About our research interests

We are interested in the mechanisms leading to Alzheimer's disease, with a special emphasis on the role of APOE and glial cells. Some ongoing research projects are detailed below.

Heterogeneity in AD

Understanding heterogeneity of clinical and pathological correlations in the Alzheimer’s disease (AD) continuum. AD is pathologically defined by the presence of sufficient amyloid plaques and neurofibrillary tangles in the brain but there is substantial heterogeneity in clinico-pathological correlations due to variability in comorbid pathologies, genetic influence, education attainments, etc. In collaboration with Profs. Rebecca Betensky and Jing Qian, our early analyses of the NACC autopsy cohort have tried to addressed this heterogeneity and revealed that (1) neuritic amyloid plaques, neurofibrillary tangles, moderate and severe cerebral amyloid angiopathy, severe ischemic small vessel disease, and hippocampal sclerosis all independently correlate with the degree of antemortem cognitive impairment; (2) a subset of patients (approx. 15%) diagnosed with probable mild-to-moderate AD, who would meet criteria for enrollment in anti-amyloid-β clinical trials, actually have none or only sparse neuritic amyloid plaques; and (3) Thal amyloid phases do not independently contribute to antemortem cognition. These findings have furthered our understanding of the heterogeneity of pathological substrates underlying age-related cognitive impairment.

  1. Serrano-Pozo A, Qian J, Monsell SE, Frosch MP, Betensky RA, Hyman BT. Examination of the clinicopathologic continuum of Alzheimer disease in the autopsy cohort of the National Alzheimer Coordinating Center. J Neuropathol Exp Neurol 2013; 72(12): 1182-1192. [PMCID: PMC3962953]
  2. Serrano-Pozo A, Qian J, Monsell SE, Blacker D, Gómez-Isla T, Betensky RA, Growdon JH, Johnson K, Frosch MP, Sperling RA, Hyman BT. Mild to moderate Alzheimer dementia with insufficient neuropathological changes. Ann Neurol 2014; 75(4): 597-601. [PMCID: PMC4016558]
  3. Serrano-Pozo A, Qian J, Muzikansky A, Monsell SE, Montine TJ, Frosch MP, Betensky RA, Hyman BT. Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer disease continuum. J Neuropathol Exp Neurol 2016; 75(6): 516-526. [PMCID: PMC6250207]


Deciphering the complexity and heterogeneity of glial responses in AD. APOEε4 remains the strongest genetic risk factor for AD and APOEε2 the strongest genetic protective factor after the several dozen risk loci identified by GWAS in the last decade. Compared to the APOEε3 allele, APOEε4 and APOEε2 clearly influence the odds of developing AD and its age of symptom onset, but whether they also impact the rate of clinical progression after symptom onset was controversial. Moreover, these APOE isoforms were thought to operate through Abεta aggregation and clearance, but not through tau neurofibrillary tangles. In collaboration with Profs. Rebecca Betensky and Jing Qian, we have investigated the associations of APOE genotype with both postmortem AD neuropathological changes and cognitive trajectories during life. We observed that (1) the allele APOEε4 is associated with more neuritic plaques and cerebral amyloid angiopathy, whereas the APOEε2 allele is associated with fewer tangles and plaques; (2) neither APOE allele is independently associated with antemortem cognitive performance but each impacts antemortem cognition (ε2 is protective and ε4 detrimental) through its effects on AD pathology; (3) APOEε4 accelerates cognitive decline and APOEε2 slows it down in subjects who end up having moderate or high AD neuropathological changes at autopsy. In collaboration with Dr. Sudeshna Das, we have investigated the differences in expression of microglia- and astrocyte-predominant genes across APOE genotypes in public datasets and observed a pro-inflammatory and phagocytic bias of microglia in APOEε4 carriers, which is present before neuritic plaques develop and remains independent of the severity of AD neuropathological changes. These observations have contributed to broaden the focus of APOE research from an Aβ-centric view to other potential mechanisms such as tau-induced neurodegeneration and glial responses.

