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Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer’s disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and Aβ propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as ‘axon related’ and the Aβ profile as ‘dendrite related’. This study reveals distinct genetic profiles that may confer vulnerability to tau and Aβ in vivo propagation in the human brain. Cross-sectional and longitudinal PET imaging of amyloid beta and tau in the human brain is combined with gene expression profiles to define the interactions between Alzheimer’s disease-related pathology propagation and brain-region-specific vulnerability.

Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOE ε4 and TDP-43 proteinopathy, and the role of APOE ε4 in the association of TDP-43 proteinopathy with hippocampal sclerosis remains to be examined. We investigated the relationships of TDP-43 proteinopathy and hippocampal sclerosis with APOE ε4. We used data from two community-based cohort studies of ageing and dementia: the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). A battery of cognitive tests examining multiple cognitive domains is given to ROS-MAP participants each year, and a measure of annual global cognitive function for each participant is derived by averaging Z scores of these tests. The final clinical diagnosis is assigned after death by a neurologist using all available clinical data without access to post-mortem pathology. Amyloid-β, paired helical filament tau, Lewy bodies, TDP-43, and hippocampal sclerosis were microscopically evaluated in the midbrain, medial temporal, and neocortical regions that capture the progression of each neuropathology. TDP-43 proteinopathy topographic stage was recorded as an ordinal variable, and TDP-43 burden was defined by averaging a semi-quantitative six-point scale across six brain regions. The relationships among APOE ε4, TDP-43 proteinopathy, and hippocampal sclerosis were tested with regression models controlled for sex and age at death, and they were further explored with a mediation analysis using the quasi-Bayesian Monte Carlo method. ROS began data collection in 1994, and MAP began data collection in 1997. The data included in this study were analysed from Jan 16, 2017, to July 12, 2017. When analysis began in January, 2017, a total of 1059 ROS-MAP participants who were deceased had APOE genotype and complete pathological measures for amyloid-β, paired helical filament tau, and TDP-43 proteinopathy stage. After excluding 15 participants with other pathological diagnoses, 1044 participants, 1042 of whom also had measures of Lewy body pathology, were included in this study (470 from ROS and 574 from MAP). APOE ε4 count was associated with higher TDP-43 proteinopathy stage (odds ratio [OR] 2·0, 95% CI 1·6–2·6; p=1·9 × 10−9) and TDP-43 burden (0·40, 0·28–0·52; p=1·2 × 10−10). Amyloid-β, paired helical filament tau, or Lewy body pathology did not fully explain this association. APOE ε4 increased the odds of hippocampal sclerosis (OR 2·1, 95% CI 1·4–3·0; p=1·7 × 10−4); this effect was largely mediated by TDP-43 burden (mediated effect p<1·0 × 10−4) but not directly by APOE ε4 (direct effect p=0·40). APOE ε4 was associated with worse global cognition proximate to death even after adjusting for amyloid-β and paired helical filament tau (estimated effect −0·18, 95% CI −0·31 to −0·04; p=0·010), but this association was attenuated by additionally adjusting for TDP-43 burden (−0·09, −0·22 to 0·04; p=0·18). APOE ε4 seems to increase TDP-43 burden, and this effect in turn was associated with higher odds of hippocampal sclerosis, a pathology potentially downstream of TDP-43 proteinopathy. TDP-43 proteinopathy contributes to the detrimental effect of APOE ε4 on late-life cognition through mechanisms independent of Alzheimer's disease pathology, and future research should consider that TDP-43 proteinopathy might be an integral component of APOE-related neurodegeneration. US National Institute on Aging and Alzheimer's Association.

Background Mitochondrial dysfunction is a feature of neurodegenerative diseases, including Alzheimer’s disease (AD). Changes in the mitochondrial DNA copy number (mtDNAcn) and increased mitochondrial DNA mutation burden have both been associated with neurodegenerative diseases and cognitive decline. This study aims to systematically identify which common brain pathologies in the aged human brain are associated with mitochondrial recalibrations and to disentangle the relationship between these pathologies, mtDNAcn, mtDNA heteroplasmy, aging, neuronal loss, and cognitive function. Methods Whole-genome sequencing data from n  = 1361 human brain samples from 5 different regions were used to quantify mtDNAcn as well as heteroplasmic mtDNA point mutations and small indels. Brain samples were assessed for 10 common pathologies. Annual cognitive test results were used to assess cognitive function proximal to death. For a subset of samples, neuronal proportions were estimated from RNA-seq profiles, and mass spectrometry was used to quantify the mitochondrial protein content of the tissue. Results mtDNAcn was 7–14% lower in AD relative to control participants. When accounting for all 10 common neuropathologies, only tau was significantly associated with lower mtDNAcn in the dorsolateral prefrontal cortex. In the posterior cingulate cortex, TDP-43 pathology demonstrated a distinct association with mtDNAcn. No changes were observed in the cerebellum, which is affected late by pathologies. Neither age nor gender was associated with mtDNAcn in the studied brain regions when adjusting for pathologies. Mitochondrial content and mtDNAcn independently explained variance in cognitive function unaccounted by pathologies, implicating complex mitochondrial recalibrations in cognitive decline. In contrast, mtDNA heteroplasmy levels increased by 1.5% per year of life in the cortical regions, but displayed no association with any of the pathologies or cognitive function. Conclusions We studied mtDNA quantity and quality in relation to mixed pathologies of aging and showed that tau and not amyloid-β is primarily associated with reduced mtDNAcn. In the posterior cingulate cortex, the association of TDP-43 with low mtDNAcn points to a vulnerability of this region in limbic-predominant age-related TDP-43 encephalopathy. While we found low mtDNAcn in brain regions affected by pathologies, the absence of associations with mtDNA heteroplasmy burden indicates that mtDNA point mutations and small indels are unlikely to be involved in the pathogenesis of late-onset neurodegenerative diseases.

Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

The availability of blood-based assays detecting Alzheimer’s disease (AD) pathology should greatly accelerate AD therapeutic development and improve clinical care. This is especially true for markers that capture the risk of decline in pre-symptomatic stages of AD, as this would allow one to focus interventions on participants maximally at risk and at a stage prior to widespread synapse loss and neurodegeneration. Here we quantify plasma concentrations of an N-terminal fragment of tau (NT1) in a large, well-characterized cohort of clinically normal elderly who were followed longitudinally. Plasma NT1 levels at study entry (when all participants were unimpaired) were highly predictive of future cognitive decline, pathological tau accumulation, neurodegeneration, and transition to a diagnosis of MCI/AD. These predictive effects were particularly strong in participants with even modestly elevated brain β-amyloid burden at study entry, suggesting plasma NT1 levels capture very early cognitive, pathologic and neurodegenerative changes along the AD trajectory. Previously it was shown that an N-terminal tau fragment (NT1) measured in plasma can differentiate individuals with Alzheimer’s disease from healthy controls. Here the authors show that plasma levels of NT1 can associate with future cognitive decline in cognitively normal elderly individuals.

INTRODUCTION Though recognized as a potential cause of autosomal dominant Alzheimer's disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared amyloid beta (Aβ) production across all missense PSEN2 variants in the AlzForum database and, when possible, to corresponding PSEN1 variants. METHODS We expressed 74 PSEN2 variants, 21 of which had known, homologous PSEN1 pathogenic variants with the same amino acid substitution, in HEK293 cells lacking presenilin 1/2. Aβ production was compared to age at symptom onset (AAO) and between PSEN1/2 homologs. RESULTS Aβ42/40 and Aβ37/42 ratios correlated with AAO across all PSEN2 variants, strongly driven by the subset of PSEN2 variants with PSEN1 homologs. Aβ production across PSEN1/2 homologs was highly correlated. PSEN2 AAO correlated with AAO in PSEN1 homologs but was an average of 18.3 years later. DISCUSSION The existence of a PSEN1 homolog and patterns of Aβ production are important considerations in assessing the pathogenicity of previously reported and new PSEN2 variants. Highlights There were associations between the patterns of amyloid beta (Aβ) production across presenilin 2 (PSEN2) variants and age at symptom onset (AAO). PSEN2 variants for which there is a known, corresponding variant in presenilin 1 (PSEN1) are more likely to have abnormal Aβ production patterns that strongly correlate with AAO, compared to those that lack a known PSEN1 counterpart (“non‐homologous PSEN2 variants”). Most PSEN2 variants lacking PSEN1 counterparts had Aβ42/40 ratios close to those of wild‐type PSN2, arguing against their pathogenicity. Homologous PSEN1 and PSEN2 variants had correlated Aβ42/40 and Aβ37/42 ratios, indicating that the corresponding amino acid substitution in each presenilin may have largely similar biochemical effects on γ‐secretase processivity.

Many of the Alzheimer’s disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD ( n  = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-β), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline. In an independent neuroimaging dataset of cognitively unimpaired elderly ( n  = 2921), astrocytic ADPRS was associated with amyloid-β, and microglial ADPRS was associated with amyloid-β and tau, connecting cell-type-specific genetic risk with AD pathology even before symptom onset. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage. Alzheimer’s disease genetic risk is enriched in glial genes. Here, the authors derive cell-type-specific polygenic risk scores and link astrocytic genes with Aβ, and microglial genes with Aβ, tau, microglial activation, and cognitive decline.

Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E ( APOE ) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors. PSEN1 E280A carriers develop dementia by midlife, but there is variability in disease trajectory. Cognitive decline is accelerated in E280A carriers who also have an APOE e4 allele. Educational attainment moderates the effect of APOE on cognition.

The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation. \"Residual cognition\" was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10-5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = -0.40, 95% CI -0.69 to -0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 × 10-5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies. Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy.