Volume 87, Number 4, IN PRESS

Review
David J. Libon, Rod Swenson, Melissa Lamar, Catherine C. Price, Ganesh Baliga, Alvaro Pascual-Leone, Rhoda Au, Stephanie Cosentino, Stacy L. Andersen ( Handling Associate Editor: David Loewenstein)
The Boston Process Approach and Digital Neuropsychological Assessment: Past Research and Future Directions
Abstract: Neuropsychological assessment using the Boston Process Approach (BPA) suggests that an analysis of the strategy or the process by which tasks and neuropsychological tests are completed, and the errors made during test completion convey much information regarding underlying brain and cognition and are as important as overall summary scores. Research over the last several decades employing an analysis of process and errors has been able to dissociate between dementia patients diagnosed with Alzheimer’s disease, vascular dementia associated with MRI-determined white matter alterations, and Parkinson’s disease; and between mild cognitive impairment subtypes. Nonetheless, BPA methods can be labor intensive to deploy. However, the recent availability of digital platforms for neuropsychological test administration and scoring now enables reliable, rapid, and objective data collection. Further, digital technology can quantify highly nuanced data previously unobtainable to define neurocognitive constructs with high accuracy. In this paper, a brief review of the BPA is provided. Studies that demonstrate how digital technology translates BPA into specific neurocognitive constructs using the Clock Drawing Test, Backward Digit Span Test, and a Digital Pointing Span Test are described. Implications for using data driven artificial intelligence-supported analytic approaches enabling the creation of more sensitive and specific detection/diagnostic algorithms for putative neurodegenerative illness are also discussed.

Review
Arash Salehipour, Motahareh Bagheri, Mohammadmahdi Sabahi, Mahsa Dolatshahi, Delphine Boche
Combination Therapy in Alzheimer’s Disease: Is It Time?
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia globally. There is increasing evidence showing AD has no single pathogenic mechanism, and thus treatment approaches focusing only on one mechanism are unlikely to be meaningfully effective. With only one potentially disease modifying treatment approved, targeting amyloid-β (Aβ), AD is underserved regarding effective drug treatments. Combining multiple drugs or designing treatments that target multiple pathways could be an effective therapeutic approach. Considering the distinction between added and combination therapies, one can conclude that most trials fall under the category of added therapies. For combination therapy to have an actual impact on the course of AD, it is likely necessary to target multiple mechanisms including but not limited to Aβ and tau pathology. Several challenges have to be addressed regarding combination therapy, including choosing the correct agents, the best time and stage of AD to intervene, designing and providing proper protocols for clinical trials. This can be achieved by a cooperation between the pharmaceutical industry, academia, private research centers, philanthropic institutions, and the regulatory bodies. Based on all the available information, the success of combination therapy to tackle complicated disorders such as cancer, and the blueprint already laid out on how to implement combination therapy and overcome its challenges, an argument can be made that the field has to move cautiously but quickly toward designing new clinical trials, further exploring the pathological mechanisms of AD, and re-examining the previous studies with combination therapies so that effective treatments for AD may be finally found.

Review
Senthilkumar Preethy, Natarajan Ranganathan, Kadalraja Raghavan, Vidyasagar Devaprasad Dedeepiya, Nobunao Ikewaki, Samuel J.K. Abraham (Handling Associate Editor: Jagannatha Rao Kosagisharaf)
Integrating the synergy of the gut microbiome into regenerative medicine: relevance to neurological disorders
Abstract: A new paradigm of cell therapy-based approaches as a solution to several diseases caused by damage or loss of cells/tissues leading to organ failure heralded the birth of a new branch in medicine called regenerative medicine (RM), which was further fueled by in vitro cell expansion and tissue engineering (TE) technologies, including the ability to grow embryonic stem cells, induce pluripotent stem cells, and so on. RM addresses organ failure by repair, regeneration, or restoration, rejuvenation using cells, stem cells, or progenitor cells as tools having added cell-derived products also as a tool, and extracellular matrix component–based support, either direct or indirect (e.g., matrix induced autologous chondrocyte implantation) using scaffolds. Now, the main objective of RM is to solve the functional loss of cells that have evolved from cells as tools to cell-derived factors and scaffolds per se as tools. In this context, an important yet indispensable group of cells that constitute the major portion of the human body in terms of the number of cells having several essential roles to play, both directly and indirectly, starting from digestion and the immune system to the growing evidence of influencing neuronal function, aging, and carcinogenesis has been ignored. We would like to focus on these in this review as they should essentially be considered as a tool of RM, especially for neurological disorders for their vital role. What we are indicating is the second genome or the gut microbiome.

Short Communication
Sarah Cato, Stephanie Ramer, Ihab Hajjar, Ambar Kulshreshtha
Alzheimer’s Disease Mortality as a Function of Urbanization Level: 1999-2019
Abstract: This study investigated Alzheimer’s disease (AD) mortality trends by urbanization level and geographical location in the U.S. The CDC’s WONDER database was used to investigate AD mortality from 1999-2019 stratified by urbanization level, census division, race, and sex. Data showed that while AD mortality increased across the U.S., rural areas, particularly in the South, had higher mortality compared to urban counterparts. AD mortality was higher among the female and White population. Data suggested that the urban-rural discrepancy is widening over time. Identifying health disparities underlying the urban-rural discrepancy in AD mortality is critical for allocating social and public health resources.

