. It is of special interest in the oldest-old (age 90+) because age is the strongest risk factor for dementia. We describe the only participant of The 90+ Study, among 367 autopsies, who maintained normal cognition despite intermediate-high levels of 3 dementia-related neuropathologic changes, advanced age, and comorbidities associated with cognitive impairment. This man remained cognitively normal throughout 13 semi-annual study visits, last one being 4 months before his death at 96. His cognitive test scores remained around the 90th percentile for non-timed tests and declined from 90th to 50th percentile (significant for semantic fluency) for timed tests. He remained physically and cognitively active until death, despite extrapyramidal signs in the last year of life. Neuropathological examination revealed intermediate level of Alzheimer's disease neuropathologic change (Thal phase 5, Braak NFT stage IV, CERAD score 3), Lewy bodies and neurites in the olfactory bulb, brainstem and limbic areas (Braak PD stage 4), TDP-43 inclusions in the amygdala and hippocampus (LATE stage 2), and a microvascular lesion in putamen. This case demonstrates that cognitive impairment is not inevitable even in the oldest-old with mutltiple dementia-related neuropathologic changes.

Dementia is associated with medial temporal atrophy even after accounting for neuropathologies.

Brain atrophy is associated with degenerative neuropathologies and the clinical status of dementia. Whether dementia is associated with atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. We used data from National Alzheimer's Coordinating Center (n = 129) and Alzheimer's Disease Neuroimaging Initiative (n = 47) participants with suitable in vivo 3D-T1w MRI and autopsy data. We determined dementia status at the visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer's disease neuropathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy and atherosclerosis. Voxel-based morphometry identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analysed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. We also examined models with dementia and Clinical Dementia Rating sum of the boxes as the outcome and explored the potential mediating effect of medial temporal lobe structure volumes on the relationship between pathology and cognition. We found strong associations for dementia with volumes of the hippocampus, amygdala and parahippocampus (semi-partial correlations ≥ 0.28, P < 0.0001 for all regions in National Alzheimer's Coordinating Center; semi-partial correlations ≥ 0.35, P ≤ 0.01 for hippocampus and parahippocampus in Alzheimer's Disease Neuroimaging Initiative). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). We also found that the volumes of the medial temporal lobe structures contributed towards explaining the variance in Clinical Dementia Rating sum of the boxes (ranging from 5% to 9%) independent of neuropathologies and partially mediated the association between Alzheimer's disease neuropathology and cognition. Even after accounting for the most common neuropathologies, dementia still had among the strongest associations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to the clinical status of dementia rather than Alzheimer's disease or other neuropathologies, with the potential exception of hippocampal sclerosis.

Diagnosis and Management of Cognitive Concerns in the Oldest-Old.

PURPOSE OF REVIEW: The fastest-growing group of elderly individuals is the "oldest-old," usually defined as those age 85 years and above. These individuals account for much of the rapid increase in cases of dementing illness throughout the world but remain underrepresented in the body of literature on this topic. The aim of this review is first to outline the unique contributing factors and complications that must be considered by clinicians in evaluating an oldest-old individual with cognitive complaints. Secondly, the evidence for management of these cognitive concerns is reviewed. RECENT FINDINGS: In addition to well-established associations between impaired cognition and physical disability, falls, and frailty, there is now evidence that exercise performed decades earlier confers a cognitive benefit in the oldest-old. Moreover, though aggressive blood pressure control is critical earlier in life for prevention of strokes, renal disease, and other comorbidities, hypertension started after age 80 is in fact associated with a decreased risk of clinical dementia, carrying significant implications for the medical management of oldest-old individuals. The oldest-old are more likely to reside in care facilities, where social isolation might be exacerbated by a consistently lower rate of internet-connected device use. The COVID-19 pandemic has not only highlighted the increased mortality rate among the oldest-old but has also brought the increased social isolation in this group to the forte. SUMMARY: Differing from the "younger-old" in a number of respects, the oldest-old is a unique population not just in their vulnerability to cognitive disorders but also in the diagnostic challenges they can pose. The oldest-old are more likely to be afflicted by sensory deficits, physical disability, poor nutrition, frailty, and depression, which must be accounted for in the assessment of cognitive complaints as they may confound or complicate the presentation. Social isolation and institutionalization are also associated with impaired cognition, perhaps as sequelae, precipitants, or both. Ante-mortem diagnostic tools remain particularly limited among the oldest-old, especially given the likelihood of these individuals to have multiple co-occurring types of neuropathology, and the presence of neuropathology in those who remain cognitively intact. In addition to the symptomatic treatments indicated for patients of all ages with dementia, management of cognitive impairment in the oldest-old may be further optimized by use of assistive devices, augmentation of dietary protein, and liberalization of medication regimens for risk factors such as hypertension.

