TABLE 1.

Replicated genes harboring rare variants (MAF < 1%) associated with AD

Gene	Inheritance pattern	Study	Implicated pathways
APP	Dominant	Alzforum	Aβ pathway 5
	Recessive	78 , 79	Immune system 131
	de novo/mosaicism	108	BBB integrity 132 Synaptic plasticity 18 , 133 Gene expression regulation 134 , 135 Axonal guidance and cytoskeleton function 135 , 136 , 137 Apoptosis, phagocytosis, and autophagy 135 , 138
PSEN1	Dominant	Alzforum	Aβ pathway 5
	Recessive	74 , 75 , 76 , 77	Immune system 139
	de novo/mosaicism	105 , 107	BBB integrity 132 Synaptic plasticity 140 , 141 Axonal guidance and cytoskeleton function 142 Apoptosis, phagocytosis, and autophagy 143 , 144 , 145
PSEN2	Dominant	Alzforum	Aβ pathway 5
	de novo/mosaicism a	146	Immune system 139 Synaptic plasticity 140 Apoptosis, phagocytosis, and autophagy 144 , 145 , 147 , 148
SORL1	Dominant	26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40	Aβ pathway 149
	Recessive b	80	Lipid metabolism 150
	de novo/mosaicism c	112
ABCA7	Dominant	41 , 42 , 43 , 44 , 45 , 46	Aβ pathway 151 Immune system 152 Lipid metabolism 153 Apoptosis, phagocytosis, and autophagy 154 , 155 , 156
TREM2	Dominant	47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64	Aβ pathway 157 Immune system 157 Lipid metabolism 158 Apoptosis, phagocytosis, and autophagy 159
BIN1	Dominant	45 , 65 , 66	Aβ pathway 160 Tau pathway 161 Synaptic plasticity 162 Apoptosis, phagocytosis, and autophagy 163 , 164
UNC5C	Dominant	67 , 68 , 69	Axonal guidance 165 Apoptosis, phagocytosis, and autophagy 165
AKAP9	Dominant	67 , 68	Synaptic plasticity 165
NOTCH3	Dominant	70 , 71 , 72 , 73	Aβ pathway 166 Gene expression regulation 167 BBB integrity 168 Apoptosis, phagocytosis, and autophagy 169 , 170
12S rRNA	Maternal	98 , 99 , 100	Mitochondrial cascade hypothesis 171
CLU	Dominant	101 , 102 , 103	Aβ pathway 172 Immune system 173 Lipid metabolism 174 Apoptosis, phagocytosis, and autophagy 145 , 175
PLCG2	Dominant	54 , 56 , 104	Immune system 56 Apoptosis, phagocytosis, and autophagy 176 , 177
ABI3	Dominant	54 , 56 , 104 , 105	Immune system 56
APOE	Modifier	114 , 115	Aβ pathway 178 Immune system 178 Lipid metabolism 178 Synaptic plasticity 178 BBB integrity 179 Axonal guidance and cytoskeleton function 180 , 181 Tau pathway 182 Mitochondrial cascade hypothesis 183 Apoptosis, phagocytosis, and autophagy 184 , 185 , 186

Note: Reported inheritance patterns and implicated pathways are mentioned alongside literature references.

Abbreviations: Aβ, amyloid beta; Alzforum, Alzforum mutation database (https://www.alzforum.org/mutations); BBB, blood–brain barrier; MAF, minor allele frequency.

^aIdentified in a Braak II control subject in a single study. ¹⁴⁶

^bBi‐allelic variants reported in SORL1 in a single study. ⁸⁰

^c De novo variant (in brain) reported in SORL1 in one study, which could not be replicated by an independent study. ¹¹² , ¹⁸⁷