Short Communication
Martina Valletta*, Marco Canevelli*, Fabrizia D'Antonio, Alessandro Trebbastoni, Giuseppina Talarico, Alessandra Campanelli, Micaela Sepe Monti, Antonella Di Vita, Emanuela Salati, Letizia Imbriano, Roberta Margiotta, Sonia Barbetti, Sofia Diana, Simona Buscarnera, Marco Toccaceli Blasi, Martina Salzillo, Giuseppe Pugliese, Nicola Vanacore, Giuseppe Bruno (Handling Associate Editor: Carlo Abbate) *These authors contributed equally to the present study.
Prevalence and Safety of COVID-19 Vaccination in Community-Dwelling People with Dementia: Findings from a Tertiary Memory Clinic in Italy
Abstract: This study aimed to explore the prevalence and safety of SARS-CoV-2 vaccination in individuals with dementia. Patients with mild cognitive impairment or dementia were recruited at a tertiary memory clinic, from March 15 to September 15, 2021. Information on COVID-19 vaccination and adverse events experienced after vaccine administration were collected from caregivers. Two-hundred-seventy subjects were finally recruited. Among them, 253 (93.7%) had received the vaccine and only 69 (27.3%) experienced adverse events. Cognitive and behavioral changes following immunization were only rarely reported. COVID-19 vaccination is safe and well-tolerated in patients with cognitive impairment who should be prioritized in the vaccination campaign.

Short Communication
Arpita Bose, Manaswita Dutta, Niladri S. Dash, Ranita Nandi, Aparna Dutt, Samrah Ahmed
Importance of Task Selection for Connected Speech Analysis in Patients with Alzheimer’s Disease from an Ethnically Diverse Sample
Abstract: Features of linguistic impairment in Alzheimer’s disease (AD) are primarily derived from English-speaking patients. Little is known regarding such deficits in linguistically diverse speakers with AD. We aimed to detail linguistic profiles (speech rate, dysfluencies, syntactic, lexical, morphological, semantics) from two connected speech tasks—Frog Story and picture description—in Bengali-speaking AD patients. The Frog Story detected group differences on all six linguistic levels, compared to only three with picture description. Critically, Frog Story captured the language-specific differences between the groups. Careful consideration should be given to the choice of connected speech tasks for dementia diagnosis in linguistically diverse populations.

Short Communication
Giulia Bommarito, Valentina Garibotto, Giovanni B. Frisoni, Federica Ribaldi, Sara Stampacchia, Frédéric Assal, Stéphane Armand, Gilles Allali Alessandra Griffa (Handling Associate Editor: Morag Taylor)
The Biological Substrate of the Motoric Cognitive Risk Syndrome: A Pilot Study Using Amyloid-/Tau-PET and MR Imaging
Abstract: We conducted a cross-sectional pilot study to explore the biological substrate of the Motoric Cognitive Risk (MCR) syndrome in a Memory Clinic cohort, using a multimodal imaging approach. Twenty participants were recruited and classified as MCR+/. Amyloid- and tau-PET uptakes, temporal atrophy, white matter hyperintensities, lateral ventricular volume (LVV), and diffusion tensor parameters were compared between groups. No significant differences were found in imaging features related to Alzheimer’s disease or gross vascular damage. MCR+ patients had increased LVV and altered diffusion parameters in the superior corona radiata. Ventricular enlargement and microstructural damage of the surrounding white matter tracts could contribute to MCR pathophysiology.

Short Communication
Christian LoBue, Brendan J. Kelley, John Hart, Jr., Jessica Helphrey, Jeff Schaffert, C. Munro Cullum, Matthew E. Peters, Peter M. Douglas for the Alzheimer’s Disease Neuroimaging Initiative
Mild Traumatic Brain Injury is Related to Elevated Cerebrospinal Fluid Tau in Alzheimer’s Disease Dementia
Abstract: Few studies have examined an association between mild traumatic brain injury (mTBI) and Alzheimer’s disease (AD). For this reason, we compared an AD dementia group with an mTBI history (n=10) to a matched AD control group (n=20) on measures of cognitive function, cerebral glucose metabolism, and markers of amyloid and tau deposition. Only a trend and medium-to-large effect size for higher phosphorylated and total tau was identified for the mTBI group. A history of mTBI may be associated with greater tau in AD, indicating a potential pathway for increasing risk for AD, though further evaluation with larger samples is needed.

Editorial
Gorka Orive, Francisco Lopera, Eva Carro
Saliva Is a Good Candidate to be the New Gold-Standard Sample for Neurodegenerative Diseases

Mohadeseh Kalari, Zeinab Abbasi, Marzieh Dehghan Shasaltaneh, Ali Khaleghian, Zahra Moosavi-Nejad (Handling Associate Editor: Valentina Bessi)
A Cobalt-Containing Compound as a Stronger Inhibitor than Galantamine to Inhibit Acetylcholinesterase Activity: A New Drug Candidate for Alzheimer’s Disease Treatment
Abstract: Background: Acetylcholinesterase (AChE) regulates the transmission of neural messages by hydrolyzing acetylcholine in synaptic spaces. Objective: The effects of many AChE inhibitors have been evaluated in the treatment of Alzheimer's disease, but the present study examined a synthetic complex containing cobalt (SC) for the first time in the field of enzyme activity to evaluate enzyme inhibitory function. Methods: Ellman's test was applied. AChE function was assessed in the presence of SC through docking and molecular dynamics analyses. The second structure of AChE was studied through circular dichroism (CD) spectroscopy. Results: Several enzymatic methods were utilized for the kinetics of AChE, which indicated the non-Michaelis and positive homotropic behavior of AChE in the absence of inhibitors (Hill coefficient = 1.33). However, the existence of inhibitors did not eliminate this homotropic state, and even AChE had a more sigmoidal shape than the galantamine at the presence of SC. Based on the CD spectroscopy results, AChE structure changed in the existence of inhibitors and substrates. Bioinformatics analysis revealed SC bonding to the channel of active site AChE. The number of hydrogen bonds was such that the flexibility of the enzyme protein structure due to inhibitor binding reduced AChE function. Conclusion: The results reflected that AChE exhibited a non-Michaelis and positive homotropic behavior, leading to a more inhibitory effect on the SC than the galantamine. The positive homotropic behavior of AChE was intensified due to the alteration in AChE protein structure by binding SC to hydrophobic region in the active site pathway and impressing Trp84.