  1. Serrano-Pozo A, Qian J, Monsell SE, Betensky RA, Hyman BT. APOE2 is associated with milder clinical and pathological Alzheimer’s disease. Ann Neurol 2015; 77(6): 917-929. [PMCID: PMC4447539]
  2. Serrano-Pozo A, Das S, Hyman BT. APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol 2021; 20(1): 68-80. [PMCID: PMC8096522]
  3. Qian J, Betensky RA, Hyman BT, Serrano-Pozo A. Association of APOE genotype with heterogeneity of cognitive decline rate in Alzheimer’s disease. Neurology 2021; 96(19): e2414-e2428. [PMCID: PMC8166439]
  4. Serrano-Pozo A, Li Z, Noori A, Nguyen HN, Mezlini A, Li L, Hudry E, Jackson RJ, Hyman BT, Das S. Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease. Nat Aging 2021; 1: 919-931. [PMCID: in process]

Glial Reaction in AD

Reactive astrocytes and microglia decorate neuritic amyloid plaques in the AD brain but whether they have neurotoxic or neuroprotective effects remains controversial. Our early stereology-based quantitative neuropathological studies provided insights about the interactions of reactive glia and both plaques and tangles over the course of the disease. Reactive astrocytes and microglia accrue linearly over the course of AD, both paralleling the extent of tangles and diverging from plaque deposition, which remains relatively stable throughout the clinical phase of the disease. This increase in reactive glia occurs in the proximity of both plaques and tangles. However, only the number of reactive (GFAP+) astrocytes and microglia (MHC2+), but not their total numbers – reactive plus homeostatic cells – significantly differs between AD and age-matched non-demented individuals, indicating that a phenotypic change but not proliferation underlies glial responses in AD.

In recent years, it is becoming clear that astrocyte and microglial responses are complex and that a combination of markers and transcriptomics are required to obtain a complete picture of their functional changes. We have characterized the postmortem brain expression of 18 kDa translocator protein (TSPO), which has been used for almost 20 years for “activated microglia PET imaging,” and found that it is surprisingly similar in postmortem AD and age-matched control brains and that it is not restricted to microglia, but also expressed by astrocytes, endothelial cells, and vascular smooth muscle cells. We have also demonstrated the context-dependent nature of astrocyte reaction, with notable differences between mouse models of acute CNS injury and neurodegenerative disease, by meta-analyzing published astrocyte-specific transcriptomic datasets from these models. Lastly, neuroinflammation emerged as one of the main pan-neurodegenerative pathways in a meta-analysis of 60 AD, LBD and ALS-FTD microarray datasets comprising 2,600 samples, further suggesting common glial responses across diseases. All these studies have broadened the scope of glia research in AD from Aβ plaques to tau neurofibrillary tangles, established that proliferation is not a feature of glial reactions in AD, and helped unveil the complexity and heterogeneity of glial reactions in AD and other CNS diseases.

  1. Serrano-Pozo A, Mielke ML, Gómez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 2011; 179(3): 1373-1384. [PMCID: PMC3157187]
  2. Serrano-Pozo A, Mielke ML, Muzikansky A, Gómez-Isla T, Growdon JH, Bacskai BJ, Betensky RA, Frosch MP, Hyman BT. Stable size distribution of amyloid plaques over the course of Alzheimer disease. J Neuropathol Exp Neurol 2012; 71(8): 694-701. [PMCID: PMC3407299]
  3. Serrano-Pozo A, Gómez-Isla T, Growdon JH, Frosch MP, Hyman BT. A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 2013; 182(6): 2332-2344. [PMCID: PMC3668030]
  4. Serrano-Pozo A, Betensky RA, Frosch MP, Hyman BT. Plaque-associated local toxicity increases over the clinical course of Alzheimer disease. Am J Pathol 2016; 186(2): 375-384. [PMCID: PMC4729270]
  5. Perez-Nievas BG, Serrano-Pozo A. Deciphering the astrocyte reaction in Alzheimer’s disease. Front Aging Neurosci 2018; 10:114. [PMCID: PMC5996928]
  6. Gui Y, Marks JD, Das S, Hyman BT, Serrano-Pozo A. Characterization of the 18 kDa translocator protein (TSPO) expression in post-mortem normal and Alzheimer’s disease brains. Brain Pathol 2020; 30(1): 151-164. [PMCID: PMC6904423]
  7. Das S, Li Z, Noori A, Hyman BT, Serrano-Pozo A. Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration. J Neuroinflammation 2020; 17: 227. [PMCID: PMC32736565]
  8. Noori A, Mezlini AM, Hyman BT, Serrano-Pozo A*, Das S*. Systematic review and meta-analysis of human transcriptomics reveals neuroinflammation, deficient energy metabolism, and proteostasis failure across neurodegeneration. Neurobiol Dis 2021; 149: 105225. [PMCID: PMC7856076]