. Author manuscript; available in PMC: 2023 Jan 1.

Published in final edited form as: Nat Rev Neurosci. 2021 Nov 23;23(1):53–66. doi: 10.1038/s41583-021-00533-w

Table 1 |.

Brain pathology associated with the three Alzheimer disease variants

Pathology	Feature	Alzheimer disease variant
Pathology	Feature	Autosomal dominant	APOE ε4 sporadic	Non-APOE ε4 sporadic
Aβ	Global burden	+++^97,98	++^117,118	+^117,118
Aβ	Topography	Precuneus; isthmus of cingulate gyrus, posterior cingulate and anterior cingulate gyri; rostral middle frontal gyrus, pars opercularis and pars triangularis of inferior frontal gyrus; orbital frontal gyrus; paracentral gyrus; postcentral gyrus; lateral temporal gyrus; lateral parietal gyrus; lateral occipital and pericalcarine gyri; and caudate nucleus^81,89,90	Precuneus; isthmus of cingulate gyrus, posterior cingulate and anterior cingulate gyri; medial and lateral orbitofrontal gyrus; rostral middle frontal and superior frontal gyri; and paracentral gyrus^113,117	Precuneus; isthmus of cingulate gyrus, posterior cingulate and anterior cingulate gyri; medial and lateral orbitofrontal gyri; paracentral gyrus; superior parietal lobe; and supramarginal gyrus^113,117
Tau	Global burden	+++⁹¹	++¹²⁶	+++¹²⁶
Tau	Topography	Precuneus; isthmus of cingulate gyrus and posterior cingulate gyrus; middle and inferior frontal gyri; medial and lateral temporal gyri; lateral parietal lobe; lateral occipital lobe⁹¹	Precuneus; isthmus of cingulate gyrus and posterior cingulate gyrus; middle frontal gyrus; medial, middle and inferior temporal gyri; lateral parietal lobe; lateral occipital lobe^{124,126–128}	Precuneus; isthmus of cingulate gyrus and posterior cingulate gyrus; superior, middle and inferior frontal gyri; medial, middle and inferior temporal gyri; lateral parietal lobe; lateral occipital lobe^{124,126–128}
TDP43	Global burden	Variable: −/+^93,94	++¹³⁰	+¹³⁰
TDP43	Topography	Hippocampus and amygdala⁹³	Amygdala, hippocampus, medial frontal gyrus¹³⁰
α-Synuclein	Global burden	Variable: −/+/++^94–96	++¹³¹	+¹³¹
α-Synuclein	Topography	Amygdala⁹⁶	Not reported	Not reported
Cerebral amyloid angiopathy	Global burden	+++^97,98	+++¹¹⁹	+¹¹⁹
Cerebral amyloid angiopathy	Topography	Type 1 or type 2 (REF.¹⁷)	Type 1 (REFS^120–123)	Type 2 (REFS^120–123)
Neuroinflammation	Topography	Colocalized with tau and Aβ pathology⁹⁹	Colocalized with tau and Aβ pathology^99,167–170	Weaker colocalization with tau and Aβ pathology^99,167–170
Neurodegeneration	Global burden	+++¹²	+¹²⁶	++¹²⁶
Neurodegeneration	Topography	Precuneus; pars opercularis of inferior frontal gyrus; medial, superior and middle temporal gyri; lateral parietal lobe; lateral occipital lobe^81,90,92	Precuneus; isthmus of cingulate gyrus and posterior cingulate gyrus; medial, superior, and middle temporal gyri; temporoparietal junction^{125–127,129}	Precuneus; isthmus of cingulate gyrus and posterior cingulate gyrus; superior, middle and inferior frontal gyri; medial, superior and middle temporal gyri; temporoparietal junction; parietal lobe^{125–127,129}

The number of plus signs reflects the global burden of brain pathology based on studies comparing autosomal dominant Alzheimer disease (AD) with sporadic AD, and APOE ε4-related sporadic variants with APOE ε4-unrelated sporadic variants. Head-to-head comparisons among autosomal dominant AD, APOE ε4-related AD and APOE ε4-unrelated sporadic AD are not available. Global burden: +, low; ++, intermediate; +++, high. Regions listed under ‘topography’ are those mainly affected by pathology. Cerebral amyloid angiopathy type 1 is with capillary involvement, whereas type 2 is without capillary involvement. The topography of Aβ, tau and neurodegeneration and their burden are graphically represented in FIG. 1. Aβ, amyloid-β; TDP43, TAR DNA-binding protein 43.