Peripheral sTREM2-Related Inflammatory Activity Alterations in Early-Stage Alzheimer's Disease.

Alzheimer's disease (AD) has been linked to multiple immune system-related genetic variants. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. In addition, soluble TREM2 (sTREM2) isoform is elevated in cerebrospinal fluid in the early stages of AD and is associated with slower cognitive decline in a disease stage-dependent manner. Multiple studies have reported an altered peripheral immune response in AD. However, less is known about the relationship between peripheral sTREM2 and an altered peripheral immune response in AD. The objective of this study was to explore the relationship between human plasma sTREM2 and inflammatory activity in AD. The hypothesis of this exploratory study was that sTREM2-related inflammatory activity differs by AD stage. We observed different patterns of inflammatory activity across AD stages that implicate early-stage alterations in peripheral sTREM2-related inflammatory activity in AD. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups that was lost in later AD-related stages with high levels in mild cognitive impairment. Although multiple other inflammatory factors either differed significantly between groups or were significantly correlated with sTREM2 within specific groups, three inflammatory factors (fibroblast growth factor-2, GM-CSF, and IL-1ß) are notable because they exhibited both lower levels in AD, compared with mild cognitive impairment, and a change in the relationship with sTREM2. This evidence provides important support to the hypothesis that sTREM2-related inflammatory activity alterations are AD stage specific and provides critical information for therapeutic strategies focused on the immune response.

Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. METHODS: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. RESULTS: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). DISCUSSION: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. HIGHLIGHTS: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.

ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium.

INTRODUCTION: The National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis. METHODS: The cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated. RESULTS: We observed a significant difference in Aß42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage. DISCUSSION: This suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity. HIGHLIGHTS: Some A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.

Initial non-amnestic symptoms relate to faster rate of functional and cognitive decline compared to amnestic symptoms in neuropathologically confirmed dementias.

INTRODUCTION: The relationship between initial cognitive symptoms and subsequent rate of clinical decline is important in clinical care and the design of dementia clinical trials. METHODS: This retrospective longitudinal, autopsy-confirmed, cohort study among 2426 participants in the National Alzheimer's Coordinating Center database included Alzheimer's disease (AD) pathology, n = 1187; Lewy body pathology (LBP), n = 331; and mixed pathology (AD-LBP), n = 904. The predominant initial cognitive symptom was assessed clinically. Linear mixed models evaluated the longitudinal outcome of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. RESULTS: Non-amnestic initial symptoms had a faster rate of decline than amnestic symptoms in all three groups. Language symptoms had a faster rate of decline in all three groups. Executive symptoms had a faster rate of decline than amnestic in AD and AD-LBP. There was a similar trend for visuospatial symptoms in AD-LBP. DISCUSSION: Initial cognitive symptoms, despite varied underlying pathology, are a predictor of longitudinal functional outcomes among dementias. HIGHLIGHTS: Initial non-amnestic symptoms had a faster rate of longitudinal cognitive and functional decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores than amnestic symptoms among Alzheimer's disease, Lewy body pathology, and mixed neuropathology. Given the relative size of CDR-SB changes in Alzheimer's disease clinical trials, clarifying the nature of initial symptoms could be an important variable in ensuring appropriately designed clinical trials.

Metabolic labeling unveils alterations in the turnover of HDL-associated proteins during diabetes progression in mice.