Emer R. McGrath, Alexa S. Beiser, Adrienne O’Donnell, Qiong Yang, Saptaparni Ghosh, Mitzi M. Gonzales, Jayandra J. Himali, Claudia L. Satizabal, Keith A. Johnson, Russell P. Tracy, Sudha Seshadri (Handling Associate Editor: Inga Zerr)
Blood Phosphorylated Tau 181 as a Biomarker for Amyloid Burden on Brain PET in Cognitively Healthy Adults
Abstract: Background: Plasma phosphorylated-tau181 (p-tau181) is a promising biomarker for Alzheimer’s disease (AD) and may offer utility for predicting preclinical disease. Objective: To evaluate the prospective association between plasma p-tau181 and amyloid-β (Aβ) and tau-PET deposition in cognitively unimpaired individuals. Methods: Plasma p-tau181 levels were measured at baseline in 52 [48% women, mean 64.4 (SD 5.5) years] cognitively unimpaired Framingham Offspring cohort participants using samples stored between 2011-2014 who subsequently underwent 11C-Pittsburgh Compound-B (PiB)-PET and/or 18F-Flortaucipir (FTP)-PET scans (n=18 with tau-PET) a mean of 6.8 (SD 0.6) years later. Our primary outcomes included Aβ-precuneus, Aβ-FLR (frontal, lateral, and retrosplenial cortices) and tau-global composite region PET deposition. Secondary outcomes included individual regional Aβ and tau PET-deposition. P-tau181 was compared with plasma neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in predicting PET outcomes. Results: P-tau181 was associated with increased Aβ deposition in the FLR (β±SE, 1.25±0.30, p<0.0001), precuneus (1.35±0.29, p<0.001), and other cortical regions. Plasma NFL (1.30±0.49, p=0.01) and GFAP (1.46±0.39, p<0.001) were also associated with FLR Aβ deposition. In models including all three biomarkers adjusted for age, sex, APOE E4 allele, AD polygenic risk score and cortical atrophy score, p-tau181 (0.93±0.31, p<0.01, R2=0.18) and GFAP (0.93±0.41, p=0.03, R2=0.11), but not NFL (0.25±0.51, p=0.62, R2=0.01), were associated with FLR-Aβ deposition. Plasma p-tau181 was not associated with tau-PET burden. Conclusion: In cognitively unimpaired adults, elevated plasma p-tau181 is associated with future increased Aβ deposition across multiple brain regions. Our results highlight the potential utility of p-tau181 as a blood-biomarker to screen for brain-amyloid deposition in cognitively healthy individuals in a community-setting.

Irundika H.K. Dias, Hala Shokr, Freya Shephard, Lisa Chakrabarti
Oxysterols and Oxysterol Sulfates in Alzheimer’s Disease Brain and Cerebrospinal Fluid
Abstract: Background: Brain cholesterol levels are tightly regulated but increasing evidence indicates that cholesterol metabolism may drive Alzheimer’s disease (AD)-associated pathological changes. Recent advances in understanding of mitochondrial dysfunction in AD brain have presented a vital role played by mitochondria in oxysterol biosynthesis and their involvement in pathophysiology. Oxysterol accumulation in brain is controlled by various enzymatic pathways including sulfation. While research into oxysterol is under the areas of active investigation, there is less evidence for oxysterol sulfates levels in human brain. Objective: This study investigates the hypothesis that AD brain oxysterols detoxification via sulfation is impaired in later stages of disease resulting in oxysterol accumulation. Methods: Lipids were extracted from postmortem frozen brain tissue and cerebrospinal (CSF) from late- (Braak stage III-IV) and early- (Braak stage I-II) stage AD patients. Samples were spiked with internal standards prior to lipid extraction. Oxysterols were enriched with a two-step solid phase extraction using a polymeric SPE column and further separation was achieved by LC-MS/MS. Results: Oxysterols, 26-hydroxycholesterol (26-OHC), 25-hydroxycholesterol (25-OHC), and 7-oxycholesterol levels were higher in brain tissue and mitochondria extracted from late-stage AD brain tissue except for 24S-hydroxycholesterol, which was decreased in late AD. However, oxysterol sulfates are significantly lower in the AD frontal cortex. Oxysterols, 25-OHC, and 7-oxocholesterol was higher is CSF but 26-OHC and oxysterol sulfate levels were not changed. Conclusion: Our results show oxysterol metabolism is altered in AD brain mitochondria, favoring synthesis of 26-OHC, 25-OHC, and 7-oxocholesterol, and this may influence brain mitochondrial function and acceleration of the disease.

Stuart J. McCarter, Timothy G. Lesnick, Val J. Lowe, Alejandro A. Rabinstein, Scott A. Przybelski, Alicia Algeciras-Schimnich, Vijay K. Ramanan, Clifford R. Jack, Jr., Ronald C. Petersen, David S. Knopman, Bradley F. Boeve, Kejal Kantarci, Prashanthi Vemuri, Michelle M. Mielke, Jonathan Graff-Radford
Association Between Plasma Biomarkers of Amyloid, Tau, and Neurodegeneration with Cerebral Microbleeds
Abstract: Background: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. Objective: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs. Methods: 712 participants from the Mayo Clinic Study of Aging with T2* GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models. Results: Among the 188 (26%) individuals with ≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8-116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with ≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC -53.0). Conclusion: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

Liling Dong*, Caiyan Liu*, Longze Sha*, Chenhui Mao, Jie Li, Xinying Huang, Jie Wang, Shanshan Chu, Bin Peng, Liying Cui, Qi Xu, Jing Gao *These authors contributed equally to this work.
PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer’s Disease: Data from PUMCH Dementia Cohort
Abstract: Background: The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1% Alzheimer’s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common. Objective: With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients. Methods: 702 AD participants, aged 30-85, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT/MRI, and next-generation DNA sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations. Results: Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher Aβ42 and Aβ42/Aβ40 levels relative to the wild-type PSEN2. The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter Aβ42, Aβ40 levels, or Aβ42/Aβ40 ratio. 1.9% (13/702) subjects harbored rare PSEN2 variants. 0.4% (3/702) subjects carried pathogenic/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization. Conclusion: The PSEN2 N141S, M239T, and I368F are functionally validated mutations.

Christian R. Salazar, Marina Ritchie, Daniel L. Gillen, Joshua D. Grill
Strategies Associated with Retaining Participants in the Longitudinal National Alzheimer’s Coordinating Center Uniform Data Set Study
Abstract: Background: Best approaches for retaining research participants in Alzheimer’s disease cohort studies are understudied. Objective: Using data from the National Alzheimer’s Coordinating Center Uniform Data Set, we evaluated the associations of unique strategies with participant retention across Alzheimer’s Disease Research Centers and explored potential effect modification by race/ethnicity and diagnostic group. Methods: We examined retention at the first follow-up visit among participants enrolled during 2015-2017. Structured surveys ascertained 95 retention tactics among 12 strategies. Strategy-specific summary scores were created based on the number of implemented tactics for each strategy and grouped into tertiles. Generalized estimating equations were constructed to evaluate associations of strategy scores and the odds of retention, controlling for age, sex, education, race and ethnicity, study partner type, marital status, visit length, battery length, and diagnostic group. Separate models were stratified by race/ethnicity and diagnostic group. Effect modification was formally tested with interaction terms. Results: Among 5,715 total participants enrolled, 4,515 were Non-Hispanic White (79%), 335 were Hispanic/Latino (6%), 651 were Non-Hispanic Black (11%), and 214 were Non-Hispanic Asian (4%). Compared to the lowest tertile of scores, the highest tertile of scores involving improvement in study personnel and communication of study requirements and details were associated with 61% higher odds of retention in fully adjusted models (adjusted Odds Ratios [aOR]=1.61, 95% Confidence Interval [CI]=1.05-2.47 and aOR=1.55, 95% CI=1.03-2.35, respectively). We did not find evidence for effect modification. Conclusion: In the setting of limited resources, specific retention strategies may be more valuable than others.

Hyun Kim, Alina Levine, Daniel Cohen, Philip Gehrman, Xi Zhu, Davangere P. Devanand, Seonjoo Lee, Terry E. Goldberg on behalf of the Alzheimer's Disease Neuroimaging Initiative
The Role of Amyloid, Tau, and APOE Genotype on the Relationship Between Informant-Reported Sleep Disturbance and Alzheimer’s Disease Risks
Abstract: Background: The association between sleep and Alzheimer’s disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD. Objective: To determine the potential interaction between sleep disturbance and Aβ, tau, and APOE4 on brain atrophy and cognitive decline. Methods: Sample included 351 participants (mean age 72.01 ±6.67, 50.4% female) who were followed for approximately 5 years as part of the Alzheimer’s Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive performance and IRSD’s interaction with cerebrospinal fluid amyloid-β (Aβ42) and p-Tau depositions and APOE4 status were examined using the linear mixed models. Results: Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aβ and p-Tau/Aβ predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (ps≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (ps≤0.02) but not for cognition. Conclusion: IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4. Early intervention for sleep disturbance could help reduce the risk of developing AD.

Xing Zhao, Wenying Du, Jiehui Jiang, Ying Han (Handling Associate Editor: Ling-Qiang Zhu)
Brain Photobiomodulation Improves Sleep Quality in Subjective Cognitive Decline: A Randomized, Sham-Controlled Study
Abstract: Background: Sleep appears to be a sensitive biomarker that facilitates early detection and effective intervention for Alzheimer’s disease, while subjective cognitive decline (SCD) is a risk factor for Alzheimer’s disease. Prefrontal cortex atrophy is associated with both sleep disruption and cognitive decline. Transcranial brain photobiomodulation (PBM) therapy can enhance frontal cortex oxygen consumption, increasing frontal cortex mediated memory function. Objective: This study aimed to test whether PBM therapy targeting the frontal cortex could improve sleep and cognitive function in SCD. Methods: Fifty-eight SCDs were divided into the PBM group (N=32) in which real light therapy was administered and a sham light therapy group (N=26). All the participants received either real light or sham light therapy for 6 days consecutively, while the sleep data were recorded. The n-back task was employed to measure each participant’s working memory. Results: We found no differences in sleep efficiency change (F=211, p=0.279), REM stage percent change (F=420, p=0.91), and wake-up time (F=212, p=0.277) between the two groups. The sleep efficiency and REM were improved within the true light group on the fifth day. The true light group perform better than the control group in the n-back test, the accuracy was higher in the 2-back test (88.6% versus 79.6%, p=0.001), and the reaction time in 1-back was shorter (544.80±202.00 versus 592.87±222.05, p=0.003). Conclusion: After five days of PBM therapy targeting the prefrontal cortex, sleep efficiency and N-back cognitive performance were improved on the fifth day.

