Title:Early Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review
VOLUME: 19 ISSUE: 7
Author(s):Erwin Lemche*
Affiliation:Section of Cognitive Neuropsychiatry, Institute of Psychiatry, Psychology and Neuroscience, King`s College London, London
Keywords:Late-onset Alzheimer`s disease, Early life stress, Stress neuropsychobiology, Candidate genes, Epigenomics, Epigenetic
programming, Gene regulation, MicroRNA, Methylation, Acetylation, Pathophysiology, Ageing biology, Mitogen activated
kinases, Neuroinflammation, Catecholamines, Corticosteroids, Insulin signalling.
Abstract:Involvement of life stress in Late-Onset Alzheimer’s Disease (LOAD) has been evinced in
longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of
catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully
demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology,
thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyperphosphorylation
and amyloidogenic processing. Discussed are relevant ELS studies, and findings from
three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK
pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy
impairment, neuroinflammation, and brain insulin resistance.
For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies
of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD
association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in
previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic
modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation
mechanisms were published for the compiled loci.
Genomic association studies support close relations of both noradrenergic and glucocorticoid systems
with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association
of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms
was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR,
INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin
stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and
MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported
for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the wellknown
LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight
a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of
inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis,
DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT,
MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling,
TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic
studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings
of childhood nucleus caeruleus degeneration for LOAD tauopathy.