Several aspects of diabetes pathophysiology and complications result from hyperglycemia-induced alterations in the structure and function of plasma proteins. Furthermore, insulin has a significant influence on protein metabolism by affecting both the synthesis and degradation of proteins in various tissues. To understand the role of progressive hyperglycemia on plasma proteins, in this study, we measured the turnover rates of high-density lipoprotein (HDL)-associated proteins in control (chow diet), prediabetic [a high-fat diet (HFD) for 8 wk] or diabetic [HFD for 8 wk with low-dose streptozotocin (HFD + STZ) in weeks 5-8 of HFD] C57BL/6J mice using heavy water (2H2O)-based metabolic labeling approach. Compared with control mice, HFD and HFD + STZ mice showed elevations of fasting plasma glucose levels in the prediabetic and diabetic range, respectively. Furthermore, the HFD and HFD + STZ mice showed increased hepatic triglyceride (TG) levels, total plasma cholesterol, and plasma TGs. The kinetics of 40 proteins were quantified using the proteome dynamics method, which revealed an increase in the fractional synthesis rate (FSR) of HDL-associated proteins in the prediabetic mice compared with control mice, and a decrease in FSR in the diabetic mice. The pathway analysis revealed that proteins with altered turnover rates were involved in acute-phase response, lipid metabolism, and coagulation. In conclusion, prediabetes and diabetes have distinct effects on the turnover rates of HDL proteins. These findings suggest that an early dysregulation of the HDL proteome dynamics can provide mechanistic insights into the changes in protein levels in these conditions.NEW & NOTEWORTHY This study is the first to examine the role of gradual hyperglycemia during diabetes disease progression on HDL-associated protein dynamics in the prediabetes and diabetic mice. Our results show that the fractional synthesis rate of HDL-associated proteins increased in the prediabetic mice whereas it decreased in the diabetic mice compared with control mice. These kinetic changes can help to elucidate the mechanism of altered protein levels and HDL dysfunction during diabetes disease progression.

DNA methylation of TOMM40-APOE-APOC2 in Alzheimer's disease.

The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer's disease (AD). Multiple regulatory elements, spanning the extended TOMM40-APOE-APOC2 region, regulate gene expression at this locus. Regulatory element DNA methylation changes occur under different environmental conditions, such as disease. Our group and others have described an APOE CpG island as hypomethylated in AD, compared to cognitively normal controls. However, little is known about methylation of the larger TOMM40-APOE-APOC2 region. The hypothesis of this investigation was that regulatory element methylation levels of the larger TOMM40-APOE-APOC2 region are associated with AD. The aim was to determine whether DNA methylation of the TOMM40-APOE-APOC2 region differs in AD compared to cognitively normal controls in post-mortem brain and peripheral blood. DNA was extracted from human brain (n = 12) and peripheral blood (n = 67). A methylation array was used for this analysis. Percent methylation within the TOMM40-APOE-APOC2 region was evaluated for differences according to tissue type, disease state, AD-related biomarkers, and gene expression. Results from this exploratory analysis suggest that regulatory element methylation levels within the larger TOMM40-APOE-APOC2 gene region correlate with AD-related biomarkers and TOMM40 or APOE gene expression in AD.

Impact of Alzheimer's Disease, Lewy Body and Vascular Co-Pathologies on Clinical Transition to Dementia in a National Autopsy Cohort.

AIMS: We examined the effect of vascular or Lewy body co-pathologies in subjects with autopsy-confirmed Alzheimer's disease (AD) on the rate of cognitive and functional decline and transition to dementia. METHODS: In an autopsy sample of prospectively characterized subjects from the National Alzheimer's Coordinating Center database, neuropathology diagnosis was used to define the groups of pure AD (pAD, n = 84), mixed vascular and AD (ADV, n = 54), and mixed Lewy body disease and AD (ADLBD, n = 31). Subjects had an initial Clinical Dementia Rating-Global (CDR-G) score <1, Mini-Mental State Examination ≥15, a final visit CDR-G >1, ≥3 evaluations, and Braak tangle stage ≥III. We compared the rate of cognitive and functional decline between the groups. RESULTS: The rate of functional and cognitive decline was lower for ADV, and ADV patients had less severe deficits on CDR-G and the CDR-Sum of Boxes scores at the last visit than pAD and ADLBD patients. No significant differences were noted between ADLBD and pAD patients. After controlling for age at death, the odds of reaching CDR ≥1 at the last visit were lower in the ADV subjects compared to the pAD subjects. CONCLUSIONS: The mean rate of functional and cognitive decline among ADV subjects was slower than among either pAD or ADLBD patients. Vascular pathology did not increase the odds of attaining CDR ≥1 when occurring with AD in this national cohort.