Wendy M. Troxel, Ann Haas, Tamara Dubowitz, Bonnie Ghosh-Dastidar, Meryl Butters, Tiffany L. Gary-Webb, Andrea Weinstein, Andrea L. Rosso (Handling Associate Editor: Shireen Sindi)
Sleep Disturbances, Changes in Sleep, and Cognitive Function in Low-Income African Americans
Abstract: Background: Sleep problems may contribute to the disproportionate burden of Alzheimer’s disease and related dementias (ADRD) among African Americans (AAs). Objective: To examine the role of sleep problems in contributing to cognitive function and clinically adjudicated cognitive impairment in a predominantly AA sample. Methods: This study (n=216, 78.8% female; mean age=67.7 years) examined associations between 1) the level (i.e., measured in 2018) and 2) change over time (from 2013 to 2018; n=168) in actigraphy-assessed sleep with domain-specific cognitive function and clinically adjudicated cognitive impairment (2018) in a community-dwelling, predominantly AA (96.9%) sample. A comprehensive cognitive battery assessed global cognitive function (3MS) and domain-specific cognitive function (attention, visuo-spatial ability, language, delayed recall, immediate recall, and executive function) in 2018. Sleep was measured in 2013 and 2018 via actigraphy. Results: Higher sleep efficiency and less wakefulness after sleep onset (WASO; measured in 2018) were associated with greater attention, executive function, and visuospatial ability. Increases in sleep efficiency between 2013 and 2018 were associated with better executive function, language, immediate recall, and visuospatial ability, whereas increases in WASO (2013-2018) were associated with poorer attention, executive function, and visuospatial ability. Level or change in sleep duration were not associated with domain-specific cognitive function, nor were any sleep measures associated with clinically adjudicated cognitive impairment. Conclusion: In a predominantly AA sample of older adults, both the level and change (i.e., worsening) of sleep efficiency and WASO were associated with poorer cognitive function. Improving sleep health may support ADRD prevention and reduce health disparities.

Sirinart Tongsiri, Sue Levkoff, Dolores Gallagher-Thompson, Linda Teri, Ladson Hinton, Bussabong Wisetpholchai, Komatra Chuengsatiansup, Siranee Sihapark, Stacy Fritz, Hongtu Chen
Cultural Adaptation of the Reducing Disability in Alzheimer’s Disease (RDAD) Protocol for an Intervention to Reduce Behavioral and Psychological Symptoms of Dementia in Thailand
Abstract: Background: The Reducing Disability in Alzheimer’s Disease (RDAD) program is an evidence-based intervention found to be feasible for implementation in community settings in the United States, and effective in reducing depression, one of the major behavioral and psychological symptoms of dementia (BPSD). Objective: The goal of the study is to culturally adapt the RDAD for persons with dementia living in community settings of Thailand. Methods: Key adaptation steps included: 1) assess the community, 2) understand/select the intervention, 3) consult with experts/stakeholders, 4) decide what needs to be adapted, 5) adapt the original program, 6) train staff, and 7) pilot test the adapted materials. Results: Modifications to the original RDAD protocol included changes in number of sessions, mode of delivery, and the specific pleasant activities targeted. The pilot test demonstrated the feasibility and acceptance of the adapted RDAD intervention protocol. Implementers were able to comprehend and implement the core components of the intervention, while family members demonstrated ability to follow instructions, gain knowledge about dementia, and improve skills for setting up realistic goals. Conclusion: Following the key adaptation steps outlined above, we were able to successfully modify the RDAD for the Thai cultural context, maintaining core components of the original protocol. Program implementers demonstrated their ability to supervise family caregivers and help them gain the knowledge and skills needed to provide care for older adults with dementia. Findings from the pilot studies were incorporated into final training and intervention protocols currently being implemented and evaluated in a randomized implementation trial in Thailand.

Franka Mühlichen, Bernhard Michalowsky, Anika Rädke, Moritz Platen, Wiebke Mohr, Jochen René Thyrian, Wolfgang Hoffmann
Tasks and Activities of an Effective Collaborative Dementia Care Management Program in German Primary Care
Abstract: Background: Recent studies have demonstrated the efficiency of collaborative dementia care, which aims to improve post-diagnostic support. However, tasks carried out of such models are currently unknown, hindering its implementation. Objective: To describe tasks of a collaborative model of dementia care, analyze the association between specific task subgroups and number of tasks with patients' and caregivers’ characteristics and the impact of specific tasks on health-related quality of life (HRQoL). Methods: The analysis was based on 183 persons with dementia (PwD) who received dementia care management conducted by dementia-specific qualified nurses. A standardized, computer-assisted assessment was used to identify patients' and caregivers' unmet needs. Tasks carried out to address unmet needs were documented, categorized, and descriptively analyzed. We used multivariate regression models to identify socio-demographic and clinical factors associated with a specific subgroup of tasks or a higher number of tasks. Results: On average, 20.5 tasks were carried out per dyad (PwD and caregiver). 41% of tasks were categorized to cooperation with other healthcare providers, 39% to nursing care, and 19% to social support. Lower HRQoL and higher age, cognitive impairment, deficits in daily living activities, and depressive symptoms were significantly associated with a higher number of tasks. A higher number of cooperation tasks were associated with a higher gain in HRQoL. Conclusion: Patients' characteristics and HRQoL significantly determine the intensity of collaborative care interventions. Variability of the intensity should be considered in developing future studies and in the implementation into routine care.

