TABLE 1.

Heterogeneities affecting clinical research and personalized medicine in AD.

Signs, Symptoms, Syndromes Cognitive deficits: memory, executive, language, visual Neurobehavioral features: mood, anxiety, psychosis, apathy, disinhibition Major variants: amnestic, posterior cortical atrophy, logopenic primary progressive aphasia, behavioral Clinical Stages Asymptomatic/pre‐symptomatic/resilient Mild cognitive impairment/prodromal Dementia, mild/moderate/severe/agonal Neuropathology Mixed pathologies Thal phases of amyloid plaques Braak stages of tau neurofibrillary tangles Tau strains Cerebral amyloid angiopathy TDP‐43 α‐Synuclein Gliosis Cerebrovascular Course Age at onset Progression stable, slow – > rapid Genetics APOE Familial PS1/PS2/APP Polygenic risk and small effect variants

Demographic and Life History Age at onset Sex Gender Sexual orientation Race Ethnicity Education Socioeconomic status Cultural factors Nutrition and diet Environmental exposures Habits and other lifestyle Health care access Stress Health Co‐morbidities: systemic, neurologic and psychiatric Concurrent medications and dietary supplements Pathophysiology Protein synthesis, folding, post‐translational modification Proteolysis, autophagy, proteasome Inflammation and immune dysregulation Oxidative stress Metabolism Mitochondrial/bioenergetic Vascular Neuroprotection Neuroplasticity

Abbreviations: AD, Alzhemer's disease; APOE, apolipoprotein E; PS1, presenilin 1; PS2, presenilin 2; APP, amyloid precursor protein.