Genetic Heterogeneity in Alzheimer Disease and Implications for Treatment Strategies

Abstract

Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer’s disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.

Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database

“…Evidence for altered APP cleavage in sporadic AD (sAD) is weaker, although there is support for altered trafficking (4–6), transport (7), and degradation (8) of Aβ playing roles. Documentation of neuropathologic distinctions between these forms of AD is critical to understanding variability in pathways leading to their development (9). …”

Síndrome de Down y enfermedad de Alzheimer: factores de riesgo, evaluación e intervención

“…El alelo b4 de la APOE es posiblemente el factor de riesgo genético más robusto para la EA, estando presente en, aproximadamente, un 50 % de las personas con un inicio tardío de la enfermedad (Ringman et al, 2014). Así, tener una copia del alelo reduce la edad en la que se manifiestan los síntomas de la EA, y tener dos copias la reduce todavía más.…”

Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1

“…However, some significant differences apart from age at onset have also raised the question to what extent one can infer from familial to sporadic, late-onset AD [18,19]. For instance, familial and sporadic AD share the neuropathological hallmarks of AD pathology such as deposition of amyloid plaques and accumulation of neurofibrillary tangles [17], but the pathological results in EOFAD are more variable and frequently include findings such as cotton wool plaques, Lewy bodies, Pick bodies, and pronounced inflammation [20,21,22].…”