Durong Chen, Fuliang Yi, Yao Qin, Jiajia Zhang, Xiaoyan Ge, Hongjuan Han, Jing Cui, Wenlin Bai, Yan Wu, Hongmei Yu, the Alzheimer’s Disease Neuroimaging Initiative
A Stacking Framework for Multi-Classification of Alzheimer’s Disease Using Neuroimaging and Clinical Features
Abstract: Background: Alzheimer’s disease (AD) is a severe health problem. Challenges still remain in early diagnosis. Objective: The objective of this study was to build a Stacking framework for multi-classification of AD by a combination of neuroimaging and clinical features to improve the performance. Methods: The data we used were from the Alzheimer’s Disease Neuroimaging Initiative database with a total of 493 subjects, including 125 normal control (NC), 121 early mild cognitive impairment, 109 late mild cognitive impairment (LMCI), and 138 AD. We selected structural magnetic resonance imaging (sMRI) feature by voting strategy. The imaging feature, demographic information, Mini-Mental State Examination, and Alzheimer’s Disease Assessment Scale-Cognitive Subscale were combined together as classification features. We proposed a two-layer Stacking ensemble framework to classify four types of people. The first layer represented support vector machine, random forest, adaptive boosting, and gradient boosting decision tree; the second layer was a logistic regression classifier. Additionally, we analyzed performance of only sMRI feature and combined features and compared the proposed model with four base classifiers. Results: The Stacking model combined with sMRI and non-imaging features outshined four base classifiers with an average accuracy of 86.96%. Compared with using sMRI data alone, sMRI combined with non-imaging features significantly improved diagnostic accuracy, especially in NC versus LMCI. Conclusion: The Stacking framework we used can improve performance in diagnosis of AD using combined features.

Minmin Leng*, Yue Sun*, Hui Chang, Zhiwen Wang *These authors contributed equally to this work.
Clustering Analysis of the Care Problems of People with Dementia Based on the Minimum Spanning Tree Algorithm: A Cross-Sectional Study
Abstract: Background: Recognizing the correlations between care problems of people with dementia could help clinicians choose treatment methods because related symptom groups might respond to the same treatment intervention. Objective: This study aimed to evaluate the prevalence of various care problems in people with dementia and to explore the core care problems and correlations between care problems of people with dementia. Methods: This cross-sectional study recruited family caregivers of people with dementia through memory clinics and WeChat groups. Care problems of people with dementia were measured using a care problems evaluation sheet, which involved three aspects: daily living care problems, behavioral and psychological symptoms, and safety risks. Clustering analysis of the care problems based on Kruskal's minimum spanning tree (MST) algorithm was performed in the Jupyter Notebook software to explore the core care problems and their correlations. Results: A total of 687 carer-patient pairs were included in the analysis. In general, the prevalence of having difficulty in language performance, agitated behavior, and incidence of falls was relatively higher than other care problems in people with dementia, which distressed their family caregivers. Through clustering analysis, the 63 care problems were clustered into 7 clusters and 7 core care problems were identified. Conclusion: The prevalence of various care problems of people living with dementia in China was relatively high. The information regarding correlations in clusters among care problems will help practitioners and policymakers to identify the core care problems and optimize more rational treatments for people with dementia.

Benjamin C. Shaw*, Henry C. Snider*, Andrew K. Turner, Diana J. Zajac, James F. Simpson, Steven Estus (Handling Associate Editor: Colin Combs) *These authors contributed equally to this work.
An Alternatively Spliced TREM2 Isoform Lacking the Ligand Binding Domain Is Expressed in Human Brain
Abstract: Background: Genetic variants in TREM2 are strongly associated with Alzheimer’s disease (AD) risk but alternative splicing in TREM2 transcripts has not been comprehensively described. Objective: Recognizing that alternative splice variants can result in reduced gene expression and/or altered function, we sought to fully characterize splice variation in TREM2. Methods: Human anterior cingulate autopsy tissue from 61 donors was used for end-point and quantitative PCR and western blotting to identify and quantify novel TREM2 isoforms. Results: In addition to previously described transcripts lacking exon 3 or exon 4, or retaining part of intron 3, we identified novel isoforms lacking exon 2, along with isoforms lacking multiple exons. Isoforms lacking exon 2 were predominant at approximately 10% of TREM2 mRNA in the brain. Expression of TREM2 and frequency of exon 2 skipping did not differ between AD samples and non-AD controls (p = 0.1268 and p = 0.4909, respectively). Further, these novel splice isoforms were also observed across multiple tissues with similar frequency (range 5.3 – 13.0%). We found that the exon 2 skipped isoform D2-TREM2 is translated to protein and localizes similarly to full-length TREM2 protein, that both proteins are primarily retained in the Golgi complex, and that D2-TREM2 is expressed in AD and non-AD brain. Conclusion: Since the TREM2 ligand binding domain is encoded by exon 2, and skipping this exon retains reading frame while conserving localization, we hypothesize that D2-TREM2 acts as an inhibitor of TREM2 and targeting TREM2 splicing may be a novel therapeutic pathway for AD.

