Exploring the Genetic Architecture of Alzheimer’s: Novel Loci and Functional Insights

What is Alzheimer’s Disease?

lzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, accounting for 60–80% of all dementia cases globally. It primarily affects older adults, causing progressive memory loss, cognitive decline, language impairment, and changes in behavior and personality. The disease severely impacts quality of life and places a significant burden on caregivers and healthcare systems.

Pathologically, AD is characterized by:

Amyloid-beta (Aβ) plaques

Protein aggregates that accumulate outside neurons, disrupting cell-to-cell communication.

Neurofibrillary tangles (NFTs)

Aggregates of hyperphosphorylated tau protein inside neurons, leading to neuronal death.

Synaptic and neuronal loss

Especially in the hippocampus and cerebral cortex, regions critical for memory and cognition.

Genetic Architecture of Alzheimer’s Disease

Early-Onset Familial AD

Caused by rare, high-penetrance mutations in APP, PSEN1, and PSEN2.
These mutations disrupt amyloid-beta processing, accelerating plaque formation.
Accounts for less than 5% of all AD cases.

Late-Onset AD (LOAD)

The more common form, influenced by multiple genetic loci with small-to-moderate effect sizes.
The APOE ε4 allele is the strongest known risk factor, influencing cholesterol metabolism and amyloid clearance.

Recent genome-wide association studies (GWAS) have identified over 75 susceptibility loci, including 42 novel loci, that contribute to AD risk. These loci are involved in:

Immune system and microglial function: Variants affect phagocytosis and clearance of cellular debris.
Lipid and cholesterol metabolism: Genes such as ABCA7 impact neuronal lipid transport.
Endocytosis and synaptic function: Affect communication and vesicle trafficking in neurons.

Unveiling Novel Genetic Loci in Alzheimer’s Disease

A comprehensive genome-wide association study (GWAS) involving over a million individuals has identified 90 independent variants across 75 AD/dementia susceptibility loci, including 42 novel loci. These loci are enriched for genes involved in amyloid plaque and neurofibrillary tangle formation, cholesterol metabolism, endocytosis/phagocytosis, and the innate immune system. Gene prioritization efforts have identified 62 candidate causal genes, many of which play key roles in macrophages and highlight phagocytic clearance of cholesterol-rich brain tissue debris by microglia (efferocytosis) as a core pathogenetic hub and putative therapeutic target for AD.

Furthermore, a multi-trait association analysis has revealed shared genetic loci between AD and cardiovascular traits, highlighting the interconnectedness of these diseases. Fine-mapping and colocalization analyses have identified 16 genetic loci associated with both AD and cardiovascular diseases, suggesting potential common pathways and therapeutic targets.

Functional Insights into Alzheimer’s Disease Risk Loci

Functional annotation of AD-associated loci has provided deeper insights into the biological mechanisms underlying the disease. For instance, a study focusing on East Asian populations identified KCNJ6 and CLIC4 as novel AD-associated functional genes, providing insight into the genetic architecture of AD in East Asians.

Additionally, a large-scale X chromosome wide association study of AD prioritized SLC9A7 as a novel risk locus, advancing our knowledge of AD genetics and providing novel biological drug targets.

Implications for Therapeutic Development

The identification of novel genetic loci and the understanding of their functional roles have significant implications for therapeutic development. Targeting the pathways associated with these loci, such as phagocytic clearance by microglia and cholesterol metabolism, could lead to the development of novel therapeutic strategies for AD. Moreover, the shared genetic loci between AD and cardiovascular diseases suggest that interventions targeting these common pathways may benefit individuals at risk for both conditions.