Higher working memory predicts slower functional decline in autopsy-confirmed Alzheimer's disease.

BACKGROUND: There is heterogeneity in the pattern of early cognitive deficits in Alzheimer's disease (AD). However, whether the severity of initial cognitive deficits relates to different clinical trajectories of AD progression is unclear. OBJECTIVE: To determine if deficits in specific cognitive domains at the initial visit relate to the rate of progression in clinical trajectories of AD dementia. METHODS: 68 subjects from the National Alzheimer's Coordinating Center database who had autopsy-confirmed AD as the primary diagnosis and at least 3 serial assessments a year apart, with a Mini-Mental State Examination (MMSE) score >15 and a Clinical Dementia Rating Scale-Global (CDR-G) score ≤1 at the initial visit were included. A mixed regression model was used to examine the association between initial neuropsychological performance and rate of change on the MMSE and CDR Sum of Boxes. RESULTS: Preservation of working memory, but not episodic memory, in the mild cognitive impairment and early dementia stages of AD relates to slower rate of functional decline. DISCUSSION: These findings are relevant for estimating the rate of decline in AD clinical trials and in counseling patients and families. Improving working memory performance as a possible avenue to decrease the rate of functional decline in AD dementia warrants closer investigation.

Hemispheric asymmetries in hippocampal volume related to memory in left and right temporal variants of frontotemporal degeneration.

In addition to Alzheimer's disease (AD), the hippocampus is now known to be affected in variants of frontotemporal degeneration (FTD). In semantic variant primary progressive aphasia (svPPA), characterized by language impairments, hippocampal atrophy is greater in the left hemisphere. Nonverbal impairments (e.g., visual object recognition) are prominent in the right temporal variant of FTD (rtvFTD), and hippocampal atrophy may be greater in the right hemisphere. In this study we examined the hypothesis that leftward hippocampal asymmetry (predicted in svPPA) would be associated with selective verbal memory impairments (with relative preservation of visual memory), while rightward asymmetry (predicted in rtvFTD) would be associated with the opposite pattern (greater visual memory impairment). In contrast, we predicted that controls and individuals in the amnestic mild cognitive impairment stage of AD (aMCI), both of whom were expected to show symmetrical hippocampal volumes, would show roughly equivalent scores in verbal and visual memory. Participants completed delayed recall tests with words and geometric shapes, and hippocampal volumes were assessed with MRI. The aMCI sample showed symmetrical hippocampal atrophy, and similar degree of verbal and visual memory impairment. The svPPA sample showed greater left hippocampal atrophy and verbal memory impairment, while rtvFTD showed greater right hippocampal atrophy and visual memory impairment. Greater asymmetry in hippocampal volumes was associated with larger differences between verbal and visual memory in the FTD samples. Unlike AD, asymmetry is a core feature of brain-memory relationships in temporal variants of FTD.

Multi-shell diffusion MRI of the fornix as a biomarker for cognition in Alzheimer's disease.

BACKGROUND AND PURPOSE: A substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early AD are lagging. Diffusion MRI (dMRI) of the fornix is a candidate biomarker for early AD-related cognitive changes but is susceptible to bias due to partial volume averaging (PVA) with cerebrospinal fluid. The purpose of this work is to leverage multi-shell dMRI to correct for PVA and to evaluate PVA-corrected dMRI measures in fornix as a biomarker for cognition in AD. METHODS: Thirty-three participants in the Cleveland Alzheimer's Disease Research Center (CADRC) (19 with normal cognition (NC), 10 with mild cognitive impairment (MCI), 4 with dementia due to AD) were enrolled in this study. Multi-shell dMRI was acquired, and voxelwise fits were performed with two models: 1) diffusion tensor imaging (DTI) that was corrected for PVA and 2) neurite orientation dispersion and density imaging (NODDI). Values of tissue integrity in fornix were correlated with neuropsychological scores taken from the Uniform Data Set (UDS), including the UDS Global Composite 5 score (UDSGC5). RESULTS: Statistically significant correlations were found between the UDSGC5 and PVA-corrected measure of mean diffusivity (MDc, r = -0.35, p < 0.05) from DTI and the intracelluar volume fraction (ficvf, r = 0.37, p < 0.04) from NODDI. A sensitivity analysis showed that the relationship to MDc was driven by episodic memory, which is often affected early in AD, and language. CONCLUSION: This cross-sectional study suggests that multi-shell dMRI of the fornix that has been corrected for PVA is a potential biomarker for early cognitive domain changes in AD. A longitudinal study will be necessary to determine if the imaging measure can predict cognitive decline.