Jordi Sarto*, Gerard Mayà*, Laura Molina-Porcel, Mircea Balasa, Ellen Gelpi, Iban Aldecoa, Sergi Borrego-Écija, Jose Contador, Teresa Ximelis, Miguel Vergara, Anna Antonell, Raquel Sánchez-Valle, Albert Lladó, for the Neurological Tissue Bank, Biobanc-Hospital Clínic Barcelona-IDIBAPS Collaborative Group (Handling Associate Editor: Andrew Robinson) *These authors contributed equally to this work.
Evolution of Clinical-Pathological Correlations in Early-Onset Alzheimer’s Disease Over a 25-Year Period in an Academic Brain Bank
Abstract: Background: Early onset Alzheimer’s disease (EOAD) represents a diagnostic challenge and is associated with a high diagnostic delay and misdiagnosis. Objective: To describe clinical and pathological data from a pathologically confirmed EOAD cohort and evaluate evolving trends in clinical-pathological correlation accuracy. Methods: Retrospective review of clinical and neuropathological data of pathologically confirmed EOAD patients (age at onset [AAO] <60). Comparison between two periods: 1994-2009 and 2010-2018. Results: Eighty brain donors were included. Mean AAO, age at death, and diagnostic delay was 55, 66, and 3 years, respectively. Twenty-nine percent had a nonamnestic presentation. Sixteen percent were given a non-AD initial clinical diagnosis (initial misdiagnosis) and 14% received a final misdiagnosis. Nonamnestic presentation patients received more misdiagnoses than amnestic presentation ones (39% versus 7% and 39% versus 3.5%, on initial and final misdiagnosis, respectively). When comparing both time periods, a trend towards a higher diagnostic accuracy in the 2010-2018 period was observed, mainly on initial misdiagnosis in nonamnestic presentation patients (53% versus 13%, p=0.069). Diagnostic delay was similar between both periods. Cerebral amyloid angiopathy (96%) and Lewy body co-pathology (55%) were very frequent, while limbic-predominant age-related TDP-43 encephalopathy pathologic changes were only present in 12.5%. Conclusion: In the last decade, there has been a trend towards improved diagnostic accuracy in EOAD, which might be explained by improved diagnostic criteria, increasing experience on EOAD and the beginning of the use of biomarkers, although diagnostic delay remains similar. Concomitant neuropathology was very frequent despite the relatively young age of brain donors.

Chit Tong Lio, Tim Kacprowski, Maik Klaedtke, Lars R. Jensen, Yvonne Bouter, Thomas A. Bayer, Andreas W. Kuss (Handling Associate Editor: Yuk Yee Leung)
Small RNA Sequencing in the Tg4-42 Mouse Model Suggests the Involvement of snoRNAs in the Etiology of Alzheimer’s Disease
Abstract: Background: The Tg4-42 mouse model for sporadic Alzheimer’s disease (AD) has unique features, as the neuronal expression of wild type N-truncated Aβ4-42 induces an AD-typical neurological phenotype in the absence of plaques. It is one of the few models developing neuron death in the CA1 region of the hippocampus. As such, it could serve as a powerful tool for preclinical drug testing and identification of the underlying molecular pathways that drive the pathology of AD. Objective: The aim of this study was to use a differential co-expression analysis approach for analyzing a small RNA sequencing dataset from a well-established murine model in order to identify potentially new players in the etiology of AD. Methods: To investigate small nucleolar RNAs in the hippocampus of Tg4-42 mice, we used RNA-Seq data from this particular tissue and, instead of analyzing the data at single gene level, employed differential co-expression analysis, which takes the comparison to gene pair level and thus affords a new angle to the interpretation of these data. Results: We identified two clusters of differentially correlated small RNAs, including Snord55, Snord57, Snord49a, Snord12, Snord38a, Snord99, Snord87, Mir1981, Mir106b, Mir30d, Mir598, and Mir99b. Interestingly, some of them have been reported to be functionally relevant in AD pathogenesis, as AD biomarkers, regulating tau phosphorylation, TGF-β receptor function or Aβ metabolism. Conclusion: The majority of snoRNAs for which our results suggest a potential role in the etiology of AD were so far not conspicuously implicated in the context of AD pathogenesis and could thus point towards interesting new avenues of research in this field.

Katherine L. Webb, Joanne Ryan, Rory Wolfe, Robyn L. Woods, Raj C. Shah, Anne M. Murray, Suzanne G. Orchard, Elsdon Storey
Test-Retest Reliability and Minimal Detectable Change of Four Cognitive Tests in Community-Dwelling Older Adults
Abstract: Background: Cognitive test-retest reliability measures can be used to evaluate meaningful changes in scores. Objective: This analysis aimed to develop a comprehensive set of test-retest reliability values and minimal detectable change (MDC) values for a cognitive battery for community-dwelling older individuals in Australia and the U.S., for use in clinical practice. Methods: Cognitive scores collected at baseline and year 1, in the ASPirin in Reducing Events in the Elderly clinical trial were used to calculate intraclass correlation coefficients (ICC) for four tests: Modified Mini-Mental State examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R), single-letter Controlled Oral Word Association Test (COWAT-F), and Symbol Digit Modalities Test (SDMT). 16,956 participants aged 70 years and over (65 years and over for U.S. minorities) were included. ICCs were used to calculate MDC values for eight education and ethno-racial subgroups. Results: All four cognitive tests had moderate (ICC > 0.5) to good (ICC > 0.7) test-retest reliability. ICCs ranged from 0.53 to 0.63 (3MS), 0.68 to 0.77 (SDMT), 0.56 to 0.64 (COWAT-F), 0.57 to 0.69 (HVLT-R total recall), and 0.57 to 0.70 (HVLT-R delayed recall) across the subgroups. MDC values ranged from 6.60 to 9.95 (3MS), 12.42 to 15.61 (SDMT), 6.34 to 8.34 (COWAT-F), 8.13 to 10.85 (HVLT-R total recall), and 4.00 to 5.62 (HVLT-R delayed recall). Conclusion: This large cohort of older individuals provides test-retest reliability and MDC values for four widely employed tests of cognitive function. These results can aid interpretation of cognitive scores and decline instead of relying on cross-sectional normative data alone.

