Alzheimer's Disease: An Updated Overview of Its Genetics

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. It is classified as familial and sporadic. The dominant familial or autosomal presentation represents 1-5% of the total number of cases. It is categorized as early onset (EOAD; <65 years of age) and presents genetic mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or the Amyloid precursor protein (APP). Sporadic AD represents 95% of the cases and is categorized as late-onset (LOAD), occurring in patients older than 65 years of age. Several risk factors have been identified in sporadic AD; aging is the main one. Nonetheless, multiple genes have been associated with the different neuropathological events involved in LOAD, such as the pathological processing of Amyloid beta (Aβ) peptide and Tau protein, as well as synaptic and mitochondrial dysfunctions, neurovascular alterations, oxidative stress, and neuroinflammation, among others. Interestingly, using genome-wide association study (GWAS) technology, many polymorphisms associated with LOAD have been identified. This review aims to analyze the new genetic findings that are closely related to the pathophysiology of AD. Likewise, it analyzes the multiple mutations identified to date through GWAS that are associated with a high or low risk of developing this neurodegeneration. Understanding genetic variability will allow for the identification of early biomarkers and opportune therapeutic targets for AD.

Keywords: Alzheimer’s disease; GWAS; genetics; loci; molecular mechanisms; neurodegeneration; neuropathology.

Figure 1

Histopathological hallmarks of Alzheimer’s disease. (a) Triple immunofluorescence showing a neurofibrillary tangle (conformational change: green channel; C-terminal tail: red channel; N-terminal of intact tau protein: blue channel). (b) Immunofluorescence showing an amyloid plaque (Aβ 1-40: green channel). Photomicrographs at 100X, calibration bar = 10 µm.

Figure 2

Schematic representation of multiple genes and their association with neuropathological events in AD. The four classical genes associated with familial AD are in the blue box, whereas other novel genes related to sporadic AD are in the red boxes. Word color-coding: red: increased production/aggregation of Aβ or tau; green: alteration in the clearance of Aβ or tau; blue: Aβ- or tau-mediated neuronal damage; purple: Tau phosphorylation. Furthermore, the respective associations with neuropathological mechanisms are indicated in yellow boxes. Abbreviations: AICD: amyloid precursor protein intracellular domain; APP: amyloid precursor protein; BACE1: β secretase; BBB: blood–brain barrier; CTF: C-terminal fragment; sAPP-β: soluble amyloid precursor protein β. This figure was created with biorender.com.

Figure 3

Heat map of the different genes associated with Alzheimer’s disease and their expressions in various regions of the brain and hippocampus. Abbreviations: AMY: Amygdala; BG: basal ganglia; CA1, CA2, CA3: Hippocampal regions; CB: Cerebellum; CTX: Cerebral cortex; DG: Dentate gyrus; Ent: Entorhinal gyrus; HP: Hippocampus; HY: Hypothalamus; M: Medulla oblongata; MB: Midbrain; P: Pons; S: Subiculum; SC: Spinal cord; TH: Thalamus; WM: White matter. Gene expression by brain region was obtained from the human protein atlas (https://www.proteinatlas.org/, accessed on 20 December 2022).