The Media Coverage of Bruce Willis Reveals Unfamiliarity With Frontotemporal Degeneration.

In 2022, Bruce Willis' family released a statement saying that he had been diagnosed with aphasia (an acquired language impairment) and would no longer be acting. Ten months later, the Willis family released another statement indicating that he received a more specific diagnosis of frontotemporal degeneration (FTD). This resulted in an explosion of media coverage, as prominent news outlets scrambled to produce stories describing FTD to a public largely unfamiliar with the disease. The quality of these stories varied widely, and in many cases the relationship between aphasia and FTD was misrepresented, as were basic descriptions and facts about FTD. FTD refers to a class of protein-misfolding diseases that are a common cause of aphasias due to neurodegeneration, or primary progressive aphasias (PPA). Rather than describing how FTD was discovered to be the underlying source of Mr. Willis' aphasia, many reports described his aphasia as "progressing into" FTD, implying they are two different disorders. Furthermore, these reports used the terminology of frontotemporal "dementia" rather than "degeneration", a term that invokes many stereotypes in the public imagination and may have contributed to misrepresentations in coverage. Instead of focusing on the language symptoms of PPA, reports often emphasized the personality and behavioral changes more closely associated with other variants of FTD. The substance of various facts, such as how common FTD is and how it can be treated, varied widely across reports. In sum, the media coverage of Mr. Willis' diagnosis reveals the extent to which the media and general public are uninformed about FTD and PPA. The remedy for this problem is to promote greater awareness of FTD, in both the public and the medical provider class. The Willis family's disclosure was a courageous act that helped bring much-needed attention to this disease.

Metabolic syndrome biomarkers relate to rate of cognitive decline in MCI and dementia stages of Alzheimer's disease.