The relation between thyroid dysregulation and impaired cognition/behaviour: An integrative review.

Despite decades of research on the relation between thyroid diseases and cognition, the nature of this relationship remains elusive. An increasing prevalence of cognitive impairment and thyroid dysfunction has been consistently observed with ageing. Also, there appears to be an association between thyroid disorders and cognitive decline. Given the increasing global burden of dementia, elucidating the relationship between thyroid disorders as a potentially modifiable risk factor of cognitive impairment was the main goal of this review. We summarise the current literature examining the relationship between thyroid hormonal dysregulation and cognition or behaviour. We present the available imaging and pathological findings related to structural and functional brain changes related to thyroid hormonal dysregulation. We also propose potential mechanisms of interaction between thyroid hormones, autoantibodies and cognition/behaviour. Effects of gender, ethnicity and environmental factors are also briefly discussed. This review highlights the need for long-term prospective studies to capture the course of brain functional changes associated with the incidence and progression of thyroid dysregulations along with the confounding effects of non-modifiable risk factors such as gender and ethnicity. Moreover, double-blind controlled clinical trials are necessary to devise appropriate treatment plans to prevent cognitive consequences of over or undertreatment of thyroid disorders.

Cystatin C, cognition, and brain MRI findings in 90+-year-olds.

Chronic kidney disease is emerging as a novel risk factor for cerebrovascular disease, but this association remains largely unexplored in older adults. Cystatin C is a more accurate measure than creatinine of kidney function in the elderly. We evaluated cystatin C, cognitive function, and brain imaging in 193 participants from The 90+ Study neuroimaging component. The mean age was 93.9 years; 61% were women. Mean cystatin C was 1.62 mg/L with estimated glomerular filtration rate 39.2 mL/min/1.73 m2. Performance on measures of global cognition, executive function, and visual-spatial ability declined at higher tertiles of cystatin C (lower kidney function). Higher cystatin C was significantly associated with infratentorial microbleeds and lower gray matter volume. Adjusted risk of incident dementia was increased in the middle and high cystatin C tertile groups compared with the low group (hazard ratio in highest tertile 3.81 [95% confidence interval 1.14-12.7]), which appeared to be explained in part by the presence of cerebral microbleeds. Overall, cystatin C was associated with cognitive performance, brain imaging pathology, and decline to dementia in this oldest-old cohort.

Clinical Assessment of Characteristics of Apraxia of Speech in Primary Progressive Aphasia.

Purpose We sought to examine interrater reliability in clinical assessment of apraxia of speech (AOS) in individuals with primary progressive aphasia and to identify speech characteristics predictive of AOS diagnosis. Method Fifty-two individuals with primary progressive aphasia were recorded performing a variety of speech tasks. These recordings were viewed by 2 experienced speech-language pathologists, who independently rated them on the presence and severity of AOS as well as 14 associated speech characteristics. We calculated interrater reliability (percent agreement and Cohen's kappa) for these ratings. For each rater, we used stepwise regression to identify speech characteristics significantly predictive of AOS diagnosis. We used the overlap between raters to create a more parsimonious model, which we evaluated with multiple linear regression. Results Results yielded high agreement on the presence (90%) and severity of AOS (weighted Cohen's κ = .834) but lower agreement for specific speech characteristics (weighted Cohen's κ ranging from .036 to .582). Stepwise regression identified 2 speech characteristics predictive of AOS diagnosis for both raters (articulatory groping and increased errors with increased length/complexity). These alone accounted for ≥ 50% of the variance of AOS severity in the constrained model. Conclusions Our study adds to a growing body of research that highlights the difficulty in objective clinical characterization of AOS and perceptual characterization of speech features. It further supports the need for consensus diagnostic criteria with standardized testing tools and for the identification and validation of objective markers of AOS. Additionally, these findings underscore the need for a training protocol if diagnostic tools are to be effective when shared beyond the research teams that develop and test them and disseminated to practicing speech-language pathologists, in order to ensure consistent application.

Risk factors of hippocampal sclerosis in the oldest old: The 90+ Study.

