Alzheimer’s disease and related dementias.
| Key information | Key pathologies | Major risk factors |
|---|---|---|
| Alzheimer’s disease (AD) | ||
| Most common dementia, accounting for an estimated 60 to 80% of cases [4]. Most AD (> 95%) occurs as sporadic, late-onset AD (usually > 65 years of age) without autosomal dominant inheritance of highly penetrant APP, PSEN1, PSEN2 mutations, which instead give rise to familial or autosomal dominant, early-onset AD. | Extracellular amyloid-β plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein [202]. Chronic neuroinflammation, synaptic dysfunction, and neuronal loss. Often accompanied by vascular abnormalities and mitochondrial and metabolic dysfunction. | Age (strongest non-genetic factor); genetics (hallmark genes include APP, PSEN1, PSEN2, APOE4, TREM2, among others [21]); cardiometabolic risk factors (diabetes, obesity, hypertension); environmental and lifestyle risk factors. |
| Vascular dementia | ||
| The second most common dementia, accounting for approximately 15% of cases. | Dementia caused by cerebrovascular injury from large-vessel strokes, small-vessel disease (white matter lesions, lacunes), chronic cerebral hypoperfusion [203, 204]. | Age; cardiometabolic risk factors (hypertension, diabetes, obesity, hyperlipidemia, stroke); environmental and lifestyle risk factors; genetics (hallmark genes include APOE4, SPRY2, FOXA2, among others [21]) as well as rare genetic forms (e.g., NOTCH3 in the most common heritable cause of stroke and vascular dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [205]). |
| Lewy body dementia | ||
| Includes dementia with Lewy bodies and Parkinson’s disease dementia [206]. | α-Synuclein aggregates of Lewy bodies and Lewy neurites accompanied by neuronal loss. | Age; genetics (hallmark genes include APOE4, SNCA, GBA, among others [21]). |
| Frontotemporal dementia | ||
| A leading type of early-onset dementia [207]. | Selective degeneration of frontal and temporal lobes. Abnormal accumulation of tau, TDP-43, or FUS proteins (depending on subtype). Neuronal loss leading to behavioral, language, or executive dysfunction. | Genetics is the primary known risk factor (hallmark genes include APOE4, GRN, C9orf72, MAPT, among others [21]). |
| Mixed pathology dementias | ||
| A substantial proportion, possibly the majority, of dementia cases develop mixed pathology. | AD neuropathology with 1, 2, and 3 other neuropathological features (microvascular brain injury, Lewy body dementia, hippocampal sclerosis, limbic predominant TDP-43 encephalopathy, cerebral amyloid angiopathy) [5, 109]. Dementia cases can also develop multiple neuropathological features without AD neuropathology. | Not applicable. |
APOE4: apolipoprotein E4; APP: amyloid precursor protein; PSEN1: presenilin-1; PSEN2: presenilin-2.
The supplementary table for this article is available at: https://www.explorationpub.com/uploads/Article/file/1006139_sup_1.pdf.
The authors thank Emily J. Koubek, PhD, for general assistance.
ZGV: Writing—original draft, Writing—review & editing, Visualization. MGS: Conceptualization, Writing—original draft, Writing—review & editing, Visualization. Both authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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