BACKGROUND: The relationship between biomarkers of metabolic syndrome and insulin resistance, plasma triglyceride/HDL cholesterol (TG/HDL-C) ratio, on the rate of cognitive decline in mild cognitive impairment (MCI) and dementia stages of Alzheimer's disease (AD) is unknown. The role of peripheral and cerebrospinal fluid (CSF) levels of Apolipoprotein A1 (ApoA1), a key functional component of HDL, on cognitive decline also remains unclear among them. Here we evaluate baseline plasma TG/HDL-C ratio and CSF and plasma ApoA1 levels and their relation with cognitive decline in the MCI and Dementia stages of AD. PATIENTS AND METHODS: A retrospective longitudinal study (156 participants; 106 MCI, 50 AD dementia) from the Alzheimer's Disease Neuroimaging Initiative, with an average of 4.0 (SD 2.8) years follow-up. Baseline plasma TG/HDL-C, plasma, and CSF ApoA1 and their relationship to inflammation and blood-brain barrier (BBB) biomarkers and longitudinal cognitive outcomes were evaluated. Multivariable linear mixed effect models were used to assess the effect of baseline analytes with longitudinal changes in Mini-Mental State Exam (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Logical Memory delayed recall (LM) score after controlling for well-known covariates. RESULTS: A total of 156 participants included 98 women, 63%; mean age was 74.9 (SD 7.3) years. At baseline, MCI and dementia groups did not differ significantly in TG/HDL-C (Wilcoxon W statistic = 0.39, p = 0.39) and CSF ApoA1 levels (W = 3642, p = 0.29), but the dementia group had higher plasma ApoA1 than the MCI group (W = 4615, p = 0.01). Higher TG/HDL-C ratio was associated with faster decline in CDR-SB among MCI and dementia groups. Higher plasma ApoA1 was associated with faster decline in MMSE and LM among MCI, while in contrast higher CSF ApoA1 levels related to slower cognitive decline in MMSE among MCI. CSF and plasma ApoA1 also show opposite directional correlations with biomarkers of BBB integrity. CSF but not plasma levels of ApoA1 positively correlated to inflammation analytes in the AGE-RAGE signaling pathway in diabetic complications (KEGG ID:KO04933). CONCLUSIONS: Biomarkers of metabolic syndrome relate to rate of cognitive decline among MCI and dementia individuals. Elevated plasma TG/HDL-C ratio and plasma ApoA1 are associated with worse cognitive outcomes in MCI and dementia participants. CSF ApoA1 and plasma ApoA1 likely have different roles in AD progression in MCI stage.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Clinical severity of Huntington's disease does not always correlate with neuropathologic stage.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a triplet-repeat, CAG expansion mutation. Although CAG repeat length is thought to correlate with pathologic burden and disease severity, considerable variability in clinical phenotype remains. This study examined whether neuropathologic burden at autopsy corresponded with severity of clinical phenotype in HD. The brains of 24 patients with a clinical and genetic diagnosis of HD were analyzed at autopsy. Subjects were stratified on the basis of Vonsattel staging as mild/moderate (stage 1-2; n = 7) or severe (stage 3-4; n = 17). Clinical severity was assessed on the basis of the Mini-Mental State Examination (MMSE; 0-30) and two Unified Huntington's Disease Rating Scale (UHDRS) functional components: the Independence Scale (10-100) and the Total Functional Capacity (0-13). Mild/moderate subjects were significantly older, had lower CAG repeat lengths, and greater fixed brain weights than those classified as severe. Patients who were pathologically classified as severe at autopsy were, on average, younger at age of onset and death and less well educated. Despite obvious clinical and pathological differences between mild-moderate and severe HD subjects at autopsy, mean MMSE scores of the two groups before death were surprisingly similar. Correlations between Vonsattel stage and functional assessment scores before death were low and not statistically significant. Our results suggest that the extent of striatal changes in HD may not always correlate with clinical disease severity as measured by UHDRS functional scales.

Seizures in juvenile Huntington's disease: frequency and characterization in a multicenter cohort.

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult-onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic-clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required.

Association of Variation in Behavioral Symptoms With Initial Cognitive Phenotype in Adults With Dementia Confirmed by Neuropathology.

