Basic Science and Pathogenesis.

Background: There is growing evidence that epigenetic age acceleration may predict late life cognitive decline and dementia, but it is unknown whether this is due to accelerated neurodegeneration or reduction in cognitive resilience. We examined the relationship between epigenetic clocks and domain specific neuropsychological (NP) factor scores, mild cognitive impairment (MCI), Alzheimer's Disease (AD), and all-cause dementia, before and after accounting for plasma total tau (t-tau), a marker of neurodegeneration.

Method: DNA methylation and plasma t-tau (Simoa assay; Quanterix) data from 2091 Framingham Heart Study Offspring cohort participants were generated from blood at the same Exam 8 visit (2005-2008).

Basic Science and Pathogenesis.

Background: Previously, we developed a co-calibrated and harmonized brain pathology score (BPS) across prospective cohort studies with research brain donation that incorporates multiple forms of postmortem neuropathology, using confirmatory factor analysis. We sought to identify genetic loci associated with BPS using a systems-biology approach, combining data from participants in the Adult Changes in Thought (ACT), the Religious Orders Study, and Rush Memory and Aging Project (ROSMAP) autopsy cohorts.

Method: We used PLINK in each cohort separately for genome-wide association studies (GWAS) of BPS using HRC imputed data from European ancestry participants, adjusting for age at death, sex, and population substructure.

Clinical Manifestations.

Background: The relationship between Alzheimer's disease (AD) pathology and the associated clinical syndrome a patient presents with remains indeterminate. Cognitively-defined subgroups of AD have revealed distinctions based on relative cognitive impairments, including AD-Language, where challenges in language are substantial, and AD-No Domain, where no relative asymmetries across cognitive domains occur. Pathological features of AD have been associated as the primary neuropathology of the logopenic variant of primary progressive aphasia (lvPPA).

Clinical Manifestations.

Background: Neuropsychiatric symptoms are uncommon at Alzheimer's Disease (AD) dementia diagnosis but are exhibited by nearly everyone during the course of dementia. Depressive symptoms are common in AD dementia. We sought to determine correlations between memory, executive functioning, language, neuropsychiatric symptoms, and depressive symptoms at AD dementia diagnosis, and to characterize neuropsychiatric and depressive symptoms across groups defined by substantial relative cognitive impairments, using data from the National Alzheimer's Coordinating Center (NACC).

Neuropathological correlates of vulnerability and resilience in the cerebellum in Alzheimer's disease.

Introduction: We investigated whether the cerebellum develops neuropathology that correlates with well-accepted Alzheimer's disease (AD) neuropathological markers and cognitive status.

Methods: We studied cerebellar cytoarchitecture in a cohort (N = 30) of brain donors. In a larger cohort (N = 605), we queried whether the weight of the contents of the posterior fossa (PF), which contains primarily cerebellum, correlated with dementia status.