Rolando I. Castillo-Passi*, Rodrigo C. Vergara*, Nicole K. Rogers, Daniela Ponce, Magdalena Bennett, María Isabel Behrens *These authors contributed equally to this work.
Cancer History Is Associated with Slower Speed of Cognitive Decline in Patients with Amnestic Cognitive Impairment
Abstract: Background: Several epidemiological studies report a negative association between Cancer and Alzheimer’s disease (AD). Objective: To characterize the trajectories of memory loss in individuals with early amnestic cognitive impairment with and without history of previous cancer. Methods: Cognitive deterioration was assessed using the Montreal Cognitive Assessment (MoCA) or MoCA-Memory Index Score (MoCA-MIS) biannually in subjects with early amnestic cognitive impairment followed-up retrospectively from 2007 to 2021. History of Cancer was obtained from clinical records. Simple linear regressions of MoCA-MIS scores were calculated for each subject and analyzed with K-means cluster analysis to identify subgroups with different cognitive decline trajectories. 2 and t tests were used for descriptive categorical and continuous variables and mixed multiple linear regressions to determine cognitive decline covariates. Results: Analysis of the trajectory of cognitive decline in 141 subjects with early amnestic cognitive impairment identified two subgroups: Fast (n=60) and Slow (n=81) progressors. At baseline Fast progressors had better MoCA-MIS (p<0.001) and functionality (CDR p=0.02, AD8 p=0.05), took less anti-dementia medications (p=0.005), and had higher depression rates (p=0.02). Interestingly, Fast progressors slowed their speed of memory decline (from 1.6 to 1.1 MoCA-MIS points/year) and global cognitive decline (from 2.0 to 1.4 total MoCA points/year) when Cancer history was present. Conclusion: Two trajectories of amnestic cognitive decline were identified, possibly derived from different neurophysiopathologies or clinical stages. This study suggests that a history of previous Cancer slows down amnestic cognitive decline, specifically in a subgroup of subjects with depression at baseline and accelerated deterioration at follow-up.

Mengzi Sun, Ling Wang, Yinpei Guo, Shoumeng Yan, Jing Li, Xuhan Wang, Xiaotong Li, Bo Li
The Association Among Inflammatory Diet, Glycohemoglobin, and Cognitive Function Impairment in the Elderly: Based on the NHANES 2011-2014
Abstract: Background: Dietary inflammatory index (DII) was associated with Type 2 diabetes mellitus and cognitive function impairment (CFI). Objective: The aim of this study was to explore whether the associations among DII, glycohemoglobin (HbA1c), and CFI were similar in the participants with or without diabetes. Methods: A total of 1,198 participants aged 60 and over from the National Health and Nutrition Examination Survey (NHANES) in 2011-2014 were involved in this study, dividing into subgroups as diabetes and non-diabetes for further analysis. Results: We found that participants with pro-inflammatory diet had higher proportion of CFI patients (p<0.05). Pro-inflammatory diet and HbA1c were positively associated with the risk of CFI; participants with pro-inflammatory diet was 1.479 times on occurrence of CFI compared with anti-inflammatory diet group. The interaction between inflammatory diet and HbA1c was positive on the risk of CFI and was negative on the CERAD-immediate and CERAD-delayed, respectively. Among the participants without diabetes, the associations of Energy-adjusted DII (E-DII) with Animal Fluency test and Digit Symbol Substitution Test (DSST) were partially mediated by HbA1c, and the mediated proportion was 5.8% and 6.6%, respectively. However, there was no such mediation effect in the diabetes patients. Conclusion: In elderly participants without diabetes, there was an interaction between inflammatory diet and HbA1c on the association with CFI, especially for the dimension of CERAD-immediate and CERAD-delayed. Besides, the associations of E-DII with Animal Fluency test and DSST were partially mediated by HbA1c. For diabetic patients, HbA1c, rather than the inflammatory diet has a positive effect on the CFI risk.

Alexandra Wuttke-Linnemann, Clara Henrici, Nadine Skoluda, Urs M. Nater, Kristina Endres, Andreas Fellgiebel
Psychobiological Monitoring of a Home-Based Dyadic Intervention for People Living with Dementia and Their Caregivers: Added Value to Evaluate Treatment Success and Understand Underlying Mechanisms
Abstract: Background: Research concerning people living with dementia (PwD) and their informal caregivers (ICs) has recently begun to focus on dyadic aspects of psychosocial interventions. Objective: We adapted a dyadic psychosocial intervention and examined its effects on psychobiological stress in daily life. Methods: Twenty-four PwD-caregiver dyads were visited seven times at home by specialized nursing staff. Momentary subjective stress, salivary cortisol (sCort), and salivary alpha-amylase (sAA) were measured in PwD and ICs before and after each home visit as well as six times per day at two days each at the beginning and end of the intervention as part of an ambulatory assessment. Hair cortisol concentrations (HCC) were measured twice. Results: After each home visit session, ICs reported lower subjective stress. sCort was lower in both ICs and PwD, whereas sAA did not change. In daily life, area under the curve (AUCg) concerning sCort secretion indicated that PwD had lower sCort daily output at the end of the intervention, and AUCg concerning subjective stress indicated that both PwD and ICs reported lower subjective stress than at the beginning of the intervention. AUCg concerning sAA did not change over time in either group. HCC did not vary over time but increased with disease severity. Conclusion: The psychosocial intervention reduced psychobiological stress but affected psychobiological stress measures differently in PwD and ICs. In particular, the discrepancy between subjective and physiological markers of stress in PwD emphasizes the added value to evaluate treatment success and understand underlying mechanisms as a complement to self-reports.