IMPORTANCE: Behavioral and psychological symptoms of dementia (BPSDs) in association with amnestic and nonamnestic cognitive phenotypes have not been evaluated across diagnoses of Alzheimer disease pathology (ADP), Lewy body-related pathology (LRP), and mixed pathology (ADP-LRP). OBJECTIVES: To determine the clinical phenotypes at the initial visit that are associated with the nature and severity of BPSDs in patients with ADP, LRP, and ADP-LRP. DESIGN, SETTING, AND PARTICIPANTS: This retrospective longitudinal cohort study included 2422 participants with neuropathologically confirmed ADP, LRP, or mixed ADP-LRP in the National Alzheimer Coordinating Center database from June 20, 2005, to September 4, 2019. Participants had a mean (SD) interval of 5.5 (2.8) years from initial visit to autopsy. MAIN OUTCOMES AND MEASURES: Clinician-determined diagnosis of change across 10 BPSDs (agitation, apathy, depression, delusions, disinhibition, auditory hallucinations, visual hallucinations, irritability, personality change, and rapid eye movement [REM] sleep behavior) and the highest severity score for behavioral change on the Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: A total of 2422 participants (1187 with ADP, 904 with ADP-LRP, and 331 with LRP) were included in the analysis (1446 men [59.7%]; mean [SD] age, 74.4 [10.1] years). Compared with initial amnestic symptoms, executive symptoms were associated with a higher risk for 7 of the 10 BPSDs (hazard ratio [HR] range, 1.28-2.45), and visuospatial symptoms were associated with a higher risk for 2 of the 10 BPSDs (HR range, 1.91-2.51), but neither were associated with a low risk for any BPSD. Language symptoms were associated with a low risk of onset for 3 of 10 BPSDs (HR range, 0.43-0.79) and a high risk for 1 BPSD (personality change) (HR, 1.42 [95% CI, 1.10-1.83]). Participants with LRP had a lower risk for agitation (HR, 0.74 [95% CI, 0.60-0.92]), disinhibition (HR, 0.78 [95% CI, 0.62-0.99]), and irritability (HR, 0.81 [95% CI, 0.68-0.96]) and a higher risk for apathy (HR, 1.19 [95% CI, 1.02-1.38]), depression (HR, 1.32 [95% CI, 1.12-1.55]), auditory (HR, 2.00 [95% CI, 1.37-2.93]) and visual (HR, 2.78 [95% CI, 2.21-3.49]) hallucinations, and REM sleep behavior changes (HR, 4.77 [95% CI, 3.61-6.31]) compared with the ADP group. The ADP-LRP group had a higher risk for delusions (HR, 1.27 [95% CI, 1.08-1.48]), auditory (HR, 1.62 [95% CI, 1.21-2.15]) and visual (HR, 1.57 [95% CI, 1.30-1.89]) hallucinations, and REM sleep behavior changes (HR, 2.10 [95% CI, 1.63-2.70]) than the ADP group and a lower risk for visual hallucinations (HR, 0.56 [95% CI, 0.45-0.71]) and REM sleep behavior changes (HR, 0.44 [95% CI, 0.34-0.57) than the LRP group. Overall, women showed a lower risk of agitation (HR, 0.86 [95% CI, 0.75-0.98]), apathy (HR, 0.79 [95% CI, 0.71-0.87]), visual hallucinations (HR, 0.76 [95% CI, 0.64-0.90]), irritability (HR, 0.77 [95% CI, 0.69-0.86]), and REM sleep behavior change (HR, 0.45 [95% CI, 0.35-0.58]) and a higher risk of depression (HR, 1.26 [95% CI, 1.13-1.41]). Older age was associated with a lower risk of most BPSDs (HR range, 0.98-0.99) except delusions (HR, 1.00 [95% CI, 1.00-1.01]) and auditory hallucinations (HR, 0.99 [95% CI, 0.97-1.00]) and a low NPI-Q composite score (ß = -0.07 [95% CI, -0.08 to -0.05]; P < .001). CONCLUSIONS AND RELEVANCE: These findings suggest that the risks of BPSDs differ with respect to the initial cognitive phenotype, underlying neuropathology, age, and sex. Awareness of these associations could be helpful in dementia management.

Association of crossword puzzle participation with memory decline in persons who develop dementia.

Participation in cognitively stimulating leisure activities such as crossword puzzles may delay onset of the memory decline in the preclinical stages of dementia, possibly via its effect on improving cognitive reserve. We followed 488 initially cognitively intact community residing individuals with clinical and cognitive assessments every 12-18 months in the Bronx Aging Study. We assessed the influence of crossword puzzle participation on the onset of accelerated memory decline as measured by the Buschke Selective Reminding Test in 101 individuals who developed incident dementia using a change point model. Crossword puzzle participation at baseline delayed onset of accelerated memory decline by 2.54 years. Inclusion of education or participation in other cognitively stimulating activities did not significantly add to the fit of the model beyond the effect of puzzles. Our findings show that late life crossword puzzle participation, independent of education, was associated with delayed onset of memory decline in persons who developed dementia. Given the wide availability and accessibility of crossword puzzles, their role in preventing cognitive decline should be validated in future clinical trials.

Impact of APOE ε4 genotype on initial cognitive symptoms differs for Alzheimer's and Lewy body neuropathology.