OBJECTIVE: To examine the risk factors and comorbidities of hippocampal sclerosis (HS) in the oldest-old. METHODS: A total of 134 participants with dementia from The 90+ Study with longitudinal evaluations and autopsy were included in this investigation. Participants were divided into 2 groups, one with and one without HS pathology, and differences in clinical and pathologic characteristics were compared. RESULTS: Persons with HS tended to have a longer duration of dementia compared to participants without HS (mean 4.0 years vs 6.7 years, odds ratio [OR] 1.26; 95% confidence interval [CI] 1.11-1.42; p < 0.001). HS was more likely in participants with a history of autoimmune diseases (rheumatoid arthritis or thyroid disease, OR 3.15; 95% CI 1.30-7.62; p = 0.011), high thyroid-stimulating hormone (OR 4.94; 95% CI 1.40-17.46; p = 0.013), or high thyroid antibodies (OR 3.45; 95% CI 1.09-10.88; p = 0.035). Lewy body disease (LBD) pathology was also associated with an increased likelihood of HS (OR 5.70; 95% CI 1.22-26.4; p = 0.027). CONCLUSION: We identified autoimmune conditions (rheumatoid arthritis and thyroid disease) as potential risk factors for HS in our cohort. LBD was the only pathology that was associated with increased odds of HS and those harboring HS pathology had a longer duration of dementia. This suggests multiple pathways of HS pathology among the oldest-old.

Current Role for Biomarkers in Clinical Diagnosis of Alzheimer Disease and Frontotemporal Dementia.

Purpose of review Alzheimer's disease (AD) and frontotemporal dementia can often be diagnosed accurately with careful clinical history, cognitive testing, neurological examination, and structural brain MRI. However, there are certain circumstances wherein detection of specific biomarkers of neurodegeneration or underlying AD pathology will impact the clinical diagnosis or treatment plan. We will review the currently available biomarkers for AD and frontotemporal dementia (FTD) and discuss their clinical importance. Recent findings With the advent of 18F-labeled tracers that bind amyloid plaques, amyloid PET is now clinically available for the detection of amyloid pathology and to aid in a biomarker-supported diagnosis of AD or mild cognitive impairment (MCI) due to AD. It is not yet possible to test for the specific FTD pathologies (tau or TDP-43); however, a diagnosis of FTD may be "imaging supported" based upon specific MRI or FDG-PET findings. Cerebrospinal fluid measures of amyloid-beta, total-tau, and phospho-tau are clinically available and allow detection of both of the cardinal pathologies of AD: amyloid and tau pathology. Summary It is appropriate to pursue biomarker testing in cases of MCI and dementia when there remains diagnostic uncertainty and the result will impact diagnosis or treatment. Practically speaking, due to the rising prevalence of amyloid positivity with advancing age, measurement of biomarkers in cases of MCI and dementia is most helpful in early-onset patients, patients with atypical clinical presentations, or when considering referral for AD clinical trials.

Data-driven classification of patients with primary progressive aphasia.

Current diagnostic criteria classify primary progressive aphasia into three variants-semantic (sv), nonfluent (nfv) and logopenic (lv) PPA-though the adequacy of this scheme is debated. This study took a data-driven approach, applying k-means clustering to data from 43 PPA patients. The algorithm grouped patients based on similarities in language, semantic and non-linguistic cognitive scores. The optimum solution consisted of three groups. One group, almost exclusively those diagnosed as svPPA, displayed a selective semantic impairment. A second cluster, with impairments to speech production, repetition and syntactic processing, contained a majority of patients with nfvPPA but also some lvPPA patients. The final group exhibited more severe deficits to speech, repetition and syntax as well as semantic and other cognitive deficits. These results suggest that, amongst cases of non-semantic PPA, differentiation mainly reflects overall degree of language/cognitive impairment. The observed patterns were scarcely affected by inclusion/exclusion of non-linguistic cognitive scores.

Communicating mild cognitive impairment diagnoses with and without amyloid imaging.

BACKGROUND: Mild cognitive impairment (MCI) has an uncertain etiology and prognosis and may be challenging for clinicians to discuss with patients and families. Amyloid imaging may aid specialists in determining MCI etiology and prognosis, but creates novel challenges related to disease labeling. METHODS: We convened a workgroup to formulate recommendations for clinicians providing care to MCI patients. RESULTS: Clinicians should use the MCI diagnosis to validate patient and family concerns and educate them that the patient's cognitive impairment is not normal for his or her age and education level. The MCI diagnosis should not be used to avoid delivering a diagnosis of dementia. For patients who meet Appropriate Use Criteria after standard-of-care clinical workup, amyloid imaging may position specialists to offer more information about etiology and prognosis. Clinicians must set appropriate expectations, including ensuring that patients and families understand the limitations of amyloid imaging. Communication of negative results should include that patients remain at elevated risk for dementia and that negative scans do not indicate a specific diagnosis or signify brain health. Positive amyloid imaging results should elicit further monitoring and conversations about appropriate advance planning. Clinicians should offer written summaries, including referral to appropriate social services. CONCLUSIONS: In patients with MCI, there is a need to devote considerable time and attention to patient education and shared decision-making. Amyloid imaging may be a tool to aid clinicians. Careful management of patient expectations and communication of scan results will be critical to the appropriate use of amyloid imaging information.

Lower likelihood of falling at age 90+ is associated with daily exercise a quarter of a century earlier: The 90+ Study.

Objective: to explore the relationship between risk of falling at age 90+ and prior physical activity at age 60-70s. Design: population-based cohort study (The 90+ Study). Setting: California retirement community. Participants: of 1596 cohort members, 1536 had both falls and prior activity data. Mean age = 94 years; 78% female; 99% Caucasian. Methods: time spent in active physical activity was self-reported in 1980s; medical history, medication, assistive devices, residence type, and falls (outcome) was collected in 2000s. Activity/fall relationships were assessed using logistic regression. Results: falls were reported by 52% of participants, recurrent falls by 32%, and severe injury by 21% of fallers. In univariate analyses risk of falling at age 90+ was significantly related to medical history (heart disease, TIA/stroke, arthritis, vision disease, depression, dementia), medication use (hypnotics, anti-psychotics, anti-depressants), use of assistive devices (cane, walker, wheelchair), residence type (living with relatives, sheltered living), and source of information (self-report vs informant). Risks of falling and recurrent falls at age 90+ were 35-45% lower in those reporting 30+ minutes/day of active physical activity at age 60-70s compared with no activity. The odds ratio of falling was 0.65 (95% CI = 0.44-0.97) for 30-45 minutes/day and 0.64 (0.44-0.94) for 1+ hour/day adjusting for age, sex, medical history (stroke/TIA, vision disease, depression), use of assistive devices, and source of information. Conclusions and Relevance: falls are extremely common among the oldest-old and a significant proportion lead to severe injury. This work is the first to show an association between exercise at age 60-70s and lower risk of falling at age 90+.

Imaging Biomarkers in Alzheimer's Disease: A Practical Guide for Clinicians.

Although recent developments in imaging biomarkers have revolutionized the diagnosis of Alzheimer's disease at early stages, the utility of most of these techniques in clinical setting remains unclear. The aim of this review is to provide a clear stepwise algorithm on using multitier imaging biomarkers for the diagnosis of Alzheimer's disease to be used by clinicians and radiologists for day-to-day practice. We summarized the role of most common imaging techniques and their appropriate clinical use based on current consensus guidelines and recommendations with brief sections on acquisition and analysis techniques for each imaging modality. Structural imaging, preferably MRI or alternatively high resolution CT, is the essential first tier of imaging. It improves the accuracy of clinical diagnosis and excludes other potential pathologies. When the results of clinical examination and structural imaging, assessed by dementia expert, are still inconclusive, functional imaging can be used as a more advanced option. PET with ligands such as amyloid tracers and 18F-fluorodeoxyglucose can improve the sensitivity and specificity of diagnosis particularly at the early stages of the disease. There are, however, limitations in using these techniques in wider community due to a combination of lack of facilities and expertise to interpret the findings. The role of some of the more recent imaging techniques including tau imaging, functional MRI, or diffusion tensor imaging in clinical practice, remains to be established in the ongoing and future studies.

Logopenic, mixed, or Alzheimer-related aphasia?

OBJECTIVE: This study tested the hypothesis that patients with primary progressive aphasia (PPA) who do not meet the proposed criteria for any of the recognized subtypes would have the atrophy pattern reported in the past for logopenic variant PPA (lvPPA), in turn suggesting that the PPA of likely Alzheimer disease origin is more variable than that captured in the current lvPPA diagnostic recommendations. METHODS: MRI gray matter volumes from 14 patients with mixed PPA who failed to meet the diagnostic recommendations for any recognized variant were compared with those of 25 matched control participants via voxel-based morphometry. RESULTS: The mixed PPA group had left temporoparietal atrophy with a pattern identical to that in previously reported lvPPA cohorts. CONCLUSION: Patients with PPA who did not meet the criteria for any recognized PPA variant at their initial assessment had the group-level atrophy pattern previously reported as the hallmark of lvPPA. We suggest that the specific language features proposed for lvPPA are too narrow to characterize the language impairments arising from likely Alzheimer pathology.