BACKGROUND: APOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ε4 genotype on initial cognitive symptoms among those with Alzheimer's disease pathology (ADP) and Lewy-related pathology (LRP). METHODS: A retrospective cohort study of 2288 participants with neuropathology confirmed ADP or LRP in the National Alzheimer's Coordinating Center database, who had initial cognitive symptoms documented and had a Clinical Dementia Rating-Global (CDR-G) score ≤ 1 (cognitively normal, MCI, or early dementia). Unadjusted and adjusted logistic regression models taking into account age at evaluation, sex, and education examined the relationship between APOE ε4 genotype and initial symptoms (memory, executive, language visuospatial) among ADP with LRP and ADP-LRP groups. RESULTS: One thousand three hundred three participants met criteria for ADP alone, 90 for LRP alone, and 895 for co-existing ADP and LRP (ADP-LRP). Younger age increased odds of non-amnestic symptoms across all three groups. In the adjusted model among ADP, APOE ε4 carriers had higher odds of amnestic initial symptoms 1.5 [95% CI, 1.7-2.14, p = 0.003] and lower odds of initial language symptoms 0.67 [95% CI, 0.47-0.96, p = 0.03] than non-carriers. The odds for these two symptoms were not different between ADP and mixed ADP-LRP groups. Female sex and higher education increased odds of initial language symptoms in the ADP group in the adjusted model. In the unadjusted model, APOE ε4 carriers with LRP had a higher odds of visuospatial initial symptoms 21.96 [95% CI, 4.02-110.62, p < 0.0001], while no difference was noted for initial executive/attention symptoms. Among LRP, the odds of APOE ε4 on amnestic symptom was not significant; however, the interaction effect evaluating the difference in odds ratios of amnestic symptom between ADP and LRP groups also did not reach statistical significance. CONCLUSIONS: The odds of specific initial cognitive symptoms differed between ADP and LRP among APOE ε4 carriers compared to non-carriers. The odds of initial amnestic symptom was higher among ADP APOE ε4 carriers and the odds of visuospatial initial symptom was higher with LRP APOE ε4 carriers. This supports the hypothesis that APOE ε4 differentially impacts initial cognitive symptoms together with underlying neuropathology.

Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes.

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aß42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ.

Hypertension and Hypercholesterolemia Modify Dementia Risk in Relation to APOEɛ4 Status.

BACKGROUND: There is significant interest in understanding the role of modifiable vascular risk factors contributing to dementia risk across age groups. OBJECTIVE: Risk of dementia onset was assessed in relation to vascular risk factors of hypertension and hypercholesterolemia among cognitively normal APOEɛ4 carriers and non-carriers. METHODS: In a sample of prospectively characterized longitudinal cohort from the National Alzheimer's Coordinating Center database, 9,349 participants met criteria for normal cognition at baseline, had a CDR-Global (CDR-G) score of zero, and had concomitant data on APOEɛ4 status and medical co-morbidities including histories of hypertension and hypercholesterolemia. Multivariable Cox proportional hazards models adjusted for well-known potential confounders were used to compare dementia onset among APOEɛ4 carriers and non-carriers by young (≤65 years) and old (> 65 year) age groups. RESULTS: 519 participants converted to dementia within an average follow up of 5.97 years. Among older APOEɛ4 carriers, hypercholesterolemia was related to lower risk of dementia (HR (95% CI), 0.68 (0.49-0.94), p = 0.02). Among older APOEɛ4 non-carriers, hypertension was related to higher risk of dementia (HR (95% CI), 1.44 (1.13-1.82), p = 0.003). These results were corroborated among a subset with autopsy data characterizing underlying neuropathology. Among younger participants, vascular risk factors did not impact dementia risk, likely from a lower frequency of vascular and Alzheimer's as etiologies of dementia among this cohort. CONCLUSION: A history of hypercholesterolemia related to a lower risk of dementia among older APOEɛ4 carriers, while hypertension related to a higher risk of dementia among older APOEɛ4 non-carriers.